Hypothalamus Lecture Notes

Dr. Salm

Lecture Notes
Hypothalamus
Dr. Salm
asalm@hsc.wvu.edu

These are your objectives for this lecture. Under point # 5 (Understand
the data...) this includes data from rodent studies that led to the
experiments on humans that have provided emerging data for a
biological basis for sexual preference, performance and gender
identity. An understanding of the animal work on what the other
hypothalamic nuclei are doing is also recommended. Many of these
studies would not be ethically feasible in humans but have
nevertheless provided valuable insight into the human condition.
Exposing students to translational studies (i.e., preclinical rodent
experiments) is an objective listed in the AAMC guidelines for medical
education and, thus, is included in this lecture.

Control of Autonomics and Horners syndrome have been removed

from this lecture.
The hypothalamo-pituitary-adrenal (HPA) axis is likewise not included
here in lieu of more interesting subject matter to which you may
otherwise never be exposed.

Weve already identified the boundaries of the hypothalamus in the

block one mid-sagittal laboratory exercise. Ventrally it is bounded by
the optic chiasm and the infundibulum. This region of basal
hypothalamus is also sometimes called the tuber cinereum. The
posterior boundary is the mammillary bodies after which you are in the
midbrain. The thalamus is separated from the hypothalamus by the
hypothalamic sulcus. The optic track winds around the lateral surface
of the hypothalamus. Rostrally, the hypothalamus is bounded by the
lamina terminalis, the most rostral part of the developing neural tube
early in development.

Nolte figure 23-2 focuses on the central role of the hypothalamus in

those drive-related activities, basically centered on both the
maintenance of the internal environment (homeostasis) and survival of
the species (feeding, affiliation, maternal care, and reproduction). It
exerts its influence on visceral structures in 3 ways: 1) through
connections with brainstem centers controlling the viscera (e.g. DMNX;
the autonomic reticular formation); 2) through hypothalamo-spinal
projections that terminate on or near the intermediolateral cell column;
and 3) through endocrine outflow from the pituitary gland. Through its
reciprocal connections with the limbic system and cortex, the
hypothalamus influences voluntary motor activity necessary to
maintain homeostasis. It also enables the cerebral cortex to exert
executive control when satisfying physiological imperatives is not
appropriate.

Slide 5. The hypothalamus does all this by integrating critical

information arriving to it from a diverse array of receptors encoding
homeostatic, sensory, endocrine, and visceral information (obviously
these categories are not mutually exclusive and there is over lap (for
example an empty stomach can be signaled though all of these).
In addition, input from cortical and limbic regions put an emotional
valance on any situation (Mayday! Mayday! Mayday! The sabre-
toothed tiger is coming-forget your stomach!!!)

Slide 6. Incoming viscerosensory afferents from the aortic arch and

carotid bodies carries information concerning blood pressure and CO2
levels (cell bodies are in the inferior ganglia of IX and X). This arrives to
nucleus solitarius which projects to DMNX, to the PVN hypothalamus
and the rostral ventrolateral medulla concerned with blood pressure.
The PVN hypothalamus additionally projects back to the rostral
ventrolateral medulla and the DMNX (Zhang and Fogel 2002, J.
Neurophysiol. 88: 49-63) to further modulate the baroreceptor reflex.
Also see Table 8-1 in Haines 8th edition atlas. Pg 236. For the
baroreceptor reflex-this does not include the loop from NTS to PVN and
back to the DMNX however.

Slide 7. In the case of cortisol for example, it feeds back onto

parvocellular neurons in the paraventricular nucleus (also hippocampal
neurons) that project to the portal system of the median eminence to
release corticotropin releasing factor (CRF) which eventually reaches
cells in the anterior pituitary. These cells release ACTH. ACTH
completes the cycle by stimulating cortisol release from corticotrophs
in the adrenal cortex.
With respect to indiscriminately letting molecules into the brain
parenchyma, the BBB is only leaky at the circumventricular organs.
However, there are transport systems within the hypothalamus that
carry molecules across the BBB and into the tissue (Zlokovic et al.,
2000, Endocrinology 141(4)) .

Slide 8. Internal Sensing systems is a term used to refer to mostly

hypothalamic cells that act as receptors for specific homeostasis-
related cues such as blood glucose, fat, temperature, and osmolality.
This figure is of a patch-clamped supraoptic nucleus neuron in a slice
preparation in response to a hypertonic saline solution. This causes the
neuron to shrink and open mechanosensitive ion channels.
Slide 9. Cognitive-affective refers to thinking (information processing
such as, sensory processing working memory, speed of computation)
and feeling (influenced by emotional responses to the world). A good
example here would be a perception of danger followed by a fear
response leading to either fight or flight.

Slide 10. The hypothalamus is the recipient of sensory information from

the visual system. Peripheral retinal ganglion cells of the retina send
information concerning luminance to the suprachiasmatic nucleus
which is a principal areas involved with circadian rhythm regulation,
and to the ventrolateral preoptic nucleus. This nucleus projects to the
monoaminergic ascending arousal system. It is thought the VL-POA
provides the means by which luminance affects sleep. The reticular
activating system also extends into the hypothalamus to influence
arousal levels.

Slide 11. Hypovolemia can occur through simple everyday dehydration,

hemorrhage and disease. Atrial stretch receptors (baroreceptors)
decrease firing and activate neurons in the nucleus tractus solitarius
(NTS). The NTS projects to the paraventricular nucleus, causing the
release of vasopressin from the posterior pituitary that will 1) increase
reabsorption of water at the renal tubules and2) increase peripheral
vascular resistance (vasopressor response). It also projects to the
lateral hypothalamus that sends descending axons to synapse onto the
IMLCC to ultimately activate neurons in the sympathetic ganglia
involved with vasoconstriction.
The cognitive aspects of this chain of events are harder to
delineate. Presumably the feelings of thirst are generated in
hypothalamic regions where injection of angiotensin II leads to rapid
and reliable drinking behavior in animal studies. These include the
subfornical organ (a small area just underneath the fornix in the
anterior 3rd ventricle), the PVN and the median preoptic area (MnPO).
Higher cortical areas involved with motor planning and generation
(PMA, SMA, M1) and target identification (parietal cortex) are likely
involved with the behaviors leading to obtaining a drink of water.

Slides 12-14. Anatomy: There are three general subdivisions of the

hypothalamus: anterior, tuberal or posterior divisions.

The anatomical territory of the hypothalamus includes both nuclei

(e.g., paraventricular, supraoptic) and areas (e.g. lateral, tuberal and
posterior). These differences in nomenclature reflect different
approaches used in the study of the hypothalamus-physiological
experiments more often used areas to describe electrode placement,
whereas histological approaches enabled precise localization of nuclei.
Nissl stains are the basis for construction the schematic diagrams of
hypothalamic nuclei and areas. You cannot see these regions without
visualizing the tightly packed cell bodies comprising the various nuclei.

Hypothalamic Acronyms defined:

MPOA: medial preoptic nucleus
PV or PVN: paraventricular nucleus
SON: supraoptic nucleus
SCN: suprachiasmatic nucleus
DM: dorsomedial nucleus
VM: ventromedial; nucleus
Po: Posterior nucleus (or area)
An: Anterior nucleus (or area).
L: lateral nucleus (or area)
MB: mammillary bodies

Because of the tight packing of the nuclei, closed head injuries, brain
surgery, meningitis, encephalitis, strokes, subarachnoid hemorrhages
and neoplasms can all present as a constellation of disturbances,
depending on which nuclei are affected.

You do not need to memorize which nuclei are included in each area.

A sampler of some of the more interesting hypothalamic

functions.

Slide 16. The medial preoptic nucleus (MPOA) is located in the most
anterior part of the hypothalamus (anterior to the anterior nucleus, in
fact). There is a medial and lateral component to it as well as other
subparts with non-reproductive functions.
I have posted an addendum in the lecture folder on SOLE with many
links and references.

Slide 17. The preoptic nucleus of humans is made up of 4 distinct

subnuclei . This area control behaviors necessary for the propagation
of the species including a large repertoire of reproductive and maternal
behaviors. Its development is under control of testosterone during
critical periods. It has different structural and functional characteristics
in males vs. females. Hence it is sexually dimorphic. In rats, Gorski et
al., demonstrated in the late 70s that rat partner preference, and
repertoire of copulatory behaviors are related to the structure of the
POA.
Slide 18. Beginning with the work of Gorski, it was discovered in the
late 70s that the development of sexual characteristics and later
sexual behaviors could be experimentally manipulated in rats by
strategic exposure to testosterone during development.

Adult sexual behavior in the rat depends on whether the brain was
organized by gonadal hormones during the first few days after birth.

Normal adult males display mounting behavior because their brains

were subjected to a dose of testosterone from the gonads just after
birth. The same effect can be produced in females by injecting the
hormone testosterone.

Depriving male pups of testosterone by castrating them at birth results

in a female brain organization. As adults these feminized males, like
normal females, display very few attempts to mount, but a high
frequency of lordosis when mounted.

Slide 19. The POA SDN is larger in males than females

Females androgenized with a testosterone proprionate (TP) injection on

day 4 have significantly larger SDN volume than control (oil-treated )
females
SDN volume is reduced in males castrated on day 1 compared with
normal males (Gorski, 1980)
Males ultimately develop larger POAs due to more neurons and larger
dendritic arbors, than do females, due the effects of androgens.
Because of these differences, the POA is also called the SDN-POA; the
sexually dimorphic preoptic nucleus. Similar data have been gained in
humans. However, due to ethical constraints, human studies have not
been systematic and have relied on case-study-type data.

Slide 20. Summary of androgen effects on The development of the POA

is under the control of circulating androgens during development.
Females rats have smaller POA nuclei than males: fewer neurons and
smaller dendritic arbors. Male rats that have been castrated at birth
develop female-like POA nuclei. Females that are given testosterone at
a critical period develop male-like POA nuclei.

Since then it has been established that sexual behaviors in many

species are under the control of the POA.

Sexual behaviors and preferences are highly correlated with the size of
the POA.
The Interstitial Nucleus of the Anterior Hypothalamus is the human
analog of the POA in rodents and similar data have been gained in
humans at this time.

The developing brain is, by default, female with respect to the POA. In
male rats, exposure to testosterone in the perinatal period (G18-21)
changes a female POA to a male POA. Males ultimately develop larger
POAs due to more neurons and larger dendritic arbors, than do
females.

A similar masculinization is believed to occur in male humans earlier in

gestation than in rats (i.e, not just prior to birth). Evidence is
accumulating for similar events in humans, albeit under more
environmental (epigenetic) control.

This masculinization process can be experimentally manipulated by

removing the source of testosterone in developing males, or by
artificially adding to developing females. These manipulations result in
animals that have altered POA morphology for their sex, and altered,
oppositely sexed, mating behaviors.

Slide 21. In this study from Oomura et al., (1983), the role of the
preoptic area in sexual functioning was amply demonstrated. Male
primates were restrained in apparatus that nevertheless let them be
sexually active. They were able to bar press in order to draw a
receptive female in a suitably flexible restraining apparatus towards
them. Firing rates of neurons in the medial POA are recorded as the
male monkey mounts, mates and ejaculates.

Slide 22. In this experimental set-up, male primates are able to bar
press in order to draw a receptive female in a flexible restraining
apparatus towards them. Neurons in the medial POA are recorded as
the male monkey mounts, mates and ejaculates.

Slide 23. Soooo what about humans?? The third interstitial nucleus of
the anterior hypothalamus appears to be the human homolog to the
sexually dimorphic preoptic area in rodents.

Slide 24 Evidence that the development of preoptic area cell groups is

developmentally regulated by testosterone exposure. This slide
demonstrates differences the size of the in the INAH 2 and 3 nuclei
anatomy between men and woman. The INAH 2 nucleus is less densely
packed, and the INAH 3 nucleus is virtually non-existent in woman vs.
men.
Slide 25. This was the study that made the leap from rodent research
to humans. When it was presented in 1990 at the Society for
Neuroscience annual meeting, the standing-room-only crowd was so
overwhelming in the triple ballroom of the Washington Hilton that one
could not get in the room.
If you are interested in this topic a concise review can be found at:
http://www.simonlevay.com/the-science-of-sexual-orientation.
http://www.simonlevay.com/gay-straight/Gay%20straight
%20framed.jpg?attredirects=0

Slide 26. These are high magnification images taken from the 1991
LeVay paper.

Slide 27. There are many non-sexual behaviors that also have a
distinctive female vs. male expression. Since most all-biological
variables are distributed normally, this explains the Bell-curve of many
gender related human behaviors.

The strongest BOLD signal were seen in the anterior hypothalamus.

Slide 28-29. More interesting data, from humans this time, that
demonstrates the role of the POA (called anterior hypothalamus here)
in sexual responsiveness and perhaps sexual identity as well. In this
study, 18 healthy, self-professed heterosexual males were given a
drawing test to determine the strength (Hetero)sexual Identity. Then
their brains were imaged with fMRI while watching hard core erotic
video clips interspersed with clips of the 2011 Mountaineer bowl game
to determine which they found more arousing oops just joking- they
were really generic sports clips which served as controls.
They also wore a penile tumescence-measuring device (also
affectionately known as the peter meter in the sexual research
community) to provide another measure of sexual arousal
(interestingly quantified as mm Hg; similar to a thermometer).

Slides 30-38. Transgenderism . With all of the accumulating data

indicating that sexual behawior is biologically based, what can be said
of sexual or gender identity? There are accounts of some individuals in
other cultures making a transition to the opposite gender roles in
adolecence without fanfar. However recent anatomical data suggest
that this also is under the control of biological processes during
development. Christine Jorgenson was the first notable case of gender
reassignement-in the 1950s!

Reference: Brain. 2008 Dec;131(Pt 12):3132-46. doi:

10.1093/brain/awn276. Epub 2008 Nov 2.
A sex difference in the hypothalamic uncinate nucleus:
relationship to gender identity.
Garcia-Falgueras A, Swaab DF., Netherlands Institute for Neuroscience,
Amsterdam, The Netherlands.

Sexual reassignment surgery is now beginning to be covered by some

insurance plans. The AMA has issued guidelines for the medical care of
transgendered individuals undergoing reassignment.

Slide 30. Supraoptic Nucleus (SON)

Located in the anterior and medial zones bilaterally adjacent to optic
chiasm.
Receives afferents from the brainstem with information about uterine
distension, nipple suckling, blood volume.
Sends axons to the posterior pituitary
Produces oxytocin and vasopressin
Functions: osmosensitivity (VP mostly) , water balance (VP), blood
volume regulation (VP), lactation: specifically, milk ejection (oxytocin),
orgasm (oxytocin), maternal behaviors (oxytocin). Because of its role
in promoting maternal and spousal harmony, oxytocin has been called
the feel-good peptide. Note that other areas and peptides have been
implicated in the initiation of maternal behaviors (prolactin, preoptic
area).
** Lesions lead to diabetes insipidus with polyuria and polydipsia
**SIADH (syndrome of inappropriate ADH release resulting in
hyponatremia and fluid.

Slide 31. SIADH- excess secretion of ADH in the absences of osmotic

stimulation or blood volume decreases.
Leads to hyponatremia and hypoosmolality.
Common causes
Drugs: tricyclic antidepressants, carbamazepine and oxcarbazepine,
phenothiazines, omeprazole, chlorpropamide, vincristine, vinblastine,
cyclophosphamide, clofibrate, haloperidol, angiotensin converting
enzyme inhibitors, narcotics, nicotine, monoamine oxidase inhibitors,
SSRIs, and many others
Post-operative stress caused by surgery, use of a mechanical
ventilator, or anesthetic agents
Hormone administration: vasopressin, desmopressin (DDAVP), or
oxytocin
CNS disturbances due to infections (meningitis, brain abscess), stroke
(embolic, hemorrhagic), trauma, or neurosurgery. Pulmonary
disorders: pneumonia, tuberculosis, emphysema.

Slide 33. Paraventricular Nucleus (PVN)

Bilaterally adjacent to third ventricle in the anterior and medial zones
Receives afferents from brainstem (n. solitary tract) concerning blood
volume, suckling, cortisol levels
Efferents to:
brainstem and spinal cord - autonomic regulation
median eminence - corticotropin releasing factor
posterior pituitary - oxytocin, vasopressin
Functions:
produces oxytocin and vasopressin
osmosensitivity: water balance, blood volume
regulation, lactation, milk ejection,
stress response
** Lesions lead to diabetes insipidus with polyuria and
polydipsia
SIADH- excess secretion of ADH in the absences of osmotic stimulation
or blood volume decreases.
Leads to hyponatremia and hypoosmolality.
Common causes
Drugs: tricyclic antidepressants, carbamazepine and oxcarbazepine,
phenothiazines, omeprazole, chlorpropamide, vincristine, vinblastine,
cyclophosphamide, clofibrate, haloperidol, angiotensin converting
enzyme inhibitors, narcotics, nicotine, monoamine oxidase inhibitors,
SSRIs, and many others
Post-operative stress caused by surgery, use of a mechanical
ventilator, or anesthetic agents
Hormone administration: vasopressin, desmopressin (DDAVP), or
oxytocin
CNS disturbances due to infections (meningitis, brain abscess), stroke
(embolic, hemorrhagic), trauma, or neurosurgery. Pulmonary
disorders: pneumonia, tuberculosis, emphysema.

Slide 34. Neuroendocrine regulation will likely appear on the shelf

exam. Review as needed.
Anti diuretic Hormone (ADH; aka vasopressin) and oxytocin are
secreted by hypothalamus and carried in axons to posterior lobe for
direct release.
ADH water retention by kidney
Oxytocin milk let-down and uterine contraction, maternal behaviors,
orgasm

Slide 35 This is the basic plan for control of all the anterior lobe
hormones: releasing factors or inhibitory factors are released to the
portal system for transport to anterior lobe. There they act on
secretory cells.

Slide 36. This slide illustrates the functions of the hormones that are
released from the anterior and posterior pituitary glands.
Slide 37. The suprachiasmatic nucleus is the clock of the body. It
gets information about luminance and this acts on clock genes that
are in these cells alone. Activation of these genes sets up cyclic
molecular events (for example, neurotransmitter synthesis, firing
rates) within the SCN cells. Such rhythms have been demonstrated to
persist for long periods of time, even in in tissue slices where the SCN
has been isolated from all other inputs.
SCN Afferents: peripheral retinal ganglion cells concerned with
luminance.
Efferents: SCN projects to the IML cell column to SCG to finally arrive
at the pineal (also see slide 39 however). Here it regulates the
production and synthesis of melatonin from the pineal gland.
Functions: entrains circadian rhythms of sleeping, eating, melatonin
synthesis and release from the pineal gland.

Slide 38 There are pacemaker type cells in different glands and tissues
of the body. It is beleived that the SCN is the main clock, and that the
other centers are entrained to it.

Slide 38.This shows the best known route of SCN regulation of the
pineal. It projects either by itself or via a relay through the
paraventricular nucleus to autonomic brainstem enters or the IMLCC to
stimulate sympathetic apparatus carried by the superior cervical
ganglion which crawls up vasculature to reach the pineal. . From there
it goes superior cervical ganglion to regulate synthesis and release of
melatonin from the pineal. Melatonin is a common jet lag remedy for
those traveling to different time zones. About 3 mgs is recommended
on the first several days after arriving-to be taken at the local bedtime.
It appears to work by helping to rapidly reset the circadian clock.

Slide 39.Figure 23.5 Nolte (page 585). Left side. Hamsters kept in
constant light will slightly deviate each day from an entrained activity
cycle until their SCNs are lesioned. Likewise when humans are placed
in a situation of only artificial light and allowed to naturally wake-up
and go to sleep, the free-running cycle drifts to about 25.3 hours.
This is perhaps why we feel sleep deprived so much of the time.

Slide 41 There is also evidence that the paraventricular nucleus

projects to the pineal via the stria medullaris thalami. Since the PVN is
thought to receive fibers from the SCN, this may represent a synaptic
relay system.

Slide 42 The lateral preoptic nucleus also receives afferents from

peripheral retina ganglion cells concerned with luminance. Sends
projections to monoaminergic cells (NE, 5-HT) involved with arousal
and sleep. This may be the means by which light levels regulate
sleepiness.

Slide 43 The hypothalamus plays a pivotal role in feeding behavior

(Nolte pg. 594)
This is a huge topic beyond the scope of one overview lecture.
However, weight loss or gain is frequently observed with hypothalamic
or pituitary tumors.

Slide 44 The Anterior and Preoptic Hypothalamic areas (cooling

system): stimulation here lowers body temperature
through:vasodilation
Increase in panting/respiration
Nolte calls the heat dissipation center the medial preoptic nucleus.
This is the same location as the cooling center, by a slightly different
name.
The Posterior Nucleus (heating system:) stimulation here
increases body temperature through:
vasoconstriction
shivering
These two centers reciprocally feedback to each other.

Slide 45 Dr. Haut will cover the types of memory loss associated with
pathology of the mammillary bodies.

Slide 46-48. Control of the ANS and Horners syndrome. Here for your
review.

49-53. This is a series of annotated images showing the location of

important hypothalamic nuclei as seen by Nissl stain. Be sure you can
recognize these nuclei in such images, and describe the functions for,
the supraoptic (SON), the suprachiasmatic (SCN) the paraventriclar
(PVN) and the anterior interstitial nuclei. Also the basal nucleus of
Meynert (Ach innervation to the cerebral cortex) and, last, but not
least, the mammillary bodies.

Slide 55. This is an admittedly not great picture of the fornix and
mammillothalamic tract as seen in a single sagittal myelin stained
section. The fornix should be an easy ID for you at this time. However,
please see Haines atlas pages 173 and 175 (plates7-2 and 7-4, 8th
edition) for better images of the mammillothalamic tract if you are
not sure about its location from this figure.

Slide 56. The median forebrain bundle is a fiber system that runs in the
lateral hypothalamus from rostral to caudal and vice versa. It is not
identifiable in sections prepared by conventional means. It connects
forebrain structures with brainstem structures and with the
hypothalamus in between. You dont need to memorize the list of
structures.

Slides 57 and 58
The DLF ascending tract has its origins in nuclei of the reticular
formation and nucleus solitarius. These fibers carry visceral sensory
information to the periventricular, paraventricular, and posterior
hypothalamus.
Hypothalamic efferents in DLF arise from the PVN, SON and
periventricular area and go to the
1) midbrain central gray for pain modulation,
2) the medullary autonomic centers for heart rate, blood pressure, and
respiration,
3) brainstem parasympathetic nuclei (dorsal motor nucleus of the
Vagus),
5) IMLCC, and
6) lumbo-sacral preganglionic parasympathetic neurons.