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Christopher Pryce
Preclinical Lab for Translational Research into Affective Disorders Clinic for Affective Disorders & General Psychiatry (christopher.pryce@bli.uzh.ch)
Emotions: caused by rewarding and punishing stimuli and their association with behaviour
Present Reward (UCS, CS)
Inescapable/Unavoidable Aversion
Contexts for Stressful life events: Employment Finance Health Housing Family Social relationships
DSM-IV classification At least one of: Depressed mood Loss of interest or pleasure
ICD-10 classification At least two of: Depressed mood Loss of interest or enjoyment Reduced energy/increased fatigability/ diminished activity At least three of: Reduced concentration and attention Reduced self-esteem and self-confidence Ideas of guilt and unworthiness Bleak and pessimistic views of the future Ideas or acts of self-harm or suicide Disturbed sleep Diminished appetite Suicide attempt/plan
At least four of: Weight loss Insomnia Psychomotor agitation or retardation Fatigue/loss of energy Feelings of worthlessness or guilt Diminished ability to think or concentrate Recurrent thoughts of death or suicide
DSM-IV: Diagnostic and Statistical Manual, American Psychiatric Association (2000) ICD-10: International Classification of Diseases: Mental and Behavioural Disorders, WHO (1992)
Major depression emotional-cognitive psychopathologies, relevant human tests and corresponding mouse tests
Psychopathology Loss of pleasure/enjoyment of reward (Anhedonia) Loss of interest in/incentive for reward (Anhedonia) High reactivity to aversive stimuli (Depressed mood) Stress uncontrollability (Depressed mood, Helplessness) High negative feedback sensitivity (Depressed mood, Catastrophization) High bias to negative expectancy (Depressed mood, Pessimistic outlook) Fatigability (Fatigue) Human Test Emotional reactivity to positive stimuli e.g. Photos of happy faces Mouse Test Relative reactivity to sucrose vs water e.g. Sucrose preference test
Motivational reactivity to reward stimuli Operant responding for reward e.g. Performing cognitive task for money e.g. Operant schedule for sucrose Emotional reactivity to negative stimuli e.g. Photos of sad or fearful faces Reactivity to aversive uncontrollability e.g. Learned helplessness effect Response to negative feedback e.g. Probabilistic reversal learning Reactivity to ambiguous stimuli e.g. Ambiguous-stimulus operant test Emotional reactivity to negative stimuli e.g. Fear conditioned freezing Escape behaviour in 2-way shuttle box e.g. Learned helplessness effect Response to negative feedback e.g. Probabilistic reversal learning Reactivity to ambiguous stimuli e.g. Ambiguous stimulus operant test
Physical effort to complete a manual task Effort-reward operant behaviour e.g. Grip strength test e.g. Treadmill running to avoid e-shock
Anger, Disgust, Fear Neutral (forced choice) Happy, Surprise Morphing of facial expressions to quantify emotion Hamilton rating scale for depression: 21 (5) p < 0.05 p < 0.05
p < 0.05
The neurobiology of fear: Amygdala as integrator of emotional stimuli and effector of emotional response
Neural pathways underlying fear: studied using fear model of conditioned freezing
Human Amygdala: increased neural (fMRI) activity in response to aversive visual stimuli
International Affective Picture System Human (conspecific) Social stimuli
dACC
dACC
Hyper-active region in MDD Hypo-active region in MDD Intact connectivity Reduced connectivity Disner et al (2011) Nature Rev Neurosci 12: 467
sgACC
Increased neural response to sad stimuli in dorsal anterior cingulate cortex in depression
dACC
dACC
sgACC
dACC
4-8 sec
5 sec
dACC
BOLD
sgACC
dACC
dACC
sgACC
Uncontrollable Stressful life events: Employment Finance Health Housing Family Social relationships
No Control/Contingency
Aversive event
Response
No Reinforcement
MDD symptoms
Generalized Helplessness
Maintenance phase
The prefrontal cortex and stress uncontrollability in rat: II. Inhibiting helplessness
Rats exposed to escapable stress (ES) exhibit escape behaviour at subsequent escape test Rats exposed to inescapable stress (IS) exhibit escape deficit at subsequent escape test Rats micro-injected with picrotoxin into mPFCv prior to IS exhibit escape behaviour equivalent to ES rats Day 1: Picrotoxin or VEH + IS Yoked to Picrotoxin or VEH + ES Measure 5-HT response of DRN Day 2: Escapable shock in 2-way Shuttle box
Day 1
Day 2
Picrotoxin = GABAAR antagonist
Proposed mechanism of mPFC (glutamate) DRN (serotonin) Limbic circuit regulating Stressor un/controllability
7 2
4 7 5 2 6 1
1. 2. 3. 4. 5. 6. 7.
Stressors activate dorsal raphe nucleus 5-HT ascending input to forebrain Uncontrollable stress leads to chronically increased DRN 5-HT input to limbic and cortical areas mPFC is a major processor of stressor controllability (achieved via behaviour-outcome processing) mPFC is a major source of inhibitory input to DRN via its glutamatergic projections Stressor controllability, as assessed at mPFC, is relayed to and inhibits DRN 5-HT system Impaired mPFC function, in part induced by high DRN 5-HT activity during a period of uncontrollable stress, will lead to increased perceived stressor uncontrollability (viscious circle) mPFC as a target of antidepressant action, to restore the circuitry and psychology of stressor controllability
The biggest mystery of human psychopathology: how does an environmental factor, external to the person, get inside the nervous system and alter its elements to generate the symptoms of a disordered mind?
Caspi & Moffitt (2006) Nature Rev Neurosci 7: 583
5-HTTLPR
5-HTTP
5HTTLPR genotype associated with potential neural endophenotypes of affective disorder healthy subjects
BOLD fMRI response to fearful face Absolute Cerebral Blood Flow at Rest
p<0.005
AMYG
p<0.001
5HTTLPR genotype associated with potential psychological endophenotypes of affective disorder healthy subjects
Neuroticism Personality Trait Scores Attention to emotional stimuli
VIGILANCE
p<0.05
Negative Positive
AVOIDANCE
5-HTTLPR polymorphism interacts with stressful life events to increase prevalence of depression
The biggest mystery of human psychopathology: how does an environmental factor, external to the person, get inside the nervous system and alter its elements to generate the symptoms of a disordered mind?
Caspi & Moffitt (2006) Nature Rev Neurosci 7: 583
Vaccine group specifically: Net response to [emotional - neutral] faces Depression-like mood predicted by sg ACC net response [emotional - neutral] faces increased in subgenual ACC
Aetio-Pathophysiology
Neurocircuit Pathology
Depression
10 min/day
CS-Freezing [% Time]
80 60 40 20 0
p < 0.001
Escape Failures
30 20 10 0
p < 0.005
p < 0.001
10 min/day
[Plasma] pg/mL
p < 0.015
Control Depressed
3 4
9 10 11 12 13 14 15 16 17 18 Behaviour Test
IDO inhibitor reverses effects of chronic social defeat on consolidation of fear learning
Fear Conditioning **
% Time Freezing
80 60 40 20 0
CON+VEH (N=8) CON+IDO Inhibitor (N=8) CSD+VEH (N=7) CSD+IDO Inhibitor (N=8) Mean +/- SD
% Time Freezing
60 40 20 0
Fluoxetine
Valid mouse models of depression psychopathology: the essential starting point for therapeutic-target discovery and validation
Uncontrollable Stressor(s) Aetio-Pathophysiology (Cytokines, Glia) Neurocircuit Pathology Psychopathology Valid Models