- Maintaining stability through change - Continuous process of energy balance by the brain to anticipate and regulate adaptive responses to environmental stressors - Dynamic or variable homeostasis (as opposed to steady state)

- Cost of adaptation - Cumulative wear and tear on the body from chronic stress - Allostatic overload (burnout) increases risk for disease

- Primary CRH receptor expressed by corticotropes - Stimulate HPA axis - Knockout reduced HPA axis function - G-protein coupled signaling through GalphaS (stimulatory) - Protein-kinase A activation = increased intracellular calcium and phosphorylation

HPA Axis Flashcards by Kiley McCarthy

Stress

Real or perceived threat to homeostasis or well-being

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Allostasis

Maintaining stability through change
Continuous process of energy balance by the brain to anticipate and regulate adaptive responses to environmental stressors
Dynamic or variable homeostasis (as opposed to steady state)

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Allostatic Load

Cost of adaptation
Cumulative wear and tear on the body from chronic stress
Allostatic overload (burnout) increases risk for disease

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True or False: following a deviation in homeostasis, biological stress systems stimulate adaptive responses to promote survival and well-being.

True

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Sympatho-Adrenal- Medullary

Preganglionic neurons target the adrenal medulla
Release of acetylcholine activates nicotinic receptors
80% epinephrine and 20% norepinephrine
Adrenaline rush
Spinal cord -> ventral root -> thoracic splanchnic nerves -> adrenal medulla

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Adrenergic Sympathetic Effects

Epinephrine and norepinephrine signaling through alpha and beta receptors on target organs
Mobilize resources to respond to threats
Inhibit processes not related to short-term survival
Norepinephrine and epinephrine: smooth muscle contraction, inhibition of transmitter release, etc.

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What is the primary hormone released by the adrenal medulla?

Epinephrine

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What is the response of the hypothalamus to a deviation in the internal state (disruption in homeostasis)?

Autonomic nervous system
Neuroendocrine systems
Behavioral alterations
Regulator of preganglionic neurons (direct input)

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Explain the HPA axis.

Paraventricular Hypothalamus: corticotropin releasing hormone (CRH)
Portal circulation
Anterior pituitary: (corticotrophs) adrenocorticotropic hormone (ACTH)
Systemic circulation
Adrenal cortex: synthesis of corticosteroids -> cortisol (primary human glucocorticoid)
Systemic circulation

Central and peripheral actions
Feedback

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Corticosteroid Actions

Primarily cortisol in humans and large mammals
Also corticosterone and/or cortisone
Catabolic steroids (glucocorticoids)
Signal through type I and type II receptors
Utilization of glucose, protein, and fat
Suppress immune system and reproduction

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Which feature best differentiates the HPA axis from the SAM axis?

Release of ACTH from the pituitary

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How is the stress response triggered?

Neuronal processing of sensory, homeostatic, emotional, and cognitive information converges on CRH neurons
Inputs from brainstem and hypothalamic nuclei transmit homeostatic signals
Limbic regions (area of brain involved in emotion and recognition): prefrontal cortex (cognitive, emotional, ability to think), hippocampus (memory), amygdala (emotion, fear, threat recognition); innervate the hypothalamus and brainstem to convey psychosocial influences

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True or False: CRH neurons receive direct synaptic inputs from brain regions that mediate memory and cognition.

False: not direct input

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Corticotropin Releasing Hormone (CRH)

41 amino acid peptide synthesized by neurons of the PVN
Made by parvocellular (small) neurons that project to the hypophyseal portal veins
Transcribed as preproCRH from 2-exon gene
Evolutionarily conserved

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CRH-R1

Primary CRH receptor expressed by corticotropes
Stimulate HPA axis
Knockout reduced HPA axis function
G-protein coupled signaling through GalphaS (stimulatory)
Protein-kinase A activation = increased intracellular calcium and phosphorylation

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CRH-R2

Low affinity for CRH
Reduces stress responses

Adrenocorticotropic Hormone (ACTH)

Synthesized from precursor proopiomelanocortin (POMC)
Prohormone convertases (PC) cleave POMC to produce ACTH (pro-ACTH -> ACTH)
Stored in vesicles
Rise in intracellular calcium leads to exocytosis of ACTH

What is the receptor for ACTH?

Melanocortin-2 receptor (MC2R)
Located in all 3 layers of the adrenal cortex
GPCR: activates cAMP and PKA
In zona fasciculata, PKA signaling leads to the expression and activation of enzymes used for cortisol synthesis
All adrenal steroids derived from cortisol
Synthetic specificity arises from enzyme expression

True or False: Pituitary receptors for CRH (CRH-R1) and adrenal cortex receptors for ACTH (MC2R) both signal through GalphaS- coupled receptors to increase PKA activity.

True

Steroidogenesis

All steroids arise from cholesterol
Steroids are synthesized on demand, not stored for secretion
Lipophilic: readily diffuse through membranes
Cholesterol -> pregnenolone -> progesterone -> mitochondria (primary glucocorticoids)

Corticosteroid Receptors

Binary receptor system
Act as transcription factors
Type I: mineralocorticoid receptors (MR) -> high affinity (bind cortisol at lower concentrations)
Type II: glucocorticoid receptors (GR) -> lower affinity (activated by elevated cortisol (stress))

Glucocorticoid Response Elements (GRE)

regulate hundreds of genes
transrepression = negative feedback
transcriptional activation = positive feedback

Explain the structure of the glucocorticoid receptor.

LBD: ligand binding domain (hormone binding)
Hinge: allows conformational change
DBD: DNA binding domain (interacts with response element in genome)
N-terminus contains: nuclear localization sequence (covered at rest by chaperone protein -> hormone binds -> conformational change -> open) and dimerization domain (GRalpha or GRbeta)

Which domain of the glucocorticoid receptor directly mediates interactions with cortisol?

Ligand binding domain

Feedback regulation of the HPA axis.

- Feedback to the HPA axis is mediated by GR and MR - Negative feedback occurs at hypothalamic CRH neurons and pituitary corticotrophs - Cortical and hippocampal GR and MR also provide negative feedback

Which process is most likely to contribute to glucocorticoid receptor-dependent negative feedback?

Transcriptional repression of POMC in the pituitary

Acute actions of glucocorticoids.

Liver gluconeogenesis, amino acid mobilization from protein, lipolysis, immune suppression, elevated blood pressure, cognitive enhancing, memory enhancing

Chronic actions of glucocorticoids.

Insulin resistance, muscle weakness, abdominal obesity, reproductive deficits, hypertension, cognitive dysfunction, impaired negative feedback

Cushing Syndrome

- Hypercortisolism (excess glucocorticoids at all times) - Excess as a result of ACTH excess (pituitary tumor) or adrenal cortical neoplasm (ACTH independent) - Results in cognitive impairment, mood disorders, hypertension, cardiac hypertrophy, obesity, muscle weakness

Addison's Disease

- Hypocortisolism - Autoimmune loss of cells in the adrenal cortex - High ACTH due to loss of negative feedback - Adrenal crisis is a medical emergency, can be fatal if left untreated