Stress Response and Depression Notes

Stress Response

• Stress response is a combination of bodily reactions to situations threatening survival or fitness.
• Triggers include being attacked, anger, fear, hunger, and extreme temperatures.
• Hans Selye discovered this default response in the mid-20th century while studying hormones in rats.
• Rats in his studies developed stomach ulcers, enlarged adrenal glands, and reduced immune system glands, regardless of the injected substance.
• Selye realized the stress of handling and injecting the rats was causing these symptoms.

Aspects of Stress

• Stress affects the entire body.
• The sympathetic nervous system is heavily involved in the stress response, while the parasympathetic nervous system is suppressed.
• Increased sympathetic activity and decreased parasympathetic activity lead to:
  • Dry mouth (less saliva production).
  • Increased heart rate and blood pressure (blood vessel constriction).
  • Cold, clammy hands (reduced blood flow).

Sympathetic vs. Parasympathetic

• The sympathetic nervous system uses noradrenaline as its primary neurotransmitter for post-ganglionic neurons.
• The parasympathetic nervous system uses acetylcholine.
• Both systems use acetylcholine for pre-ganglionic neurons.
• The adrenal gland releases two types of hormones: adrenaline and cortisol.

Adrenal Glands

• The adrenal gland sits atop the kidneys and consists of two parts: the adrenal medulla (inner part) and the adrenal cortex (outer layer).
• The adrenal medulla releases
  • adrenaline (epinephrine) and
  • noradrenaline (norepinephrine) in response to neural signals.
• The adrenal cortex releases cortisol (a glucocorticoid) in response to hormonal signals.

Adrenaline

• Adrenaline and
  • noradrenaline are very similar chemically, differing by only one enzymatic step.
• The adrenal medulla is a modified version of post-ganglionic neurons from the sympathetic nervous system.
• It is stimulated by pre-ganglionic neurons releasing acetylcholine.
• This stimulation causes the release of adrenaline and noradrenaline into the bloodstream.

Cortisol

• Cortisol is the primary glucocorticoid in humans, while corticosterone is common in rodents and birds; all have similar functions.
• Glucocorticoids stimulate the release of glucose, providing energy during stressful conditions.
• Cortisol is released by the adrenal cortex in response to adrenocorticotropic hormone (ACTH).
• ACTH comes from the anterior pituitary gland, which is part of the hypothalamic-pituitary-adrenal (HPA) axis.
• The release of ACTH is triggered by corticotropin-releasing factor (CRF) or corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus.
• Summary of Hormone Release:
  • Adrenaline is released quickly due to neural signals.
  • Cortisol is released more slowly as a result of the HPA axis activation.

Response Times

• Adrenaline is released almost instantaneously due to rapid neural signals.
• Cortisol release takes longer because it involves hormone release and circulation through the bloodstream.
• Adrenaline effects are quicker but shorter, while cortisol effects are slower but longer lasting.
• Both hormones facilitate the release of energy.
• Adrenaline and noradrenaline have slightly different effects, but both increase heart rate and blood pressure.

Brain Areas

• The amygdala and anterior cingulate cortex are involved in activating the stress response.
• The amygdala has two key subdivisions:
  • The central nucleus responds to homeostatic challenges (e.g., blood loss).
  • The medial nucleus responds to psychogenic challenges (e.g., social stress, threats).
• Both subdivisions activate the sympathetic nervous system and the HPA axis.
• The anterior cingulate cortex, specifically the subgenual part, also activates the stress response.

Deactivation of Stress Response

• Important for preventing chronic stress and pathological problems.
• The HPA axis is the primary focus for stress response deactivation.
• When stress ends, cortisol levels decrease due to hormone clearance and cessation of production.
• Cortisol has a negative feedback effect, inhibiting the release of ACTH and CRH.

Regulatory Mechanisms

• Immediate negative feedback within the HPA axis where high cortisol levels inhibit CRH production to maintain normal physiological cortisol levels.
• The hippocampus, particularly the anterior hippocampus, is involved in HPA axis regulation through dense cortisol receptors (glucocorticoid receptors, GR).
  • Mineralocorticoid receptors (MR) are more sensitive and regulate everyday cortisol levels.
• Glucocorticoid receptors (GR) become more important when cortisol concentrations are high.
• The dorsal anterior cingulate cortex also helps shut down the stress response,
  • reducing both the strength and duration of cortisol release via multiple synapses.

Memory Formation

• The anterior hippocampus regulates stress, while the posterior hippocampus is involved in memory formation.
• These regions have different functions due to different connectivity.

Major Depressive Disorder (MDD)

• Also known as unipolar depression.
• Twice as common in women as in men.
• Symptoms include depressed mood, sleep problems (too much or too little), fatigue, appetite changes, lethargy, and feelings of worthlessness.
• Symptoms must be persistent, debilitating, and not due to obvious external factors.
• People with affective disorders often have a dysregulated HPA axis, commonly with constantly high cortisol levels.
  • Normal circadian rhythm of cortisol is disrupted.
• Some patients exhibit lower cortisol levels.

HPA Axis

• Conditions with HPA axis problems (e.g., Cushing's disease, Addison's disease) are linked to a higher likelihood of major depressive disorder.
• Chronic stress is a major risk factor for developing major depressive disorder.

Feedback Loop

• The amygdala stimulates the HPA axis, leading to cortisol release.
• Cortisol activates the locus coeruleus, which releases noradrenaline onto the amygdala, creating a positive feedback loop.
• In chronic stress, this self-reinforcing system spirals out of control.
• The locus coeruleus controls alertness.

Response Sensitivity

• Chronic stress reduces the negative feedback mechanisms that control the stress response.
• Repeated stimulation of glucocorticoid receptors makes them less sensitive in the dorsal anterior cingulate, PVN, and hippocampus.
• Chronically high cortisol can damage or kill hippocampal neurons, reducing negative feedback.
• This leads to a stress response that is easier to activate and lasts longer, potentially leading to depression in some individuals.