Neurobiology of emotion and emotional disorders

Christopher Pryce
Preclinical Lab for Translational Research into Affective Disorders Clinic for Affective Disorders & General Psychiatry ([email protected])

Emotions: caused by rewarding and punishing stimuli and their association with behaviour
Present Reward (UCS, CS)

Omit or Stop Reward (UCS, CS)

Omit or Stop Punisher (UCS, CS)

Present Punisher (UCS, CS)

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

Psychiatric diagnosis of depression

Symptom type Typical/Core Typical/Core Typical/Core

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

Common Common Common Common Common Common Common

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 depressive episode

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: dont care anymore, not interested 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

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

Laboratory tasks to measure dysfunctional emotional processes in depression

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

Gollan et al (2008) Psychiatry Research 159: 18

Joorman & Gotlib (2006) J Abnorm Psychol 115: 705

The neurobiology of fear: Amygdala as integrator of emotional stimuli and effector of emotional response

LeDoux (1994) Sci Amer 6: 50

Neural pathways underlying fear: studied using fear model of conditioned freezing

Phelps & LeDoux (2005) Neuron 48: 175

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

Increased BOLD fMRI amygdala reactivity to negative stimuli in depression

Response duration Response size

Siegle et al (2002) Biol Psychiatry 51: 693

Victor et al (2010) Arch Gen Psychiatry 67: 1128

BOLD fMRI-based model of processing of negative stimuli in depression

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

Elliott et al (2002) Arch Gen Psychiatry 59: 597

Increased neural response to painful stimuli in amygdala and dACC in depression

Painful Heat stimulus Stimulus Anticipation

5 sec 4-8 sec Nonpainful warm stimulus Stimulus Anticipation

dACC

4-8 sec

5 sec

Anticipation period [painful heat - nonpainful warmth]

dACC

BOLD

sgACC

Strigo et al. (2008) Arch Gen Psych 65: 1275

Increased neural response to uncontrollability of painful stimuli in dACC in healthy humans

dACC

dACC

sgACC

Diener et al. (2010) NeuroImage 50: 717

From Uncontrollability to Helplessness to Depression

Uncontrollable Stressful life events: Employment Finance Health Housing Family Social relationships

Aversive events Emotionality Motivation Cognition

No Control/Contingency

Aversive event

Response

No Reinforcement

Pryce et al. (2011) Pharm Therapeut 132: 242

MDD symptoms

Generalized Helplessness

Aetiological phase Learned helplessness

Maintenance phase

The learned helplessness effect in rats

Day 1 Electro-shock pre-exposure Day 2 Escapable shock in 2-way Shuttle box

Jackson et al. (1978) Learn Motivation 9: 69

The prefrontal cortex and stress uncontrollability in rat: I. Inhibiting control

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 Day 1 Muscimol or VEH + IES Yoked to Muscimol or VEH + ES
Muscimol = GABAAR agonist

Day 2 Escapable shock in 2-way Shuttle box

IES+VEH IES+Muscimol ES+Muscimol ES+VEH

Amat et al. (2005) Nature Neurosci 8:365

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

Amat et al. Neuroscience (2008) 154:1178

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

Robbins (2005) Nature Neurosci 8:261

Aetiology Pathophysiology CNS Pathology - Psychopathology

Uncontrollable Stressor(s) Aetio-Pathophysiology Neurocircuit Pathology Psychopathology Valid Models

Aetiology (Epi-)Genome Life history

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

5-HTTLPR

5-HTTP

Murphy & Lesch (2008) Nature Rev Neurosci 9: 85

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

Hariri et al. (2002) Science 297: 400

Canli et al (2006) PNAS 103: 16033

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

Lesch et al. (1996) Science 274: 1527

Fox et al. (2009) Proc Roy Soc B 276: 1747

5-HTTLPR polymorphism interacts with stressful life events to increase prevalence of depression

Stressful life events: Employment Finance Health Housing Social relationships

Caspi et al. (2003) Science 301: 386

Kendler et al. (2005) Arch Gen Psych 62: 529

Aetiology Pathophysiology CNS Pathology - Psychopathology

Uncontrollable Stressor(s) Aetio-Pathophysiology Neurocircuit Pathology Psychopathology Valid Models

Aetiology (Epi-)Genome Life history

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

Salmonella typhi-induced inflammation increases ACC reactivity and lowers mood

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

Harrison et al. (2009) Biol Psychiatry 66: 407, 415

Studying effects of chronic psychosocial stress on depression-relevant states in young-adult mice

Stressors

Chronic social defeat (CSD) Days 1-15

Stress Systems: Neuroendocrine Autonomic Neuro-immune

Behaviour Cognition e.g. Control

Threat: Visual Olfactory Auditory

Aetio-Pathophysiology

Threat+Attack: Physical No wounds

Neurocircuit Pathology

Emotion e.g. Fear

Motivation e.g. Escape, Reward

Depression

10 min/day

Effects of chronic social defeat on emotional-cognitive behaviour

Day 16 CS Fear Conditioning
CON N=13 CSD N=14 10 x 12-s CS + 0.15 mA x 3-s IES 50-s ITIs CON N=13 CSD N=14 30 x 10-s CS + 0.15 mA x 5-s ES 50-s ITIs

Day 18 Active Escape/Avoid (Control)

CS-Freezing [% Time]

80 60 40 20 0

Escape-Avoid Latency (sec)

p < 0.001
Escape Failures

30 20 10 0

p < 0.005

p < 0.02 15.0 12.5 10.0 7.5 5.0 2.5 0.0

Mouse chronic social defeat leads to depression-relevant inflammatory responses

Immune system biomarkers Stressors Day 20: Spleen 150 Weight (mg) 125 100 75 50 25 0 Chronic social defeat (CSD) Days 1-15

p < 0.001

Threat: Visual Olfactory Auditory

10 min/day

[Plasma] pg/mL

Threat+Attack: Physical No wounds

Day 20: Tumor necrosis factor (TNF) 3 2 1 0

p < 0.015

The stress - cytokine - kynurenine pathway: central to depression aetio-pathophysiology ?

IDO = Indoleamine 2,3 dioxygenase

IDO Inhib. or VEH

Control Depressed

3 4

9 10 11 12 13 14 15 16 17 18 Behaviour Test

Chronic Social Defeat or Control Stressors

Dantzer et al (2008) Nature Neurosci Kim et al. (2012) J Clin Invest

IDO inhibitor reverses effects of chronic social defeat on consolidation of fear learning
Fear Conditioning **

Day 16: Fear Conditioning

% Time Freezing

80 60 40 20 0

24 hr Day 17: Fear expression test Fear Expression ** **

80

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

Current-generation antidepressant pharmacology: selective serotonin reuptake inhibitors (SSRIs)

SSRI Efficacy: meta-analysis

Fluoxetine

Kirsch et al. (2008) PLoS Medicine 5(2): e45

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

Aetiology (Epi-)Genome Life history