HPA Axis Flashcards
Stress
Real or perceived threat to homeostasis or well-being
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)
Allostatic Load
- Cost of adaptation
- Cumulative wear and tear on the body from chronic stress
- Allostatic overload (burnout) increases risk for disease
True or False: following a deviation in homeostasis, biological stress systems stimulate adaptive responses to promote survival and well-being.
True
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
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.
What is the primary hormone released by the adrenal medulla?
Epinephrine
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)
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
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
Which feature best differentiates the HPA axis from the SAM axis?
Release of ACTH from the pituitary
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
True or False: CRH neurons receive direct synaptic inputs from brain regions that mediate memory and cognition.
False: not direct input
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
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
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
