Inverted HPA axis/stress

Question 1

Set out the concepts for hypothalamic control of the pituitary gland, detailing criteria for hypothalamic releasing factors, spatial localization of function in the hypothalamus, and identifying the pituitary stalk as the final common motor pathway to the pituitary.

Answer 1

Geoffrey Harris (1955)

Concepts of hypothalamic control

Question 2

Discovered corticotropin-releasing hormone (CRH) in sheep, identifying it as the key hypothalamic factor stimulating ACTH release from the anterior pituitary.

Answer 2

Vale et al. (1981)

Hypothalamic hormone discovery

Question 3

Awarded the Nobel Prize for their discoveries related to adrenal cortex hormones: identifying the relationship between pregnancy and RA symptom alleviation (Hench), isolating cortisol (Kendall), and devising synthesis methods for adrenal hormones (Reichstein), and collaboratively demonstrating cortisone’s therapeutic efficacy in rheumatoid arthritis.

Answer 3

Hench, Kendall & Reichstein (1950)

Glucocorticoid therapeutics

Question 4

Generated homozygous 11βHSD2 knockout mice via targeted homologous recombination, finding neonatal motor weakness and death in 50%, hypokalaemia, polyuria, hypertension, and renal hypertrophy, illustrating 11βHSD2’s role in cortisol regulation.

Answer 4

Kotelevtsev et al. (1999)

Glucocorticoid metabolism

Question 5

Compared dermal vasoconstriction in hypertensive and normotensive patients following topical cortisol application, showing increased tissue sensitivity to glucocorticoids in hypertensive individuals.

Answer 5

Walker (1996)

Glucocorticoid sensitivity

Question 6

Used a perifusion system to expose cultured pituitary cells to constant CRH and precisely timed corticosterone pulses, demonstrating rapid, non-genomic inhibition of CRH-stimulated ACTH secretion that was not blocked by actinomycin D.

Answer 6

Deng et al. (2015)

Biphasic ACTH inhibition

Question 7

Identified the biphasic response of corticosterone on ACTH mediated by type II glucocorticoid receptors but erroneously concluded rapid inhibition required genomic activation, a limitation attributed to their broader time definition of ‘rapid.’

Answer 7

Dayanithi & Antoni (1989)

Biphasic CRH inhibition

Question 8

Compared Lewis and Fischer rats’ corticosterone rhythms, finding Lewis rats showed circadian variation with stress responses tied to pulse phase, whereas Fischer rats lacked post-pulse inhibition, highlighting ultradian rhythm’s role in stress reactivity.

Answer 8

Windle et al. (1998)

Pulse dependent stress responses

Question 9

Used adrenalectomised rats with automated corticosterone infusion, showing that constant levels blunted ACTH responses to noise stress, emphasizing the importance of pulsatile glucocorticoid rhythms.

Answer 9

Sarabdjitsingh et al. (2010)

Pulsatility for regulation

Question 10

Conducted a randomized, double-blind placebo-controlled pilot study administering high-dose IV hydrocortisone within 6 hours of trauma in 25 patients. Patients given hydrocortisone had reduced incidence of PTSD 3 months later.

A parallel study was conducted adminstering hydrocortiosne to rats exposed to predator scent stress. Found increased dendritic growth and spine density and increased BDNF levels in treated subjects.

Answer 10

Zohar et al. (2011)

Glucocorticoids in the trauma response

Question 11

Proposed the concept of allostatic load, demonstrating that repeated or intense stress leads to system overstimulation and failure to adapt, contributing to disease states.

Answer 11

McEwan (1998)

Pathway from stress to disease

Question 12

Hypothesised that adverse in utero environments (or during infancy) lead to permanent changes in metabolism, supported by Margaret Burnside’s (form 1911 onwards) detailed birth records showing negative correlations between birth weight and systolic blood pressure at 60-70 years.

Answer 12

Barker Hypothesis (1989)

In utero environment effects

Question 13

Linked prenatal undernutrition during 1944–45 to increased chronic disease risk in later life through metabolic programming.

Answer 13

Roseboom et al. (2011)

In utero environment effects

Question 14

Examined the behaviour of Long-Evans hooded ratmothers and their litters over the first 10 days of life.
Mothers of handled pups showed increased levels of licking and grooming of pups and arched abck nursing (LG-ABN) compared to mothers of nonhandled pups.
As adults, the offspring of high-LG-ABN mothers had significantly reduced plasma ACTH and corticosterone resposnes to restraint stress. There were no differences in basal hormone levels. CRH mRNA expression in the PVNh was significantly decreased in the offspring of high-LG-ABn mothers and significatnly negatively correlated with the frequency of maternal lickign and grooming in the first 10 days of life.

Answer 14

Liu et al. (1997)

Maternal care effects

Question 15

Found hypermethylation of the NR3C1 promoter in hippocampal tissue of suicide victims with childhood abuse, correlating with decreased glucocorticoid receptor mRNA and implicating epigenetic regulation by early maternal care.

Answer 15

McGowan et al. (2009)

Epigenetic effects