(Ch. 15, 16) Neurobiology of Stress and Related Mental Disorders

Stress

The body’s multisystem response to any challenge that overwhelms, or is judged to overwhelm, selective homeostatic response mechanisms

• First popularized by Hans Selye as “the rate of all wear and tear caused by life”

• negative emotions were hypothesized to be one source of “wear and tear”

General Adaptation Syndrome (Hans Selye)

1. Alarm Reaction - initial response to stress

2. Adaptation Stage - includes activation of appropriate response systems and reestablishment of homeostatic balance

3. Exhaustion stage - occurs when stress is prolonged or severe; characterized by increased susceptibility to disease

2 parts of the stress response

1. The sympathetic nervous system

2. Hypothalamo-pituitary-adrenal (HPO) axis

The sympathetic nervous system

“fight or flight” response that prepares the body for brief emergency responses

Hypothalamo-pituitary-adrenal (HPA) axis

Produces endocrine changes to enable adaptation; complements sympathetic response

• activation predominates during prolonged stressors

• activation is initiated when afferent information enters into the brain, ultimately conveyed to the paraventricular nucleus of the hypothalamus

paraventricular nucleus of the hypothalamus (PVH)

Final common pathway in the brain for activation of HPA axis

CRF → anterior pituitary portal system → ACTH → bloodstream → Cortisol

Corticotropin Releasing Factor (CRF)

A peptide synthesized and secreted by neurons in the PVH

• released into the anterior pituitary portal system

Anterior Pituitary

• Contains a portal system, blood vessels that connect to the hypothalamus

• cells here synthesize and secrete adrenocorticotropic hormone (ACTH) into the blood stream

Adrenocorticotropic Hormone (ACTH)

Stimulates the release of cortisol from the cortex of the adrenal gland

Cortisol

A glucocorticoid hormone that broadly affects the body and brain

Physiological Stress pathway to PVH

Brain stem projects to PVH

• mostly from nucleus of solitary tract and ventrolateral medulla

• e.g. blood loss, low oxygen, infection

Psychological Stress Pathway to PVH

Pathways are more sensory; relayed to limbic regions such as hippocampus and prefrontal cortex, then onto the PVH

• Primary pathways: avBST, dorsomedial and posterior hypothalamus

• e.g. predator exposure, psychosocial (public speaking)

4 things cortisol does in response to threats

1. Increases blood sugar by activating glucose metabolism

2. Catabolizes/breaks down fat and proteins (also for energy use)

3. inhibits immune function, esp. inflammation

4. promotes cognitive adjustments via direct actions in the brain

Glucocorticoid-Mediated Negative Feedback

Once the stressor subsides, cortisol “feeds back” onto the brain to shut off HPA axis response

Glucocorticoid Receptors Process

1. CORT diffuses through plasma membrane into cell

2. Binds to glucocorticoid receptor (GR) CORT-GR forms a dimer

3. Activated GR dimer translocates to the nucleus

4. Binds to DNA “promoter” regions at two locations to alter gene expression

Two Factors for Stress Appraisal

predictability and controllability

Short Term Negative Effects of Chronic Stress (Adaptation)

• mobilization of energy reserves

• increased cardiovascular output

• suppression of digestion

• suppression of growth

• suppression of reproduction

• altered immune function

• heightened awareness, cognition

Long Term Negative Effects of Chronic Stress (Pathology)

• myopathy, fatigue, type 2 diabetes

• hypertension

• ulcers, irritable bowel disorder

• psychosocial dwarfism

• amennorrhea, impotency, loss of libido

• immunosuppression, risk of infection

• synaptic pruning

Psychosocial Dwarfism

Growth failure that results from psychosocial and social factors

• mediated through the CNS and its control over hormone systems

• when children are removed from such stress, may begin to grow rapidly

• prolonged cortisol secretion from HPA hyperactivity may inhibit growth hormone release

Effects of Early Life Stress

Based on experiments on rats

• rats being more stress reactive in adulthood

• early maternal experiences produce epigenetic changes

• early life trauma is also associated with a greater risk of MDD later in life → now thought to have an epigenetic basis

Prolonged elevations in cortisol in rats

• Cause atrophy in pyramidal neurons

• destroy excitatory synapses in the hippocampus and prefontal cortex

Cushing’s Disease

Endocrine syndrome where cortisol levels are chronically elevated

• patients show massive hippocampal shrinkage and cell loss

Post-Traumatic Stress Disorder (PTSD)

Occurs in some people after certain crises or terrifying experiences

• victims have smaller hippocampal and prefrontal cortical volumes

• larger amygdala

• shower greater sensitivity of autonomic/sympathetic output

• thought to be manifested by amygdala overactivity and prefrontal underactivity

PTSD (symptoms)

Symptoms

• frequent distressing recollections

• nightmares

• avoidance of reminders of the event

• exaggerated arousal in response to noises and other stimuli

Comorbidity

overlap between the occurrence of disorders

Psychosurgery

the use of surgical manipulation to treat severe mental illness

• risk and have not been reliable

• rare and only used on the most severe cases as a last resort

Lobotomy

Frontal lobe lesions

• supposed to induce relaxation and calmness in individuals with severe or intractable mental disorders

• side effects - mood swings, change in personality

• procedure was eradicated

Walter Freeman

American psychiatrist that performed and aggressively advocated for prefrontal lobotomy

Schizophrenia (SZ)

A disease marked by cognitive abnormalities

• it is not one disease, but many

Schizophrenia (Characteristics)

• loose associations, tangential thinking

• trouble with making abstractions

• delusions

• paranoia

• structured hallucinations

• social withdrawal

• absence of affect

Schizophrenia risk factors

• poor nutrition of mother during pregnancy

• premature birth

• low birth weight

• complications during delivery

• increased stress in mother early in pregnancy

• season of birth being winter

Neurodevelopmental Hypothesis (SZ)

Suggest that subtle abnormalities in prenatal and neonatal development of nervous system leads to major behavioral abnormalities later in life

• accounts for environmental affects,

• but environmental factors are not believed to be the ultimate cause of the disease

Heritability of SZ

There is a genetic bases, but complicated.

• highly heritable, but hard to link with mechanism - variations genes have been found

Brain abnormalities of SZ

• Decreased frontal cortex activity during memory tasks

• ventricular enlargement

• some studies show synapse loss in frontal cortex

SZ Causes

Tightly coupled to the final stages of prefrontal cortical development in late teens early 20s

• suggests that risk factors are not to manifest until later in life

Dopamine Hypothesis of SZ

Idea that too much DA somewhere in brain causes SZ

• DA by-products increased in periphery in SZ

• Drugs that block DA reduce positive symptoms, and vice versa

Neuroleptics (Antipsychotics)

Drugs that block DA receptors

• medication for SZ

Typical Antipsychotics

Medication for SZ that blocks D2 receptors

Atypical Antipsychotics

Medication for SZ that blocks D2 receptors, but have other effects less well understood.

Limitations of Antipsychotic Meds for SZ

• Slow-acting (2-3 weeks)

• Only relieves positive symptoms

• they have a variety of side-effects

Glutamate Hypothesis of SZ

Deficient activity at glutamate synapses in the frontal cortex accounts for SZ

• based on postmortem studies that show synapse loss in frontal cortex of SZ patients

• High levels of DA activity in frontal cortex can decrease Glu activity at synapses

Major Histocompatibility Complex (MHC)

Represents a family of genes involved in the immune response to infection

• C4, one of the gene products is upregulated in SZ patients

C4 Protein

Gene product of major histocompatibility complex, upregulated in SZ patients.

• plays an important role in cortical synapse elimination during development through interaction with microglia

• Synapse loss in SZ may result from higher levels of C4 expression due to allelic variation in this gene

Reactive Depression

Caused by an adverse life event

• contrasted from normal grieving

• usually resolves within 6 months with therapy/meds

Major Depressive Disorder (MDD)

Extreme feelings of sadness and helplessness everyday for weeks on end

• may be precipitated by trauma, but not necessarily

• lack of energy

• feelings of worthlessness

• suicidal thoughts

• feelings of hopelessness

• disrupted sleep patterns

• difficulty concentrating

• loss of pleasure

Concordance

Presence of same trait in both members of a family

MAOIs (Monoamine Oxidase Inhibitors)

Antidepressant drug;

MAO: presynaptic enzyme that degrades neurotransmitters into metabolites

MAOIs inhibit MAOs and prevents the breakdown of monoamine NTs

• ex. Iproniazid

Monoamine Hypothesis of Depression

Depression is caused by low 5-HT and NE neurotransmitter activity

Tricyclics

Antidepressant; block transporter proteins that reabsorb 5-HT, NE, and DA back into presynaptic terminal

• increases monoamine NT levels in synaptic cleft

Side effects

• drowsiness

• dry mouth, difficulty urinating, decreased sex drive

• heart irregularities

Atypical Antidepressants

A family of drugs with different pharmacology than tricyclics or SSRIs that also act as antidepressants

• ex. bupropion inhibits reuptake of DA and NE but not 5-HT

Electroconvulsive Therapy

Electrical current is passed through the brain induced in patients under anesthesia and it produces mild seizure-like activity

• now only used for treatment of MDD (esp. high suicidal risk)

• produces immediate antidepressant response in ~50% that lasts for at least several months

Side Effects

• impairing short-term memory

• mild increase in risk of heart attack

Deep Brain Stimulation (DBS)

Treatment of severe depression involving stimulating ventral portion of medial prefrontal cortex with a surgically implanted electrode

Downside

• requires implantation of an electrode in the brain

• carries lots of other health risks and complications

Transcranial Magnetic Stimulation (TMS)

MDD treatment involving applying a mild magnetic field over the surface of the scalp; induces an electrical current in a targeted brain region via electromagnetic induction

Downside

• can not be well-targeted to deeper-lying brain regions (the most important ones)

Causes of depression

Depression results from dysfunction of the brain serotonergic system (probably not right)

• genetic predisposition involving altered SERT activity

• synapse loss in prefrontal cortex, esp. caused by stress

• low levels of hippocampal neurogenesis

• low levels of brain neurotrophins

Overarching theme of Depression Causes

Depression is marked by changes in key stress-sensitive brain circuits (esp. hippocampus, prefrontal cortex, amygdala) that have a reduced capacity for plasticity and adaptation.

Unipolar Disorder

Cycling between feeling normal and depressed

Bipolar Disorder

Cycling between two extremes, generally mania and depression

• mania - restless activity

Bipolar I Disorder

Full blown episodes of mania w/ bouts of depression

Bipolar II Disorder

Milder episodes of mania, also w/ bouts of depression

Symptoms of Mania

• Sustained over-activity

• talkativeness

• grandiosity

• increased energy

Cycles vary in length and severity

Lithium

Most common treatment for bipolar disorder

• discovered by accident decades ago as a control treatment from a drug different trial

• mechanism is poorly understood, but has wide-ranging effects

• treats manic episodes, prevents manic relapses, treats depressive stages

• severe side effects

Side effects:

• increased urination & inability to control

• shakiness of hands

• increased thirst

• Diarrhea, vomiting, poor coord., sleepiness, tinnitus

Mood Stabilizers

More modern treatment of bipolar disorder, have less dangerous side-effects

• work by altering conduction of action potentials in the brain

• decrease the effects of AMPA-Rs in cortex and lower glutamate activity