Physiologically grounded RL environment modelling the HPA axis. Adapted to match in-depth analysis of PMC3181830 and PMC4867107.

Biological components modelled: --- CORE CASCADE ---

• Full CRF → ACTH → Cortisol cascade
• AVP (Arginine Vasopressin): co-secretagogue (V1b / Gq / PKC pathway) Expression increases with chronic stress; potentiates ACTH release
• POMC processing: ACTH, beta-endorphin (stress buffering), melanocortins (alpha-MSH: anti-inflammatory, metabolic; CART: reward/stress/feeding)
• CRFR1 / CRFR2 receptor populations
• Urocortins (Ucn1, Ucn2, Ucn3): CRF-family peptides modulating CRFR1/2 Ucn1: Edinger-Westphal nucleus; high affinity CRFR1+CRFR2 agonist Ucn2: PVN and LC; CRFR2 preferring Ucn3: perifornical hypothalamus, BNST, lateral septum, amygdala; CRFR2

--- FEEDBACK MECHANISMS ---

• Fast nongenomic feedback: sensitive to rate of cortisol rise (membrane GR)
• Slow genomic feedback: sensitive to cortisol level (nuclear GR)
• MR vs GR: MR dominates at basal levels; GR dominates under stress
• Hippocampal feedback: MR+GR in hippocampus suppress basal/stress HPA (hippocampal lesion → elevated basal cortisol, prolonged ACTH response)

--- PVN AFFERENTS ---

1. NTS (Nucleus Solitary Tract): major excitatory drive to PVN Receives input from mPFC (social cognition) and CeA (fear/anxiety)
2. SFO (Subfornical Organ) / Lamina Terminalis: angiotensinergic input to PVN based on blood pressure and osmotic composition of blood; promotes CRF secretion and biosynthesis
3. GABAergic inhibition (DMH / POA): stress-activated inhibitory brake on PVN; POA integrates gonadal steroids with HPA; lesions amplify HPA
4. Arcuate Nucleus neuropeptides (metabolic-HPA bridge): NPY / AGRP: activate HPA, directly increase CRF alpha-MSH / CART: increase ACTH and corticosteroids, stimulate CRF
5. Limbic structures: Amygdala (CeA): physical stressors → NTS → PVN; glucocorticoids potentiate CRF expression in CeA (chronic-stress amplification loop) Amygdala (MeA): emotional/social stressors → BNST/MePO → PVN Hippocampus: inhibitory (multisynaptic via BNST/peri-PVN GABA) PFC (mPFC / prelimbic): inhibitory on HPA; damage amplifies ACTH/cortisol
6. LC (Locus Coeruleus): noradrenergic; activated by stress/CRF; elicits ACTH release, anxiety behaviour, immune suppression

--- PLASTICITY ---

• Gland plasticity: adrenal hypertrophy/atrophy, pituitary adaptation
• Receptor downregulation under chronic cortisol (GR, MR)
• CRFR1 downregulation (homologous desensitisation), CRFR2 upregulation
• Hippocampal damage index accumulates with chronic stress (GR/MR loss)
• CeA sensitisation: glucocorticoids increase CeA CRF expression
• Circadian rhythm (SCN-driven, modulated by AVP projections)
• Ultradian pulsatility (~60-90 min periodicity)
• Allostatic load: cumulative biological cost