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Neurobiology of emotion and emotional disorders
Christopher Pryce Preclinical Lab for Translational Research into Affective Disorders
Clinic for Affective Disorders & General Psychiatry
Present Reward (UCS, CS)
Present Punisher (UCS, CS)
Omit or Stop Punisher (UCS, CS) Omit or Stop Reward
(UCS, CS)
Emotions: caused by rewarding and punishing stimuli and their association with behaviour
Rolls (2000) Behav Brian Sci 23: 177
Individuals respond to and learn efficiently about environmental factors
Approaching/Consuming Reward Escaping/Avoiding Aversion
Inescapable/Unavoidable Aversion
Contexts for Stressful life events: • Employment • Finance • Health • Housing • Family • Social relationships
Symptom type DSM-IV classification ICD-10 classification
At least one of: At least two of: Typical/Core Depressed mood Depressed mood Typical/Core Loss of interest or pleasure Loss of interest or enjoyment Typical/Core Reduced energy/increased fatigability/ diminished activity At least four of: At least three of: Common Weight loss Reduced concentration and attention Common Insomnia Reduced self-esteem and self-confidence Common Psychomotor agitation or retardation Ideas of guilt and unworthiness Common Fatigue/loss of energy Bleak and pessimistic views of the future Common Feelings of worthlessness or guilt Ideas or acts of self-harm or suicide Common Diminished ability to think or concentrate Disturbed sleep Common Recurrent thoughts of death or suicide Diminished appetite Suicide attempt/plan
DSM-IV: Diagnostic and Statistical Manual, American Psychiatric Association (2000) ICD-10: International Classification of Diseases: Mental and Behavioural Disorders, WHO (1992)
Psychiatric diagnosis of depression
Major depressive episode
Associated descriptive features: Individuals frequently present with tearfulness, irritability, brooding, obsessive rumination, anxiety, phobias, excessive worry over physical health, complaints of pain, panic attacks. Difficulty in intimate relationships, less satisfying social interactions, difficulties in sexual functioning. Marital problems (e.g. divorce), occupational problems (e.g. loss of job), academic problems (e.g. truancy, school failure). Alcohol or other Substance abuse. Attempted or completed suicide. Associated laboratory findings: No laboratory findings that are diagnostic of major depressive episode have been identified. State-dependent abnormalities include: Sleep-EEG (40-60% outpatients, 90% inpatients; dysregulation in neurotansmitters e.g. serotonin, noradrenaline, dopamine, acetylcholine, GABA; dysregulation in neuropeptides e.g. corticotropin releasing hormone (CRH), neuropeptide Y; increased cortisol; fMRI findings; structural MRI findings. Sex, Age, Culture: Female (4-10%) > Male (3-5%); Children – Elderly; Cross-cultural Course: Symptoms develop over days-weeks; typical episode 4 months; 20-30% 12 mth; 5-10% > 2 years
Features: A period of at least 2 weeks during which there is either depressed mood or loss of interest or pleasure in nearly all activities, plus at least 4 additional symptoms. Must be accompanied by clinically significant distress or impairment in social, occupational, or other important area of functioning, or functioning requires more effort. Depressed mood: “sad”, “hopeless”, “no feelings”, “frustration”, “anger” Loss of interest/pleasure: “don’t care anymore”, “not interested”
Major depression emotional-cognitive psychopathologies, relevant human tests and corresponding mouse tests
Psychopathology Human Test Mouse Test
Loss of pleasure/enjoyment of reward Emotional reactivity to positive stimuli Relative reactivity to sucrose vs water (Anhedonia) e.g. Photos of happy faces e.g. Sucrose preference test Loss of interest in/incentive for reward Motivational reactivity to reward stimuli Operant responding for reward (Anhedonia) e.g. Performing cognitive task for money e.g. Operant schedule for sucrose High reactivity to aversive stimuli Emotional reactivity to negative stimuli Emotional reactivity to negative stimuli (Depressed mood) e.g. Photos of sad or fearful faces e.g. Fear conditioned freezing Stress uncontrollability Reactivity to aversive uncontrollability Escape behaviour in 2-way shuttle box (Depressed mood, Helplessness) e.g. Learned helplessness effect e.g. Learned helplessness effect High negative feedback sensitivity Response to negative feedback Response to negative feedback (Depressed mood, Catastrophization) e.g. Probabilistic reversal learning e.g. Probabilistic reversal learning High bias to negative expectancy Reactivity to ambiguous stimuli Reactivity to ambiguous stimuli (Depressed mood, Pessimistic outlook) e.g. Ambiguous-stimulus operant test e.g. Ambiguous stimulus operant test Fatigability Physical effort to complete a manual task Effort-reward operant behaviour (Fatigue) e.g. Grip strength test e.g. Treadmill running to avoid e-shock
Hamilton rating scale for depression: 21 (5)
Anger, Disgust, Fear Neutral (forced choice) Happy, Surprise
p < 0.05 p < 0.05
Gollan et al (2008) Psychiatry Research 159: 18
p < 0.05
Joorman & Gotlib (2006) J Abnorm Psychol 115: 705
Laboratory tasks to measure dysfunctional emotional processes in depression
Morphing of facial expressions to quantify emotion
The neurobiology of fear: Amygdala as integrator of emotional stimuli and effector of emotional response
LeDoux (1994) Sci Amer 6: 50
Phelps & LeDoux (2005) Neuron 48: 175
Neural pathways underlying fear: studied using fear model of conditioned freezing
Electrophysiological evidence for fear neurons in mouse amygdala
Herry et al. (2008) Nature 454: 600
Human Amygdala: increased neural (fMRI) activity in response to aversive visual stimuli International
Affective Picture System Human (conspecific)
Social stimuli
Phelps & LeDoux (2005) Neuron 48: 175
Siegle et al (2002) Biol Psychiatry 51: 693
Increased BOLD fMRI amygdala reactivity to negative stimuli in depression
Victor et al (2010) Arch Gen Psychiatry 67: 1128
Response duration Response size
Hyper-active region in MDD
Hypo-active region in MDD
dACC
Intact connectivity
Reduced connectivity
dACC
sgACC
BOLD fMRI-based model of processing of negative stimuli in depression
Disner et al (2011) Nature Rev Neurosci 12: 467
Increased neural response to sad stimuli in dorsal anterior cingulate cortex in depression
dACC
sgACC
Elliott et al (2002) Arch Gen Psychiatry 59: 597
dACC
Strigo et al. (2008) Arch Gen Psych 65: 1275
Painful Heat stimulus Anticipation Stimulus
4-8 sec 5 sec Nonpainful warm stimulus Anticipation Stimulus
4-8 sec 5 sec
Anticipation period [painful heat - nonpainful warmth]
BOLD
dACC
sgACC
dACC
Increased neural response to painful stimuli in amygdala and dACC in depression
dACC
sgACC
dACC
Increased neural response to uncontrollability of painful stimuli in dACC in healthy humans
Diener et al. (2010) NeuroImage 50: 717
Pryce et al. (2011) Pharm Therapeut 132: 242
From Uncontrollability to Helplessness to Depression
Emotionality
Motivation
Cognition
Aetiological phase Learned helplessness
Maintenance phase
Aversive events
Aversive event Response No
Reinforcement
No Control/Contingency
MD
D sy
mpt
oms
Gen
eral
ized
H
elpl
essn
ess
Uncontrollable Stressful life events: • Employment • Finance • Health • Housing • Family • Social relationships
Day 1 Electro-shock pre-exposure
Day 2 Escapable shock in 2-way Shuttle box
The learned helplessness effect in rats
Jackson et al. (1978) Learn Motivation 9: 69
The prefrontal cortex and stress uncontrollability in rat: I. Inhibiting control
Amat et al. (2005) Nature Neurosci 8:365
• Rats exposed to inescapable stress (IES) fail to escape at subsequent escape test • Rats exposed to escapable stress (ES) with PFC inhibited also fail to escape
Muscimol = GABAAR agonist
IES+VEH IES+Muscimol ES+Muscimol ES+VEH
Day 1 Muscimol or VEH + IES Yoked to Muscimol or VEH + ES
Day 2 Escapable shock in 2-way Shuttle box
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 2: Escapable shock in 2-way Shuttle box
Picrotoxin = GABAAR antagonist
Amat et al. Neuroscience (2008) 154:1178
Day 1
Day 2
The prefrontal cortex and stress uncontrollability in rat: II. Inhibiting helplessness
Day 1: Picrotoxin or VEH + IS Yoked to Picrotoxin or VEH + ES Measure 5-HT response of DRN
1. Stressors activate dorsal raphe nucleus 5-HT ascending input to forebrain 2. Uncontrollable stress leads to chronically increased DRN 5-HT input to limbic and cortical areas 3. mPFC is a major processor of stressor controllability (achieved via behaviour-outcome processing) 4. mPFC is a major source of inhibitory input to DRN via its glutamatergic projections 5. Stressor controllability, as assessed at mPFC, is relayed to and inhibits DRN 5-HT system 6. 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”) 7. mPFC as a target of antidepressant action, to restore the circuitry and psychology of stressor controllability
Proposed mechanism of mPFC (glutamate) – DRN (serotonin) – Limbic circuit regulating Stressor un/controllability
1
2
2
3 4
5
6
7
7
Robbins (2005) Nature Neurosci 8:261
Aetiology – Pathophysiology – CNS Pathology - Psychopathology
(Epi-)Genome
Life history
Uncontrollable Stressor(s)
Neurocircuit Pathology
Psychopathology Valid Models
Aetiology
Aetio-Pathophysiology
“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
Serotonin transporter promoter (5-HTTP) gene-linked polymorphic region (5-HTTLPR): (s)hort and (l)ong genotypes, and their impact on 5-HTT (SERT) expression and function
Murphy & Lesch (2008) Nature Rev Neurosci 9: 85
5-HTTP
5-HTTLPR
5HTTLPR genotype associated with potential neural endophenotypes of affective disorder – healthy subjects
BOLD fMRI response to fearful face
Hariri et al. (2002) Science 297: 400 Canli et al (2006) PNAS 103: 16033
Absolute Cerebral Blood Flow at Rest
p<0.005
p<0.001
AMYG
5HTTLPR genotype associated with potential psychological endophenotypes of affective disorder – healthy subjects
Lesch et al. (1996) Science 274: 1527
Neuroticism Personality Trait Scores
p<0.05 VIGILANCE
AVOIDANCE
Fox et al. (2009) Proc Roy Soc B 276: 1747
Attention to emotional stimuli
Negative Positive
5-HTTLPR polymorphism interacts with stressful life events to increase prevalence of depression
Caspi et al. (2003) Science 301: 386
Kendler et al. (2005) Arch Gen Psych 62: 529
Stressful life events: • Employment • Finance • Health • Housing • Social relationships
Aetiology – Pathophysiology – CNS Pathology - Psychopathology
(Epi-)Genome
Life history
Uncontrollable Stressor(s)
Neurocircuit Pathology
Psychopathology Valid Models
Aetiology
Aetio-Pathophysiology
“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
Stress-induced activation of the inflammatory response and CNS effects
Miller et al. (2009) Biol Psychiatry 65: 732
Net response to [emotional - neutral] faces increased in subgenual ACC
Depression-like mood predicted by sg ACC net response [emotional - neutral] faces
Vaccine group specifically:
Salmonella typhi-induced inflammation increases ACC reactivity and lowers mood
Harrison et al. (2009) Biol Psychiatry 66: 407, 415
Studying effects of chronic psychosocial stress on depression-relevant states in young-adult mice
Stress Systems: Neuroendocrine
Autonomic Neuro-immune
Neurocircuit Pathology
Depr
essi
on
Emotion e.g. Fear
Cognition e.g. Control
Motivation e.g. Escape, Reward
Behaviour
Aetio-Pathophysiology
Chronic social defeat (CSD)
Days 1-15
10 min/day
Threat: Visual Olfactory Auditory Threat+Attack: Physical No wounds
Stressors
Effects of chronic social defeat on emotional-cognitive behaviour
Day 16 CS Fear Conditioning
0
20
40
60
80
CS-F
reez
ing
[% T
ime]
p < 0.001
10 x 12-s CS + 0.15 mA x 3-s IES 50-s ITIs
Day 18 Active Escape/Avoid (Control)
30 x 10-s CS + 0.15 mA x 5-s ES 50-s ITIs
CON N=13 CSD N=14
CON N=13 CSD N=14
p < 0.02
0.0
2.5
5.0
7.5
10.0
12.5
15.0
Esca
pe-A
void
Lat
ency
(sec
)
Esca
pe F
ailu
res
0
10
20
30 p < 0.005
Mouse chronic social defeat leads to depression-relevant inflammatory responses
Chronic social defeat (CSD)
Days 1-15
10 min/day
Immune system biomarkers
0
1
2
3
[Pla
sma]
pg/
mL
p < 0.015
0
25
50
75
100
125
150
Wei
ght (
mg)
Day 20: Spleen
p < 0.001
Day 20: Tumor necrosis factor (TNF)
Stressors
Threat: Visual Olfactory Auditory Threat+Attack: Physical No wounds
The stress - cytokine - kynurenine pathway: central to depression aetio-pathophysiology ?
IDO = Indoleamine 2,3 dioxygenase Control Depressed
Dantzer et al (2008) Nature Neurosci Kim et al. (2012) J Clin Invest
Stressors
18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0
Chronic Social Defeat or Control Behaviour Test
IDO Inhib. or VEH
IDO inhibitor reverses effects of chronic social defeat on consolidation of fear learning
CON+VEH (N=8) CON+IDO Inhibitor (N=8) CSD+VEH (N=7) CSD+IDO Inhibitor (N=8)
Fear Conditioning
% T
ime
Free
zing
**
0
20
40
60
80
Mean +/- SD
Day 16: Fear Conditioning
Day 17: Fear expression test
Fear Expression
% T
ime
Free
zing
0
20
40
60
80 ** **
24 hr
SSRI Efficacy: meta-analysis
Kirsch et al. (2008) PLoS Medicine 5(2): e45
Current-generation antidepressant pharmacology: selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine
Valid mouse models of depression psychopathology: the essential starting point for therapeutic-target discovery and validation
(Epi-)Genome
Life history
Uncontrollable Stressor(s)
Neurocircuit Pathology
Psychopathology Valid Models
Aetiology
Aetio-Pathophysiology (Cytokines, Glia)