Neurobiology of emotion and emotional disorders

Christopher Pryce Preclinical Lab for Translational Research into Affective Disorders

Clinic for Affective Disorders & General Psychiatry

(christopher.pryce@bli.uzh.ch)

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)