jnmaciuch
Senior Member (Voting Rights)
I'll have to go back and see the discussion--I also didn't know about this transcriptional mechanism then
Peripheral neurons, CRH, and sickness behavior
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Jonathan Edwards
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I saw plenty of jumpy mice being non-mobile when I used to do animal experiments. Freezing still is a usual response to fear. But admittedly that isn't 'lethargy'. And maybe the local adrenergic signals are nothing to do with a systemic adrenergic response. I do think it is becoming complicated though! Not that that is a bad thing. I suspect we need to discover in what way we have been oversimplifying things, in order to see the wood for the trees.
jnmaciuch
Senior Member (Voting Rights)
The people I’ve talked to that do mouse models of Covid say it’s pretty distinctive. They call it “loafing” or “ragdolling.” Apparently theyre the easiest mice to handle by far.
I might be misremembering something read a long time ago, but I’m pretty sure that ACTH is increased in prolonged sepsis. Plus cortisol spikes alongside the first burst of cytokines as a negative feedback mechanism during regular infection. So it doesn’t seem surprising that CRH activation happens in infection, just that the connection to sickness behavior is surprising.
Maybe the sickness behavior mechanism just cancels out the expected jumpiness of HPA-axis activation. It makes perfect sense from an evolutionary standpoint—keep the immunoregulatory mechanism, but make sure that the animal still collapses in a corner away from other animals.
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Jonathan Edwards
Senior Member (Voting Rights)
That is the strange bit. Yes, ACTH will be up in infection I think.
There is a rabbit loose but it may be a real rabbit and worth chasing.
V.R.T.
Senior Member (Voting Rights)
Could you explain this part for the more brain fogged among us (i.e. me!)
This discussion is really interesting but I dont quite follow this bit.
jnmaciuch
Senior Member (Voting Rights)
Oh sure, it’s just spitballing to find a way to reconcile the mouse studies and the human autopsy study. If CRH upregulation is necessary for people to feel sick during infection, and pwME feel sick in similar ways, you would expect that there’s more CRH activity in ME/CFS.
But we have one study showing the opposite in ME/CFS, a stark depletion. The study presents this as evidence of neuron death but I and @ME/CFS Science Blog were discussing the likelihood that it’s actually just transcriptional silencing of the CRH gene rather than death of neurons.
So one possibility is that the autopsy study is showing the late stage consequences of having CRH neurons be active long term from an immune response. I think the HPA axis people have latched onto a form of this idea with chronic stress causing “burn out,” which seems pretty unlikely for many reasons. There might be a small kernel of truth in it though, in that there is at least one known inbuilt mechanism that suppresses CRH production the more the neuron is activated. It’s not “burn out” per se and “chronic stress” may not be enough to induce this mechanism all that much, but cytokine stimulation would be more prolonged and constant than brief fight or flight responses so maybe that suppression could happen from an immune response.
Or this particular transcriptional mechanism might not be relevant, and the thing causing CRH suppression is actually an epigenetic response to something that isn’t totally related to the CRH-sickness-behavior pathway.
V.R.T.
Senior Member (Voting Rights)
But surely in that model if the neurons burnt out people would stop having the sickness behavior symptoms. Even if they had other horrible symptoms from having no CRH neurons?
Thanks for the explaination, it's appreciated.
jnmaciuch
Senior Member (Voting Rights)
There are definitely some outstanding mysteries, and a lot of unknowns. First, it's not a complete lack of CRH neurons, but a substantial depletion. A few functioning CRH neurons might be enough for some of the fundamental functioning, in both ME/CFS and type I narcolepsy. The fact that cortisol levels were a little lower but not completely depleted in the autopsy study seems to support this (though there's also the possibility that something downstream of CRH compensates specifically for cortisol production).
The second question is whether the people with depleted CRH in the autopsy study actually experienced what we'd call typical "sickness behavior". Or, if they were on the very severe end of the spectrum, does that state represent how the brain responds to some extreme neuroimmune signaling in the absence of CRH? We know from in-vitro studies that cytokines like interferon and CXCL10 can cause direct changes in neurons, independent of any CRH. Maybe the extreme sensory sensitivity, the "poisoned feeling" that many describe, and other hallmarks of very severe ME/CFS are more attributable to the immune signaling rather than the specific "sickness behavior" pathway that goes through CRH neurons.
There is also other possibilities to explain it, like maybe CRH is only necessary for sickness behavior if the immune signals are coming from peripheral nerves from the lungs, which was the mouse model in all of these studies. If the immune signaling is happening directly in the brain, maybe it can trigger sickness behavior without CRH.
poetinsf
Senior Member (Voting Rights)
Sounds like you are making an assumption that ME/CFS is a form of sickness behavior. Another possibility is a non-response, rather than hyper-response, to environmental demand, thus producing the sensation of fatigue and other maladies, stemming from overactive default mode network (courtesy of another article from our favorite blogger, Cort). Anecdotes of stimulants or dopamine making some difference could be tied to this. And the depletion of CRH neurons could be a contributing factor to overactive DMN, if not the cause.
Are you talking about the same study as CRH findings? I think there was a huge difference in cortisol too.
The plot for cortisol levels in cerebrospinal fluid looks similarly striking to the CRH finding. I would think that this would have already been tested in people who are alive, though I can't immediately find a study looking at CSF cortisol in ME/CFS. I don't see any mentions of CSF on the cortisol thread.
If it hasn't been tested before, it seems this should be a priority to replicate.
Edit: This is from the YouTube video at 8:26.
Andy
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Not my favourite blogger. @ME/CFS Science Blog , @Simon M and @Grigor are all far better bloggers than Cort.
jnmaciuch
Senior Member (Voting Rights)
Given several past discussions with other grad students, I'm not sure I could get a roomful of neuroscience experts to even agree whether the DMN is a real or useful concept. It's been tied to everything under the sun with poorly done research.
If "overactive DMN" is a thing it's been found in lots of diseases like ADD and alzheimer's which don't really look anything like ME/CFS
jnmaciuch
Senior Member (Voting Rights)
Maybe I remembered it as less striking because the y axis range spans less here than the CRH one? In narcolepsy the evidence is better since we can assume that the narcolepsy autopsy cases were more representative of an average T1N case, whereas there's a big chance the ME/CFS autopsy is skewed towards very severe.
No evidence of failure to produce cortisol in T1N, where the autopsy study found a comparable depletion of CRH:
Physiological and psychological stress reactivity in narcolepsy type 1 - PMC
Narcolepsy type 1 (NT1) is a chronic sleep–wake disorder, characterized by a loss of hypocretin production. Unexpectedly, in postmortem tissue of people with NT1, there is a loss of corticotrophin-releasing hormone (CRH) in the paraventricular ...
pmc.ncbi.nlm.nih.gov
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Jonathan Edwards
Senior Member (Voting Rights)
That sounds as garbled as Mark Edwards and Jon Stone.
ScoutB
Senior Member (Voting Rights)
Maybe @jnmaciuch you remembered the cortisol as less striking because of the other CSF cortisol data @forestglip was able to share that came from the deep phenotyping study.
jnmaciuch
Senior Member (Voting Rights)
That might be it, thanks for bailing me out haha
[Edit: and if we assume both sets of cortisol results are real, that does suggest that the autopsy participants were probably more severely affected than the NIH group]
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