Nature: A preoptic neuronal population controls fever and appetite during sickness, 2022, Osterhout et al

A preoptic neuronal population controls fever and appetite during sickness
Osterhout, Kapoor, Eichhorn, Vaughn, Moore, Ding Liu, Lee, DeNardo, Liqun Luo, Xiaowei Zhuan, Dulac


Abstract

During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue1,2. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown.

Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic/polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite.

Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPOLPS) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPOLPS neurons.

Finally, we show that VMPOLPS neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite.

Together, these results uncover VMPOLPS neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.

https://www.nature.com/articles/s41586-022-04793-z

 

I see this as the sort of 'bit of knowledge' that might trigger a flash of insight in some other researcher. "Oh, that might explain why ...".

 

Reviewed in this article: https://www.nih.gov/news-events/nih-research-matters/brain-cells-control-sickness-symptoms

And mentioned in this podcast in relation to a possible mechanism for ME.
https://www.nih.gov/news-events/nih-research-matters/brain-cells-control-sickness-symptoms

 

One of the authors has shared an open access link on Twitter

 

Per this article, it would seem that sickness behaviour (including increased pain sensitivity) is very much a body->mind phenomenon.

Perhaps in our perspective, that is, with regards to ME (or fibromyalgia), the most important point to take away may not be the existence of these neurons as much as the fact that they are activated by an immune response? Does this not strongly hint towards immune dysregulation in ME, particularly during PEM?

If that is so, it suffices to disprove the (bio)psychosocial models of CFS and of chronic primary pain.

Edit: that said, fever is not a component of ME.

 

We have known about cells in hypothalamus sensitive to bacterial endotoxin, causing fever and nausea for a long time. It may be interesting that they have been characterised further. It would be more interesting if they had found cells with separate effects - some for fever, some for fatigue etc.

If these cells get stuck signalling when they shouldn't then ongoing immune dysregulation may or may not be involved. I don't think anything is proved or disproved.

The main problem with the biopsychosocial theory is that it does not hold water anyway. I think trying to 'disprove' it with biomedical findings is probably a blind alley.

 

Fever isn't something that has been recorded, and it's not something that patients typically complain of - however perhaps it should be an area of enquiry. N=1 low grade fever/chills were always part of my PEM experience.

More broadly if ME/CFS were to involve immune dysregulation then perhaps we might expect to see difference between older PwME who may be affected by immunosenescence and younger patients.

 

https://twitter.com/user/status/1548612650631921665

 

They didn't really discuss fatigue at all in the manuscript - they focused on fever and appetite suppression. The role of fatigue being associated with "sickness behaviour" itself is merely speculative.

We know the motor-related central fatigue has a different mechanism - stimulation of muscle afferents which leads to suppression of motor cortex excitibility, leading to a perception of more effort for a given level of force as well as increased ventilatory drive relative to the level of muscle force. (the increased ventilatory drive why central fatigue and peripheral fatigue are coupled together by the brain).

 

If the sickness behaviour translates to humans and pwME it would be rather important to figure out which of these mechanisms is at work before rushing into treatment trials.

If it's a matter of the VMPO being 'stuck' for no good reason or if it's misinterpreting harmless signals as dangerous then treatments aimed at 'unsticking' or dialling down the VMPO response make sense. But such treatments could backfire if the VMPO is responding to a real and relevant danger signal.

 

Interesting paper, especially since there's a lot of talk about the sickness response in ME. But the more I think about the sickness response the more doubts I have about its role in ME. Superficially it's an attractive idea but start digging into it and things get murky pretty quick.

Yes, I feel decidedly ill in a malaise-y sort of way, especially during PEM, yet the above stereotypical sickness response doesn't fully match my experience, and in part even contradicts it.

For example, the stereotypical sickness response includes fever and some pwME do report fevers. Yet quite a few pwME report a distinct lack of fevers and very low core body temps. So what's going on here? Did the initial illness blow the fuse on the brain thermostat? Has some fever-reducing feedback system gone into overdrive? Is some other part of the sickness response waiting for a fever before it deems it safe to turn itself off, and keeps ratcheting up its own signals in a vain effort to prompt the fever part of the system into gear? Is the problem not a sickness response stuck on 'on' as is often speculated, but rather that parts of it that should be 'on' are in fact 'off'?

The other sickness response features listed - lethargy, appetite loss, warmth-seeking, social withdrawal and increased pain sensitivity - aren't clear-cut either.

Lethargy: Not quite sure what lethargy as observed in mice represents, lack of motivation, lack of energy, fatigue, malaise? If the latter, then yes, that's a feature of ME and even more so of PEM.

Loss of appetite: Some pwME report this, for others it's secondary to nausea and still others don't lack appetite but struggle with all the lifting and chewing. Observed behaviour is the same, all eat less, but for different reasons. And another group doesn't seem to have any appetite problems at all.

Warmth-seeking: Some pwME report feeling better at warmer temps, others at colder temps and others in a very narrow range of comfortable temperature. This sounds more like a broken thermostat than a classical sickness response.

Social withdrawal: Depending on severity in pwME any observed social withdrawal could be a feature of the sickness response itself for some but it often is just a calculated learned move to avoid future PEM.

Increased pain sensitivity: Some pwME report this, others don't.

In summary, to me it doesn't look like ME or PEM resemble the stereotypical coordinated sickness response as described in this paper.
Though that doesn't exclude the possibility of individual parts of the sickness response being inappropriately on or off, similar to how elderly people with an infection can have atypical sickness responses without fever.

We need to be careful we don't fall int the trap of using the term 'sickness response' too loosely and have it end up meaning different things to different people (as so many other terms in ME).

 

That is my impression too.

 

There are similarities and distinctive dissimilarities between sickness behaviors and M.E. This chart in this paper describes it quite well. Open the separate window in full.

 

Haven't read that paper but it's interesting that it was published way back in 2013 with the conclusion that "sickness behavior and ME/CFS are two different conditions".

Yet recently Komaroff(?) in a podcast enthused about this(?) mouse paper and suggested that these neurons could help explain ME. He seemed to give a lot of credence to the 'stuck' sickness response idea.

Round and around and around in circles we go (which may still be preferable standing on them)

 

Again is this the sort of thing which, if it is really relevant to ME/CFS, would turn up via GWAS - some copies of genes related to this response increasing/decreasing risk of ME/CFS?