Stress-relapse axis
CRF/stress-relapse axis
Also searched as CRF/stress-relapse axis.
Acute vs chronic: crf starts the stress response, which is a necessary thing to be able to do. Sustained, it is the signal that degranulates mast cells and opens the intestinal barrier. Essential to answer a genuine threat, corrosive when it fires without pause. You want it responsive, not chronically lit.
In depth
Corticotropin-releasing factor — the hypothalamic spark that launches the cortisol stress cascade.
What drives it
Stress & cortisol increases it.
Stanton 2023, J Neuroendocrinol — stress activates CRH neurons of the hypothalamic PVN, the initiating step of the HPA axis. DOI 10.1111/jne.13268. CRF is produced in the hypothalamic paraventricular nucleus in response to stress and is the initial activator of the HPA axis, stimulating ACTH from the anterior pituitary, which drives adrenal glucocorticoid release. Norepinephrine and glutamate stimulate CRF release under stress; GABAergic inputs inhibit it; CRF and AVP act synergistically on ACTH. The two receptors do opposite things, and this should not be collapsed: CRF receptor type 1 mediates the stress response, depression, anorexia and seizure, while CRF receptor type 2 mediates 'stress coping' — including anxiolysis in the brain. Whether CRF signaling is harmful or protective depends on which receptor is engaged. The axis is self-limiting: the activated HPA axis is suppressed by negative feedback from glucocorticoids, via the negative glucocorticoid response element and the serum response element on the Crf promoter. doi 10.1111/jne.13268.
Calm reduces it.
10.3389/fpsyg.2020.588068 — ,Completes the chain oxytocin -> GABA -> CRF: oxytocin inhibits CRF mRNA expression in the hypothalamus, producing anti-stress and anti-anxiety effects — and the source is explicit that the inhibitory effect of oxytocin on CRF mRNA is not a direct one on CRF neurons. GABAergic neurons in the peri-PVN project into the PVN and inhibit CRF expression via GABA-A receptors. doi 10.3389/fpsyg.2020.588068
Mood (serotonin) increases it.
Serotonin and crf both sat on the anxiety enumeration as parallel items. They are not parallel. Serotonin from the dorsal raphe enhances fear and anxiety and activates a subpopulation of crf neurons in the bed nucleus of the stria terminalis. The route is specified to the receptor: 5-HT-drn projections to the bnst act at 5-HT2C receptors to engage a crf-bnst inhibitory microcircuit that silences anxiolytic bnst outputs to the ventral tegmental area and lateral hypothalamus. And the authors name the clinical phenomenon it explains: this crf-bnst inhibitory circuit underlies aversive behavior following acute exposure to SSRIs — the initial worsening every patient is warned about. A single arrow was hiding two opposite behaviors. PMC5124365
Feeding drive reduces it.
10.3389/fnins.2020.629003 — ,NPY inhibits firing rate of the locus coeruleus, inhibits release of crf and norepinephrine, and is anxiolytic in a variety of animal models. Receptor coupling is inhibitory: Y receptors associate with Gi/o proteins and inhibit adenylyl cyclase and cAMP accumulation. doi 10.3389/fnins.2020.629003
What it drives
It increases Lowers cortisol.
Vale 1981, Science 213:1394 — the 41-residue CRF peptide that drives pituitary ACTH secretion (→ cortisol). DOI 10.1126/science.6267699 Verbatim: “CRF stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary”. doi 10.1126/science.6267699 · PMID 34830130
It increases Calms histamine response.
The stress hormone opens the gut by way of the mast cell, and this was shown in humans with a blocking agent: in a randomized study, peripheral CRH reproduced the effect of psychological stress on small-intestinal permeability, and the mast-cell stabiliser disodium cromoglycate blocked the effect of both the stress and the CRH (Vanuytsel et al., Gut 2014;63:1293-9, PMID 24153250). CRH and other stress mediators degranulate mast cells, releasing TNF-α and tryptase. PMID 24153250 · PMC10670774
It increases Pituitary stress signal.
The actual chain: CRF synthesized in the paraventricular nucleus is transported axonally to the median eminence and released into the hypophyseal portal circulation, where it binds CRHR1 on anterior pituitary CORTICOTROPHS, stimulates POMC transcription, and releases ACTH. CRF does not touch the adrenal. CRHR1 is required: the presence of CRH1 receptors in the pituitary is stated as essential to maintain ACTH secretion. And there is a whole brake: CRH-binding protein (CRH-BP) binds CRH with an affinity greater than the CRH receptors themselves, competitively inhibiting it — a regulator sitting between the peptide and its receptor. But its knockout disappoints, and that is recorded here too: after acute restraint stress, corticosterone and ACTH profiles did not differ in CRH-BP knockout or pituitary-overexpressing mice versus controls — because the system compensated, with PVN CRH and AVP mRNA rising 82 percent and 35 percent in the overexpressing animals. Induced, buffered, not required. And CRF is not alone at the CORTICOTROPH: arginine vasopressin directly stimulates ACTH and synergises with CRF, and vasopressin raises CRHR1 mRNA — so AVP both pushes the same lever and widens it. doi 10.1080/10253890.2017.1322575 · PMC7885796
It increases Calm under stress.
10.1371/journal.pone.0008528 — Stress reaches anxiety through the HPA axis, but CRF also acts in the amygdala in its own right: corticotropin-releasing factor coordinates the endocrine, autonomic, behavioral and immune responses to stress and also acts as a neurotransmitter OR neuromodulator in the amygdala, dorsal raphe, hippocampus and locus coeruleus. Abnormal signaling at CRF1 and CRF2 receptors is proposed to contribute to anxiety and depression. This is a second, parallel route alongside the CRF → ACTH → HPA Axis / Cortisol link — the peptide reaches behavior without going through cortisol at all, which is why the two arms can dissociate. doi 10.1371/journal.pone.0008528
It increases The Two-Faced Peptide.
It shows the CRF → Anxiety link runs through dynorphin rather than beside it. Blockade proves the order: using a phosphoselective antibody to identify sites of dynorphin action, CRF increased KORp-immunoreactivity in the basolateral amygdala of WILDTYPE mice but not in mice pretreated with the selective CRF1-receptor antagonist ANTALARMIN — CRF1 is upstream of dynorphin release. Two receptors, two behaviors, one peptide. PMC2795205
It reduces Social bonding hormone.
The atlas carries oxytocin -> GABA -> CRF as inhibitory; this is the return arm. Anatomy first: oxytocin neurons project from the hypothalamus to the dorsolateral bed nucleus of the STRIA TERMINALIS, and those oxytocin terminals express presynaptic CRF receptor type 2 — CRF receptors sitting on oxytocin terminals is a physical substrate for direct control. The experiment and its asymmetry: oxytocin was measured by microdialysis in freely-moving rats with drugs delivered directly into the BNST. Blocking CRFR2 with astressin-2B caused an increase in oxytocin content, whereas CRFR2 activation with UROCORTIN 3 had NO effect. The antagonist works and the agonist does not — which means the receptor is already tonically occupied. CRF is not waiting to suppress oxytocin; it is suppressing it continuously, and the drug simply lifts the lid. The relationship is explicitly reciprocal: neuroanatomical work describes reciprocal regulation of the CRF and oxytocin systems in the hypothalamus and BNST, framed by its authors as a mechanism for balancing stress and affect. Two peptides holding each other down is what a set-point looks like. doi 10.3389/fnins.2018.00183 · PMC5871712
Blends that modulate it
Each blend page names this pathway and carries the study behind its claim.
See it on the map
Open the causal map to follow this pathway upstream and downstream, arrow by arrow, each with its study.