The Neurobiology of Psychiatric Disorders

Transcription

1 The Neurobiology of Psychiatric Disorders Vikaas S. Sohal, MD PhD Department of Psychiatry Center for Integrative Neuroscience Sloan Swartz Center for Theoretical Neurobiology

2 Overview 1. Classification of psychiatric disorders 2. Animal models and some neurobiological theories of psychiatric disorders 3. What can psychiatry teach neuroscience?

3 Classification of psychiatric disorders What is a psychiatric disorder? Condition that is associated with a significant impairment in functioning Cluster of specific symptoms which together define a syndrome Most psychiatric disorders that are the focus of biological study are lifelong

4 Classification of psychiatric disorders 1. Disorders that appear during childhood 1. Autism spectrum disorders (0.5%) 2. ADHD (5%) 2. Mood disorders 1. Major Depressive Disorder (10-20%) 2. Bipolar disorder (1-2%) 3. Anxiety disorders 1. Generalized anxiety disorder (5%) 2. Obsessive-compulsive disorder (0.5%) 3. PTSD 4. Panic disorder 5. Social Anxiety Disorder 6. Specific phobia 4. Psychotic disorders 1. Schizophrenia (1%) 5. Personality disorders 1. Schizophrenia-spectrum 2. Borderline personality disorder 3. Antisocial personality disorder 6. Substance Use Disorders

5 Classification of psychiatric disorders Autism ADHD OCD SZ Bipolar GAD Depression PTSD Borderline

6 Depression ADHD GAD Schizophrenia Borderline PTSD Autism Bipolar d/o

7 Measures of depression-like behaviors 1. Forced swim test 2. Tail suspension test 3. Sucrose preference test

8 Animal models of depression-like states 1. Learned helplessness 2. Chronic mild stress 3. Social defeat

9 Neural correlates of depression-like states Chronic mild stress (Depression-like state) propagation of hippocampal activity R D Airan et al. Science 2007;317: Immobility (Depressive-like behavior)

10 Measures of depression-like behaviors Does depression suppress neurogenesis? Does ablation of neurogenesis cause depression? Do antidepressants increase neurogenesis? If so, is increased neurogenesis necessary for their effects? A depressive-like state (CMS) doesn t suppress neurogenesis Ablating neurogenesis does not cause a depressive-like state Ablating neurogensis does eliminate antidepressant-like effects of FLX Ablating neurogensis does eliminate the effects of FLX on hippocampal activity R D Airan et al. Science 2007;317:

11 A model for the effects of antidepressants Chronic mild stress (Depression-like state) Antidepressants propagation of hippocampal activity Neurogenesis propagation of hippocampal activity Immobility (depressive-like behavior)

12 GABA A d receptor KO mice model postpartum depression Maguire and Mody, Neuron, 2008

13 GABA A d receptor KO mice model postpartum depression Maguire and Mody, Neuron, 2008

14 An animal model of postpartum depression Virgin Pregnant Postpartum Neurosteroids GABA A d Tonic inhibition WT KO WT KO WT KO Maguire and Mody, Neuron, 2008

15 Chronic social defeat a mouse model of depression Berton et al., Science, 2006 Krishnan et al., Cell, 2007

16 Chronic social defeat a mouse model of depression

17 Mechanisms of avoidant and depression-like behaviors in chronic social defeat BDNF released from the VTA NAc is necessary for depression-like behavior BDNF synthesis in NAc has no effect BDNF synthesis in VTA social avoidance, wt loss, sucrose preference The resistant phenotype is associated with K + channels in NAc Virally-driven expression of K + channels in NAc resistant phenotype Expression of dominant negative K+ channels resistant phenotype

18 Summary: 3 mouse models of depression 1. Chronic Mild Stress 1. Depression-like behavior is associated with propagation of hippocampal activity in vitro 2. hippocampal neurogenesis is neither necessary nor sufficient for the depression-like behavior 3. However, hippocampal neurogenesis is necessary for the ability of antidepressant drugs to rescue depression-like behavior 2. GABA A R d subunit knockout 1. Causes a postpartum depression-like phenotype 2. Associated with changes in hippocampal GABA currents 3. Rescued by pharmacologic enhancement of GABA A R d subunit function 3. Social Defeat 1. Causes a depression-like phenotype 2. Requires BDNF release from VTA projections NAc 3. Increases in K + channels on NAc neurons mediate resiliance

19 Measures of anxiety-like behaviors Measures of innate anxiety 1. Plus maze 2. Open field locomotion Measures of learned anxiety 1. Fear conditioning

20 Measures of psychosis-like behaviors Measures of altered sensory processing: 1. Paired-pulse inhibition Measures of positive symptom-like behaviors: 1. Stereotyped movements 2. Amphetamine-induced hyperlocomotion Measures of cognitive deficits: 1. Working memory 2. Social behavior 3. Latent inhibition

21 Animal models of schizophrenia 1. Pharamacologic 1. PCP (acute, chronic) 2. ketamine 2. Genetic 1. DISC1 2. Velocardiofacial syndrome 3. Immune challenge

22 The (evolution of the) dopaminergic hypothesis of schizophrenia Drugs that directly (L-dopa, dopamine, dopamine agonists), or indirectly (amphetamine, cocaine, other stimulants) activate dopamine receptors can induce or exacerbate psychosis dopamine in the brain schizophrenia All existing antipsychotics block D2 dopamine receptors D2R schizophrenia In the striatum: DA release, D2R density, D2R occupancy Striatal D2R hyperactivity schizophrenia TH positive axons in deep layers of PFC (Akil et al., Am J Psych, 1999) dopamine in the PFC Cognitive dysfunction SZ is associated with COMT variants that result in DA metabolism in the PFC and impaired cognition (Egan et al., PNAS, 2001) dopamine in the PFC Cognitive dysfunction An imbalance of D1R, D2R activation in the PFC Cognitive dysfunction?

23 The glutamatergic hypothesis of schizophrenia Phencyclidine and related drugs (ketamine) block NMDA receptors NMDAR activity schizophrenia NMDAR blockade causes a paradoxical increase in glutamate release Blocking this increased glutamate release rescues psychotomimetic effects in animal models (Moghaddam and Adams, 1998) Excessive glutamate release in the PFC cognitive dysfunction Moghaddam and Adams, Science, 1998

24 The GABAergic hypothesis of schizophrenia CONTROL SCHIZOPHRENIA Akil et al., Am J Psych, 1999 Parvalbumin Fast-spiking 250 Hz (0.5 na, 0.25 s) FS GAD67 1 PV 2 PY GAT-1 3 GABA A a Lewis et al., Nat Rev Neurosci, Hashimoto et al., J Neurosci, Woo et al., PNAS, 1998; Volk et al., Am J Psych, Volk et al., Cereb Cortex, 2002 Parvalbumin / FS Interneuron dysfunction Schizophrenia

25 What can psychiatry teach neuroscience? 1. There are common failure modes for brain function 2. Relatively simple pharmacologic manipulations can push complicated brain circuits towards / away from these modes. Paradoxically, single gene mutations rarely push brain circuits into one of these modes 3. Seemingly higher level cognitive phenomena (mood) can be strongly associated with seemingly lower level neurovegetative functions (sleep, appetite) suggesting they are generated by highly overlapping circuits 4. Psychiatry has been trying to explain behavior for a long time so the dominant hypotheses of modern behavioral neuroscience are likely to seem hopelessly antiquated in a few decades