HPA Axis Flashcards
What is stress
Actual or anticipated disruption to homeostasis or well being (perturbation to homeostasis)
Types of stress
Systemic/physical: (CV and metabolic) haemorrhage/visceral and somatic pain/ inflammation/malnutrition
Psychogenic/psychological: (social stress) isolation, hierarchy, unemployment
Stress activation in the brain stem
BS:
medullary and SC system - sympathetic NS
nucleus of solitary tract (NTS) - Limbic–>PVN
central pathways regulating the stress response
inputs from higher centres: memory (medial septum/entorhinal cortex/cingulate cortex) & sensory processing (olfactory nuclei/piriform and insurlar cortex)
to… limbic processing: prefrontal cortex/hippocampus/amygdala
how does stress affect the hippocampus
severe deficits in hippocampal dependent object recognition after multi-modal stress
structural neural remodelling (cortisol/glutamate/CRF/trophic factors)
connectomics
Maras PM et al., 2014
increase functional network connectivity between the hippocampus/amygdala/BNST and thalamus (gateway to the cortex) - cause restraint
experimental approaches
- species (rodents) since primates more expensive
- stress (majority acute psychogenic/restraint which is easy to observe/physical)
- pharmacological/surgical manipulation
- optogenetics - activate a specific neuronal population
- DREADDS
- fibre photometry
- gradient-index (GRIN) lens imaging of neural activity via miniture fluorescent microscope
what to measure when studying the HPA axis
- ACTH/glucocorticoid
- CRH/AVP in portal blood (hard to access in rodents then use sheep)
- cfos (gene activation) - marks neuronal population activation
- CRH/AVP/GR/MR glucocorticoid expression receptors
- GRIN lens calcium imaging (observe neuronal firing)
- in vivo studies
HPA axis steps
- stress
- hypothalamus/PVN
releases CRH/AVP - pituitary
releases ACTH - adrenal cortex
releases glucocorticoid
PVN
located at the 3rd ventricle
parvocellular -dorsomedial/autonomic
increased c-fos mRNA during PVN activation in stress (timing is important)
CRH neurons labelled with dTomato –> in stress, there is an increase in c-fos
hypoglycaemic stress increases CRH mRNA in parvocellular PVN /restraint stress activates parvocellular neurons
GCamP inserted into PVN CRH neurons (in-vivo calcium imaging)
Yuan et al., 2019
produces heatmap plot
sucrose = less stress response
shock increases the stress response
what is glucocorticoid feedback
limits prolonged exposure to catabolic and other actions of GC
GC can cause neuropsychiatric pathologies
glucocorticoid receptors
mineralocorticoid (MR) high affinity/basal activation
glucocorticoid (GR) low affinity/high levels needed for binding/activated during stress
MR/GR location
MR in limbic neurons (medial PFC)/amygdala/hippocampus
GR is ubiquitous (highly expressed in the PVN)
responses to GC
genomic (delay) response - MR/GR TF, alters gene expression >30mins
non genomic (fast) response - membrane localised, mediated by secondary effectors (modulate ion channels, R,NT) 1-2 mins
delayed feedback/rapid in the PVN
CRH/AVP have delayed response
rapid feedback: measure ACTH and cortisol - basal ACTH rise and decline as morning progresses (same in cortisol) = normal/provide prednisolone (GC) ACTH/cortisol decline = rapid pituitary response
rapid response
iPVN dexamethasone (Dex) decreases stress response (restraint)
stress increases endocannabinoids in PVN
endocannabinoids initiate retrograde inhibition of glutamate:
CORT - CRHn R - release endocannabinoids - feedback to glutamatergic presynaptic neuron- switches OFF (silent -lost drive)
CRH neurons in the PVN
CRF1 on GABA neurons - remove the CRF1 receptor - increase corticosterone
24hrs of ACTH and cortisol
portable microdialysis pump attached to microdialysis catheter
pulsatile GC release (critical for normal functioning)
occurs in circadian rhythm and disease states
what is the effect of proteasomes
removes GR only = pulsatile GR translocation
gene pulsing occurs
functions of glucocorticoids
metabolism
regulates innate and acquired immunity
cell growth/differentiation
CV function
provide energy
bone turnover
role of pulsatile cortisol
improves cognition and sleep
Hypercortisolism (consequences of oversecretion of GCs)
cushing syndrome
hypertension
steroid diabetes
muscle wasting
immunosuppression
peripheral pulse oscillator
continuous CRF signal induces pulses
continuous CRH stimulates ACTH and CORT therefore pulsatile CRH not needed, lag between ACTH/CORT
pulsatile is the most efficient method of neuropeptide release
cluster action potentials = more release
pulses of ACTH and CORT
feedforward = ACTH stimulates CORT synthesis from the adrenal cortex
feedback = CORT fast inhibit of ACTH release
both are the role of a peripheral oscillator
CRH (executive organiser)
41aa - humans and rats have identical peptides, differ by 7 aa
CRH and CRH-R associated with stress response (hippocampus and amygdala)
family of ligands which bind to CRH-R: Urocortin 1 (Ucn1)/UcnII/UcnIII
CRH system
in the cortex/cerebellum: amygdala/BSTN/hippocampus (activate fight or flight)
CRH receptors:
CRH-R1 (pituitary-ACTH)
CRH-R2:
R2a - septum/hypothalamus/raphe/NTS
R2B - glia/endothelial/amygdala
R2y - (not in rodents) - septum/amygdala/hippocampus/frontal cortex
CRH receptor binding
preference for CRH-R1 (less to R2)
UcnI - R1/R2
UcnII/III - R2 selective
R1 = anxiogenic
R2 = anxiogenic and anxiolytic
CRH-BP = influences amount of peptide available
CRH antagonists
a-helical CRH1-41
CRH-R1 antagonist is antalarmin
genetic manipulation of CRH system
conditional KO of CRH R/overexpress CRH
stress increases ACTH
CRH-R1 KO in stress: no effect
conditional limbic CRH-R1 KO/CRH-R2 KO
at d20 - reduce ACTH feedback, CaMKII expressed (allows development of neuronal circuitries)
R2 KO - increases anxious behaviour (compared to R1 KO)
R2 ligand = stresscopin (enhances the behavioral response)
Limbic CRH-R1 required for central control of HPA system feedback (functions independenly of HPA axis so does not affect cortisol levels)
DREADD inhibition of UcnIII in the medial amygdala/optogenetic activation of UcnIII terminals in the PVN nucleus
Ivanova et al., 2021
blocks predator odour (TMT) stress-induced CORT rise in female mice
ChR2 increases CORT release in female mice
dysregulation of the CRH system
chronically elevated CRH implicated in human stress related/affective disorders/anxiety/major depression
potential depression treatment
CRH-R1 antagonist NBI 30775/R121919 improves depression
