Peripheral neurons, CRH, and sickness behavior

[ScoutB]

That Familial Episodic Pain Syndrome paper (apparently I only remember the most recent paper I've read) had an interesting example of how the ion channel works differently in different species:

A fascinating aspect of TRPA1 activation lies in interspecies discrepancies. Some electrophilic thioaminal-containing compounds are able to activate rat TRPA1 while others inhibit human TRPA1 (Chen et al., 2008). This difference is due to key amino acids situated in the S6 segment. A similar story applies to caffeine, which was shown to activate mouse TRPA1 but to inhibit the human channel (Nagatomo and Kubo, 2008), and menthol, which activates mammalian TRPA1, blocks nonmammalian TRPA1 (Xiao et al., 2008), and exerts a bimodal action on murine TRPA1 (Karashima et al., 2009). Therefore, similar compounds are able to exert opposite effects in different species and this suggests a complex gating mechanism for TRPA1 in which amino acid substitutions at key positions determine agonist binding and gating.

It reminded me of how human biology likes to reuse the same molecules in different tissues in different, and sometimes opposing, ways. And made me think that maybe this is not just convenience, but also because that molecule has "strong relationships" with other molecules in the relevant system (meaning high binding affinities or something, idk, I'm over my head), and then it only takes a tweak somewhere else to swap the actual direction of its effect. (?)

So all that to say, I wonder if it makes sense to view CRH's interactions with immune things in mice as clues that CRH might interact with similar parts of the human immune system, but that the exact problem it solves and actual direction of some of its effects in humans could be different or even opposite? This idea would probably be more useful if we knew exactly *how* CRH was mediating the sickness behaviour in mice.

Basically, I guess it seems like the answer to the below question could be "yes, involved, but possibly in a different way." ?

So I guess it comes down to whether CRH is involved in regular human "sickness behavior" or not.

I wonder if we know anything about CRH in primates..

 

[jnmaciuch]

That Familial Episodic Pain Syndrome paper (apparently I only remember the most recent paper I've read) had an interesting example of how the ion channel works differently in different species:


It reminded me of how human biology likes to reuse the same molecules in different tissues in different, and sometimes opposing, ways. And made me think that maybe this is not just convenience, but also because that molecule has "strong relationships" with other molecules in the relevant system (meaning high binding affinities or something, idk, I'm over my head), and then it only takes a tweak somewhere else to swap the actual direction of its effect. (?)

So all that to say, I wonder if it makes sense to view CRH's interactions with immune things in mice as clues that CRH might interact with similar parts of the human immune system, but that the exact problem it solves and actual direction of some of its effects in humans could be different or even opposite? This idea would probably be more useful if we knew exactly *how* CRH was mediating the sickness behaviour in mice.

Basically, I guess it seems like the answer to the below question could be "yes, involved, but possibly in a different way." ?


I wonder if we know anything about CRH in primates..

Could be! Though in the case of CRH, my instinct is that it’s more likely to be evolutionarily conserved. TRPA1 is one of many different chemosensitive proteins, where all the proteins that class have varied structures specifically so they can be attuned to different stimuli. There’s a lot of wiggle room for things to mutate without inducing a fitness cost for the animal.

In contrast, CRH is a pretty central linchpin in a lot of fundamental homeostatic processes. And in the case of its potential connection to sickness behavior, it would be a linchpin for a mechanism that spans multiple parts of the body, neural circuits, etc. Those types of fundamental multisystem processes tend to be conserved across species because small mutations are way more likely to throw a wrench in the whole system. Though it may have just happened to work out differently between human and mouse for reasons I couldn’t account for!

 

[ScoutB]

Thanks for the insights @jnmaciuch, that's all very helpful to know.

Just adding something here I'd like to remember to ponder in the future. And maybe others have thoughts. In the new presentation by the Dutch Autopsy study (aka the the first post in this thread) they mention that they are now looking at orexin/hypocretin neurons and that (so far) those look like they are decreased in ME/CFS patients too.

So, a super preliminary result, but maybe interesting to speculate about? Before, we were thinking orexin/hypocretin was normal in ME/CFS and so maybe ME/CFS could be some form of "narcolepsy minus something". But if orexin/hypocretin neurons do turn out to be affected, then could we imagine a scenario where ME/CFS is "narcolepsy plus something"? I've been reading posts on the narcolepsy subreddit about what it's like to resist a sleep attack and some of them mention feeling very ill.

In any case, if the lack of orexin pans out, the fact that pwME don't usually report feeling sleepy (and in fact report feeling unpleasantly wired+tired at times) seems like a really interesting apparent contradiction.

 

[ScoutB]

(Reviewing other threads where these ideas were discussed and found this)

it seems that IFN-a has been found to actively repress both hypocretin production and cAMP signaling in neurons (some evidence in supplementals). So I'm not sure it provides answers if we're trying to find something that represses CRH + vasopressin through cAMP but not hypocretin.

This might be a point in favour of INF-a then?

 

[jnmaciuch]

So, a super preliminary result, but maybe interesting to speculate about? Before, we were thinking orexin/hypocretin was normal in ME/CFS and so maybe ME/CFS could be some form of "narcolepsy minus something". But if orexin/hypocretin neurons do turn out to be affected, then could we imagine a scenario where ME/CFS is "narcolepsy plus something"? I've been reading posts on the narcolepsy subreddit about what it's like to resist a sleep attack and some of them mention feeling very ill.

That’s really interesting, thank you for sharing! I did not know they also looked at orexin. I’m almost positive I or someone else linked a study on CSF from ME/CFS which found no difference in orexin levels from controls, but I don’t remember which thread it was on. I’ll have to look for the study again to confirm.

If I am remembering it correctly, then I think it’s really vital to find out if all the people in the autopsy study were very severe. We can pretty much assume anyone consenting to travel to a hospital and do a lumbar puncture is on the milder end. So I’m wondering if that might explain the discrepancy. In which case neither orexin nor CRH would probably be the disease mechanism on their own since they would have to be abnormal even in mild ME/CFS to explain disease, but they could be suppressed as a side effect of some other abnormal signaling and only become substantially different from controls when that abnormal signaling is very strong. In which case, yes, neuronal IFN-a is one possibility.

Alternatively, we just have contradictory results on our hands, which would be disappointing.

 

[ScoutB]

Yeah, I also felt like some previous study suggested normal orexin, but couldn't immediately find it. I belatedly remembered that cataplexy is supposed to be caused by a lack of orexin -- I haven't heard of pwME reporting cataplexy, so that would also support the missing orexin being downstream of the disease mechanism, if it is a real effect.

 

[jnmaciuch]

Yeah, I also felt like some previous study suggested normal orexin, but couldn't immediately find it.

Couldn't find anything after a quick search--I may have been thinking of an -omics study done on CSF where orexin, if it was strongly differential, should have been detectable. For all the complaints with the Walitt study I think it's a safe assumption that it would have shown up there if it was a strong hallmark of the disease

I belatedly remembered that cataplexy is supposed to be caused by a lack of orexin -- I haven't heard of pwME reporting cataplexy, so that would also support the missing orexin being downstream of the disease mechanism, if it is a real effect.

Maybe I'm reading too much into it but the presenter in that video said "decrease in orexin neurons" rather than "depletion" or any more dramatic words, which makes me think it's not nearly as dramatic as the CRH depletion. I'm pretty sure decreased (but not substanitally depleted) orexin has been found in other conditions without cataplexy necessarily. All of which is to say that yeah, if these findings are real, a mild downstream effect on orexin seems more likely to me--maybe strong enough to induce some level of sleepiness in the more severe but not strong enough to induce cataplexy