Lecture 15: Neurobiology of Mental Illness

Mental illness

• Brain disorders caused by changes in the functions of neurons/neural circuits (and glial cells)

• Understanding the neurobiology of the disorder allows us to develop better biomarkers for intervention and therapeutic targets

How are mental illnesses diagnosed?

• Diagnostic and Statistical Manual of Mental Disorders 5th edition

• Diagnoses are based on symptoms and severity of impairment

Anxiety Disorders

• Inappropriate expressions of fear

  • panic disorder, agoraphobia, generalized anxiety disorder, specific phobias, social phobia

Other disorders characterized by anxiety

• PTSD and OCD

Biology of Anxiety Disorders

• Fear is normally evoked by threatening stimuli, stressors

• Anxiety = fear when stressor is not present or is not immediately threateneing

• HPA axis activation: vigilance, arousal, avoidance behavior, ect.

• CRH(/F): corticotropin releasing hormone/factor

CRH(/F)’s role in anxiety behaviors

• In mice, CRH overexpression increases anxiety-like behaviors

• CRH receptor knock-out mice exhibit less anxiety-like behavior

Regions important for anxiety disorders

• Both the amygdala and hippocampus (and other regions lie frontal cortex) regulate activity of the HPA axis

  • Amygdala is hyperactive which increases HPA

  • Breakdown in hippocampus negative feedback, diminishing inhibitory feedback

• Prefrontal and cingulate cortices send top-down projections to modulate activity in these regions

  • sends inhibitory projections down to the HPA axis, damage to these regions impact anxiety levels

Treatments for Anxiety Disorders

• Psychotherapy: exposure therapy, reprogramming learned associations

• Anxiolytic medications: benzodiazepines, selective serotonin reuptake inhibitors (SSRIs)

Benzodiazepines and Anxiety

• GABA_A receptors: GABA-gated Cl-channels

• GABA binding opens the channel and leads to IPSPs

• Benzodiazepines (Valium, Klonopin): bind to a different site on GABA_A receptor and make it easier, more sensitive for GABA binding to open the channel and promote inhibition

  • used for to treat ACUTE anxiety

Serotonin System

• diffuse neuromodulatory system

• 14 (at least) different gPCR receptors

• Regulates mood, emotion, sleep, and more

SSSRIs (selective Serotonin reuptake inhibitors)

• Block serotonin from being reuptaken (cleared) from synaptic cleft—MORE SEROTONIN in the synaptic cleft

• Not an acute drug—takes months

• Serotonin may increase glucocorticoid receptors in hippocampus, more inhibitory feedback for the HPA axis

Affective Disorders

• Major Depressive disorder: persistent sadness, loss of interest, low energy, lasting at least 2 weeks

• Bipolar disorder: periods of mania intermixed with periods of depression

Monoamine Hypothesis of Defective Disorders

• Monoamines like serotonin regulates mood:

  • Reserpine, monoamine oxidase inhibitors (MAOIs)

Reserpine

• depletes catecholamines + serotonin (blocks vesicular loading)

  • given for blood pressure but caused severe depression 20% of the time

Monoamine oxidase inhibitors

• inhibits degradation of catecholamines + serotonin

  • given to treat tuberculosis and elevated mood

Modern SSRIs

• Prozac, Zoloft, Paxil

  • increase serotonin bioavailability without impacting catecholamines

Monamine Hypothesis of Depression

• Depression results from a deficit in one of the diffuse neuromodulatory systems

  • too simplistic

Stress-Diathesis Hypothesis of Depression

• early life experience has a profound impact on the HPA axis and glucocorticoid receptor number in the brain

• Depression is associated with hyperactivity of the HPA axis:

  • elevated CRH in cerebrospinal fluid

  • elevated blood cortisol

  • Early life stress can be a risk factor for depression

Prefrontal Cortex and Depression

• patients with ventromedial PFC damage show very low levels of depression

• Damage to dorsolateral PFC make depressive symptoms worse

• Anterior Cingulate cortex = hyperactive in depression, involved in rumination/recursive thoughts

Neuroinflammation and Depression

• Depression and inflammation are linked

  • increased circulating levels of proinflammatory cytokines in patients with depression

• Anti-inflammatory drugs have been effective in early clinical trials are reducing depressive symptoms only in patients with elevated cytokines at baseline

Lithium and Bipolar Disorder

• lithium is very effective at treating bipolar disorder

• messes with several qPCR signaling cascades