Stress and Adaptation

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STRESS AND
ADAPTATION:
FROM SELYE'S CONCEPT TO
APPLICATION OF
MODERN FORMULATIONS
This documents arises from a WHO meeting held in Montreal, Canada, on
2 !2" #e$tem%er &&'. (t considers the definition of stress and ada$tation:
from #elye)sconce$t to the a$$lication of modern formulations.
Edited by C. L. Bolis and J. Licinio
Wold !ealt" O#ani$ation
%ene&a
Wold !ealt" O#ani$ation' ()))
This document is not issued to the general $u%lic, and all rights are reser*ed %y the World
Health Organi+at(on ,WHO-, The document may not %e re*ie.ed, a%stracted, /uoted,
re$roduced or translated, in $art or in .hole, .ithout the $rior .ritten $ermission of WHO,
0o $art of this document may %e stored in a retrie*al system or transmitted (n any form or %y any means !
electronic, mechanical or other .ithout the $rior .ritten $ermission of WHO,
The *ie.s e1$ressed in documents %y named authors are solely the res$onsi%ility of those authors
PREFACE
The impact of stress on the effort of organisms to control the "milieu
interieur" in order to maintain efficient physiological activities was the
topic of the W! meeting held in "ontreal on #1$#% Septem&er 1''( at
the "ontreal )nstitute of Neurology *"ontreal+ ,anada-.
2n important contri&ution made &y the participants at the meeting
was a clear definition of stress and it was proposed to define stress as mecha$
nisms of acute and chronic adaptation necessary for evolution and sur$
vival. The integrated stress response is part of the homoeostatic &alance+
and dysfunction of such response may contri&ute to disease. The response
to stress is therefore re/uired for survival and evolution.
This volume &rings together the contri&utions of a distinguished in$
ternational group of scientists who wor0 with various techni/ues and in
various areas of &iomedical research+ &ut whose research has as a common
theme the elucidation of the pathways and mechanisms &y which the &ody
responds to and adapts to stressors.
,. 1iana 2olis and 3ulio 1icinio
LIST OF CONTRIBUTORS
C.liana Bolis
4niversity of "ilan+ )taly+ and ,onsultant+ !ffice of Research 5olicy and ,oop$
eration+ World ealth !rgani6ation+ 7eneva+ Swit6erland
Ste*an R. Bonstein and Moni+a E""at,Bonstein
National )nstitute of ,hild ealth and uman Development+ and National
)nstitute of ealth+ 2ethesda+ "aryland+ 4SA
Willia- Feindel
5rofessor of Neurosurgery+ William ,one 1a&oratory for Neurosurgical Re$
search+ "ontreal Neurological )nstitute+ "c7ill 4niversity+ "ontreal+ ,anada
Mic"el .o/&et
,laude 2ernard 4niversity+ 1yon+ 8rance
./lio licinio and Paolo Polo
4nit on ,linical Research+ ,linical Neuroendocrinology 2ranch+
National )nstitute of "ental ealth+ N)+ 2ethesda+ "aryland+ 4SA
Piee .. Ma#istetti and l/c Pellein
)nstitute of 5hysiology+ 4niversity of 1ausanne+ Swit6erland
Ste*ano P/#lisi,Alle#a
Dipartimento di 5sicologia+ 4niversita degli Studi di Roma "1a Sapien6a"+
Rome+ )taly
Donald .. Reis and E/#ene 0. %olano&
Department of Neurology and Neurosciences+ Weill "edical ,ollege of ,ornell
4niversity+ New 9or0+ 4SA
Se#e Ri&est
1a&oratory of "olecular Endocrinology+ ,41 Research ,entre+
1aval 4niversity+ :ue&ec+ ,anada
B. MeA. Sa1es
8ormer Dean+ )mperial ,ollege of Science+ Technology and "edicine+
1ondon+ 4nited ;ingdom
Y&ette I. S"eline
Department of 5sychiatry+ Washington 4niversity School of "edicine+
Saint 1ouis "issouri+ 4SA
S"en Y/c/n et al.
Director+ )nstitute of "ental ealth+ 2ei<ing "edical 4niversity+ 2ei<ing+ ,hina
Y&ette Tac"e
4,1A Department of "edicine+ ,4RE+ Digestive Diseases Research ,entre+
1os Angeles+ ,alifornia+ 4SA
W!O Secetaiat
Dr 2. "ansourian+ Director+ !ffice of Research 5olicy and Strategy ,oordination
5rofessor c.L. 2olis+ ,onsultant+ !ffice of Research 5olicy and Strategy ,oordination
TABLE OF CONTENTS
Stress: adaptation and hooeostasis
,.1iana 2olis 1
Stress and adaptation: A psy!hobio"o#i!a" interpretation
o$ Se"yes !on!epts
S. 5uglisi$Allegra '
%ooeostati! pro!esses in ne&roendo!rino"o#y
3. 1ieinio+ 5. 5rolo #=
Centra" ne&ra" e!haniss prote!tin# the brain
$ro hypo'ia and is!haeia
D. 3. Reis+ E. 4. 7olanov %=
Ne&rotransitters re#&"ate ener#y etabo"is in
astro!ytes: Ip"i!ations $or $&n!tiona" brain ia#in#
5. 3. "agistretti+ L. 5ellerin >%
Cir!adian rhyths and s"eep in hooeostasis and
their re"e(an!e to stress
". )ouvet >=
Brain ia#in#) the h&an ay#da"a and stress
W. 8eindel ?'
Stress and the hippo!ap&s: Depression*ind&!ed
hippo!apa" atrophy
9vette 5. Sheline ='
Intera!tion o$ the stress systes in the adrena": Basi!
and !"ini!a" aspe!ts
S. R. 2ornstein+ ". Ehrhart$2ornstein ('
I&ne response and brain #ene e'pression in
re"ation to stress
S. Rivest 1@'
Biopsy!ho"o#i!a" rea!tions to stress
Shen 9ueun et al 1%1
%o+ the brain stresses the #&t: The ro"e o$ brain CRF
9. Tache 1A1
Identi$yin# bio"o#i!a" and hea"th !orre"ates o$ stress
2. "eA. Sayers 1>=
STR,SS: ADAPTATION AND
%O-O,OSTASIS
,. Liana 6olls
The word stress was first coined and used in physics to mean the force
or pressure applied &etween &odies+ generally eBpressed as units of weight
per units of surface. The eBpression "stress and strain" has &een used in
relation to the theory of elasticity descri&ed &y oo0e at the end of the
1(
th
century. e descri&ed the relationship &etween the applied force
and deformation. The relationship for limited stress and small defor$
mation is linear and reversi&le. )f the applied stress produces large strains+
the linearity is lost. )f the stress continues to grow+ an irreversi&le defor$
mation will followC that is the plastic regime.
This concept of stress applied in physics is theoretically suita&le
also for &iology. )ndeed living matter responds to applied forces &y
temporary adaptation and then &y plastic changes. These plastic changes
in response to acute stress are mostly &iochemical+ fast and reversi&le+
whereas long$lasting stress may induce changes at gene level.
The concept that in living matter the natural condition is not static
is ancient+ dating &ac0 to ,hinese philosophy+ &ut its eBpression was
&etter developed and descri&ed &y 7ree0 and Roman philosophers
*Taylor+ 1'##D Singer+ 1'A1-. eraclitus was among the first to sug$
gest that living things undergo constant dynamic changes. Empedocles
&ased his theory on dynamic opposition or alliance of elements+ ma0$
ing e/uili&rium a necessary condition for survival. 1ater+ ippocrates
defined health as a &alance of elements+ and disease as a disharmony of
them eBcluding the intervention of supernatural forces. Roman phi$
losophers and physicians later adopted these general concepts of har$
mony in living matter. Epicurus applied the same e/uili&rium concept
to &ehaviour+ giving importance to the mind in maintaining &ody e/ui$
li&rium. These concepts have &een followed over the centuries+ as wit$
nessed &y the wor0 of Thomas Sydenham+ an English physician who
lived in the 1=
th
century. )n the middle of 1'
th
century the great 8rench
physiologist+ ,laude 2ernard refined these concepts &y putting for$
ward the theory of milieu inierieur and proposing the eBistence of a
. Stress and adaptation
dynamic internal physiological e/uili&rium *2ernard+ 1(=(-. This theory
was announced and discussed in a series of lectures emphasi6ing the
importance of a constant internal environment+ maintained &y several
compensatory reactions and rendering the &ody independent of the
eBternal environment.
The milieu interieur theory led to the development of the cy&er$
netic concept of feed&ac0. William ,annon in the first half of the #@
th
century coined the term "homoeostasis" to define coordinated physi$
ological processes which maintain the steady state of temperature+ p
and osmotic pressure of internal fluids *,annon+ 1'##-. e also first
introduced the role of the adrenomedullary system in maintaining ho$
moeostasis and in the "fight and flight" reaction+ thus emphasi6ing the
importance of adaptation.
)ndependently+ ,harles Darwin had already contri&uted to the
theory in his &oo0 "The eBpression of emotions in man and animals"
*1(=#-+ where he asserted that emotional eBpressions and their &ehav$
ioural correlates can &e inherited as physical characteristics. Emotions
are therefore central in the eBpression of the response to stress+ although
Darwin never used this term.
ans Selye for the first time in 1'%? introduced the concept of
stress as we 0now it today+ and descri&ed the relationship &etween stress
and disease. At first he utili6ed the term stress+ derived from physics+ to
indicate the mutual action of forces that happens throughout the &ody.
e later defined stress as the non$specific response of the &ody to any
demand upon it *Selye 1'%?+ 1'=A-. e also introduced the idea that
the level of stress is important as it can eBert &oth positive and negative
effects as determined &y intensity and duration.
The response to stress events was a series of system activations to
maintain homoeostasis of the organism. )n humans and in animals there
was activation of the adrenomedullary+ parasympathetic and
mesocorticolim&ic systems+ and of the amygdala.
The participation of the nervous system is highly efficient and is
effected &y means of integrated+ cooperative processes involving
neurotransmitters and neurohorrnones.
The autonomic nervous system responds to stressors and controls
a wide range of functions. The cardiovascular+ respiratory+ gastro$intes$
tinal+ renal+ endocrine and other systems are regulated &y the sympa$
thetic nervous system+ the sympathetic system+ or &oth. 7enerally+ the
parasympathetic system can &oth assist sympathetic functions &y with$
drawing and antagoni6e them &y increasing its activity. )n addition to
the neurotransmitters acetylcholine and norepinephrine+ &oth the sym$
pathetic and parasympathetic su&divisions of the autonomic nervous
Stress: adaptation and hooeostasis /
system include several neurochemically coded neurones that eBpress a
variety of neuropeptides and adenosine triphosphate *AT5-+ nitric oB$
ide+ or lipid mediators *,hrousos+ 1''=-.
2oth the mesocortical and mesolim&ic components of the
dopaminergic system are activated &y glucocorticoids during stress.
The mesocortical system+ which includes dopaminergic neurones of
the ventral tegmentum that send pro<ections to the prefrontal corteB+
is thought to &e involved in anticipatory phenomena and cognitive
functions and to eBert a suppressive effect on the stress system *Tsigos+
1''>-.
The amygdala is activated during stress primarily &y ascending
catecholaminergic neurones originating in the &rainstem. Activation of
the amygdala is important for retrieval and emotional analysis of rel$
evant information for any given stressorsD the amygdala can directly
stimulate &oth central components of the stress system.
An important discovery in the field of stress is related to heat$
shoc0 proteins+ also 0nown as stress proteins. Ritossa *1'?#- o&served
novel puffs in the giant chromosomes from the salivary gland of Dro-
sophila during stress *heat shoc0-. Since RitossaEs original report+ the
structures of the proteins associated with heat$related chromosomal
puffs have &een now identified. "oreover+ it is now clear that heat$
shoc0 or stress proteins are induced not only &y thermal &ut also &y
chemical and psychological stressors as well as sei6ures and trauma.
eat shoc0 or stress proteins *hsp- are a family of proteins eB$
pressed in response to a variety of &oth &iotic and a&iotic stressors
*8orsyth and Fi<ayan+ 1''(-. They show an eBtraordinarily high de$
gree of similarity of the amino acid se/uence across species *homology
of >@G for hsp =@ among &acteria+ yeast and Drosophila). The fact that
this cellular stress response has &een descri&ed in nearly all organisms
studied ma0es this group of proteins uni/ue.
As specific functions are elucidated for each heat shoc0 protein+
they are named accordingly *for eBample+ hsp 1? is now 0nown as
u&i/uitin-. "ore recent studies have shown that in addition to ena$
&ling cells to respond to various types of stressors+ hsp have 0ey func$
tions in homoeostasis and can act as chaperons in various intracellular
processes. sp '@ &inds to the glucocorticoid receptor in the cyto$
plasm+ thus regulating cortisol$receptor interaction. sp =@+ which as$
sists protein folding and aggregation of proteins *Westwood et al.+ 1''1-+
is composed of &oth environmentally induci&le and constitutively eB$
pressed family mem&ers *Di )orio et al.+ 1''?-. )nterestingly+ analysis
of this protein in an out&reed population of tropical top minnows
(Poeciliopis gracilis) showed that constitutive hps =@ family mem&ers
0 Stress and adaptation
A Stress and ada2tation
had no variation in protein isoforms+ whereas induci&le synthesised hps
=@ was polymorphic *Norris et al.+ 1''>-.
7iven the high level of conservation in hsp structure across spe$
cies+ their eBistence in all organisms+ and their 0ey constitutive and stress$
related functions+ it is now widely accepted that hsp are 0ey elements in
cell function. )nterestingly+ hsp are eBpressed in the central nervous
system of various organisms across the evolutionary scale+ from Dro-
sophila to man+ in discrete &rain areas such as the hippocampus. The
role of hsp in the modulation of &asal and stress$related neural trans$
mission remains to &e elucidated and constitutes at present an active
area of investigation.
8ish are a very important model for studying the compleB succes$
sion of &iochemical events ta0ing place during homoeostatic adapta$
tion in the whole animal during stress. 8ish tissues also represent a
valua&le and easily reproduci&le model ofhsp eBpression. 1i0e all other
organisms+ fish face the challenge of 0eeping a constant milieu interieur
despite continuous environmental change. 8ish are eBposed to many
stressors in nature+ as well as in artificial situations such as in a/uaculture
conditions or in the la&oratory. "oreover+ increasing contamination of
freshwater and marine ecosystems &y anthropogenic su&stances repre$
sents a clear environmental stressor. )ntensive culture methods are also
accompanied &y various stressors such as grading+ transportation+ and
vaccination. The response of fish involves all levels of the &ody organi$
6ation+ from the cell to the whole organism+ and finally to the entire
population *)wama+ 1''(+ review-. A num&er of fish cell lines have
&een used in hps research+ and all have shown increased eBpression of
various hps *for eBample+ #($+ A1$+ A?$+ >1$+ ?>$+ ?($+ =@$+ and (A$
0Da- in response to heat shoc0 or heavy metal eBposure. )ncrease in
hsp =@ is the most noticea&le response to heat shoc0. The eBpression of
hsp in fish has &een descri&ed in primary cultures of various cell lines
and in the tissues of whole organisms+ in response to &iological stressors
such as infectious pathogens+ as well as to a&iotic stressors such as heat
and cold shoc0 and environmental contaminants *Norris et al.+ 1''>-.
)n general+ the hsp response is li0ely to &e related to the perceiving of
the stressor and the su&se/uent cellular effects that adapt the cells to
cope with the stressor *)wama et al.+ 1''(-+ and may affect primarily
reproduction *)an6 et al.+ 1''=-.
Recently+ several studies have o&served hps eBpression in intact
fish and have demonstrated a possi&le relation &etween hsp eBpression
and the generali6ed stress response in fish. 1iver+ 0idneys+ and gill tis$
sues seem to &e the most sensitive to the hps response. )ncrease in
plasma glucose concentration is a common indicator of meta&olic ef$
Stress: adaptation and hooeostasis 1
fects due to stress. 7lucose production provides the &rain+ gills and
muscles with the energy needed to respond to the stressor. 1iver is the
main source of glucose production &y glycogenolysis andHor gluco$
neogenesis. Adrenaline and cortisol may increase glucose production
in fish and playa &asic role in the stress$associated increase in glucose
levels. Adrenaline is cleared rapidly from the circulation *%@ min-. !n
the other hand+ plasma glucose+ as well as cortisol+ remains high for a
longer period of time. ,ortisol may thus playa role in the long$term
maintenance of glucose in fish+ long after the stressful event *8a&&ri et
al.+ 1''(+ review-.
Evidence of a strict relation &etween intracellular responses and
cortisol has &een suggested. )n fact+ cortisol is central in the meta&olic
response to #A$ hour confinement stress in tilapia (Oreochromis
mossambicus) *Fi<ayan et al.+ 1''=a-. Tilapia given cortisol implants
*>@ mg 0gE &ody weight- had significantly higher plasma cortisol+ glu$
cose+ free aminoacids+ hepatic phosphoenolpyruvate car&oBychinase and
aspartate aminotransferase activity+ whereas the pyruvate 0inase activity
ratio was significantly &lunted in comparison with the same group. Also
cytochrome 5A>@ activating compounds such as &eta$naphthoflavone
may affect cortisol dynamics &y decreasing interrenal responsiveness to
A,T stimulation+ there&y impairing the physiological responses that
are compulsory for the animal to react to the stressor *Wilson et al.+
1''(-.
Although further analysis is needed to clarify the compleB interac$
tion &etween the cellular hsp response and the meta&olic ad<ustment to
stress+ it has &een suggested that hsp =@ may have a role as a &iomar0er
for toBic stress in rain&ow trout. )n fact+ induction of hsp =@ in the liver
of rain&ow trout eBposed to 1CIF! toBic agents occurred at concentrations
several times lower than the 1,
oo
value *lethal concentration of >@ G of
the population in '? hours+ a standard indeB of toBicity-+ showing that
changes in hsp may represent a sensitive indicator of stressed states in fish
*Fi<ayan et al.+ 1''=&-. ,urrent molecular techni/ues are ena&ling us to
discover the compleB mechanisms of the cellular response to stressors.
owever+ research is needed in areas such as the &ehavioural response to
stress perception+ in order to clarify the processes at different levels of
organi6ation which are involved when organisms sense stress.
(t is important to note that all species have developed strategic
patterns of response according to different stimuli ..As an eBample+ studies
of hps have &een carried on in a/uatic organisms other than fish. 2ps
activity has &een found in algae+ proto6oa+ cnidaria+ rotifera+ nematoda+
mollusca+ arthropoda+ and echinodermata *)wama et al.+ 1''(+ review-+
thus suggesting a possi&le physiological role for hps in these organisms.
)n fact in man and in animals+ &oth physical and emotional stressors
induce central and peripheral homoeostatic responses. The central re$
sponse to stress includes arousal+ alertness+ vigilance+ attention and ag$
gression. 5eripheral responses are aimed at redirecting energy resources
to the &rain+ the cardiovascular system+ and other target sites. or$
mones such as A,T and cortisol and neurotransmitters such as nore$
pinephrine control the effect of stimuli and mediate the response to
stress and certainly playa fundamental role *,hrousos et al.+ 1'((-. )n
fact+ it is well 0nown *7old et al.+ 1'((D 1icinio+ 1''(- that the two
main components of the general adaptation response are the
hypothalamic$pituitary$adrenal *5A- aBis and the locus coeruleus$
norepinephrine sympathetic nervous system aBis. Farious neuropeptides
and hormones regulate &oth systems and their mutual interaction is
the o&<ect of active investigation.
Stress has &een studied also in plants. The concept of stress in
plants has &een well developed over the past ?@ years. The definition of
plant stress is+ however+ /uite different from the definition of the stress
in animals and human &eings. 5lants are &ound to their ha&itat+ they
cannot run away from the many threatening environmental or anthro$
pogenic stressors+ and they need special mechanisms of stress avoid$
ance and stress adaptation. 5lants have few response options to stressD
plants are acclimated and usually react fleBi&ly &y means of changes in
cell meta&olism and physiological activities as a response to changing
environmental conditions.
Any unfavoura&le condition or su&stance that affects or &loc0s a
plantEs meta&olism+ growth or development is regarded as stress. Feg$
etation stress can &e induced &y various natural and anthropogenic stress
factors. )t is necessary to differentiate &etween short$term and long$
term stress effects as well as &etween low$stress events that can &e par$
tially compensated &y acclimation+ adaptation+ and repair mechanisms+
on the one hand+ and strong stress or chronic stress events causing
considera&le damage that may eventually lead to cell and plant death+
on the other hand. Some essential stress syndrome responses of plants
are may&e summari6ed in a unifying stress concept.
2efore stress eBposure+ the plants are in a certain standard physi$
ological situation that is an optimum within the limits set &y the growth+
light+ water and mineral supply conditions of the location. When stress
occurs+ the plants respond with a decline of one or several physiological
functions+ such as the performance of photosynthesis+ transport of
meta&olites+ andHor upta0e and translocation of ions. Due to this de$
crease in meta&olic activities+ the plants deviate from their normal physi$
ological standardD as a conse/uence their vitality declines. Acute damage
Stress: adaptation and hornoeostasis 3
and senescence will occur rapidly in those plants that posses only low or
no stress tolerance mechanisms+ and thus have a low resistance mini$
mum. )n this alarm phase most plants will activate their stress coping
mechanisms such as acclimation of meta&olic fluBes+ activation of re$
pair processes+ and long$term meta&olic and morphological adaptation.
)n conclusion+ the whole of the stress response+ including the stress$
ful /uality of stimuli and eBperiences+ is determined &y organism$envi$
ronment interactions. This view has important implications for stress
management. )n fact+ new developments in psychological tecni/ues and
in psychopharmacology provide uni/ue tools to affect the environment+
the organism+ and interaction &etween them.
R,F,R,NC,S
2ernard ,+ 1econs sur les phenomenes de Ja vie commune auB animauB et auB
vegetauB+ 5aris+ 2alliere+ 1(=(.
,annon W2+ The wisdom of the &ody+ New 9or0+ Norton+ 1'##.
,hrousos 75+ 1oriauB D1+ 7old 5W *eds- "echanisms of physical and emotional
stress+ New 9or0+ 5lenum+ Advances in EBperimental "edicine and 2iology+ vol.
#A>+1'((.
,hrousos 75+ Stressors+ stress+ and neuroendocrine integration of the adaptive
response. Ann. N. 9. Ac. Sci. %11$%%>.1''=.
Di )orio 5)+ olsinger ;+ Schult6 R3+ :uantitative evidences that &oth sc =@ and
sp =@ contri&ute to thermal adaptation in hy&rids of the live&earing fishes
5oeciliopsis. ,ell Stress 7 ,haperones 1 *#-+1%'$1A=+1''?.
8a&&ri E+ ,apu66o A, "oon nv. The role of circulating catecholamines in the
regulation of fish meta&olismC An overview+ ,omparative 2iochemistry and
5hysiology , $ 5harmacology ToBicology and Endocrinology 1#@+1==$1'#+
1''(.
8orsyth RE+ Fi<ayan ""+ eat shoc0 protein eBpression in fish. Reviews in 8ish
2iology and 8isheries (+ %>$>?+ 1''(.
7old 5W+ 7oodwin 8;+ ,hrousos 75. ,linical and &iochemical manifestations of
depressionCRelation to the neuro&iology of stress. New Engl. 3. "ed. %1'+ %A($
%>% and A1A$A#@+ 1'((.
)wama 7;. Stress in fish. Ann. N.9. Acad. Sci. (>1+ %@A$%1@+1''(.
)wama 7;+ Thomas 5T+ 8orsyth R2+ Fi<ayan ".tFl. eat shoc0 protein eBpression
in fish. Rev. 8ish 2iol+ 8isheries ( *1-+ %>$>?+1''(.
Kari6 D"+ "c"aster )vlE+ "un0ittric0 ;R+ Fan der ;raa0 7. Elevated ovarian
follicular apoptosis and heat shoc0 protein$=@ eBpression in white suc0er eBposed
to &leached 0raft pulp mill effluent. ToBicology and Applied 5harmacology 1A=+
%'1$(+1''=.
1icinio 3. The neuro&iology of stress. )nC 2olis ,1+ 1icinio 3+ *eds-. Suess and the
Nervous Svstem *FF! documentW!HR5SH'(.#-+ 1''(+ pp. %$1A.
Norris ,E+ Di )orio 5)+ Schult6 R3+ ightower 1E. Fariation in heat shoc0 proteins
within tropical and desert species of fishes. "olecular 2iologv 7 Evolution 1#
*?-+1@A($?#+1''>.
Ritossa 8;+ A new puffing pattern induced &y a temperature shoc0 and DN5 in
Drosophila. EBperientia 1(+ >=1$>=%+1'?#.
Selye + A syndrome produced &y diverse nocuous agents+ Nature 1%(+%#+1'%?.
Selye + Stress without distress+ New 9or0+ New American 1i&rary+ 1'=A.
Singer ,+ A short history of science+ !Bford+ England+ !Bford 4niversity 5ress+ 1'A1.
Smaging 7N et al. 5eripheral administration of interleu0in$l increases eBtacellular
concentrations of norepinephrine in rat hypothalamusC ,omparison with plasma
corticosterone. #1C (%$'%. 1''?.
Taylor !+ 7ree0 &iology and medicine+ 2oston+ "A+ "arshall 3ones+ 1'##.
Tsigos ,+ ,hrousos 75. Stress+ endocrine manifestations and diseases. )nC and&oo0
of stress medicine. ,.1. ,ooper *ed-+ 2oca Raton+ 81+ ,R, 5ress 1''>+ pp. ?1$
?>.
Fi<ayan ""+ 5ereira ,+ 7rau E7+ )wama 7;. "eta&olic responses associated with
confinement stress in tilapiaC The role of cortisol. ,omparative 2iochemistry and
5hysiology , $ 5harmacology ToBicology and Endocrinology 11?+ ('$'>+
1''=a.
Fi<ayan ""+ 5ereira ,+ 8orsyth R2+ ;ennedy ,3+ )wama 7;. andling stress does
not affect the eBpression of hepatic heat shoc0 protein =@ and con<ugation
en6ymes in rain&ow trout treated with &eta $naphthoflavone. 1ife Sci. ?1+ 11=$
1#=+1''=&.
Westwood 3T+ ,los 3+ Wu ,. Stress$induced oligomeri6ation and chromosomal
relocation of heat shoc0 factor. Nature #>%+ (##$(#=+1''1.
Wilson 3"+ Fi<ayan ""+ ;ennedy ,3+ )wama 7;+ "oon TW. 2eta$ naphthoflavone
a&olishes interrenal sensitivity to A,T stimulation in rain&ow trout. 3.
Endocrinol. 1>=+?%$=@+ 1''(.
STR,SS AND ADAPTATION: A
PS5C%OBIOLO6ICAL
INT,RPR,TATION OF S,L5,7S
CONC,PTS
Ste*ano P/#lisi,Alle#a
The concept of stress as presently understood in medical and in &ehav$
ioural sciences has largely &een the outcome of SelyeEs theoretical and
empirical wor0 on the effects of nocuous agents *Selye+ 1'%?-.
Although SelyeEs attempt to define the stress concept went through
several modifications it has achieved a recogni6ed place inside and out$
side scientific literature and has encouraged research &y scientists in
many disciplines into the effects of stress on health and &ehaviour.
8orty years after the pu&lication of the letter to the editor of Na$
ture entitled "A syndrome produced &y diverse nocuous agents" *1'%?-+
Selye pu&lished a survey of the main pro&lems and misconceptions in
the clinical and theoretic evaluation of the stress concept that he envis$
( aged in 1@ main pro&lems. According to the author+ "irrespective of
the speciality &y which the stress concept is used+ the same 1@ pro&lems
*some partly overlapping- confuse its applications" *Selye+ 1'=?-.
The points were the folio$wingC
1. The definition of stress+ stressors+ and the general adaptation syn$
drome.
#. The concept of nonspecificitCy versus specificity.
%. The conditioning of stress responses &y diverse endogenous *mainly
genetically determined- and eBogenous *environmental- factors.
A. The relation &etween the general and the local adaptation syndromes.
>. The difference &etween direct and indirect pathogens
?. The definition of the diseases of adaptation or stress$induced mala$
dies+ i.e. the mor&id lesions in Ewhose pathogenesis stress plays a
particularly &iological role.
=. The role of genetics versus that of factors under voluntary self$
control in mastering stress and its pathological conse/uences.
(. The mode of action of syntoBic and catatoBic hormones+ drugs
and &ehavioural attitudes.
'. The so$called first mediator of the stress response.
1@. The prophylaBis and treatment of stress$induced damage &y phar$
macological and &ehavioural techni/ues.
)n the last two decades+ however+ research on stress in the fields of
neurosciences+ psychiatry+ and &ehavioural sciences has produced eB$
tensive clinical and eBperimental results that have thrown light on the
hypothesis and clarified many of the pro&lems concerning the topics
considered &y Selye.
Developments in endocrinology+ in psychoneuroimmunology+ in
personality theory+ and in psychopharmacology have opened new per$
spectives in understanding stress and the adaptation processes leading
to healthy outcomes or to disease.
5ro&a&ly the most important and novel contri&utions to the stress
concept are those resulting from research on psychopathology. The last
decades have seen ma<or developments in genetic analysis of &ehav$
ioural disorders. A wealth of data derived from family+ twin and adop$
tion studies support the view of a ma<or role of genetic lia&ility in
schi6ophrenia and affective disorders+ including ma<or depression and
manic$depressive disorders *7ottesman 7 Shields+ 1'(#D ;endler 7
Ro&inette+ 1'(%D Fanden&erg et al+ 1'(?D Wender et al+ 1'(?D Rice+
1'(=-. owever+ &ehaviour+ hence &ehavioural distur&ance+ involves
multiple genes rather than one or two ma<or genes+ as well as non$
genetic sources of variance *5lomin+ 1''@-. As regards non$genetic+
environmental contri&utions to psychopathology+ increasing attention
has &een devoted to the involvement of stressful eBperiences *2id6ins0a+
1'(AD 7ottesman 7 Shields+1'(#D Willner+ 1''1D 8owels+ 1''#+ for a
review-. The most relevant concept of stress involvement in psycho$
pathogenesis is the diathesis$stress hypothesis proposed for the etiology
of schi6ophrenia *Rosenthal+ 1'=@+ 8owels+ 1''#-. This hypothesis not
only states that the environmental factors *stress- promote pathologi$
cal outcomes in the presence of a genetic lia&ility &ut also that these
factors are not specific for a given pathology+ whereas the genetic *dia$
thesis- are.
The relationship &etween adaptation promoted &y stressful eBpe$
riences and lia&ility to pathology has &een always a difficult point to
clarify in stress theories. The classic view relates pathological ris0 to the
intensity and duration of stressful conditions. According to SelyeEs in$
terpretation+ persistence of a stressful condition leads to eBhaustion of
defensive mechanisms+ thus promoting pathological outcomes. The
diathesis$stress hypothesis+ &y stating that lia&ility to stress effects is
dependent on genetic fragility+ suggests a ma<or role for individual char$
acteristics in determining the intensity of stress response.
A 2s1c"o3iolo#ical inte2etation o* Sel1e's conce2ts ((
)ndeed+ &oth genetic factors and previous stress eBperiences may
contri&ute to produce stressful conditions+ thus increasing lia&ility deriv$
ing from environmental sources. 2ehavioural and cognitive disa&ilities
interfering with social interactions or personal achievement may promote
negative attri&ution to events. (t has &een demonstrated that mice previ$
ously defeated &y an aggressive male conspecific show species$specific
patterns of defensiveHsu&missive &ehaviour during su&se/uent social in$
teractions. Since su&missive &ehaviour tends to elicit aggressive$domi$
nant reaction &y the interacting male the altered pattern of social &ehaviour
may increase chances of stressful social eBperiences *see 5uglisi $Allegra et
al.+ 1'(' for a review-. !n the other hand+ it has &een shown that previ$
ous eBposure to unescapa&le shoc0 impairs su&se/uent learning of avoid$
ance &ehaviour *Seligman+ 1'=>-+ indicating that previous eBperiences
with unavoida&le stressors may have disruptive effects on coping responses+
leaving the organism helpless in the face of environmental threat. )nter$
estingly+ comparison of these effects of unavoida&le shoc0 in in&red strains
of mice revealed dramatic differences further supporting the ma<or role
of the interaction &etween genetic factors and environmental pressure
*Lachar0o 7 Anisman+ 1''1-.
A second+ important aspect highlighted &y the diathesis$stress
theory is the role of genetic factors in determining the type of patho$
logical outcome of a stressful eBperience. )ncreasing evidence points to
alterations in dopamine *DA- receptors in different types of psycho$
pathologies *Seeman et a1.+ 1''%D Schmauss et al.+ 1''%D 5earlson et
al.+ 1''>D "urray et al.+ 1''>-. Nevertheless+ lin0age studies do not
support the idea of genes having the role of encoding for the different
types ofDA receptor in such pathologies *Wiese et al+ 1''%D 2yerley et
al.+ 1''AD ,ampion et a1.+ 1''AD De &ruyn et al.+ 1''AD "acciardi et
al.+ 1''AD Nan0o et al.+ 1''A-. These discrepancies suggest that spe$
cific alterations of &rain DA receptors may arise from the impact of
stress on a specific genetic suscepti&ility.
Such a possi&ility has recently &een tested in la&oratory animals
*,a&i& et al.+ 1''=-. 8ollowing repeated or chronic stressful eBperi$
ences+ mice of the ,>=21H? and D2AH# strains show distinct+ strain$
dependent &ehavioural distur&ances. Thus+ stressed D2AH# mice show
enhanced locomotor response to amphetamine challenge *2adiani et
al.+ 1''#D ,a&i& et al.+ 1''>D ,a&i& 7 2onaventura+ 1''=-+ reduced
sensitivity to &ehavioural inhi&ition promoted &y acute stress eBperi$
ences *5uglisi$Allegra et al.+ 1''@D ,a&i& et a1.+ 1''>D ,a&i& 7 5uglisi$
Allegra+ 1''?-+ and spontaneous stereotypes *,a&i& 7 2onaventura+
1''=-. !n the other hand+ stressed mice of the ,>=21H? strain show
no changes *,a&i& 7 2onaventura+ 1''=- or reduced *2adiani et a1.+
8. Stress and adaptation
1''#- locomotor response to amphetamine+ enhanced sensitivity to
&ehavioural inhi&ition promoted &y acute stress eBperiences *5uglisi$
Allegra et al.+ 1''@D ,a&i& 7 5uglisi$Allegra+ 1''?- and no sign of
spontaneous stereotypes *,a&i& 7 2onaventura+ 1''=-.
The &ehavioural responses which are affected in a strain$depend$
ent manner &y stressful eBperiences are considered preclinical models
of different psychopathologies *Segal 7 Schuc0it+ 1'(%D Ro&inson+
1'((D 1yon+ 1''1D Willner+ 1''1D Ro&inson 7 2erridge+ 1''%D ,a&i&
7 5uglisi$Allegra+ 1''?- related to different alterations of &rain DA
functioning *5uglisi$Allegra et al.+ 1''@D 2adiani et al.+ 1''#D ,a&i& et
al.+ 1''>D ,a&i& M 2onaventura+ 1''=D ,a&i& M 5uglisi$Allegra+ 1''?-.
)ndeed+ increasing evidence points to mesoaccum&ens DA receptors as
the neural su&strate of the strain$dependent effects of stress. Some of
the ma<or effects of stress involve D#$li0e receptors in the
mesoaccum&ens DA system that also show the most relevant strain$
dependent differences in unstressed mice *,a&i& et al.+1''(- . "oreo$
ver+ the stress effects were in the direction opposite to the initial strain
differences. Thus+ in comparison with ,>=21H? mice+ D2AH# mice
are characteri6ed &y a higher density ofD#$li0e receptors in the ventral
tegmental area *FTA-. The same stressful condition reduces FTA DA
receptors in D2AH# mice and increases them in ,>=21H? mice *,a&i&
et al.+ 1''(-. 8inally+ a classic genetic analysis as well as an analysis of
/uantitative trait loci in recom&inant in&red strains have &een conducted
on a &ehavioural indeB of DA autoreceptor sensitivity in stressed mice
*,a&i& et al.+ 1'(>D ,a&i& et al.+ 1''=-. These results indicate that
mesoaccum&ens DA autoreceptors density is a polygenic trait control$
led &y a ma<or genotype B stress interaction. This possi&ility is relevant
for clinical research since it supports the view that different pathologi$
cal profiles might derive from genotype$dependent adaptation of &rain
systems to environmental pressure.
)n line with the diathesis$stress theory+ these results suggest that
&rain adaptation under stress condition may &e highly specific. ow$
ever+ adaptation of specific &rain systems to stress might &e considered
a local adaptation syndrome thus maintaining the characteristic of
aspecificity for 7AS. A different series of preclinical eBperiments has
concentrated on the neuroendocrine stress response and more EclassicE
stress related pathologies. 5hysiological studies in animals indicate that
one of the primary conditions that activates the neuroendocrine mecha$
nisms leading to a su&se/uent adrenal response is a change in eBpectan$
cies concerning well$esta&lished &ehaviours *ennessy 7 1evine+ 1'='D
Wein&erg 7 1evine+ 1'(@-. Thus+ it was possi&le to demonstrate that
the degrees of novelty of a given stimulus as well as the degrees of
A 2s1c"o3iolo#ical inte2etation o* Sel1e's conce2ts (4
predicta&ility of an aversive stimulus determine the eBtent of
pituitary$adrenal activation in animals. "oreover+ elevation of plasma
corticosterone+ the primary stress response &y the hypothalamus$pitui$
tary$adrenal *5A- aBis in rodents+ is consistently o&served under many
eBperimental conditions where reinforcement contingencies are altered.
These data support the view that the stress response is elicited when$
ever the organism detects discrepancies &etween eBpected and o&served
conditionsD in other words+ frictions &etween eBpectancies &ased on
species$specific information and eBternal or internal events. ,onse$
/uently+ the first step in stress response is cognitive appraisal of intero$
ceptive and heteroceptive indeBes within the conteBt of innate or
ac/uired eBperiences. These consideration are in line .ith theories put
forward &y "ason *1'?(D 1'=>-+ who suggested that stimuli lead to a
stress reaction only if accompanied &y an "emotional" response and
that non$specificity is related to the initial+ non$differential emotional
arousal induced &y the stressor that+ however+ is soon followed &y re$
sponses relevant to the nature of the stimulus and &y specific psycho$
logical and physiological adaptation.
As for ulcers+ Weiss and colleagues have demonstrated that animals
allowed to fight with conspecifics during shoc0 delivery+ will present a
dramatically reduced num&er of gastric ulcerations in comparison with
animals receiving the same amount of shoc0 &ut prevented from fight$
ing. These o&servations relate lia&ility to a prototypical stress disease
with controlla&ility. The discovery of the relevance of control over stress$
ful situations has revolutioni6ed the concept of stress *Anisman 7
Lachar0o+ 1''@D Weiss et al.+ 1'(1-. Studies on the &ehavioural re$
sponses o&serva&le during and following eBposure to eBperimental
stressors in animals indicate that controlla&le and uncontrolla&le stress$
ful eBperiences promote opposite responses. The &asic techni/ue used
&y these studies is the shoc0ed$yo0ed situation in which pairs of ani$
mals are su&<ected to a series of electric shoc0s with only one su&<ect
*shoc0ed- &eing a&le to interrupt shoc0 delivery for &oth &y mean of
various &ehavioural responses. )n this vlay the two su&<ects receive the
same amount of shoc0 &ut eBperience it either in a "coping" or in a
"non$coping" *yo0ed- situation. 4sing this techni/ue it was demon$
strated that controlla&le aversive eBperiences promote learning of new
strategies and facilitate affective responses to stimuli that are encoun$
tered immediately thereafter. )nstead+ uncontrolla&le eBperiences im$
pair su&se/uent learning and &lunt affective responses *Anisman 7
Lachar0o+ 1''@D Weiss et al.+ 1'(1D Lachar0o and Anisman+ 1''1D
Anisman et al.+ 1''%-. "oreover+ opposite responses &y the immune
system were o&served depending on the levels of controlla&ility of stress$
ful stimuli *Anisman et al.+ 1''%- and only uncontrolla&leHunpredict$
a&le stress was o&served to promote activation of endogenous opioid
systems *"aier et al+ 1'(%-.
2oth controlla&le and uncontrolla&le stressors activate the
neurondocrine response to stress+ suggesting a negligi&le role of5A
response in differentiating the effects of the two stressful conditions
*5rince 7 Anisman+ 1''@-. !n the other hand+ dramatic differences
have &een o&served in the central effects of controlla&le and uncon$
trolla&le stressors.
This point may shed some light on one crucial aspect ofSelyeEs stress
concept+ namely the so$called "first mediator". 5A hormones have &een
considered the candidates for this role+ although more recently Selye *1''%-
pointed to endogenous opioids as possi&le first mediator. !ne argument
to support this view was the fact that some eBperiments had shown that
typical activation of the 5 A aBis can &e effected &y decortication+ deaffer$
entation of pituitary from the &rain+ or deep anaesthesia *see Selye+ 1'=?-.
owever+ a num&er of contrasting eBperimental results have /uestioned
this view+ also showing that psychological factors are crucial in pituitary$
adrenal cortical activation *"ason+ 1'=1-
"ore recent evidence has pointed to the main role of several &rain
structures in regulating 5A system functioning+ thus indicating that a
"first mediator" should &e envisaged in the central nervous system and
in its compleB and integrated functions. A specific lesion of dopamine
mesencephalic neurones in the FTA producing a depletion in dopamine
in the frontal corteB and in &asal ganglia+ produced in rats a lower &asal
and stress$induced corticosterone secretion+ thus indicating that &rain
dopaminergic systems have a stimulatory influence on the 5A aBis
*,asolini el al.+ 1''%-.
"oreover+ it is well 0nown that receptors for steroid hormones are
located in different &rain areas *those of the mosocorticolim&ic sys$
terns- involved in the integration of cognitive information as well as in
emotion and motivation *5ia66a 7 1e "oal+ 1''?-. The activation of
glucocorticoid receptors in the hippocampus or in the prefrontal cor$
teB appears necessary in order to control 5A hormones response to
stress+ through a feed&ac0 mechanism that inhi&its hormone release
when it reaches high functional levels *5ia66a 7 Le "oal+ 1''?-. This
means that &rain structures are involved in the 5A response to stres$
sor &oth &y stimulating and &y inhi&iting them in a sort of dynamic
functional loop . )n other words+ there is strong cross$ tal0 &etween &rain
and 5A aBis during the stress response+ thus suggesting that cognitive
and emotional integration of the eBperience is eBtremely important in
the stress response.
A 2s1c"o3iolo#ical inte2etation o* Sel1e's conce2ts (5
.6 7
Recent studies have shown that eBposure of animals to novel situ$
ations results in increased eBpression of c$ 8os protein and 8os$related
antigens *8RAs- in the &rain *,ovenas et al.+ 1''%D 7iovannelli et al.+
1''@D anda et al.+ 1''%D Rya&inin et al.+ 1''AD Sharp et al.+ 1''1D
Stone et al.+ 1''%-. This increase is widespread and affects many &rain
regions+ ma0ing it difficult to identify the neural circuitry of the stress
response. "oreover+ this stress$related induction of immediate early
genes *lE7- is eBperience$specific and reflects the central nervous sys$
tem *,NS- response to the &ehavioural or eBperimental situation *"elia
et al.+ 1''AD Watana&e et al.+ 1''A-.
Recently+ it has &een shown that there are two main circuits lead$
ing to activation of the 5A aBis+ processive *originating in the associa$
tive areas of the &rain- and systemic *originating in the &rainstem-.
)nvolvement of one or &oth circuits depends on the type of stressor
which activates the 5A aBis *,ampeau et al.+ 1''=D erman 7
,ullinan+ 1''=D 1i et al.+ 1''?D Sen&a 7 4eyama+ 1''=-. This evi$
dence could eBplain some discrepancies in eBperiments on the effects
of anaesthesia on the 5A aBis response to stressors. (t may &e that in
some instances anaesthesia affects upper &rain areas without affecting
&rain stem neurons+ thus allowing some 0ind of stimuli only *i.e. those
affecting the &rainstem- to activate 5A hormones.
The role of &rain functioning in the response to stress and its inde$
pendence of5A aBis response was indicated &y a study showing that
restraint *a stressor commonly used in animal studies- stimulated the
release and the meta&olism of dopamine in the prefrontal corteB and
NAS+ as well as of acetylcholine release in the hippocampus in a time$
related manner. The time course of plasma corticosterone did not par$
allel that of dopamine and acetylcholine release. Adrenalectomi6ed rats
responded to the stressor as intact animals. The administration of eB$
ogenous corticosterone affected dopamine and acetylcholine only at
very high concentrations that had never &een attained during stress.
"oreover+ R4 %(A(?+ an antagonist of &rain glucocorticoid receptors+
did not antagoni6e the stress$induced release of &oth neurotransmitters
*)mperato et al.+ 1''1-. These results show that there is no cause$effect
relationship &etween increase in plasma corticosterone and increase in
dopamine and acetylcholine release.
At &rain levels+ several neurochemical changes have &een o&served
in response to stressors *see Anisman et al.+ 1''%+ for a review-+ includ$
ing enhanced release of norepinephrine *NE-+ dopamine *DA- and se$
rotonin *>$ T-. The amine variations occur across several &rain regions+
&ut transmitter variations are provo0ed more readily in some areas than
in others. 8or instance+ the NE changes induced &y stressors are readily
induced in the hypothalamus and locus coeruleus+ &ut are less mar0ed
in the hippocampus and corteB. Stressor$induced DA alterations are
apparent in the arcuate+ lateral septum+ and in mesocorticolim&ic struc$
tures+ including all areas of pro<ections of neurones located within the
FTA+ whilst regions receiving DA pro<ections from a different area+ the
su&stantia nigra *SN-+ appear to respond only to severe stressors. 8i$
nally+ also within the mesocorticolim&ic system there is a region$spe$
cific degree of suscepti&ility to stress.
Neurochemical changes in selected &rain areas are also different
depending on the degree of controlla&ility of the stressor. Thus+ in
animals eBposed to avoida&le or controlla&le stressors an increase in
meta&olism and release of the different neurotransmitter was o&served.
!n the other hand+ during eBposure to uncontrolla&le stressors+ NE
utili6ation eBceeds synthesis+ resulting in a net transmitter reduction.
owever+ the most stri0ing differences in response to controlla&le and
uncontrolla&le stressors have &een o&served for changes in DA release
within the NAS+ the principal area of pro<ection ofFTA DA neurones.
4sing the shoc0edHyo0ed techni/ue it was demonstrated that mice
eBposed to a series of foot shoc0s show an increase of DA release in the
NAS if they were allowed to control shoc0 duration *shoc0ed condi$
tion- and a decrease ofDA release if they were not allowed to eBert any
control *yo0ed condition- *,a&i& 7 5uglisi$Allegra+ 1''A-. "oreover+
in contrast with what was o&served for NE+ the inhi&ition of DA re$
lease induced &y uncontrolla&le stress in the NAS was not due to eB$
haustion of intracellular DA supplies since termination of the stressful
eBperience promoted a new increase of DA release *5uglisi$Allegra et
al.+ 1''1-. These results indicate that mesoaccum&ens DA release in
uncontrolla&le stressful conditions is inhi&ited &y an active mechanism.
The NAS is the principal area of pro<ection of dopaminergic inputs
from neurones located within the FTA. Nevertheless+ the presynaptic
and postsynaptic activity of the mesoaccum&ens DA system is controlled
&y the hippocampus+ the amygdala and the prefrontal corteB *p8,- + which
also receive DA inputs from the FTA. 8inally+ activity of the cortical and
lim&ic pro<ection towards the accum&ens is modulated &y DA release
from the mesoaccum&ens afferences *Nicola et al.+ 1''?-. ,onse/uently+
the pro<ections of mesencephalic DA neurons constitute a compleB net$
wor0 of interactions among different cortical and su&cortical &rain areas
that is referred to as the mesocorticolim&ic DA system.
,ontrol eBerted &y cortical and lim&ic structures+ phylogenetically
more recent than the accum&ens+ may play a ma<or role in tuning
mesoaccum&ens DA activity+ hence &ehavioural responses+ to informa$
tion coming from interoceptive and heteroceptive systems.
8
Although mild+ short$lasting stressful eBperiences are una&le to
promote activation of the mesoaccum&ens DA pathway+ intense or
relatively long$lasting stressors eventually induce a detecta&le in$
crease of mesoaccum&ens DA release *A&ercrom&ie et al.+ 1'('D
)mperato et al.+ 1''1D 5uglisi$Allegra 7 ,a&i&+ 1''@D Rouge$5ont
(
et al.+ 1''%D Sorg 7 ;alivas+ 1''1-. Enhanced mesoaccum&ens DA
,
,
release increases the rate of &ehavioural responses *Ro&&ins et al.+
1''@-+ thus increasing the effectiveness of defensive strategies. !n
the other hand+ mesoaccum&ens DA release in stressful conditions
may also &e directly involved in the mediation of some defensive
responses.
4ncontrolla&le stressors appear to promote passivity towards &oth
aversive and rewarding stimuli that+ as already discussed+ is related to
an active inhi&ition of mesoaccum&ens DA release. (t should &e pointed
out that &oth the &ehavioural and central responses develop progres$
sively during uncontrolla&le stressful eBperiences. Thus+ the initial stress
response to a novel situation will &e &ehavioural activation and en$
hanced mesoaccum&ens DA release. This response is maintained in
stressful conditions that allow control whilst in unavoida&le and un$
controlla&le situations the initial activation of &ehaviour and
mesoaccum&ens DA release change into profound inhi&ition *see ,a&i&
7 5uglisi$Allegra+ 1''?+ for a review-. These o&servations further sup$
port the ma<or role of the interaction &etween the organism and the
environment in stressful eBperiences.
The final phase of stress response in uncontrolla&le situations ap$
pears to &e mediated &y endogenous opioids. 2loc0ade of endogenous
opioid systems has &een shown to prevent inhi&ition of DA release in
the NAS promoted &y uncontrolla&le stressful situations *,a&i& et al.+
1'('-. "oreover+ uncontrolla&le stressful situations promote massive
release of endogenous opiods mediating so$called auto analgesia *Amir
et al.+ 1'(1- that depends on reduced emotional reactivity toward
noBious stimuli. Thus+ endogenous opioids+ &y shutting down
mesoaccum&ens DA transmission+ contri&ute to the generali6ed emo$
tional withdrawal involved in adaptation to unavoida&le and uncon$
trolla&le stressful situations.
The earliest stress theories identified stressors with noBious agents
whose impact on the organisms determined a non$specific+ stereotyped
and generali6ed response. A first step away from these views was ta0en
&y "ason *1'?(D 1'=>-+ who suggested that stimuli lead to a stress
reaction only if accompanied &y an "emotional" response and that non$
specificity is related to the initial+ indifferent emotional arousal induced
&y the stressor that+ however+ is soon followed &y responses relevant to
the nature of the stimulus and &y specific psychological and physiologi$
cal adaptation.
2ased on previous considerations+ the stress response is elicited
whenever the organism detects discrepancies &etween eBpected and
o&served conditionsD in other words+ friction &etween eBpectancies &ased
on species$specific information and eBternal or internal events.
)n mammals+ mesencephalic DA neurons participate in a num&er
of important cognitive and physiological functions including motiva$
tional processes+ reward processing+ wor0ing memory and conditioned
&ehaviour. )t is also well 0nown that eBtreme motor deficits correlate
with loss of mid&rain DA neuroncsD however+ activity of DA cells does
not show any systematic relationship with the various 0inds of move$
ments (see "ontague et al.+ 1''?+ for a review-. )nstead+ physiological
recordings from alert mon0eys have shown that mid&rain DA neurons
respond to food and fluid rewards+ novel stimuli+ conditioned stimuli
and stimuli eliciting &ehavioural reactions such as eye or arm move$
ment to a target. 8inally+ it was demonstrated that transient responses
in these neurons transfer among significant stimuli during learning+ i.e.
from actual rewarding stimuli to predictive cues *1<un&erg et al.+ 1''#-.
These data support the view that the mesocorticolim&ic DA system
plays a ma<or role in the control of goal$oriented &ehaviour.
!ne interesting point is that activation of mid&rain DA neurons
hardly occurs after non$noBious aversive stimuli *air puff- *"irenowic6
7 Schult6+ 1''?-. These data appear to contradict the o&servation that
stressful *hence aversive- stimuli promote enhanced DA release in the
terminal areas of FTA DA neurons+ an effect that re/uires increased
cell activity. owever+ as previously discussed+ aversiveness of a given
stimulus cannot &e considered either sufficient or necessary to pro$
mote the stress responses since these are induced &y changes in the
internal or eBternal environment that are in conflict with eBpectancies
&ased on the organismES innate or ac/uired eBperience.
A recent theory appears to support a ma<or involvement of mes$
encephalic DA neurons in cognitive processes related to eBpectancies.
)t has &een postulated that "the fluctuating delivery of dopamine from
the FTA to cortical and su&cortical target structures in part delivers
information a&out prediction errors &etween the eBpected amount of
reward and the actual reward" *"ontague et al.+ 1''?-. This theory
relates increased DA release in target areas to indication that the cur$
rent state is &etter than eBpected+ whilst decrease of DA release indi$
cates that the current state is worst than eBpected+ thus strengthening
or loosening neural connections related to specific &ehavioural re$
sponses.
!n the other hand+ it was o&served that when aversive stimuli
appear in close proBimity with physically very similar appetitive stimuli+
the discrimination &etween aversive and appetitive stimuli &y DA neu$
rones loses its all$or$none character and is eBpressed &y a /uantitative
preference for appetitive stimuli *"irenowic6 7 Schult6+ 1''?-. This
o&servation supports the idea that conflict$eliciting + hence stressful+
stimuli are different from simply aversive stimuli and may &e identified
&y their a&ility to generali6e cell activation in dopaminergic nuclei. This
generali6ed activation of mesencephalic DA cells and the neurochemi$
cal events that it promotes may thus represent the first response to
stressors+ possi&ly involved in arousal$related processes.
,onse/uently+ the first step in stress response is cognitive appraisal
of interoceptive and heteroceptive indices within the conteBt of innate
or ac/uired eBperiences. )n line with this hypothesis+ physiological studies
in animals indicate that one of the primary conditions that activate the
neuroendocrine mechanisms leading to a su&se/uent adrenal response
is a change in eBpectancies concerning well$esta&lished &ehaviours
*ennessy M 1evine+ 1'='D Wein&erg M 1evine+ 1'(@-.
The following step in the stress response will &e attempts to cope
with discrepantHconflicting information. 2ehavioural responses that are
part of the species$specific repertoire and individual history represent
the fundamental tool for coping. ,lassical+ physiological stress responses
may help the organism to sustain homoeostatic &alance in the presence
of the increasing demands re/uired &y these strategies. "oreover+ when
&ehavioural responses that are part of the esta&lished repertoire of an
organism are insufficient for coping with the stressful situation+ the
individual may &e forced to develop new coping strategies. )f attempts
at coping meet success+ learning will reorgani6e individual &ehavioural
strategies on the &asis of the newly gained information.
!n the other hand+ if no coping is possi&le due to eBternal *envi$
ronmental- or internal *genetic or historical &ac0ground- constraints+
the organism will cease any attempt at &ehavioural coping and undergo
a different type of adaptation.
4ncontrolla&le stressful eBperiences promote a compleB syndrome
involving also reduced responding to positive+ rewarding stimuli *an$
hedonia-E which suggests that a specific neurophysiological adaptation
to uncontrolla&le stressors may disrupt motivational processes *Lachar0o
and Anisman+ 1''1-.
8rom a historical point of view the first studies on the response of
the organism to stressful situations were pro&a&ly those of ,annon and
de la 5a6+ the physiologists who showed in 1'11 mat the adrenal me$
dulla and the sympathetic system are involved in emergency situations.
An alternative line of research was carried out &y ans Selye+ centred
on the role of the adrenal corteB in the stress response. The cNmcept of
adaptation is central in stress theories. Selye called
the whole of stress responses the "general adaptation syndrome".
owever+ the earliest theories considered adaptation as activation of a
num&er of peripheral defensive responses against nocuous stimuli.
igher species+ such as verte&rates+ are characteri6ed &y a high
capa&ility to gain+ to store and to apply species$specific information
a&out their ecological niche in an individual manner. Thus+ learning
represents a form of adaptation that renders the organism fleBi&le+ al$
lowing prediction and control over the changing environment. When$
ever changes in the internal or eBternal environment render species$
specific responses inappropriate+ the organism may reorgani6e these
responses through learning+ adapting to the new situation. Thus+ in
higher species+ the process of adaptation promoted &y stress may result
in reorgani6ation of &ehavioural strategies.
Another form of adaptation involves &rain functioning. Several
aspects of &rain functioning undergo plastic changes in the course of
the organismEs life. Some of these changes+ especially those involving
neuronal electric activity+ may underly learning at central levels *;andel+
1'(>-. Nonetheless+ much slower and eBtensive changes in &rain neu$
rochemistry appear to &e unrelated to learning processes. Among these
the most studied are changes in the meta&olism and release of chemi$
cals involved in neural transmission *neurotransmitters- &etween neu$
rones+ and in the densities or sensitivity of the sites that receive chemical
messages *receptors-. Alterations of these parameters change the state
and activity of specific &rain pathways in a more or less permanent
way through sensiti6ation *enhanced activity- and desensiti6ation *re$
duced activity-. ,onse/uently+ the net result of these processes is the
reorgani6ation of the compleB networ0s that connect &rain structures.
These 0inds of change are presumed to underlie psychopathol$
ogy for which a ma<or role of stress as etiological factor is proposed.
The last o&servation &rings us to the pathogenic effects of stress re$
sponses. !ver the years+ evidence has accumulated indicating that
stressors contri&ute to the provocation andHor eBacer&ation of a range
of illnesses+ including the classical psychosomatic disorders+
immunologically related illnesses+ neoplasia+ cardiovascular diseases
and psychological distur&ances. The relationship &etween adaptation
promoted &y stressful eBperiences and lia&ility to pathology has al$
ways &een a difficult point to clarify in stress theories. The classic view
relates pathological ris0 to the intensity and duration of stressful con$
ditions. According to SelyeEs interpretation+ persistence of a stressful
condition leads to eBhaustion of defensive mechanisms+ thus promot$
ing pathological outcomes.
owever+ the duration and intensity of a stressful eBperience does
not depend only on stressors *i.e. the stimuli capa&le of eliciting the
stress response- &ut also on organism varia&les. Thus+ the outcomes of
stressful eBperiences depend on the interaction &etween the organism
and the environment. )ndeed+ the organism is an open system con$
stantly eBchanging information with the environment *von 2ertalanffy+
1'?(-. This o&servation has strongly influenced the most recent theo$
ries a&out stress+ leading to the suggestion that the entire stress re$
sponse+ including the stressful /uality of stimuli and eBperiences+ is
determined &y organism$environment interaction *5uglisi$Allegra et
ai.+1''@-.
This view has important implications for stress management. )n
fact+ new developments in psychological techni/ues as well in psychop$
harmacology+ provide uni/ue tools to act on the environment+ the or$
ganism+ and the interaction &etween them.
R,F,R,NC,S
A&ercrom&ie+ E.D.+ ;eefe+ ;.A.+ Di 8rischia+ D.8.+ Ligmond+ ".3. *1'('-
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%O-O,OSTATIC PROC,SS,S
IN N,URO,NDOCRINOLO65
./lio Licinio and Paolo Polo
INTRODUCTION
omoeostasis is the a&ility of an organism to maintain internal e/uili&$
rium &y ad<usting internal processes. All living organisms survive &y
maintaining their &alance &etween intrinsic and eBtrinsic forces or
stressors. !ne organ which is particularly connected to responding to
changes in &ody &alance is the anterior pituitary+ the intermediary &e$
tween the central nervous system *,NS- and peripheral endocrine glands
*1icinio and 7old 1''=D 2urrows et al1''(D ,hrousos and 7old 1''(-.
,entral and peripheral responses are designed to preserve homoeosta$
sis. During conf ..entation with an acute stressor or change in the
envi$ ronment+ neural pathways involved in arousal+ alertness+
vigilance+ cognition and focused attention are activated+ while
pathways that mediate vegetative functions+ such as feeding and
reproduction+ are inhi&ited *1icinio and 7old 1''=D 7old et al1'((a-.
5eripheral changes facilitate redirection of energy to the central
nervous system and the stressed &ody sites. Restraint of growth and
reproduction saves energy that could &e used more efficiently to flee or
fight the stimulus. A suc$ cessful adaptive response depends not only
on the a&ility to respond /uic0ly to a stressor+ &ut also on the
capacity to respond to counter$ regulatory effectors that prevent all.
oI"erresponse. !therwise+ if an ele$ ment of the stress response+
including those originating from an inflammatoryHimmune
reaction+ is not a&le to respond to restraining forces+ such a response
loses its adaptive capacity and leads to disease.
.4 Stress and adaptation
) )
P!YSIOLO%Y
The systems responsi&le for reproduction+ growth+ and immunity are
integrated to the stress system. The hypothalamic hormone corticotro$
pin releasing factor *,RR- plays a 0ey role in adaptive &ehaviours during
stressful events. These include not only activation of the hypothalamic$
pituitary$adrenal *5A- aBis+ &ut also activation of the sympathetic nerv$
ous system *SNS-. As an eBample+ ,RR suppresses luteini6ing hormone
releasing hormone *1RR- secretion &y the arcuate nucleus of the
hypothalamus. The ,RR system is locali6ed in widespread &ut discrete
areas throughout the &rain. A 0ey area for ,RR function is the
paraventricular nucleus of the hypothalamus *7old et a)1''?-. The ac$
tions of ,RR in the &rain and in the periphery are mediated through
multiple &inding sites. There are five receptor isoforms encoded &y two
distinct genes+ ,RR
5a
, ,RR
11
8, ,RR
2a
, ,RR
2$
and ,RR
2y
,RR
receptor activation increases the intracellular levels of calcium and cA"5D
however+ the DNA responsive elements ,RE *cA"5 responsive element-
and ,ARE *calcium responsive element-+ &oth variants of the &asic
palindromic motifT7A,7T,A+ are not present in the promoter region
of the proopiomelanocortin *5!",- gene+ a ma<or target of ,RR
&ioactivity. Recently highaffinity non$peptide ,RR receptor antagonists
have &een identified. "oreover+ the various actions of ,RR are modu$
lated &y a &inding protein *,RR$25-. 1igands of,RR$25 raise &rain
levels of EfreeE ,RR. They playa ma<or role in improving learning and
memory without stress$li0e side effects. 4 rocortin is a mammalian ,RR$
related peptide with close se/uence homology to fish urotensin *Faughan
et al1''>D vFong et al1''?a-. )t interacts with ,RR
5a
, ,RR
5$
) ,RR
2a
,
,RR
2$
) and ,RR
2y
receptors and with ,RR$25 *2ehan et al1''?- and
affects 5A function *see Ta&le 1-.
2rain ,RR is elevated in several disease states including ma<or
depression+ anoreBia nervosa+ and stro0eD therefore+ ,RR receptor
!o-oeostatic 2ocesses in ne/oendocinolo#1 8)
antagonists could &e useful for the treatment of these diseases. Another
strategy to modulate endogenous levels of ,RR &ioactivity is through
the ,RR $25+ which is a modulator of a larger family of ,RR $related
peptides and ligands. )nhi&itors of ,RR $25 may &e used to raise &rain
levels of EfreeE ,RR+ urocortin and other ,RR $related peptides.
,RR secreted into the hypophyseal portal circulation &inds to
,RR
1
receptors+ enhancing the production of transcription factors which
&ind to the 5!", promoter+ resulting in augmented 5!", gene
transcription. 5!", mfu"3A is then translated in many peptides+ mostly
A,T and N$endorphin. A,T serves as a potent stimulus for the
adrenal production of the steroid hormone cortisol. ,ortisol modu$
lates the functioning of most organs and systems and acts as negative
feed&ac0 signal to the 5A Q1"T)S *1icinio and 7old 1''=-. 2asal corti$
sol levels are relevant to optimal function of the immune system+ while
high cortisol levels cause immunosuppression *7atti 7 1''%D Stern$
&erg et a)1'('-.
,RR lowers appetite+ inhi&its reproduction+ and raises alertness.
1eptin+ a peptide hormone produced &y fat cells+ reduces food con$
sumption in mammals. 1eptin levels in humans are pulsatile and their
diurnal rhythm is inverse to that of5Ahormones *1icinio et a)1''=-.
The availa&le preclinical and clinical data suggest that leptin+ a periph$
erally$secreted and pulsatile signal of nutritional status+ modulates 5A
aBis activity.
The role of immune mediators+ such as interleu0ins+ in the activa$
tion of the 5A aBis has &een the topic of active investigation. )ndeed+
the study of neural$immune interactions is one of the fastest$growing
areas of neuroscience. )nterleu0ins+ such as interleu0in$) *)1$l- and
interleu0in$# *)1$#-+ are potent stimulators of ,RR release+ whereas
,RR is a&le to downregulate cyto0ine release through the immune$
suppressive effects of cortisol *Stern &erg and 1icinio 1''>-.
Dysregulation of peripheral )1$l N maD.E have an important impact on
specific &rain circuitries. )1$1 N modulates hypothalamic$pituitary func$
tion in infection and inflammation. 5eripheral )1$1 N modulates pro$
duction of )1$1 N within the &rain+ thus inducing nitric oBide synthase
type # *iN!S-. The resulting nitric oBide *N!- diffuses into ,RR$
secreting neurons and may inhi&it hypothalamic$produced ,RR
*"c,ann 1''=-.
N! is a uni/ue informational su&stance+ a free radical+ first identi$
fied as the endothelium$derived relaBing factor *"urad 1''(-. (t is
generated &y N! synthases and plays a prominent role in controlling a
variety of organ functions in the cardiovascular+ immune+ reproductive+
and nervous systems. )nduci&le nitric oBide synthase *iN!S- is not
49 Stess and ada2tation
normally present in the &rain in youth+ &ut it can &e detected in the
&rain after inflammatory+ infectious+ or ischaemic damage+ as well as in
normal+ ageing &rains. 2rain iN!S seems to contri&ute to the patho$
physiology of many diseases that involve the central nervous system+
&ut the role of iN !S appears to go &eyond tissue damageC &rain iN!S
may &e re/uired for ade/uate repair following in<ury or damage. The
effects of &rain iN!S on the &alance &etween damage and repair ma0e
this en6yme a promising therapeutic target for human disease. Systemic
inflammation can &e considered an eBtreme stressful event. Systemic
inflammation causes rapid induction of iN!S gene eBpression in dis$
crete areas of the rat &rain *Wong et al1''?& -. This causes spillover of
N! meta&olites such as nitrate into the &rain parenchyma and cere&ro$
spinal fluid+ which may &e a clinically useful mar0er for the early diag$
nosis of sepsis *Wong et al1''=-.
PAT!OP!YSIOLO%Y
7enerally the stress response should &e acute or of a limited duration.
EBcessive stress+ on the contrary+ leads to the syndrome descri&ed &y
Selye in 1'%? *Selye 1'=?-. 2e hypothesi6ed that severe diseases of
any 0ind could show symptoms of anoreBia+ loss of weight+ mood de$
pression+ hypogonadism+ peptic ulcers+ and immnosuppression. Detec$
tion of increased production of,RR in severely ill su&<ects could eBplain
the pathogenesis of the syndrome+ since ,RR can &e responsi&le of
everyone of those symptoms. "elancholic depression represents a model
of dysregulation of the generali6ed stress response and shares many
&iochemical similarities with acute stress *7old et al1'((a-. 2oth con$
ditions are associated with a hyperactive 25A aBis and locus coeruleusyE
norepinephrine *1,HNE- systemD that means elevated ,RR+ cortisol
and catecholamine secretion+ increase of the catecholamine$induced
interleu0in$? *)1$?- concentration *5apanicolaou et al 1''(-+ inhi&i$
tion of growth+ thyroid+ and gonadal systems+ and suppression of the
immune system.
The chronic or repeated hyperactivity of the stress system can even$
tually produce long$term medical mor&idity in patients with depres$
sion+ including effects on &one and cardiovascular system. An history
of melancholic depression is indeed associated with mar0ed osteoporo$
sis in premenopausal women *"ichelson et al1''?-. ,RR$mediated
hypercortisolism is li0ely to eBert more deleterious effects on &one than
hypercortisolism of either ,ushingEs disease or eBogenous glucocorti$
coid administration *;ling et al1''1-. 7lucorticoid$induced osteoporo$
sis is characteri6ed &y decreased &one formation and in situ death of
isolated segments of &one+ and is third in fre/uency after postmeno$
i
. R1
)(
95
(
!o-oeostatic 2ocesses in ne/oendocinolo#1 4(
pausal and senile osteoporosis. Recent clinical studies have demonstrated
a mar0ed decrease in &ody mass indeB *2"D-+ as determined &y dual
energy radiographic a&sorptometry *DEPA-+ in women with a history
of depression *"ichelson+ 1''?-. This is of interest from a pu&lic health
perspective+ as ma<or depression affects >$' G of the general population
and it is well 0nown that a decrease in 2"D of 1 @ percent is associated
with an increase in hip fractures at the rate of A@G over a period of 1@
years *"ichelson et al1''?-. The presence of specific+ satura&le+ high$
affinity glucorticoid receptors *7R-+ androgen and estrogen receptors
has long &een demonstrated in human osteo&lasts *1iesegang et al
1''A-. 7, are therefore a&le to influence production and action of
cyto0ines and growth factors that regulate &one microenvironment.
8or eBample+ deBamethasone can inhi&it &oth &asal and )1$1 mediated
)1$? mRNA eBpression in human osteo&lasts *1ittlewood et a)1''1-.
Reduced 2"D has &een found for &oth male and female patients suf$
fering from ma<or depressionC however+ males were more severely af$
fected than females *al&reich et al 1''>-. Although clinical and
eBperimental findings clearly suggest that patients Ewith mood disorders
may &e at increased ris0 of &one fractures+ this issue is still widely ne$
glected.
"oreover+ patients Ewith depression have a decreased life eBpectancy
primarily due to cardiovascular diseases. Depression has &een associated
with increased incidence and a worse outcome of coronary artery disease
*7lassman and Shapiro 1''(D "usselman et al 1''(-. )t is of note that
o&esity and myocardial ischemia are represented in the so$called Emeta$
&olic syndromeE+ which is characteri6ed &yC insulin resistance+
hypertriglyceridemia+ hypertension and reduced fi&rinolytic activity *Sirtori
and 5asi0 1''A-+ and whose pathogenesis involves &oth hypercortisolism
*5ic0up et al1''=- and vagal withdrawal *1ee et al1''(-.
8undamental manifestations of melancholic depression are the
hyperarousal and redirection of energy and &ehaviour typical of gener$
ali6ed stress response. owever+ ade/uate adaptive counterregulation
&ecomes maladaptive and prolonged in melancholic depression. Thus+
arousal turns into dysphoric hyperarousal+ and vigilance into hyper$
vigilance and insomnia. The dysphoria o&served in melancholic depres$
sion may represent hyperactivation of the mesocorticolim&ic system in
response to chronic stress. 5atients focus their attention. memory and
cognition o&sessively on depressive ideas+ impairing the a&ility of the
su&<ect to focus on+ remem&er+ or solve practical pro&lems. 8urther$
more+ decreased interest in feeding and reproduction+ which is adap$
tive in the generali6ed stress syndrome+ turns into anoreBia and a&sence
of li&ido+ which are &oth hallmar0s of melancholic depression. !ther
48 Stess and ada2tation
conditions may &e associated with increased and prolonged ,RR se$
cretion or activity. 8or eBample+ anoreBia nervosa is also characteri6ed
&y hypersecretion of,RR. 5atients with anoreBia nervosa show family
history of ma<or depression+ are often depressed themselves and present
also immune alterations typical of ma<or depression *Staurenghi et al
1''=-. !n the other hand+ they show neural mechanisms of hunger
and satiety+ as hypersecretion of arginine vasopressin+ that could direct
them towards pathological eating &ehaviour *7old et a)1''?-.
The theory that depression is associated with hyperactivity of ,RR
neurons cold not at first &e reconciled with atypical depression and
,ushingEs syndrome+ in which polyphagia+ weight gain and hypersom$
nia eBist in the conteBt of decreased ,RR secretion *7old et a)1'((&-.
Studies in seasonal affective disorder showed chronically decreased ,RR
secretion in the winter depressed state *7old et al 1''>D 3oseph et al
1''1-+ together with increased plasma cortisol sensitivity to
glucocorticoids+ and reduced cortisol production rate *Wal0er et al
1''=-. Those data have led to the new hypothesis that there is another
form of stress system dysregulation characteri6ed &y hypoarousal of the
,RR system. This category could include some forms of o&esity char$
acteri6ed &y hypoactive+ hyposerotonergic 25A aBis *2ernini+ Argenio
et a)1'('-. ,RR release could &e further decreased in o&esity &y the
effects ofleptin *1icinio et al1''=D Wand and Schumann 1''(-. Su&$
groups of patients with post$traumatic stress disorder have shown de$
creased urinary free cortisol secretion and increased sympathetic system
activity in reaction to memories of past stressors *"c8all et al 1''@D
9ehuda et al 1''@-. Fery recent research+ however+ contradicts these
findings *1audenslager et al1''(-.
(t is now evident that distinct ,RR systems coeBist in the &rain+
including hypothalamic and eBtrahypothalamic cortical and su&cortical
sites. ,RR action in the amygdala is of particular importance in the
regulation of fear$related &ehaviours. An eBcess in glucocorticoids and
,RR leads to allostatic load+ a new concept that refers to the pressure
on &ody and &rain arising from failing attempts at adaptation *Rosen
and Schul0in 1''(D Schul0in et al1''(-.
CONCLUSION
Dysregulation of the stress system+ resulting in either hyperfunction
or hypofunction+ involves several health disorders with a tremendous
impact on society. AnoreBia nervosa+ melancholic depression+ panic
disorder+ o&sessive$compulsive disorder+ and hyperthyroidism are as$
sociated with increased stress system activity. !n the other hand+ atypi$
cal depression+ ,ushingEs syndrome+ seasonal affective disorder+ chronic
!o-oeostatic 2ocesses in ne/oendocinolo#1 44
fatigue syndrome+ post$traumatic stress disorder+ and hypothyroidism
are associated with decreased stress system activity. )t is sometimes
difficult to distinguish &etween cause and effect+ since this system
tends to interact with internal and eBternal pertur&ations in a Enon$
specificE manner. Nonetheless+ maladaptive responses can act as
stressors themselves+ sustaining and feeding a vicious cycle. Fery re$
cent studies *5anarelli et a11''(D Rosmond et a11''(- demonstrate
an attempt to verify whether normal$life stress$related hypersecretion
of cortisol or hypersensitivity to glucocorticoids may affect systemic
&lood pressure or car&ohydrate and lipid meta&olism+ leading to del$
eterious long$term impairments in meta&olic function. ui6enga et
al. *1''(- have recently demonstrated that a polymorphism of the
glucocorticoid receptor is present in ? G of normal Dutch men that is
associated with a significant greater cortisol suppression &y deBam$
ethasone+ tendency to o&esity+ and lower &one mineral density. )t is
possi&le that a variation in target$gene responsivity to glucocorticoids
is the result not only of glucocorticoid receptor gene function+ &ut
also of the function of genes that are involved in the glucocorticoid
signal$transmission pathway+ inducing variations that can &e either
harmful or protective *,hrousos and 7old 1''(-. With recent ad$
vances in molecular genetics+ many cyto0ine and hormone$related
genes have already &een identified. owever+ the relation &etween
suscepti&le genes and phenotype definition is yet to &e achieved.
8inally+ stress$responsive neuroendocrine$neuroimmune systems
show either a circadian organi6ation or one &ased on a sleepHwa0e
cycle. 8or eBample+ A,T and cortisol levels correlate directly with
the active period &oth in diurnal and nocturnal animals+ indicating that
higher levels of adrenal corticosteroids are needed in the awa0e state.
In contrast+ ,RR cere&rospinal levels are higher in the everting and
lower in the early morning+ in a cycle that is opposite to that of plasma
cortisol+ which shows a pea0 around @(C@@ and a nadir around ##C@@
*;ling et a)1''A-. 4nfortunately+ many studies have considered only
few time points+ usually in the morning. )n this +vay+ most pea0 andHor
nadir points are not detected. Detailed studies are re/uired+ with as
many evaluation points as possi&le+ under rigorous research conditions.
)n summary+ the homoeostatic regulation of stress$responsive neu$
roendocrine$neuroimmune systems is a compleB+ multifactorial+
polygenically determined+ developmental+ and environmentally$depend$
ent phenomenon of great importance to medicine and society. Novel
treatment strategies &ased on the emerging mechanistic understanding
of those systems should improve the treatment of common and com$
pleB medical and psychiatric disorders which have considera&le mor$
/0 Stress and adaptation
&idity and mortality+ as well as high economic and social cost+ and that
represent ma<or pu&lic health pro&lems &oth in developed and devel$
oping countries.
TABLE (
T"e CR! Net:o+ , Se2te-3e ());
1igands 2inding sites
S ,RR$la
S ,RR$lN
R,R
; 4rocortin
1egendC
S ,RR$#a
S ,RR$#N
S ,RR$#y
S ,R$25
,RC corticotropin releaseing hormone
,RRC corticotropin releasing hormone receptor
,R$25C corticotropin releasing hormone$&inding protein
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C,NTRAL N,URAL
-,C%ANIS-S PROT,CTIN6
T%, BRAIN FRO- %5PO:IA
AND ISC%A,-IA
Donald J. Reis and E/#ene V. %olano&
INTRODUCTION
CENTRAL NEURO%ENIC NEUROPROTECTION AND STRESS
Stress not only activates the hypothalamic$pituitary aBis+ &ut also in$
varia&ly coactivates the sympathetic nervous system. Sympathetic acti$
vation initiates circulatory ad<ustments that+ in part+ function to protect
the &rain from threats to its &lood supply arising from stresses such as
&lood loss+ sepsis+ or hypoBia. The need to protect the cere&ral circula$
tion relates to the uni/ue vulnera&ility of &rain to alterations in !
#
and
glucose+ the o&ligate su&strates for cere&ral meta&olism. )n support is
the fact that interruption of &lood flow to &rain results within a&out 1@
secs in unconsciousness+ and in 1@ mins in neuronal death.
)n nature there are several states in which the &rain may withstand
reductions in oBygenation andHor &lood flow which otherwise would
&e eBpected to &e fatal. These are the mar0ed hypoBaernia sustained
during su&mersion in diving verte&rates *2utler 7 3ones+ 1''=- and
the profound reductions in regional cere&ral &lood flow *r,28- that
accompany hi&ernation *8rerichs 7 allen&ec0+ 1''(-. The fact that
these &ehaviours are part of a natural repertoire and recur without o&$
vious loss of cere&ral function suggests that the &rain may contain in$
trinsic mechanisms designed to protect it. )t is li0ely that the pathways
that protect the &rain from in<ury relate to those which initiate the
&ehaviours.
!ver the past several years+ we have uncovered 8:)i4O different+ yet
interrelated+ homoeostatic neuronal mechanisms in rat &rain which may
act to protect the organ from in<ury. ,ollectively+ these have &een called
central neurogenic neuroproiection *see Reis et al.+ 1''=-. !ne+ re8le0
neurogenic neuroproieciion, acts to rapidly initiate autonomic responses
that elevate r,28 through mechanisms compara&le to the diving re$
fleB. The second+ con+itione+ central neurogenic neuroproteciion, elicits
long$lasting protection against ischaemia and eBcitotoBicity+ Each of
these neuroprotective mechanisms is represented in intrinsic neuronal
pathways closely lin0ed to central autonomic regulation+ systems which
would &e activated in stress.
REFLE< NEURO%ENIC NEUROPROTECTION
S1ste-ic and cee3o&asc/la es2onses to e=citation
o* R0L ne/ons
The diving refleB *see 2uder 7 3ones+ 1''=- is a special case of what
Wolf has termed the oBygen$conserving refleB *Wolf et al.+ 1'?>-. )t
consists of a stereotyped autonomic response comprised of eBpiratory
apnoea+ &radycardia+ and widespread and potent peripheral vasocon$
striction in s0eletal muscle and viscera. The function of the diving re$
fleB is to redistri&ute &lood flow to the &rain to counteract dwindling
concentrations of > .A compara&le refleB respiratory and circulatory
response can &e elicited &y selective ischaemia of the &rainstem+ the
cere&ral ischaemic response *;umada et al.+ 1'='-+ and &y &rainstem
distortion+ the ,ushing refleB *off 7 Reis+ 1'=@D Do&a 7 Reis+ 1'=#-.
2oth are triggered from specific areas of the lower &rainstem *Dampney
7 "oon+ 1'(@D off 7 Reis+ 1'=@D Do&a 7 Reis+ 1'=#D ;umada et
al.+ 1'='-.
The neural su&strate for much of the diving andyE or ischaemic re$
fleB involves a small group of neurons residing within the reticular for$
mation of the rostral ventral medulla o&longata *Dampney 7 "oon+
1'(@-. The critical neurons are a su&population of adrenergic neurons
of the ,1 adrenergic cell group which reside in a su&area of the rostral
ventrolateral reticular nucleus *RF1- of the medulla+ the ,1 area *Ross
et al.+1'(A&-. These are tonically active+ discharge with a firing pro&$
a&ility lin0ed to the cardiac cycle *2rown 7 7uyenet+ 1'(>-+ and pro<ect
to the spinal cord+ where their innervation is restricted to autonomic
laminae and cell groups *Ross et al.+ 1'(Aa-. The neurons represent
the so$called "tonic vasomotor centre" of the &rainstem+ i.e. those neu$
rons whose activity is essential for maintaining normal resting levels of
activity of spinal preganglionic sympathetic neurons and hence arterial
pressure *A5-. They also maintain resting levels of release of the stress
hormone adrenaline from the adrenal medulla.
When eBcited+ RF1 neurons increase sympathetic activity and cat$
echolamine release+ and elevate A5 *Ross et al.+ 1'(%-. When inacti$
vated+ A5 collapses *Ross et al.+ 1'(%D 7ranata et al.+ 1'(%-. These
"premotor" sympathoeBcitatory reticulospinal vasomotor neurons are
also essential in mediating a range of refleBes acting upon the systemic
circulation. "odulation of their discharge accounts for changes in A5
elicited+ for eBample+ &y stimulation of arterial &aroreceptors *7ranata
Cental ne/al -ec"anis-s 2otectin# t"e 3ain 4)
et al.+ 1'(%D Terui et al.+ 1'(?- and chemoreceptors *Sun 7 Spyer+
1''1-+ &y pain *Stornetta et al.+ 1'('-+ and &y the emotional stress of
conditioned fear *1eDouB et al.+ 1'((-. They are eBcited &y &rainstem
ischaemia *7uyenet 7 2rown+ 1'(?- and are the mediators of the cer$
e&ral ischaemic response *Dampney 7 "oon+ 1'(@-.
Several years ago+ we also discovered that vasomotor neurons of
the ,1 area are also central oBygen$detectors and are responsi&le for
the rapid and acute elevations associated "with hypoBaemia andHor
&rainstem ischaemia. In %i%o, microin<ection into RF1 of sodium cya$
nide *Na,N-+ an agent that &loc0s the electron transport chain+ pro$
duces histotoBic hypoBia and replicates the peripheral components
of the diving refleB+ initiating &radycardia+ sympathetic eBcitation+
hypertension +and apnoea *Sun et al.+ 1''#-. The responses elicited
from RF1 &y microin<ection of the agents are cytologically and
topographically specific and restricted to reticulospinal sympatho$
eBcitatory neurons of the ,1 area *Sun et al.+ 1''#-. "oreover+ it is
only these neurons that are eBcitedD microiontophoresis of Na,N al$
most immediately eBcites them+ while ad<acent respiratory neurons are
inhi&ited *Sun 7 Reis+ 1''Aa-. The ma<ority of neurons in the region+
which are non$respiratory and non$cardiovascular+ are unaffected. The
neurons are eBcited &y systemic hypoBaemia in the a&sence of arterial
chemoreceptors. This indicates that the responses are not attri&uta&le
to eBcitation of arterial chemoreceptors+ although stimulation of these
receptors will also+ via an intramedullary refleB arc+ eBcite RF1 neurons
refleBively *Sun Reis+ 1''AaD ,averson et al.+ 1'(A-. 2loc0ade of their
activity &y lesions or drugs inhi&its the responses to cere&ral ischemia
*;umada et al.+ 1'='D Dampney 7 1v1@@n+ 1'(@-.
In %itro analysis has demonstrated that the cellular mechanism of
hypoBic eBcitation is an intrinsic property of REF1 neurons. )n slices of
the medulla *Sun 7 Reis+ 1''A&- Na,N or hypoBia will rapidly in$
crease the discharge of pacema0er neurons ofRF1+ neurons which cor$
respond to the reticulospinal vasomotor neurons in intact animals.
"oreover+ the sensitivity of these neurons to hypoBia cannot &e &loc0ed
&y tetrodotoBin+ nor &y a range of antagonists to neurotransmitters+
indicating that the response is not synaptically generated.
)n response to hypoBia+ reticulospinal RF1 neurons will also repli$
cate the characteristic cere&rovascular responses to hypoBaernia $ a glo$
&al elevation in regional r,28 unaccompa.nied &y changes in regional
cere&ral meta&olism *eBpressed as regional cere&ral glucose utili6ation+
r,74- *Allen et al.+ 1''#D amer et al.+ 1'=?-. Thus+ stimulation of
RF1 electrically or chemically with eBcitatory amino acids+ Na,N+ or
dinitrophenol will dose$dependently and site$selectively elevate r,28+
>9 Stess and ada2tation
&ut not r,74D while lesions of the region will reduce+ &y over >@G+ the
vasodilation elicited &y systemic hypoBia. The interruption of hypoBic
vasodilation appears specific since the lesions do not pertur& the eleva$
tion of r,28 elicited &y hypercar&ia *7olanov 7 Reis+ 1''?D
4nderwood et al.+ 1''A-. "oreover+ they appear after peripheral chem$
oreceptor refleBes are interrupted+ a finding supporting earlier evidence
that arterial chemoreceptor stimulation will not alter r,28 *eistad et
al.+1'=?-.
)nterestingly+ eBcitation of the RF1 also alters the electrical activ$
ity of the &rain *7olanov 7 Reis+ 1''>-. All stimuli ofRF1 that el$
evates r,28 also synchroni6es+ in anaestheti6ed rats+ the EE7+ resulting
in a significant increase in the power oflower$fre/uencywaves+ particu$
larly those of the A$? 6 spectrum.
Cental 2at":a1s o* t"e cee3o&asc/la es2onses to
"12o=ic e=citation o* t"e R0L
Me+ullary nuclei. While it is clear that hypoBic stimulation of RF1 will
elevate r,28+ the pathways and cere&ral mechanisms have &een o&$
scure. The pro&lem is compounded &y the facts that *a- RF1 neurons
do not pro<ect to the cere&ral corteB *Tuc0er et al.+ 1'(=D Ruggiero et
al.+ 1'('-+ the region of greatest changes in r,28D and *&- neurons of
the ,1 area+ also designated as the rostral RF1 *RF1r- + primarily pro<ect
caudally to innervate autonomic segments of the spinal cord.
We have recently discovered a novel area of the medullary reticular
formation that lies <ust caudal to the RF1 in rat+ a paraam&igual region
termed the caudal RF1 *RF1c-+ which acts as the medullary region
through which eBcitation of oBygen$sensitive neurons of the RF1 relay
to mediate the cere&ral effects of stimulation+ i.e. elevation of r,28
and synchroni6ation of EE7. )n evidence are the facts that * a- electrical
or chemical stimulation ofRF1c evo0es /ualitatively similar+ &ut /uan$
titatively greater+ elevations of r,28 and EE7 synchroni6ation than
that o&tained &y stimulating RF1rD and *&- lesions of RF1r &loc0 the
changes in r,28 and EE7 o&tained &y stimulating RF1r+ &ut not el$
evations in A5+ while &ilateral lesions of RF1r have no effect upon the
cere&ral effects elicited from RF1c. "oreover+ *c- the two regions have
distinct pharmacological characteristics+ for Na,N will only elevate r,28
from RF1c+ while nicotine only elevates it from RF1c. The hypothesis
is supported &y anatomical evidence that *d- the RF1r innervates RF1c
over a short intrareticular pathway.
.scen+ing relays. A second /uestion involves the identity of the
ascending pathways over which neurons from RF1c ascend to influ$
ence r,28. While the identity of the pathway has yet to &e fully esta&$
?
Cental ne/al -ec"anis-s 2otectin# t"e 3ain >(
8
):
:
5)5
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+)+
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lished+ there are some clues to part of its identity. Since the elevations
of cortical r,28 elicited &y stimulating RF1c increase r,28 glo&ally+
stimulation must engage neuronal pathways which+ in aggregate+ in$
nervate the entire corteB. Nuclei with the most widespread cortical
innervation include those of the upper &rainstem and fore&rain+ in$
cluding midline thalamic nuclei *5rice+ 1''>-+ lateral hypothalamus
*Sapcr+ 1'(>-+ and &asal fore&rain *7rove+ 1'((D )de 7 "ar0owitsch+
1'(A-.
We have recently investigated the contri&utions of some of these
regions to the neural control of r,28 &y eBploring regions of the mid$
line thalamus+ su&thalamus+ and parts of the hypothalamus for regions
from which microstimulation elevates r,28. We have discovered
*7olanov 7 Reis+ 1''(- that &ilateral elevations in r,28 and synchro$
ni6ation of the EE7 could &e o&tained &y stimulation of a small and
specific area lying in a su&thalamic area in the &oundary &etween the
6ona incerta *L)- and lateral hypothalamus. )n contrast+ stimulation of
thalamic nuclei with diffuse pro<ections *e.g. midline nuclei+ including
the centrum medianum- were without effect.
Stimulation at the active site with a >$sec train increased r,28 in
a&out #$% sec+ pea0ing %>$A@ seconds after the stimulus terminated+
and recovering % min later. Stimulation also synchroni6ed the EE7+
largely &y increasing the A$? 6 waves. The effects of electrical stimu$
lation were replicated &y topical microin<ection of the eBcitatory amino
acid l$glu+ indicating that the response arose from eBcitation of local
neurons. Small &ilateral lesions of the region &loc0ed the vasodilation
and EE7 responses elicited from RFlc. Thus+ neurons in this func$
tionally restricted region of su&thalamus relay signals from RF1c that
elevate r,28 and synchroni6e the EE7 in response to hypoBia.
Intra-cortical mechanisms. Another /uestion relating to the neuro$
genic cere&rovascular vasodilation concerns mechanisms in the target
&y which hypoBic activation of medullary neurons initiates an increase
in r,28. While a traditional view would hold that all neurogenic va$
sodilation results from local meta&olic events+ the mar0ed cere&rovas$
cular vasodilation elicited &y hypoBia or &y electrical or chemical
eBcitation of neuronal pathways emanating from RF1 *RF1r or RF1c-
or fastigial nucleus *8;- are not associated with changes in r,74 in
regions sustaining maBimal elevations of &lood flow+
Rather+ we have proposed that the neurovascular transduction in
the cere&ral corteB involves the activation of local interneurons. Sev$
eral arguments support this view+ 8irst+ while vasodilation results from
relaBation of vascular smooth muscle in cere&ral arterioles+ there is no
evidence that cortical afferent neurons eBtend &eyond the limiting
0. Stress and
adaptation
glia to innervate muscular arteries. Second+ destruction of intra cortical
neurons &y eBcitotoBins+ while preserving the integrity of afferent in$
nervation+ &loc0s the vasodilation elicited from the cere&ellar 8N+ an
effect which effectively trans duces the neural signal into a vascular
event. Third+ we have identified a population oflocalneurons whose
activity correlates with stimuli that are associated with primary eleva$
tions of r,28 *i.e. not coupled to changes in r,74-. These cortical
vasodilator neurons+ locali6ed in deep cortical layers and representing
a&out >G of spontaneously active cortical neurons+ are eBcited 1$# sec
&efore elevation of flow. We would propose that these "vasodilator
neurons"+ widely distri&uted across the corteB+ are essential in neuro$
genic vasodilation. They can &e activated alone to increase r,28 in$
dependently of r,74 &y+ for eBample+ stimulation of the 8N or RF1+
or in response to hypoBia. !n the other hand+ they may &e activated
in concert with stimuli that may mar0edly elevate local meta&olic proc$
esses+ there&y appearing to affect flow and meta&olism. owever+ we
would suggest that the events are not se/uential *i.e. meta&olism leads
to flow-+ &ut rather they are parallel events *i.e. remote stimulus in$
creases r,74 an+ r,28-.
CONDITIONED CENTRAL NEURO%ENIC NEUROPROTECTION
Potection a#ainst *ocal isc"ae-ia by sti-/lation o* t"e FN
Several years ago+ we sought to determine whether stimulation of the
8N+ which profoundly activates the sympathetic nervous system+ was
neuroprotective. The rationale was &ased on our o&servation that stimu$
lation of the 8N would profoundly elevate r,28+ sometimes &y over
#@@G. This neurogenic elevation in r,28+ was site$specific+ graded+
&asically stimulus$loc0ed+ persisted only for a few minutes after stimu$
lation was terminated+ and was unaccompanied &y changes in r,74+
i.e. a primary vasodilation. 2ecause 8N stimulation elevated r,28 .ith!
out concomitant meta&olic cost+ we reasoned that stimulation of the
8N might &e helpful in alleviating the ischaemia associated with focal
cere&ral ischaemia and+ hence+ reduce infarct si6e.
This rationale was particularly relevant in view of the increasing
evidence that focal cere&ral infarctions+ commonly produced in eB$
perimental animals &y ligating the middle cere&ral artery *",A-+ are
heterogenous. Thus+ following ",A occlusion *",A!-+ a lesion is
produced with several components. Typically+ the ischaemic lesion
consists of a central core in which r,28 and r,74 are maBimally
reduced+ and neurons rapidly die &y necrosis+ which cannot &e sal$
vaged from in<ury. Surrounding the core is an ischaemic penumbra, a
region in which r,28 is partially reduced+ r,74 is unaffected or
elevated+ and in which neurons die over hours to days+ largely &y
apoptosis. The ischaemic penum&ra is electrically unsta&le+ eBhi&it$
ing spontaneous waves of depolari6ation *peri $infarction depolari6$
ing waves+ 5)Ds- that directly contri&ute to neuronal death.
(t is within the penum&ra that the so$called glutamate hypoth$
esis of ischaemic in<ury is relevant. Thus+ it is proposed that ischae$
mia+ with its attendant hypoBia and acidosis+ leads to a cycle of eBcessive
accumulation of eBtrasynaptic glutamate which+ acting through N"DA
and possi&ly A"5A receptors+ and along with the opening of volt$
age$gated channels &y depolari6ation+ mar0edly increases the
intraneuronal accumulation of toBic amounts of ,a VV+ initiating the
toBic cascade. )n addition+ the necrotic penum&ra stimulates an in$
flammatory response *7alea et al.+ 1''( &- that may also contri&ute
to delayed neuronal death *o et al.+ 1''(-. !f relevance is the fact
that &loc0ade of a num&er of steps in this chain+ including calcium+
N"DA receptors *pharmacologically or &y anti$sense oligo$
nucleotides-+ inflammation *9u et al.+ 1''=D 5atel et al.+ 1''%-+ or
eBpression of 5)Ds *7olanov 7 Reis+ 1'''- may &e neuroprotective
and salvage neurons from in<ury+ primarily in the penum&ra.
We therefore undertoo0 a series of eBperiments in which we stimu$
lated the 8N for one hour in anaestheti6ed rats and+ at the same time+
permanently occluded the ",A. ,hanges in ill) andHor &lood gases
were carefully controlled. At the end of stimulation+ wounds were
closed and animals returned to their cages. Twenty$four hours later+
they were sacrificed+ and the volume and distri&ution of the cere&ral
infarction was eBamined. ,ontrols were rats in which an electrode
was inserted in 8N &ut not stimulated *sham$stimulation-+ or animals
in which the cere&ellar dentate nucleus *DN-+ a region whose activa$
tion does not elevate r,28 *7olanov et al.+ 1''?-+ or other inert
areas of cere&ellar white matter+ were stimulated.
As demonstrated in our initial study *Reis et al.+ 1''1- and con$
firmed numerous times thereafter *Reis et al.+ 1''(D 7olanov et al.+
1''?D 9amamoto et al.+ 1''%D Lhang 7 )adecola+ 1''%D 1''#-+ one
hour of8N stimulation reduced+ &y almost >@G+ the volume of a focal
cere&ral infarction. Sham$stimulation or stimulation of the DN were
without effect. Topographically the area of salvage+ the retrieva&le
6one+ corresponded to the ischaemic penum&ra+ while the area unaf$
fected &y stimulation+ the irretrieva&le 6one+ corresponded to the is$
chaemic core. !ur eBperiment therefore demonstrated+ for the first
time+ that eBcitation of the ,NS could protect the &rain from ischae$
rruc ll13ury.
>> Stess and ada2tation
MEC!ANISMS OF SALVAGE
Role o* CBF and C%U
While our rationale had &een to effect salvage &y increasing r,28+ sev$
eral eBperiments indicate that salvage did not relate to changes in &lood
flow. 8irst+ we o&served that when r,28 was directly measured over
the ischaemic core+ penum&ra+ and normal corteB in rats su&<ected to
",A!+ r,28 was not elevated in the penum&ra &y 8N stimulation+
despite the fact that in the same animal the area was salvaged. Second+
stimulation of the RF1+ the principal relay for vasodilation elicited from
8N stimulation and from which stimulation elevates r,28 in the a&$
sence of elevations of r,74+ was not neuroprotective. Third+ when
r,28 and r,74 were measured &y autoradiographic methods+ not
only was r,28 not elevated in the area corresponding to the penum$
&ra+ &ut r,74 was not decreased+ a mechanism that conceiva&ly would
also align r,28 and r,74.
5erhaps the most compelling evidence that changes in r,28 are not
the &asis of salvage came from the o&servation that 1 h of8N stimulation
will protect the &rain from in<ury+ even when the ",A is occluded 1@
days later. Such long$lasting protection+ however+ is not permanent and
disappears &y one month. The finding indicates that electrical stimula$
tion can "condition" cere&ral neuroprotection+ a phenomenon we have
termed con+itione+ central neurogenic neuroprotection.
E**ects on in*la--ato1 es2onses
Since alterations in perfusion do not contri&ute to salvage+ what other
mechanisms may &e involvedT !ne which we have recently investigated
is an action upon the local inflammatory response.
8ocal ischaemia elicits an inflammatory response within the area of
the infarct *9u et al.+ 1''=D 8euerstein et al.+ 1''A-. Such inflammation
is characteri6ed within the 6one of ischaemia &y up$regulation of such
proinflammatory molecules in cere&ral microvessels as ),A"1*;ato et
al.+ 1''?D 7alea et al.+ 1''(a-+ and the induci&le isoform of nitric oBide
synthase *iN!S+ N!S$#- *7alea et al.+ 1''(&D Stros6na<der 7
,halimoniu0+ 1''?D Lhang 7 )adecola+ 1''>-. The microvascular
changes promote the infiltration into &rain of macrophages and
leu0ocytes which+ when activated+ synthesi6e and release pro$
inflammatory cyto0ines+ including )1$lN+ which in turn may initiate a
compara&le cascade in microglia. That some of these molecules+ nota$
&ly N!S$#+ may contri&ute to the initiation of cell death in the ischae$
mic penum&ra has &een suggested &y studies in which treatment with
drugs that inhi&it N!S$# activity reduces lesion volume *)adecola et
al.+ 1''>D 9oshida et al.+ 1''A-.
We investigated whether 8N stimulation might contri&ute to con$
ditioned neuroprotection &y reducing the inflammatory response to
focal ischaemia *7alea et al.+ 1''(aD 1''(&-. )n our initial study+ we
focused on the effects of8N stimulation on the eBpression of N!S$#
induced in the ischaemic core+ penum&ra+ and undamaged &rain *con$
tralateral corteB- &y ",A!.lvl,A! will increase the mRNA and cata$
lytic activity ofN!S$# *7alea et al.+ 1''(&- &eginning within ?$( h
after ischaemia+ pea0ing &etween 1A$#A h+ and recovering &y A( h. At
#A h+ iN!S$li0e immunoreactivity appears in microvessels and
macrophages *ED$1 positive cells- throughout the infarction+ and the
catalytic activity of iN!S is increased. When the 8N was electrically
stimulated for 1 h+ A( h &efore ",A!+ the infarct volume was reduced
&y A>G+ while the eBpression ofN!S$# mfuEITAand protein was almost
completely suppressed in the salvaged penum&ra+ &ut not in the core.
The eBperiment+ however+ raised a difficult pro&lem. )s the reduc$
tion of inflammation within the salvaged territory merely secondary to
inhi&ition of neuronal deathT !r+ does 8; stimulation suppress the
reacti%ity of cere&ral vessels to inflammatory stimuliT To discriminate
&etween these possi&ilities+ we eBamined the effects of 8N stimulation
on the response of cere&ral microvessels to )1$l in %i%o and in %itro. In
%i%o, )1$l induces a model of inflammation that+ unli0e ischaemia+ is
devoid of cellular death *Relton 7 Rothwell+ 1''#D Stroemer 7
Rothwell+ 1''(-.
(n the first study+ we eBamined in %i%o the effects of8N stimula$
tion on the magnitude of the infiltration of leu0ocytes induced &y
microin<ection of )1$l into the striatum of anaestheti6ed rats.
"icroin<ection of)1$1 mar0edly increased the infiltration ofleu0ocytes
identified &y immunostaining with the cell surface mar0er ,D$A> into
the striatum. 8N stimulation inhi&ited the accumulation of leu0ocytes
elicited &y )1$1 &y >@G *pQ@.@>-+ and decreased the distance from the
in<ection site at which cells were found. )n contrast+ stimulation of the
DN and the num&ers of infiltrating leu0ocytes and their rostro$caudal
distri&ution did not differ from naive controls. Thus+ 8N stimulation
selectively antagoni6ed the pro$inflammatory action of )1$l .
We then eBamined whether stimulation of the 8N would alter the
a&ility of cyto0ines to induce the mRNAs of the proinflammatory mol$
ecules ),A"$l+ N!S$# and ) 2+ the inhi&itory su&unit of the pro$
inflammatory transcription factor N8+ in isolated cere&ral microvessels.
We discovered that )1$1 elicited a dose$ and time$dependent induction
of N!S$#+ ),AlI1.$1+ and ) 2 and that+ in microvessels isolated from
rats whose 8N+ &ut not DN+ were stimulated earlier+ the )1$1$induced
induction of iN !S and ),AlI1$1 mfuEITAwas reduced &y one$half+ while
the induction of ) 2 mRNA was mar0edly facilitated. 8N stimulation
alone+ however+ did not effect the &asal level of these molecules. The
findings indicate that eBcitation of the 8N elicits long$lasting inhi&i$
tion of inflammation in cere&ral rnicrovessels+ possi&ly mediated &yover$
production of) 2 and suppressed N8yfunction. Suppression of vascular
inflammation may contri&ute to the central neurogenic neuroprotection+
wherein stimulation of 8N can reduce the volume of focal and glo&al
ischaemic infarctions. 8N stimulation renders cere&ral microvessels re$
fractory to inflammatory stimuli &y as yet un0nown mechanisms.
E**ects on neuronal excitability
",A! also triggers 5)Ds in the territory of salvage that may contri&$
ute to neuronal death and promote infarct eBpansion. We investigated
whether 8N stimulation would modify eBpression of 5)Ds and+ as an
indeB of cortical eBcita&ility+ the thresholds for evo0ing cortical spread$
ing depression *,SD-+ a process sharing characteristics with 5)Ds. Stimu$
lation of8N immediately or =# h &efore ",A! decreased infarction
volumes &y $ A>G *p$!.7l -+ increased &y over 1@@@G the latency to
the first 5)D+ and decreased the num&er of5)Ds &y W>@G *pQ!.!!l-.
)n intact rats+ stimulation of 8N increased the threshold current for
eliciting ,SD &y 1=>G and slowed its propagation velocity &y %>G
*p$D.!El for each- when tested immediately+ &ut not at =#h+ after 8N
stimulation. Thus+ 8N stimulation elicits long$lasting suppression of
5)Ds in parallel with neuroprotection. owever+ 5)D suppression over
time is unli0ely to result from a ma<or increase in cortical tolerance to
depolari6ation and pro&a&ly is not the principal mechanism of salvage.
E**ects on ot"e -odes o* cerebral da-a#e6
Global isc"ae-ia and e=citoto=icit1
We have also investigated whether 8N stimulation can protect against
other forms of neuronal in<ury+ specifically the selective neuronal loss in
the ,Al area of hippocampus produced &y a &rief episode of glo&al
ischaemia and the locali6ed neuronal degeneration elicited &y
microin<ection of an eBcitotoBin in &rain.
7lo&al ischaemia was produced in rats &y transiently occluding+
for A@ min+ the carotid arteries in rats in which &oth verte&ral arteries
were permanently occluded. Seven days later+ the rats were 0illed and
the hippocampus analysed for cell loss. This treatment resulted in the
well$0nown death of su&stantial num&ers of pyramidal neurons of the
,Al su&field+ with neuronal num&ers falling from #1@X>Hmm to
%%X1lHmm *nY?D 5Q!.!!l-. owever+ electrical stimulation of 8N
immediately+ or #A h+ &efore ischaemia significantly increased+ to 1 %AX' H
mm *5Q@.@>-+ the num&er of neurons that survived+ indicating that
this mode of neuronal loss is also protected.
Stimulation of the 8N is also highly effective in protecting against
eBcitotoBic damage. Thus+ the lesion produced &y microin<ecting the
eBcitotoBin i&otenic acid *)2!- unilaterally into the striatum was re$
duced &y up to (@G Ewhen )2! was in<ected 1> min+ =# h+ or 1@ days
*&ut not %@ days- after stimulating the 8N for 1 h. Stimulation of the
DN had no effect. 5rotectiori could not &e attri&uted to alterations in
the &inding of ligand to the receptor *NlvlDA-+ nor to an action of
stimulation to impede diffusion of the toBin through &rain.
These studies demonstrate that cere&ellar stimulation can protect
against neuronal damage in regions of the &rain other than the cere&ral
corteB+ and also can protect against damage produced &y different in$
sults to the &rain.
Path+ays
Electrical stimulation of the 8N+ while eBciting intrinsic neurons+ also
activates aBons pro<ecting to or through the 8N. These would in$
clude efferents from 5ur0in<e cells of the overlying cere&ellar vermis
*Armstrong 7 Schild+ 1'=(- and aBons arising from a system of
&rainstem neurons with collaterals that pro<ect into the cere&ellum
*7on6alo$Rui6 7 1eichnet6+ 1''@-. These facts raise the /uestion of
which element is responsi&le for the neuroprotection. That the in$
trinsic neurons and aBons in 8N may su&serve different functions has
&een shown eBperimentally. Thus+ while electrical stimulation of the
8N ele%ates A5 and r,28 without altering r,74 *Na0ai et al.+ 1'(%D
7olanov et al.+ 1''?-+ selective stimulation of intrinsic 8N neurons
with eBcitatory amino acids lo9ers A5+ r,28 and r,74. "oreover+
following selective destruction of 8N neurons &y eBcitotoBins+ the
elevations of A5 and r,28 elicited &y electrical stimulation persist+
while all responses elicited &y chemical stimulation of the nucleus
disappear *,hida et al.+ 1'(?D 1'('-. Therefore+ intrinsic neurons
mediate sympathoinhi&itory responses coupled to widespread reduc$
tions in cere&ral meta&olism+ there&y resulting in reduced r,28+ an
effect mediated over as yet to &e identified pro<ection fields. )n con$
trast+ the sympathoeBcitatory responses and cere&rovascular vasodila$
tion depend upon eBcitation ofaBons innervating the 8N and the
RF1+ since lesions of the latter a&olish the response. The presence of
neurons with &ranches to &oth 8N and RF1 has &een reported
*"oolenaar 7 Ruc0er+ 1'=?-.
We have recently attempted to determine which of these two func$
tionally distinct systems represented in the 8N mediates neuroprotection.
>; Stess and ada2tation
To answer the /uestion+ we destroyed intrinsic neurons of 8N *or+ as
control+ DN- &y pretreatment with )2!D > days later the 8N was stimu$
lated+ and =# h later an eBcitotoBic lesion was placed in the striatum.
1esions of 8N+ &ut not DN+ a&olished neuroprotection+ &ut not the
elevations of r,28 and A5 elicited from the nucleus. EBcitotoBic le$
sions of 8N+ &ut not DN+ also a&olished the %=G reduction of focal
ischaemic infarctions produced &y occlusion of the ",A. Thus+ it is
eBcitation of intrinsic 8N neurons which provides the long$lasting+ su&$
stantial and reversi&le protection of central neurons from eBcitotoBicity
and focal ischaemia. 1ong$lived protection against a range of in<uries is
an unrecogni6ed function of 8N neurons transmitted over pathways
distinct from those regulating r,28.
SU--AR5 AND CONCLUSIONS
The &rain can protect itself from ischaemia andHor hypoBia &y two
distinct mechanisms that pro&a&ly involve two separate systems of neu$
rons in the ,NS. !ne+ which mediates a re8le0i%e neurogenic
neuroprotection, emanates from oBygen$sensitive sympathoeBcitatory
reticulospinal neurons of RF1. These cells are eBcited within seconds
&y a reduction in &lood flow or oBygen+ initiating the systemic vascular
components of the oBygen$conserving *diving- refleB. They profoundly
increase r,28 without changing r,74 and+ hence+ rapidly and effi$
ciently provide the &rain with oBygen. 4pon cessation of the stimulus+
the systemic and cere&rovascular ad<ustments return to normal. The
system mediating refleB protection pro<ects via as$yet$undefined pro$
<ections from RF1 to upper &rainstem andHor thalamus to engage a
small population of neurons in the corteB that appear to &e dedicated
to transducing a neuronal signal into vasodilation. )t also appears to
relay the central neurogenic vasodilation elicited from other &rain re$
gions+ including eBcitation ofaBons innervating the cere&ellar 8N. This
mode of protection would &e initiated under conditions of glo&al is$
chaemia andHor hypoBaemia since the signal is detected &y medullary
neurons.
The second neuroprotective system is represented in intrinsic neu$
rons of the cere&ellar 8N and mediates a con+itione+ central
neurogenic neuroprotection. The response can &e initiated &y eBcitation
of intrinsic neurons of the 8N+ and does not appear to &e dependent
upon RF1. The pathways and transmitters mediating the effect are
un0nown. The neuroprotection afforded &y this networ0 is long$lasting+
persisting for almost two wee0s+ and is associated with reduced
eBcita&ility of cortical neurons and reduced immunoreactivity of
cere&ral microvessels. This mode of neuroprotection+ moreover+ is not
restricted to focal ischae$
mia+ as we have demonstrated that it also protects the &rain against
glo&al ischaemia and eBcitotoBic cell death. That the &rain may have
neuronal systems dedicated to protecting itself from in<ury+ at first ap$
pearing to &e a novel concept+ is+ upon reflection+ not surprising since
in diving and hi&ernation+ natural states characteri6ed &y very low lev$
els of r,28+ the &rain is not in<ured. An understanding of the path$
ways+ transmitters+ and molecules engaged in such protection may
provide new insights into novel therapies for a range of disorders char$
acteri6ed &y neuronal death. (t is pro&a&le that these networ0s are+ in
fact+ activated during a num&er of stress states that threaten the integ$
rity of the ,NS.
R,F,R,NC,S
Allen ;+ 2us6a A1+ ,roc0ard A+ 7adian D7 *1''#- 2rain meta&olism and &lood
flow in acute cere&ral hypoBia studied &y N"R spectroscopy and hydrogen
clearance. N"Rin 2iomedicine+ >CA($>#.
Armstrong D"+ Schild R8 *1'=(- 2n investigation of the cere&ellar cortico$nuclear
pro<ections in the rat using an autoradiographic tracing method.T+ 5ro<ections
from the vermis. 2rain Res+ 1A1C1$1'.
2rown D1+ 7uyenet 57 *1'(>- Electrophysiological study of cardiovascular
neurons in the rostral ventrolateral medulla in rats. ,irc Res+ >?C%>'$%?'.
2utler 5)+ 3ones DR *1''=- 5hysiology of diving of &irds and mammals. 5hysiol
Rev+ ==C(%=$(''.
,averson 0iM, ,iriello )+ ,alaresu 8R *1'(A- ,hemoreceptor and &aroreceptor
inputs to ventrolateral medullary neurons. Am 3 5hysiol+ #A=C(=#$(='.
,hida ;+ )adecola ,+ 4nderwood lEv)D+ Reis D3 *1'(?- A novel vasodepressor
response elicited from the rat cere&ellar fastigial nucleusC the fastigial depressor
response. 2rain Res+ %=@C%=($%(#.
,hida ;+ )adecola ,+ Reis D3 *1'('- Differences in selective cardiovascular
characteristic of vasopressor responses elicited from the cere&ellar fastigial
nucleus and the rostral ventrolateral medulla in rats. Ther Res+ 1@C%=$>>.
Dampney RA and "oon EA *1'(@- Role of ventrolateral medulla in vasomotor
response to cere&ral ischemia. 2m 3 5hysiol+ #%'C%A'$>(.
Do&a N and Reis D3 *1'=#- 1ocali6ation within the lower &rainstem of a receptive
area mediating the pressor response to increased intracranial pressure *the
,ushing response-. 2rain Res+ A=CA(=$A'1.
8euerstein 7L+ 1iu T+ 2arone 8, *1''A- ,vto0ines+ inflammation+ and &rain in<uryC
role of tumor necrosis factor$alpha. ,ere&rovasc 2rain "eta& Rev+ ?C%A1$%?@.
8rerichs ;4 and allen&ec0 3+I1 *1''(- i&ernation in ground s/uirrels induces
state and species$ specific tolerance to hvpoBia (.Zl1daglycemia $ an in vitro study
in hippocampal slices. 3 ,ere& 2lood 83mIE DElE1eta&+ 1(C1?($1=>.
7alea E+ 7lic0stein S2+ 8einstein D1+ 7olanov EF+ Reis D3 *1''(a- Stimulation of
cere&ellar fastigial nucleus inhi&its inrerleu0in$) &eta$induced cere&rovascular
inflammation. 2m 3 5hysiol+ AAC#@>%$#@?%.
7alea E+ 7olanov EF+ 8einstein D1+ ;o&vlar6 ;EI+ 7lic0stein S2+ Reis D3 *1''(&-
,ere&ellar stimulation reduces induci&le nitric oBide synthase eBpression and
protects &rain from ischemia. 2m 3 5hysiol+ A%C#@%>$#@A>.
7olanov EF+ Reis D3 *1''>- Fasodilation evo0ed from medulla and cere&ellum is
coupled to &ursts of cortical EE7 activity in rats.Am 3 5hvsiol+ #?(CRA>A$RA?=.
7olanov EF+ Reis D3 *1''?- ,ontri&ution of oBygen$sensitive neurons of the rostral
ventrolateral medulla to hypoBic cere&ral vasodilatation in the rat. 3 5hysiol+
A'>*1-C#@1$#1?.
7olanov EF+ 9amamoto S+ Reis D3 *1''?- Electrical stimulation of cere&ellar
fastigial nucleus fails to rematch &lood flow and meta&olism in focal ischaemic
infarctions. Neurosci 1ett+ !1&(()1-1-1-'.
7olanov EF+ Reis D3 *1''(- Neurons of a small region of caudal su&thalamus
mediate diffuse elevations in cere&ral &lood flow and synchroni6ation of EE7
elicited from oBygen sensitive neurons of rostral ventrolateral medulla. Soc
Neurosci A&s+ #AC11=@.
7olanov EF+ Reis D3 *1'''- Neuroprotective electrical stimulation of cere&ellar
fastigial nucleus attenuates eBpression of periinfarction depolari6ing waves *5)Ds-
and inhi&its cortical spreading depression. 2rain Res *in press-.
7on6alo$Rui6 A+ 1eichnet6 7R *1''@- Afferents of the caudal fastigial nucleus in a
New World mon0ey (Cebus apella). EBp 2rain Res+ -&"&&-"&-.
7ranata 2<, Ruggiero DA+ 5ar0 D+ 3oh T+ Reis D3 *1'(%- 1esions of epinephrine
neurons in the rostral ventrolateral medulla a&olish the vasodepressor components
of &ar orefleB and cardiopulmonary refleB. ypertension+ >*>-CF(@$F(A.
7rove EA *1'((- Efferent connections of the su&stantia innominata in the rat. 3
,omp Neurol+ #==C%A=$%?A.
7uyenet 57+ 2rown D1 *1'(?- 4nit activity in nucleus paragigantocellularis
)ateralis during cere&ral ischemia in the rat. 2rain Res+ %?AC%@1$%1A.
amer 3+ oyer S+ Al&erti E+ Weinhardt 8 *1'=?- ,ere&ral &lood flow and oBidative
&rain meta&olism during and after moderate and profound arterial hypoBaemia.
Acta Neurochirurgica+ %%C1A1$1>@.
eistad DD+ "arcus "1+ Ehrhardt3,+ A&&oud 8" *1'=?- Effect of stimulation of
carotid chemoreceptors on total and regional cere&ral &lood flowC,irc Res+ %(C#@$
#>.
o 1+ !sa0a + Aisen 5S+ 5asinetti 7" *1''(- )nduction of cyclooBygenase *coB-$
# &ut not coB$) gene eBpression in apoptotic cell death. 3 Neuroimmunol+
('C1A#$1A'.
off )ET+ Reis D3 *1'=@- 1ocali6ation of regions mediating the ,ushing response in
,NS of cat. Arch Neurol+ #%C##($#A@.
)adecola ,+ Lhang 89+ Pu P *1''>- )nhi&ition of induci&le nitric oBide synthase
ameliorates cere&ral ischaernic damage. Amer 3 5hysiol+ %=CR#(?$R#'#.
)de E+ "ar0owitsch 3 *1'(A- 2asal fore&rain efferents reach the whole cere&ral
corteB of the cat. 2rain Res 2ull+ 1#CA'%$>1#.
;ato + ;ogure ;+ 1iu P+ Ara0i T+ )toyama 9 *1''?- 5rogressive eBpression of
immunomolecules on activated microglia and invading leu0ocytes following focal
cere&ral ischemia in the rat. 2rain Res+ =%A*1$#-+ #@%$#1#.
;umada "+ Dampney RA+ Reis D3 *1'='- 5rofound hypotension and a&olition of
the vasomotor component of the cere&ral ischaernic response produced &y
restricted lesions of medulla o&longata in ra&&it. relationship to the so$called
tonic vasomotor center. ,irc Res+ A>C?%$=@.
1eDouB 3E+ )wata 3+ ,icchetti 5+ Reis D3 *1'((- Different pro<ections of the central
amygdaloid nucleus mediate autonomic and &ehavioral correlates of conditioned
fear. 3 Neurosci+ (C#>1=$#>#'.
"oolenaar 7"+ Ruc0er ; *1'=?- Autoradiographic study of &rain stem
pro<ections from fastigial pressor areas. 2rain Res+ 11ACA'#$A'?.
Na0ai "+ )adecola ,+ Ruggiero DA+ Tuc0er 1W+ Reis D3 *1'(%- Electrical
stimulation of cere&ellar fastigial nucleus increases cere&ral cortical &lood flow
without change in local meta&olismC evidence for an intrinsic system in &rain for
primary vasodilation. 2rain Res+ #?@C%>$A'.
5atel 5"+ Drummond 3,+ Sano T+ ,ole D3+ ;al0man ,3+ 9a0sh T1 *1''%- Effect of
i&uprofen on regional eicosanoid production and neuronal in<ury after fore&rain
ischemia in rats. 2rain Res+ ?1AC%1>$%#A.
5rice 31 *1''>- Thalamus. )nC The rat nervous system. 7. 5aBinos+ ed. Academic
press+ San Diego+ pp. ?#'$?A(.
Reis D3+ 2erger S2+ 4nderwood "D+ ;hayata " *1''1- Electrical stimulation of
cere&ellar fastigial nucleus reduces ischaemic infarction elicited &y middle
cere&ral artery occlusion in rat. 3 ,ere& 2lood 8low "eta&+ 11C(1@$(1(.
Reis D3+ 7olanov EF+ 7alea E+ 8einstein D1 *1''=- ,entral neurogenic
neuroprotectionC central neural systems that protect the &rain from hypoBia and
ischemia. AnnN"E9 Acad Sci+ (%>C1?($1(?.
Reis D3+ ;o&ylar6 ;+ 9amamoto S+ 7olanov EF *1''(- 2rief electrical stimulation of
cere&ellar fastigial nucleus conditions long$lasting salvage from focal cere&ral
ischemia $ conditioned central neurogenic neuroprotection. 2rain Res+ $-&1"1-1"#.
Relton 3;+ Rothwell NJ *1''#- )nterleu0in$) receptor antagonist inhi&its ischaemic
and eBcitotoBic neuronal damage in the rat. 2rain Res 2ull+ #'C#A%$#A?.
Ross ,A+ Ruggiero DA+ 3oh T+ 5ar0 D+ Reis D3 *1'(%- Adrenaline synthesi6ing
neurons in the rostral ventrolateral medullaC a possi&le role in tonic vasomotor
control. 2rain Res+ #=%C%>?$%?1.
Ross ,A+ Ruggiero DA+ 3oh T+ 5ar0 D+ Reis D3 *1'(Aa- Rostral ventrolateral
medullaC selective pro<ections to the thoracic autonomic cell column from the
region containing cl adrenaline neurons. 3 ,omp Neurol+ ##(C1?($1(>.
Ross ,A+ Ruggiero DA+ 5ar0 D+ )oh T+ Sved A8+ 8ernande6$5ardal 3+ Saavedra
3"+ Reis D3 *l'(A&- Tonic vasomotor control &y the rostral ventrolateral
medullaC effect of electrical or chemical stimulation of the a.rea containing ,1
adrenaline neurons on arterial pressure+ heart rate+ and plasma catecholamines
and vasopressin. 3 Ncurosci+ ACA=A$A'A.
Ruggiero DA+ ,ravo S1+ Arango F *1'('- ,entral control of the circulation &y the
rostral ventrolateral reticular nucleusC anatomical su&strates. 5rog 2rain Res+
(1CA'$='.
Saper ,2 *1'(>- !rgani6ation of cere&ral cortical afferent systems in the rat. )).
ypothalamocortical pro<ections. 3 ,omp Neurol+ #%=C#1$A?.
Stornetta R1+ "orrison S8+ Ruggiero DA+ Reis D3 *1'('- Neurons of rostral
ventrolateral medulla mediate somatic pressor refleB. Am 3 5hysiol+ #>?CRAA($?#.
Stroemer R5+ Rothwell N3 *1''(- EBacer&ation of ischaemic &rain damage &y
locali6ed striatal in<ection of interleu0in$1&eta in the rat. 3 ,ere& 2lood 8low
"eta&+1(C(%%$(%'.
Stros6na<der 3, ,halimoniu0 " *1''?- 2iphasic enhancement of nitric oBide
synthase activity and c7"5 level following &rain ischemia in ger&ils. Acta
Neuro&iol EBp+ >?*1-C=1$(1.
Sun " $;+ Spyer ;iI1 *1''1- Responses of rostroventrolateral medulla spinal
vasomotor neurones to chemoreceptor stimulation in rats. 3 Auton Nerv Syst+
%%C='$(A.
Sun "$;+ 3es0e )T+ Reis D3 *1''#- ,yanide eBcites me dull anE sympathoeBcitatory
neurons in rats. Am 3 5hysiol+ #?#CRl(#$R1('.
Sun "$;+ Reis D3 *1''Aa- ypoBia selectively eBcites vasomotor neurons of rostral
ventrolateral medulla in rats. Am 3 5hysiol+ #??CR#A>$R#>?.
Sun "$;+ Reis D3 *1''A&- ypoBia$activated ,a
#
$ currents in pacema0er neurones
of rat rostral ventrolateral medulla in vitro. 3 5hvsiol *1ond-+ A=?C 1 @ 1$11?.
Terui N+ Sae0i 9+ ;umada " *1'(?- 2arosensory neurons in the ventrolateral
medulla in ra&&its and their responses to various afferent inputs from peripheral
and central sources. 3 5hvsiol+ %?C11A1$11?A.
Tuc0er D,+ Saper ,2+ Ruggiero DA+ Reis D3 *1'(=- !rgani6ation of central
adrenergic pathwaysC 1. relationships of ventrolateral rnedullarv pro<ections to the
hypothalamus and spinal cord. 3 ,omp Neurol+ #>'C>'1$?@%.
4nderwood "D+ )adecola ,+ Reis D3 *1''A- 1esions of the rostral ventrolateral
medulla reduce the cere&rovascular response to hypoBia. 2rain Res+ ?%>C#1=$
##%.
WolfS+ Schneider RA+ 7roover "E *1'?>- 8urther studies on the circulatory and
meta&olic alterations of the oBygen$conserving *diving- refleB in man.
Transactions of the Association of the American 5hysicians+ =(+ #A#$#>A.
9amamoto S+ 7olanov EF+ Reis D3 *1''%- Reductions in focal ischaemic infarctions
elicited from cere&ellar fastigial nucleus do not result from elevations in cere&ral
&lood flow. 3 ,ere& 2lood 8low "eta&+ 1%C1@#@$1@#A.
9oshida T+ 1immroth F+ )ri0ura ;+ "os0owit6 "A *1''A- The N!S inhi&itor+ =$
nitroinda6ole+ decreases focal infarct volume &ut not the response to topical
acetylcholine in pial vessels. 3 ,ere& 2lood 8low "eta&+ 1AC'#A$'#'.
9u L8+ ,heng 73+ uang P8+ 1i ;9+ ,ao PD *1''=- Neuro0inin$1 receptor
antagonist sr1A@%%% $ a novel type of drug to treat cere&ral ischemia.
Neuroreport+ (C#11=$#11'.
Lhang 89+ )adecola , *1''#- Stimulation of the fastigial nucleus enhances EE7
recovery and reduces tissue damage after focal cere&ral ischemia. 3 ,ere& 2lood
8low "eta&+ 1#C'?#$'=@.
Lhang 89+ )adecola , *1''%- 8astigial stimulation increases ischaemic &lood flow
and reduces &rain damage after focal ischemia. 3 ,ere& 2lood 8low "eta&+
1%C1@1%$1@1'.
Lhang 89+ Pu S+ )adecola , *1''>- Time dependence of effect of nitric oBide
synthase inhi&ition on cere&ral ischaemic damage. 3 ,ere& 2lood 8low "eta&+
1>C>'>$?@1.
N,UROTRANS-ITT,RS
R,6ULAT, ,N,R65
-,TABOLIS- IN ASTROC5T,S:
I-PLICATIONS FOR
FUNCTIONAL BRAIN I-A6IN6
Piee .. Ma#istetti and L/c Pellein
During stress a series of homoeostatic processes ta0es place in the
organism. The responses of &rain to stress involve neurotransmitter$
mediated synaptic activity which is lin0ed to energy meta&olism. Since
functional &rain imaging techni/ues are &ased on meta&olic signals+ it
is important to understand the mechanisms that lin0 activity to me$
ta&olism. Recent evidence indicates that astrocytes playa 0ey role in
the regulation of &rain energy meta&olism.
Astrocytes are ideally positioned to couple neuronal activity with
energy meta&olism. Thus particular astrocytic profiles+ the end$feet+
surround intraparenchymal capillaries+ implying that they form the first
cellular &arrier that energy su&strates entering the &rain parenchyma+
in particular glucose+ encounter. )n addition+ astrocytes possess receptors
and reupta0e sites for neurotransmitters+ and astrocytic processes
ensheath synaptic contactsD these features imply that astrocytes are ide$
ally positioned to sense increases in synaptic activity and to couple them
with energy meta&olism. Elife have characteri6ed three meta&olic proc$
esses regulated &y neurotransmitters in primary astrocyte cultures pre$
pared from neonatal mouse cere&ral corteBC glycogenolysis, glycogen
resynthesis and glycolysis *for a review+ see ,ere&ral ,orteB+ 1''?+ ?C
>@$?1-. 7lycogen is the largest energy reserve of the &rain+ locali6ed
almost eBclusively in astrocytes. F)5 and noradrenaline *NA- promote
glycogenolysis via 5;A *F)5 and N$receptors- and 5;, *o.)$receptors-
at a rate of>$1@ nmolyEmg protHmin+ "which is a rate of the same order
as that of glucose utili6ation &y the grey matter. 5A,A5 and AT5 eBert
a similar effect. 8ollowing this rapid *within 1$> min- glycogenolysis+
F)5 and NA induce a massive glycogen resynthesis maBimally eBpressed
after ( hours+ which &rings glycogen to levels 1@ times higher than
&efore F)5 or NA application. This glycogen resynthesis is mediated &y
cA"5$dependent induction of gene eBpression. Searching for the genes
induced we found &oth early and late genes related to energy meta&o$
lism. Thus+ F)5 and NA induce C/BBP ~ and @+ which are mem&ers of
an immediate$early gene family acting as transcription factors for genes
involved in energy meta&olism regulation in liver and adipose tissue ,3
1eurosci, 1''?+ 1?C'1'$'#'-. )n addition+ transfection of cultured
astrocytes with cDNA encoding for C/BBP ~ amplifies the resynthesis
of glycogen evo0ed &y NA. We have also o&served &y Northern &lot
analysis that the mRNA encoding for glycogen synthase is massively
induced within A to ? hours &y F)5 and NA (Mol ,rain 4es, 1))",
%(C1'1$1''-. These results strongly suggest that F)5 and NA can regu$
late the eBpression of early and late genes that encode for gene$prod$
ucts involved in their meta&olic effects.
We have also descri&ed another neurotransmitter$regulated meta$
&olic process in astrocytes. Thus+ the eBcitatory neurotransmitter gluta$
mate+ in addition to its receptor$mediated effects on neuronal eBcita&ility+
stimulates glycolysis+ i.e. glucose upta0e and lactate production in
astrocytes (P1.S,1))', '1C1@?#>$1@?#'-. This effect is mediated &y
the Na" $dependent upta0e of glutamate into astrocytes which triggers
a cascade of molecular events involving NaVH;V$AT5ase+ leading to the
glycolytic processing of glucose and to the release oflactate &yastrocytes.
The stoichiometry of this process is such that for one glutamate ta0en
up with three Na"+ one glucose enters astrocytes+ two AT5s are pro$
duced through glycolysis and two lactate are released *"agistretti and
5ellerin+ Cerebral Corte0, ?C>@$?1+ 1''?-. Within the astrocyte+ one
AT5 fuels one "turn of the pump" while the other provides the energy
needed to convert glutamate to glutamine &y glutamine synthase. Since
glutamate release occurs following the modality$specific activation of a
&rain region+ these data are consistent with the view that during activa$
tion+ glutamate upta0e into astrocytes leads to increased glucose utili$
6ation and lactate production+ which can &e su&se/uently used &y
neurons to meet their energy needs. 8urther support for this notion of
an "astrocyte$neuron lactate shuttle" in the &rain has &een provided &y
the recent identification of two lactate transporters+ ",T$l and ",T$
#+ and two isoforms of lactate dehydrogenase+ 1D$l and 1D$>+
selectively eBpressed in astrocytes *",T$l+ 1D$>- or neurons *",T$
#+ 1D$l- *5ellerin et al.+ 1''(+ P1.S, '>C%>'@$%>'>-. In %i%o l%,
"RS studies support this model. Thus the simultaneous measurements
over a range of synaptic activity of tricar&oBylic acid cycle and the cy$
cling of glutamate to glutamine *a process which occurs eBclusively in
astrocytes- using 1%, "RS has revealed a stri0ing stoichiometric rela$
tionship of 1C1 &etween glutamate cycling *a reflection of synaptic ac$
tivity- and glucose utili6ation *Si&son et al.+ 1''(+ P1.S, )#(1"-(!1).
[
t
Neurotransmitters regulate energy meta&olism in astrocytes 55
These data suggest a prominent role of astrocytes in the generation of
the lS8D7$ 5ET signal *see 8igure-.
7lutamate is the principal eBcitatory neurotransmitter of the &rain+
released from activated+ modality$specific afferents to a given cortical
area. Since astrocyte end$feet surround intraparenchymal &lood ves$
sels+ which are the source of glucose+ while other processes sense synaptic
activity associated with glutamate release+ the glutamate$evo0ed glyco$
lysis that we have descri&ed provides a direct lin0 to couple neuronal
activity to energy meta&olism. These in %itro data have implications for
understanding the cellular &asis of functional &rain imaging &y 5ET
with 3S8$deoA-Tglucose. )ndeed they are consistent with an astrocytic
origin of the signal+ directly lin0ed to neuronal activity+ since neuronally$
released glutamate provides the trigger (Cerebral Corte0, 1''?+ ?C>@$
"1: Science, 1'''+#(%CA'?$'=-.
This model proves to &e a much$needed integration &etween &io$
chemical process and functional &rain energy imaging studies+ and will
clarify several functional aspects at the cellular and su&$cellular levels.
FI%URE (
N @lutamate
2s$artate
E"
PYRU0ATE
tA
LACTATE
e
7
A2A
A
)?
PY
E
R
"
U0AT
E
N *
1D
>-
GLUCOS~
REFERENCES
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"agistretti PI, 5ellerin L. Regulation &y neurotransmitters of glial energy
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CIRCADIAN R%5T%-S AND
SL,,P IN %O-O,OSTASIS AND
T%,IR R,L,;ANC, TO STR,SS
Mic"el .o/&et
)t is a popular &elief that the &est method to get a good nightEs sleep is
to stay awa0e longer. owever+ as we will demonstrate &elow+ the d&*
ration of sleep is not linearly related to previous "wa0ing. 8or twenty
years+ the regulation of sleep duration and "intensity" &y two different
processes has &een documented. Those two processes will &e firstly
summari6ed according to the model of 2or&ely *1'(#-. Then the con$
se/uences of the stress which is provo0ed either &y short$term altera$
tion of sleep homoeostasis *the <et lag model- or &y long$term alteration
*shiftwor0- "will &e considered.
T!E TWO,PROCESS MODEL OF SLEEP RE%ULATION
Slee2,de2endent as2ects o* slee2 e#/lation
Slo9 9a%e sleep an+ sleep intensity
With the progression of wa0ing time+ the level of sleepiness increases
and sleep latency shortens. owever+ the relationship &etween sleep
parameters and the duration of prior wa0ing is not linear. 8or eBample+
the "sleep de&t" incurred during a prolonged vigil is only to a small
part compensated &y an increase in the duration of recovery sleep. This
was dramatically shown in an eBperiment in which a su&<ect stayed awa0e
for #?A h and then slept only for 1A.A h. The /uestion therefore arises
whether sleep loss can &e compensated &y an enhancement of "sleep
intensity". What are the characteristics of a putative intensity parameter
of sleepT As a presuma&ly monotonic function of the antecedent wa0$
ing period+ this parameter would &e eBpected to have a high value im$
mediately after sleep onset+ and decline pro gressively .ith ongoing sleep.
"oreover+ following an eBtended wa0ing period+ the initial value of
sleep intensity should &e increased.
Slow wave sleep (S;lS: stages % and A of nonRE" sleep- appears
to &e a good candidate for a high$intensity sleep stage. (t predominates
in the first part of sleep and is enhanced after sleep deprivation. ,on$
versely+ if sleep time in the previous night is eBtended or if daytime
napping is allowed to occur+ the amount of SWS is reduced. (f SWS
is indeed a high$intensity sleep stage+ it should &e a "deeper" form
of sleep. Therefore a high arousal threshold would &e eBpected to
prevail in this stage. Recent studies have confirmed that the
thresholds for EE7 changes elicited &y pain or acoustic stimuli are
higher in SWS than in stage #.
Sleep stages are insufficient for investigating sleep intensity in more
detail. They are generally defined &y criteria such as the prevalence of
high$amplitude slow waves *stages % and A-. All$night spectral analysis
of the sleep EE7 revealed+ however+ that the nonRE" stages 1$A rep$
resent a crude and rather ar&itrary su&division of a continuous process.
The attenuation of slow wave pea0s over successive sleep cycles is clearly
evident from the spectral plots+ &ut it is incompletely represented &y
the sleep stage pattern.
The effects of sleep deprivation have &een clarified &y the spectral
analysis of the sleep EE7. An eBtended wa0ing period of A@.> h caused
a massive increase of slow wave activity during recovery sleep. The en$
hancement of the EE7 power density in the low fre/uency &ands and
its increasing trend throughout the sleep period were also o&served for
individual sleep stages.
)n an effort to /uantify the trends in die sleep EE7+ the integrated
power density values *range @.=>$#>.@ 6- were calculated for the suc$
cessive nonRE" $RE" cycles+ standardi6ed with respect to the first
cycle *1@@G-+ and plotted on a logarithmic scale at the cycle midpoint
times. The changes across the first three sleep cycles can &e descri&ed
&y an eBponential function+ since the logarithmic values fit closely with
a linear regression line. )n the night after sleep deprivation+ the initial
value is significantly higher than the corresponding &aseline value *p
@.@1-+ while the slope of the regression does not differ significantly
from the control.
)n conclusion+ the data support the hypothesis that the EE7 power
density in the low fre/uency range is an indicator of a progressively
declining sleep process whose initial level is determined &y the duration
of prior wa0ing. EE7 slow wave activity may therefore represent an
intensity parameter of the sleep process.
4egulation o8 para+o0ical sleep (PS) an+ slo9 9a%e sleep
While the proposed "high density" fraction of SWS can &e readily re$
lated to prior wa0ing+ it is more difficult to esta&lish such a relationship
for 5S. The proportion of 5S increases across successive sleep cycles.
The fact that SWS and 5S eBhi&it opposite trends in the sleep period
suggests either that the two states are antagonistically coupled or that
Cicadian "1t"-s and slee2 in "o-oeostasis 5)
they are controlled &y separate regulatory mechanisms. The latter pos$
si&ility is supported &y sleep deprivation eBperiments+ which indicate
that sleep loss has a differential effect on the two sleep states. Thus an
eBtended wa0ing period of approBimately A@ h increased the amount
of SWS+ while 5S was not affected. The greater sensitivity of SWS to
sleep loss is also evident from partial sleep deprivation eBperiments in
which 5S sleep was reduced while the amount of S+iFSwas maintained
or even increased.
)n summary+ fundamental differences are apparent in the regula$
tion of S+FS and 5S . While even minor deviations from the regular
level ofSWS cause an immediate+ short$lasting compensatory response+
only a severe deficit in 5S results in a re&ound which is often delayed
and prolonged.
Slee2,inde2endent' cicadian as2ects o* sleep e#/lation
Sleep propensity is not only a function of wa0ing time. This was clearly
demonstrated in a =#$h sleep deprivation eBperiment in which the fa$
tigue ratings showed a mar0ed circadian rhythm throughout the eB$
periment. The prominent effect of circadian factors on sleep parameters
was impressively demonstrated in a recent study where sleep duration
first decreased &elow its regular level+ and then increased well &eyond
the &aseline+ as the time of sleep onset was successively delayed &y A$ h
intervals.
The investigation of circadian factors is difficult under regular eB$
perimental conditions in which a variety of environmental and social
influences act as synchroni6ers of circadian rhythms. EBperiments con$
ducted in the a&sence of time cues have therefore &een of paramount
importance. Aschoff and Wever *1'?#- were the first to record in man
circadian rhythms of rest$activity and other varia&les. )n su&se/uent
studies+ non$entrained *i.e. free$running- circadian rhythms were also
documented for the polygraphically recorded sleep$wa0e cycle *3 ouvet
et al.+ 1'=A-.
8or the analysis of the circadian facet of sleep regulation the rela$
tionship of sleep and &ody temperature is very importantC the varia$
tions of vigilance are closely related to the #A$h rhythm &ody
temperature. Several studies concur that the variations in sleepiness are
a mirror image of the &ody temperature rhythm. owever+ in the course
of a prolonged non$entrained schedule+ more dramatic changes may
occur. The rhythms of sleep and &ody temperature may develop differ$
ent periodicities+ a condition that has &een designated as "internal
desynchroni6ation". EWhile the rhythm of &ody temperature usually
eBhi&its periods close to #> h+ the rhythm of sleep can assume a much
?9 Stess and ada2tation
larger range of values. owever+ despite the apparent independence of
the two rhythms+ a preferred phase$relationship still persists. Thus sleep
propensity is highest at the time of the circadian temperature mini$
mum+ and lowest at the time of the maBimum. Also sleep duration
eBhi&its a specific phase relationship to &ody temperature. 5S eBhi&its a
prominent circadian rhythm even under regular entrained schedules
and+ in addition+ shows a close association with &ody temperature. Nap
studies have shown that more 5S occurs early in the day than during
later daytime hours. The coincidence of maBimum 5S with minimum
&ody temperature was o&served in studies where su&<ects underwent a
?@ min sleepH1?@ min wa0e schedule for A@ h or a 1#@ min sleepH?@
min wa0e schedule for 1@ days. These results led to the hypothesis that
the circadian 5S propensity rhythm reflects the activity of a self$sus$
tained circadian oscillator with which the &ody temperature rhythm is
also closely coupled.
)n summary+ the two$process model provides a lin0 &etween the
circadian rest$activity rhythm+ a u&i/uitous feature ofliving organisms+
and sleep+ a process that has &een specified only in verte&rates. )t is
proposed that mammalian sleep is the com&ined result of a circadian
and a sleep$dependent process. The circadian component of sleep ap$
pears to &e related to the circadian rhythms of meta&olic and endocrine
processes. ,ircadian rhythms may have &een of adaptative significance
on an evolutionary scale. "Need$fulfilment" can &e advanced as an eB$
planatory construct to account for the sleep$dependent component of
sleep regulation. Nevertheless+ the specification of the "need" in terms
of physiological and neurochemical processes remains an unsolved pro&$
lem and continues to constitute a ma<or challenge in sleep research.
STR,SS DU, TO ACUT, P%AS, S%IFT: T%, J,T LA6 -OD,L
A constellation of symptoms 0nown as <et lag fre/uently afflicts people
who travel rapidly across time 6ones. )t includes insomnia+ fatigue+
wea0ness+ sleepiness+ gastrointestinal complaints+ irrita&ility and ma$
laise. Travel across time 6ones has also &een associated with impaired
cognitive performance+ recurrence of depression+ dia&etic 0etoacidosis+
sleep paralysis and decreased athletic a&ility.
The symptoms of <et lag have &een attri&uted to the slow and un$
even rate of ad<ustment of internal circadian rhythms to the new time
6one or schedule. The circadian timing system *&iological cloc0- re$
sponds to eBternal time information and synchroni6es &iological rhythms
such as temperature+ sleep and alertness to the #A$hour solar day. 1ight$
dar0 patterns and social cues seem to &e the most important eBternal
time sources for humans.
Cicadian "1t"-s and slee2 in "o-oeostasis ?(
There is a limit to the amount &y which the circadian timing sys$
tem can ad<ust on a daily &asis and there is a directional asymmetry. (t is
easier to delay the sleep$wa0e cycle+ i.e. stay up later and sleep later as in
west&ound travel+ than it is to advance it. This asymmetry is pro&a&ly
eBplained &y the tendency of the human timing system to run slow
(
relative to solar time. This tendency can &e shown &y eliminating eBter$
nal sources of temporal information. 4nder such conditions+ rhythms
free$run at periods slightly greater than #A l$EZours.
The rates of ad<ustment to a new schedule are not the same for
every &iological rhythm. As a result+ the phase relationships of several
rhythms following a schedule change may differ from their usual pat$
tern. This has &een hypothesi6ed to &e the cause of symptoms. ow$
ever+ sleep deprivation invaria&ly accompanies <et lag+ and it is possi&le
that the symptoms associated with <et lag and shiftwor0 are mostly caused
&y the sleep loss.
These /uestions &ecome especially important for older travellers+
who may &e more at ris0 for impaired ad<ustment to travel across time
6ones. The age$related differences have &een attri&uted to decreased
a&ility of circadian rhythms to ad<ust+ increased amplitude of rhythms+
more time re/uired to recuperate and more sleep distur&ances in older
individuals. owever+ not all authors agree that age affects the a&ility
to ad<ust to schedule shifts.
Recently an eBperimental study of simulated <et lag was conducted
in ? young men *1($#> years old- and middle$aged men *%=$># years
old- 0ept in isolation during adaptation nights. Then a simulated <et lag
*? hours phase advance- as during an eastward flight from New 9or0 to
5aris was scheduled for ( days following the a&&reviated night. Data
included core temperature+ polygraphic sleep recording+ self ratings of
mood and alertness and tests of performance.
This study employed a uni/ue eBperimental model of <et lag to
study the acute and long$term effects of a single ?$hour advance in
schedule. A sustained effect on sleep continuity and architecture and a
transient increase in sleepiness and malaise were produced &y this change
in schedule. )n general+ the effects were more severe in the middle$
aged su&<ects.
Slee2
The schedule shift produced a reduction in total sleep time and sleep
efficiency for &oth groups. The reduction was greater in the middle$
aged su&<ects in the early post$shift interval+ mostly due to impairment
of sleep continuity. The amount of 5S also decreased after the shift in
&oth groups. 2y contrast+ the amount of #B)iC# increased in the early
?8 Stess and ada2tation
post$shift interval in &oth groups. )n the middle$aged su&<ects+ the in$
crease in SWS persisted through the late post$shift interval+ while SWS
returned to normal in the young su&<ects.
2ecause the schedule shift included &oth a change in timing of the
sleep period as well as sleep deprivation+ the literature on &oth topics
may help eBplain the pattern of sleep changes in response to a schedule
advance. There are at least three possi&le eBplanations that are not
mutually eBclusive. The first involves the effect of sleep deprivationC
sleep deprivation results in increased TST and sleep efficiency+ increased
SWS and increased 5S. "iddle$aged su&<ects were a&le to respond as
young su&<ects did. )n addition+ 5S latency decreased in older su&<ects.
!f these effects+ our su&<ects showed only the increase in SWS+ imply$
ing that the schedule shift strongly influenced their response to sleep
deprivation. !ne might conclude from these data that only SWS is
relatively free to vary in response to sleep deprivation produced &y phase
shifts+ whereas total sleep and 5S are constrained &y circadian factors
from responding as they would to sleep deprivation alone. These con$
straints may &e stronger in middle$aged su&<ects.
A second eBplanation is that the decrease in 5S is a primary and
direct effect of the schedule shift. This is consistent with the report &y
,6eisler and colleagues on free$running su&<ects+ who showed a de$
crease in the percentage of 5S during the part of the circadian day
spanned &y the schedule shift in our study. There may &e an inverse
interaction &etween SWS and 5S such that SWS increases passively to
fill the gap left &y decreased 5S+ thus accounting for the increase in
SWS shown &y the su&<ects.
A third eBplanation is suggested &y the reported positive correlation
&etween a&solute core temperature and amount ofSWS. In the study &y
orns and Shac0ell+ passively elevating the core temperature &eginning
#.> hours &efore &edtime resulted in increased SWS and decreased 5S.
To investigate the possi&ility that the sleep changes in the su&<ects were
associated with a rise in core temperature+ the average core temperatures
were calculated for the A hours preceding &edtime for &oth the &aseline
period and the early postshift interval. 8ollowing the shift+ temperatures
were higher than during &aseline for the middle$aged su&<ects and for
the young su&<ects. Although produced &y a different eBperimental para$
digmE these findings are consistent with their report.
Aletness and -ood
Su&<ective ratings of weariness+ sleepiness+ well$ &eing and effort re/uired
for daily activities worsened <ust after the schedule shift. In general+ the
negative effect was greater in the middle$aged su&<ects.
Cicadian "1t"-s and slee2 in "o-oeostasis ?4
Te-2eat/e 2attens
The amplitude of the temperature rhythm decreased significantly in
&oth groups after the phase advance. This can &e eBplained &y incom$
plete ad<ustment of the phase of the endogenous components of the
temperature rhythm+ which were therefore out of phase with the faster$
ad<usting sleep and activity$related components.
Temperature minima occurred earlier in the middle$aged su&<ects
across the whole study. Earlier temperature minima with respect to the
sleep$wa0e have &een reported in older su&<ects during free$running.
The rate at which the temperature minima responded to the shift did
not differ &etween the two groups. The middle$aged su&<ects showed a
larger variance &etween su&<ects+ which can &e accounted for in large
part &y the two su&<ects who apparently delayed in response to the
schedule advance. The mean time of the minimum in the middle$aged
su&<ects actually overcompensated on some days as a result of the two
su&<ects who phase$delayed.
Mec"anis-s o* @et la# and e**ects o* a#e
4nder the eBperimental conditions+ it ta0es longer than ( days for sleep
and temperature to ad<ust to a ?$hour advance in schedule. (t is nota&le+
therefore+ that daytime symptoms from the simulated <et lag occurred for
the most part only during the early post$shift interval. During this time+
the symptoms appeared to &e worse in the middle$aged group. This is also
the time that sleep efficiency differed most &etween the two groups.
)n eBploring the mechanisms &y which <et lag symptoms are pro$
duced+ and the reasons why they are worse in middle$aged persons+
three alternative hypothesis could &e considered. The first+ and perhaps
simplest+ is that <et lag symptoms are produced when one &egins to live
in the new time 6one+ and the myriad &iological rhythms controlled &y
the circadian timing system have not yet fully ad<usted to the sudden
shift in schedule. (t is possi&le that symptoms remit when the discrep$
ancy &etween the social schedule and the circadian timing system falls
&elow a certain threshold that may depend on age.
Another hypothesis is that the stress of sleep deprivation produces
many of the symptoms of <et lag+ and the severity of symptoms depends
on the a&ility to o&tain recovery sleep and there&y recover from the
effects of sleep deprivation .. "iddle$aged persons may not respond as
fully to sleep deprivation as young persons.
The third hypothesis is a com&ination of the a&ove two. )t would
re/uire the presence of &oth a circadian timing system that has not fully
ad<usted to a change in schedule and of sleep deprivation which di$
rectly produces some of the symptoms of <et lag.
?> Stess and ada2tation
The results of this study support the third eBplanation. The ampli$
tude of the temperature rhythm remained lower than &aseline+ and the
time of the minima had either not completely ad<usted *young su&$
<ects- or was mar0edly varia&le *middle$aged su&<ects- at the end of the
study+ suggesting that the circadian timing system had not fully ad$
<usted to the new schedule.
The more severe symptoms of <et lag in the middle$aged su&<ects
moreover do not appear to &e due to their ina&ility to respond to sleep
deprivation with SWS re&ound. !n the contrary+ the middle$aged su&$
<ects had &oth SWS re&ound and more intense symptoms of <et lag.
)na&ility to recover lost S3S therefore could not &e directly responsi$
&le for the symptoms.
The su&<ective effects were more pronounced in the middle$aged
su&<ects on those days when they were sleeping less well than the young
men. Thus+ the symptoms of <et lag may increase in severity with age as
a result of difficulties in sleeping at an unusual phase of the circadian
day+ which in middle$aged su&<ects seems to &loc0 the a&ility to com$
pensate for sleep deprivation.
STRESS DUE TO C!RONIC DISRUPTION OF T!E
CIRCADIAN SYSTEM6 S!IFTWORIA
All of the effects of acute pertur&ations of the circadian system are not
yet defined+ &ut it does appear that the effects of such disruption are
usually transient and self$limited. !f more concern are the potential
effects of chronic+ repeated disruption. At ris0 is the large and increas$
ing segment of the population in industriali6ed societies called upon to
wor0 evening+ night+ and rotating shifts. A num&er of studies have &een
conducted since the first o&servations of increased medical complaints
in shift wor0ers in the armaments industry during the 8irst World War.
owever+ epidemiological studies of shift wor0ers are hampered &y
methodological difficulties. )n particular+ the incidence of pathology in
shift wor0ers tends to &e seriously underestimated &ecause of a num&er
of characteristics of the population.
8irst+ those shift wor0ers who have serious pro&lems ad<usting to
rotating schedules or night wor0 tend to move to day <o&s whenever
they can find them. They are therefore continually self$selecting them$
selves out of the shift wor0er population and may &e missed in a retro$
spective survey. )n addition+ older wor0ers who appear to have particular
pro&lems with shiftwor0 are artificially removed from the shiftwor0
population &y the seniority system+ which promotes some of them to
supervisory day$shift positions. Thus epidemiological studies failing to
carefully age$match the populations under study+ or failing to follow
Cicadian "1t"-s and slee2 in "o-oeostasis ?5
the shiftwor0 drop$out population+ artificially underestimate the im$
pact of shifrwor0 as a ris0 factor. Second+ shift wor0ers tend to visit
physicians less than day wor0ers+ in part &ecause they view the se/uelae
of rotating schedules as unavoida&le+ and hence pathology remains
undiagnosed for longer. Third+ there appears to &e a considera&le dif$
ference in the health effects of different shift schedules+ yet many stud$
ies do not distinguish &etween them in their surveys.
Studies of the effects of chronically phase$shifting schedules have
so far &een limited to retrospective epidemiological comparisons of shift
wor0ers with the population at large. As with all such studies+ interpre$
tation of these results must &e cautious. Nonetheles+ there appears to
&e significant evidence to support the hypothesis that shiftwor0 and
the associated chronic circadian disruption are associated with increased
ris0 for a num&er of health pro&lems. A closer eBamination of the avail$
a&le data now provides a profile of specific medical pro&lems that can
&e identified as a characteristic shiftwor0$induced syndrome. Specifi$
cally+ medical complaints in shiftwor0ers appear to &e more common
than in their day$wor0ing compatriots in three specific areasC sleep$
wa0e+ gastrointestinal+ and cardiovascular systems.
Slee2,:a+e disodes
,omplaints related to sleep and wa0efulness are the most predicta&le
conse/uences of shiftwor0. The length of daytime sleep is significantly
shorter in night and rotating shift wor0ers+ and night$time sleep after
a return to daytime wor0 is also disrupted. Even in young wor0ers
*mean age %1 years-+ two$thirds of shift$wor0ers complained of chronic
insomnia. Sleeping pill use is correspondingly higher in night$shift
wor0ers.
The pro&lem of wor0ers falling asleep on the <o& is a serious issue
for those who must staff continuous operations. )n a series of confiden$
tial surveys of industrial plants+ &etween one$third and two$thirds of
shift wor0ers report that they fall asleep at least once a wee0 on the <o&+
and this occurs+ &ecause of the chronic circadian phase disruption+ not
only during the night shift &ut also during day and evening shifts. With
the increasing technological compleBity of the <o&s that shift$wor0ers
are called upon to perform+ and the conse/uences for the health of
others $whether it &e flying aircraftC or operating the control rooms of
chemical+ manufacturing+ and nuclear plants $ this pro&lem is &ecom$
ing one of serious dimensions.
The disrupted sleep of the shift wor0er presuma&ly represents one
of the causes of the higher incidence of accidents among shift wor0ers+
especially during off$duty hours. )n addition+ wor0ers re/uired to per$
?? Stess and ada2tation
form at the nadir of their performance rhythms are at considera&ly higher
ris0 of accidents.
%astointestinal disodes
7astrointestinal complaints are also considera&ly more common among
rotating and night$shift wor0ers than among daywor0ers+ This includes
&oth general gastric discomfort and documented peptic ulcer disease.
!ne careful study of this pro&lem shows that the incidence of peptic
disease in the two groups diverges significantly and progressively only
after five years of eBposure to the respective wor0 environments. This
argues that the impact of shiftwor0 re/uires accumulation or a latency
period &efore &ecoming overt+ and this presents a potential complica$
tion in the interpretation of epidemiological data.
The pathophysiological mechanisms lin0ing chronic circadian dis$
ruption and gastrointestinal disease remain unclear+ though there are
several potential factors. 1a&oratory studies show that intestinal en$
6ymes are secreted with a regular circadian rhythmicity. Shift wor0ers
as a group report disrupted eating schedules+ and 1A G of rotating shift
wor0ers reported that it too0 more than two wee0s to ad<ust to the
new meal schedule dictated &y the shift. 4sually wor0ers rotate &e$
tween shifts at intervals of a wee0 or less+ so some must never ad<ust.
4nfortunately+ there are currently no data on the medical conse/uences
of eating at an inappropriate circadian phase. Alcohol and to&acco con$
sumption+ 0nown factors in the etiology of peptic ulcer disease+ are also
higher in shift$wor0ers.
Cadio&asc/la disodes
A num&er of studies identified a higher incidence of cardiovascular dis$
ease+ especially acute myocardial infaction+ among shift wor0ers than
among age$ and seB$matched counterparts who wor0 days. )n one ret$
rospective study of Swedish men living in greater Stoc0holm+ those
with a history of myocardial infarction were significantly more li0ely to
&e shift wor0ers than were age$ and seB$matched controls without a
history of myocardial infarction. While the increased cigarette consump$
tion among shift$wor0ers may account for much of this increased ris0+
a su&se/uent study of Swedish policemen matched for cigarette con$
sumption as well as for age showed significant dependence of a num&er
of hypothesi6ed cardiac ris0 factors+ particularly triglyceride levels+ on
the direction of the rotation of the shift schedule. Thus policemen on a
schedule re/uiring phase$advance shifts had significantly higher
triglycerides than did those wor0ing a schedule re/uiring a less disrup$
tive se/uence of phase$delay shifts.
Cicadian "1t"-s and slee2 in "o-oeostasis ?B
These studies argue that the nature and eBtent of circadian disrup$
tion per se may playa role in the etiology of pathologies associated with
shift$wor0. Since it is unli0ely that the need for continuous #A$hour
staffing of factories+ military installations+ hospitals+ and support serv$
ices will decrease in the future+ there will continue to &e a fundamental
conflict &etween the re/uired wor0 hours in a #A$hour society and the
diurnal orientation of human physiology. 2ecause of their potential for
addressing this pro&lem+ studies of shift scheduling designed to mini$
mi6e circadian disruption are &ecoming of increasing importance.
S"i*t -alada2tation s1ndo-e
Several lines of evidence indicate that there are significant inter$indi$
vidual differences in a&ility to adapt to rotating shiftwor0 schedules.
Those who fail to adapt have an unusually high incidence of sleep$
wa0e+ gastrointestinal+ and possi&ly cardiovascular pathology. Studies
of those who had left shiftwor0 and were wor0ing day shifts showed
that they had a twofold higher incidence of gastrointestinal disease than
did shift wor0ers who stayed on the shiftwor0 schedule. After transfer
to daywor0+ the incidence of gastrointestinal disease decreased &ut re$
mained significantly higher than that of either day wor0ers or shift
wor0ers staying on the shiftwor0 schedule. (t is currently not possi&le
to distinguish &etween two possi&le eBplanations for this resultC either
the occurrence of disease renders an individual less tolerant of shiftwor0+
or shiftwor0 increases the disease ris0 among predisposed individuals
who are intolerant of their wor0 schedule.
With further research it may &e possi&le to define a "shift malad$
aptation syndrome" sufficiently rigorously to eBclude the larger num&er
of individuals who would prefer to o&tain daytime <o&s rather than
rotate shifts. Every shift wor0er is fatigued andHor has pro&lems sleep$
ing at certain phases of his or her schedule+ &ut these complaints typi$
cally resolve with a long wee0end &rea0 when they can catch up on
sleep. Those with more serious complaints typically have a more frag$
mented sleep$wa0e cycle that is not corrected &y two or three days of
rest. Similarly+ transient dyspepsia related to an ill$advised meal should
&e distinguished from more serious and prolonged gastrointestinal pa$
thology.
A reduction of ris0 could potentially &e o&tained &y prospective
identification of a su&group of wor0ers who seem particularly prone to
the adverse effects of shifuvor0. )t is possi&le that intolerance to shiftwor0
may &e associated with a low$amplitude &ody temperature rhythm+ which
may &e an indication of a lac0 of ro&ustness of the endogenous circa$
dian system+ or it may &e a result of chronic desynchroni6ation of the
?; Stess and ada2tation
&ody temperature rhythm from the wor0$rest schedule. )t is not clear
whether this o&servation is cause or effect and+ therefore+ whether it
has prospective value or+ alternatively+ diagnostic value in defining cases
of "shift maladaptation syndrome". owever+ this conclusion lends
support to the notion that the pathophysiology of "shift maladaptation
syndrome" relates to a loss of internal coherence in the multioscillator
circadian timing system.
POSSIBL, TR,AT-,NT
New advances in the 0nowledge of the human circadian cloc0 have
made possi&le some chrono&iological treatment of the acute or chronic
stress which follows disruption of the circadian rhythm. EBposure to
strong light *>@@@$1@ @@@ luB- may synchroni6e the cloc0 at a morn$
ing hour whereas melatonin *#$% mg- given &y mouth+ one hour &e$
fore scheduled &edtime may also help to synchroni6e the cloc0 for sleep.
These methods may help for <et lag. owever+ the chronic use of mela$
tonin is still the su&<ect of discussion alTl!ng clinicians.
R,F,R,NC,S
!nly references to eBtensive reviews are given.
A0erstedt+ T. *1'(>- Shifted sleep hours. Ann. ,lin Res. 1=C#=%$#='.
2or&ely+ A.A. *1'(#- A two process model of sleep regulation. uman Neuro&iol.
1C1'>$#@A.
Daan+ S., 2eersma+ D.7.".+ 2or&ely+ A.A. *1'(A- Timing of human sleepC recovery
process gated &y a circadian pacema0er. Amer. 3. 5hysiol. #A?CRl?1$Rl=(.
7ander et al. *1'('- Ad<ustment of sleep and the circadian temperature rhythm after
flights across nine time 6ones. Aviation+ Space and Environmental "ed.
?@+(C=%%$=A%.
"oline+ ".1. et al. *1''#- Age related differences in recovery from simulated <et
lag. Sleep 1>C#($A@.
"oore$Ede+ ".,.+ Sul6man+ ".+ 8uller+ ,.A *1'(#- The cloc0s that time us.
5hysiology of the circadian system. ,am&ridge+ "A+ arvard 4niversity 5ress.
"oore$Ede+ ".+ Richardson+ 7.S. *1'(>- "edical implications of shift wor0.
Ann.Rev. "ed. %?C?@=$?1=.
BRAIN I-A6IN6) T%, %U-AN
A-56DALA AND STR,SS
Willia- Feindel
SELYE'S DEFINITION OF T!E %ENERAL ADAPTATION
SYNDROME
!n the &asis of investigations carried out at )vlc7ill 4niversity in the
early 1'A@s+ and from a critical review of the literature at that time+
ans Selye summari6ed the evidence for the general adaptation syn$
drome and the diseases of adaptation *Selye+ 1'A?-. e proposed that+
in addition to specific organ reactions to various forms of stress+ there
was a general systemic reaction. e defined the general adaptation syn$
drome as "the sum of all non$specific systemic reactions of the &ody
which ensue with long continued eBposure to stress". These reactions
are manifested at first &y signs of damage or shoc0+ /uic0ly followed &y
the alarm reaction+ then &y a stage of resistance+ ending with a stage of
eBhaustion *8igure 1- )n other studies Selve had shown that hormones+
and especially the adrenocortical hormones+ played a su&stantial role in
phenomena related to adaptation to stress *Selye+ 1'A@-.
The response to stress can &e correlated in the human with the
emotional eBpression of fear. The present report reviews evidence that
such a reaction can &e su&served &y the lim&ic system and particularly
&y its amygdalo$hypothalamic components.
E<PERIMENTAL E0IDENCE FOR T!E AMY%DALA STRESS
The eBperimental evidence for the role of the amygdala in the physi$
ological and &ehavioural eBpression of fear has &een recently summa$
ri6ed &y Eleftheriou *1'=#-+ 2en$Ari *1'(1-+ Aggleton *1''#- and
7loor *1''=-. Early results from stimulation of the amygdala in ani$
mals demonstrated how this elicited defensive or fearful &ehaviour
*7astaut+ 1'>#D ilton and L&ro6vna+ 1'?%D L&ro6yna+ 1'=#-. The
central nucleus of the amygdala in the rat seems essential for fear$con$
ditioning and for some of the autonomic effects of fear$induced stress
such as stress ulcers of the gastric mucosa. )n order to induce a condi$
tioned fear response the central nucleus seems to depend upon im$
pulses relayed from the lateral amygdaloid nucleus+ the latter acting as
a "sensory interface" *1eDouB+ 1''@-. Although these studies in rats
have supported the role of the central amygdala nucleus in mediating
fear+ other studies in cats have indicated that a defensive response is
mediated &y the &asal nucleus *ilton and L&ro6yna+ 1'?%-. The cen$
tral nucleus has also &een reported to &e involved in rewarding eBperi$
ences. To reconcile these differences+ the suggestion has &een made
that the central nucleus is involved in the conditioned attention to
meaningful events regardless of the rewarding or aversive nature of the
unconditioned stimulus *Davis+ 1''#D 1eDouB+ 1''>-.
Recent studies have detailed the anatomical organi6ation of the
amygdaloid compleB and its rich reciprocal connectivity to the hippoc$
ampus and the entorhinal corteB+ as well as to the hypothalamus+ &asal
fore&rain+ thalamus+ striatum and &rainstem *Amaral et al+ 1''#-. !f
great significance also are the massive reciprocal connections of the
amygdala with areas of neocorteB+ either directly+ or indirectly via the
thalamus+ that represent all sensory modalities. Thus+ the anatomical
networ0s involving the amygdala provide a &asis for interaction &e$
tween potent su&cortical structures and the widespread cortical man$
tle+ &ringing into play visceral$autonomic and &rainstem functions with
cortical sensory function. This pivotal role of the amygdala is therefore
relevant to the pathophysiology of emotions such as fear and the adap$
tations to stress. )t also helps to eBplain the auras and other features of
the sei6ure patterns relating to epileptic discharge in the temporal lo&e+
which are initiated &y sei6ure discharge in the amygdala or evo0ed &y
electrical stimulation in that compleB *8eindel and 5enfield+ 1'>AD
8eindel+ 1'=A-.
FEAR RESPONSE AND T!E TEMPORAL LOBE
8ear appears to &e &y far the most fre/uent emotion reported to &e
associated with spontaneous epileptiform discharge originating in the
temporal lo&e *5enfield and 3asper+ 1'>#D 5enfield and 3asper+ 1'>AC
"acrae+ 1'>AD Williams+ 1'>?D Weil+ 1'>'-. "ore than a century ago+
3ac0son+ in 1(='+ descri&ing fear as a symptom of an epileptic attac0+
distinctly emphasi6ed that it was not the fear of a fit+ &ut "fear which
comes &y itself $ the symptom 8ear< .
8eindel and 5enfield *1'>A- reported a well$documented case
where fear was a prominent feature in spontaneous sei6ures+ and was
reproduced at operation &y electrical stimulation of the anterior insula+
and the lateral margin of the amygdala *8igure #-. This study provided
the first evidence for the involvement of the human amygdala in emo$
tional and visceral responses.
2rain imaging+ the human amygdala and stress 38
8ear or "nervousness" was produced at operation *"ullan and
5enfield+ 1'>'- at sites located deep in the su&stance of the anterior
and medial aspect of the temporal lo&e. (t is of great interest that arrest
of memory recording+ confusion+ lac0 of awareness+ and automatisms
had also &een produced &y stimulation in this same mesial temporal
periamygdaloid region *8eindel et al+ 1'>#D 8eindel and 5enfield+ 1'>A-
*8igure %-.
!ther wor0ers have also o&tained reports offear+ mostly from stimu$
lation of the amygdala or of ad<acent parts of the mesial temporal re$
gion *2ancaud et al+ 1'??D ,hapman et al+ 1'>AD 7loor et al+ 1'(1D
algren et al+ 1'=(D 3asper and Rasmussen+ 1'>(D Wieser+ 1'(%D 8ish
et a)+ 1''%-.
"uch evidence on the association of fear with temporal lo&e epi$
leptic discharge has also resulted from the detailed clinical analysis of
sei6ure patterns. The fre/uency of fear as a feature of temporal lo&e
sei6ures involving &ehaviour automatism was first noted &y 8eindel and
5enfield *1'>A-. )n a large series studied &y Williams *1'>?- compris$
ing 1@@ epileptics who eBperienced an ictal emotion+ ?1 eBperienced
fear. )n a series of ># patients eBperiencing an ictal affect+ #> reported
fear and 1A reported feelings of anBiety or other feelings a0in to fear
*Daly+ 1'>(-. 2ingley *1'>(- reported that %?G of '@ temporal lo&e
epileptics eBperienced ictal fear.
8rom these clinical o&servations on fear occurring with temporal
lo&e sei6ures and stimulations it can &e concluded that the emotion of
fear is produced as a distinct eBperience+ and is not a secondary psycho$
logical ela&oration due to the fact that the patient is aware of an impend$
ing sei6ure *7loor+ 1'=#+ 1'=>+ 1''@-. (t is initiated &y locali6ed cortical
discharge+ &eginning within the amygdala or the temp oro$insular corteB+
which then pro&a&ly spreads to other structures *8eindel and 5enfield+
1'>AD "ullan and 5enfield+ 1'>'D 7loor and 8eindel+ 1'?%-.
These emotional responses in man can &e seen as the su&<ective
and ver&ally communica&le counterpart of the various &ehavioural re$
sponses o&served in animals upon stimulation of the lim&ic portion of
the temporal lo&e. According to 7loor *1''=-+ these responses can &e
understood as manifestations of a central nervous integrative process
that allows the organism to adapt successfully to its environment &y
choosing a &ehavioural response+ which in the light of past eBperience
is relevant and appropriate to the present one.
BRAIN IMA%IN% STUDIES
)ctal fear is significantly related to more pronounced atrophy of the
amygdala+ as revealed &y "R) measurements using thin cuts and a high
resolution techni/ue *,endes at al+ 1''A-. )ctal fear is also more fre$
/uent in patients with more severe amydgaloid pathology. This is sup$
ported &y o&servations o&tained &y stimulation of the amygdala during
stereotactic investigation or at the time of surgery.
"orris and associates *1''?- in 5ET studies o&served that the
response in the left amygdala was significantly greater to images dis$
playing fearful as opposed to happy eBpressions. Their findings provide
evidence that the human amygdala is engaged in processing the emo$
tional reaction to fearful facial eBpressions. !ther o&servations &y 2ro0s
and associates *1''(- indicated that in patients .ith damage in the
region of the amygdala after encephalitis there was impaired recogni$
tion of a fearful stimulus. )n general+ their findings were confirmed &y
a study of patients with post$traumatic stress disorder *Shin et al+ 1''=-
which indicated that in patients with damage in the region of the amy$
gdala after encephalitis there was impaired recognition of a fearful stimu$
)us. The important role of the amygdala in steroid release associated
with stress *7ray and 2ingaman+ 1''?- is of interest in relation to SelyeEs
early study *1'A@- of stress and adrenal cortical hormonal responses. A
pivotal role for the amygdala in anBiety and fear has &een su&stantiated
in a recent review *,harney and Deutch+ 1''?-. 2ilateral+ &ut not uni$
lateral+ damage to the human amygdala impairs the process of recogni$
tion of fearful facial eBpressions *Adolphs et al+ 1''>-. 5hillips et al
*1''=- using functional magnetic resonance imaging found that pres$
entation of faces showing disgust activated the anterior insular corteB
while fearful faces activated the amygdala. 8urther imaging studies may
&e eBpected to define in more detail the role of the amygdala in condi$
tions of fear and stress.
CONCLUSION
The amygdaloid compleB with its widespread reciprocal connections to
su&cortical+ &rainstem and cortical areas has &een shown in eBperimen$
tal as well as human studies to playa prime role in the emotional eB$
pression of fear and in physiological and &ehavioural phenomena related
to adaptation to stress.
*
u .,
2rain imaging+ the human amygdala and stress 3/
Fi#/e (
Diagram to show the stages reactions to stress manifested at first &y
shoc0+ then &y countershoc0+ followed &y the stage of resistance and
the stage of eBhaustion *from Selye+ 1'A?-.
11
D :
$
8::
w
..
A A
?) u
w~--~~~--------------------------,_ ~
D E !,
FE
A I .
,-
ill
.Z+
~~~~
#H
~
o
~
e:
--
CA
-
T
-
E<
--------~-.~-~--~.-~-.~--~.~--~-.~--~-~--~--~--~-~--~-~.-~----
~+------~+
#HOC:
STA7E CAlAR" REA,T)!N #T2@E .. <E#(#T20CE
STACIE .. E=H2D#T(O0
Fi#/e 8
SurgeonEs s0etch to show negative response to electrical stimulation of
the insula at "@" and a positive response of fear from stimulation at
point "P" in the anterior insula. The electrical activity recorded from
the &lac0 <oined circles showed desynchroni6ation of cortical waves *from
8eindel and 5enfield+ 1'>A-.
G
I
0:9"&>
VII
Fi#/e 4
The dotted area indicates where electrical stimulation during operation
produced features of fear or "nervousness" as well as interference with
memory recording+ confusion+ lac0 of awareness and automatism. The
area includes the amygdala+ anterior insular corteB and part of the
entorhinal corteB *modified from 8eindel and 5enfield+ 1'>A-.
Ins/la and
3ain ste-
r.o(ed
S
R,F,R,NC,S
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