Thinking about CRH (Corticotropin-releasing hormone) and ME/CFS

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Making a thread to start collecting some of the CRH ideas floating around. Everyone free to add anything that seems relevant. Note there is also jnmaciuch's Peripheral neurons, CRH, and sickness behavior thread, which is a bit more focused.

I'll probably come back and clean up this first post later. For now, it's going to include a todo list of stuff I've found as I'm looking at the old cortisol research (some of which looked into CRH). For instance, Cleare mentions 4 studies where CFS patients were administered CRH. All seem to have found totally different results. Not sure if there's any meaning to be wrung out of that (or if that's an interesting question to ask in the first place) but maybe I'll check them out at some point:

• Demitrack et al. 1991 -> Thread here now.
• Scott et al. 1998
• Cleare et al. 2001
• Kavelaars et al. 2000

Other CRH things we might want to think about/look into in more detail:
As mentioned in the BTN2A2 and BTN3A3 (BTN2A1) thread:

Discussion of other roles for CRH came up on this thread I think. We may need a CRH thread. Nightsong has picked up a paper in Science Signalling - on the miscellaneous research findings thread - that indicates CH may be very relevant aside from an HPA axis role.

(Nightsong's post is here)

The earlier conversation being referenced in that thread included this suggestion:

My guess is that there may be a lot of evidence from elsewhere indicating that CRH is not just the lord and master of cortisol production in the way students may be taught. Hypothalamic damage produces a range of clinical pictures including polyphagy with morbid obesity and growth hormone failure but I am not sure that it commonly leads to hypocortisolism. I rather suspect that CRH may have a more subtle role in cortisol regulation and, importantly, other roles, that we tend to ignore. I wouldn't be surprised if CRH knockouts had fairly normal cortisol levels.

So if we take the post mortem findings on CRH cells seriously (but not as gospel), which seems fair, and add in what we know about narcolepsy (where there isn't symptomatic hypocortisolism either) then my guess is that we should be thinking in terms of some other regulatory role of CRH that has been overlooked. that might have to do with sleep cycles, lipid metabolism, leptin, or whatever.

For completeness: here's the thread on the University of Amsterdam autopsy study that kicked off our interest in CRH.

 

[ScoutB]

Was trying to answer a question about cortisol and got distracted reading this paper:
Sex differences in stress responses: a critical role for corticotropin-releasing factor
The authors seem to be assuming that women (as well as female mice, rats, and marmosets) get more 'stressed' than men, and cite the higher rates of diagnosed depression, anxiety etc. in women (oddly they do not cite any studies on the gender breakdown of depression in marmosets). I don't know if I love that framing, but I found a few of the results they quoted interesting enough they might be worth checking out.

Oh and CRF = corticotropin-releasing factor = corticotropin-releasing hormone = CRH.

CRF levels in CSF are thought to reflect extrahypothalamic release of CRF and do not correlate well with plasma cortisol levels [31]

Sex differences in CRF receptors

CRF dose-dependently impaired sustained attention in both male and female rats. However, the effect of CRF on sustained attention in females was dependent on the estrous cycle [60]. When females were in diestrus, where ovarian hormones are low, CRF profoundly disrupted attention. However, when females were in cycle phases characterized by elevated levels of ovarian hormones, CRF had no effect on attention [60].

This might be useful to keep in mind for the various ACTH-challenge studies we see done with suboptimal gender-matching:

In healthy humans, an intravenous CRF challenge increases ACTH levels more in women than men, suggesting heightened sensitivity to CRF in women [64].

Evidence for sex differences in CRF receptors first comes from binding studies. Specifically, CRF1 receptor binding in regions of the amygdala and cortex is higher in adult female rats, while CRF2 receptor binding is higher in regions of the amygdala and hypothalamus in male rats [65, 66]. Interestingly, many of these changes in binding emerge following puberty, implicating pubertal hormone surges in these sex differences [65, 66].

In addition to sex differences in CRF receptor distribution in different types of neurons, we identified sex differences in CRF1 receptor localization within neurons in the locus coeruleus (LC)-arousal center. During a stressful event, CRF is released into the LC where it binds to CRF1 receptors [70,71,72]. This receptor activation causes LC neurons to increase their firing rate, thereby releasing norepinephrine into the forebrain to increase arousal [70,71,72,73].

Typically, activation of this circuit increases alertness to facilitate responding to stressors. However, overactivation of the circuit can lead to the dysregulated state of hyperarousal, which is characterized by restlessness, lack of concentration, and disrupted sleep [74, 75].

Curious if that looks at all like wired-but-tired.

One cellular mechanism that compensates for excessive CRF release is receptor internalization. During internalization, β-arrestin2 binds to the CRF1 receptor, initiating its trafficking from the plasma membrane to the cytosol where the receptor can no longer be activated [76,77,78,79,80].

In male rats, acute swim stressor exposure causes β-arrestin2 to bind to the CRF1 receptor, an effect accompanied by CRF1 receptor internalization in LC dendrites [81, 82]. However, β-arrestin2 binding and internalization are not observed following exposure to swim stress in female rats [82]. Further, studies in CRF-OE mice with overexpression throughout their lifespan revealed a similar pattern of CRF1 receptor internalization in LC dendrites of males, but not females (Fig. 1c) [83]. This lack of internalization in females may render their LC neurons more sensitive to conditions of excessive CRF release.

Accordingly, overexpression of CRF induces greater cAMP-PKA signaling in female than in male mice [84, 85]. In the LC, this increased CRF1 receptor signaling through the cAMP-PKA pathway in females is associated with increased sensitivity to CRF [84].

Sex differences in CRF expression and the regulation of CRF effects

CRF neurons express NMDA receptors, suggesting glutamatergic regulation of these cells [109]. Knocking out Grin1 subunits of the NMDA receptor results in a loss of NMDA function, and mice genetically modified so that Grin1 is deleted specifically from their CRF-containing neurons have been produced [110,111,112]. These mice display increased fear expression and social withdrawal if they are male [111, 112]. However, female mice are unaffected by this loss of NMDA receptor function in CRF neurons [111]. Thus, glutamatergic regulation of CRF neurons via NMDA receptors appears sex-specific.