Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour, 2022, Ilanges et al

Abstract

Infections induce a set of pleiotropic responses in animals, including anorexia, adipsia, lethargy and changes in temperature, collectively termed sickness behaviours1. Although these responses have been shown to be adaptive, the underlying neural mechanisms have not been elucidated2,3,4.

Here we use of a set of unbiased methodologies to show that a specific subpopulation of neurons in the brainstem can control the diverse responses to a bacterial endotoxin (lipopolysaccharide (LPS)) that potently induces sickness behaviour. Whole-brain activity mapping revealed that subsets of neurons in the nucleus of the solitary tract (NTS) and the area postrema (AP) acutely express FOS after LPS treatment, and we found that subsequent reactivation of these specific neurons in FOS2A-iCreERT2 (also known as TRAP2) mice replicates the behavioural and thermal component of sickness. In addition, inhibition of LPS-activated neurons diminished all of the behavioural responses to LPS. Single-nucleus RNA sequencing of the NTS–AP was used to identify LPS-activated neural populations, and we found that activation of ADCYAP1+ neurons in the NTS–AP fully recapitulates the responses elicited by LPS. Furthermore, inhibition of these neurons significantly diminished the anorexia, adipsia and locomotor cessation seen after LPS injection.

Together these studies map the pleiotropic effects of LPS to a neural population that is both necessary and sufficient for canonical elements of the sickness response, thus establishing a critical link between the brain and the response to infection.

Open access, https://www.nature.com/articles/s41586-022-05161-7

 

It sounds as if they have identified some of the signalling characteristics of neutrons involved in feeling ill following endotoxin (as in typhoid vaccine and bacterial infection in general).

This might lead to creation of inhibitors with a specific anti-sickness effect. At the moment paracetamol and aspirin are about the only things I now of that have an effect on tis pathway - other than perhaps anti-emetic antihistamines.

 

Have only read the abstract so don't know if there's anything relevant to ME in the paper itself.

Generally speaking I'm not convinced it's helpful to look at ME simply as an abnormal activation of the normal sickness response.

Just taking the four elements of the sickness response cited in the abstract here, anorexia, adipsia, lethargy and changes in temperature (i.e. fever in the context of the sickness response) suggests it's a poor match.

Only one of them, lethargy, is reported pretty much universally in ME. Anorexia and fever are certainly present in individuals but far from universal in ME. And adipsia is probably rare, if anything I've seen more reports of increased thirst than lack thereof.

Not saying it's impossible that bits of the sickness response are involved in ME in some way, e.g. there could be a problem mounting the full sickness response or all manner of other permutations, but the popular theory that ME is the just the normal sickness response not switching off when it should strikes me as too simplistic.

 

I red-flagged them at "sickness behavior". In my book it's little more than a dog whistle.

Are we talking about symptoms? Then call them symptoms.

 

I know what you mean, but I've seen definitions that include at least one behavioural aspect to the sickness response (as it applies to humans): withdrawal from social contact. There might be others, it's just that that one stuck in my memory.

I prefer the term sickness response, as it seems a bit less loaded than sickness behaviour. They use both in the abstract, though, and it's possible they just didn't give much thought to it; I'd be more critical if they'd been reporting on a human study, where the politics of language does come into sharper focus.

 

My understanding is that it is postulated that behaving in a certain way when sick has an evolutionary advantage, such as shutting yourself away in a darkened enclosed space and resting meaning you are less likely to become prey when you are least likely to evade predators. Though there seems some confusion about whether this involves voluntary behaviour or autonomic responses or aspects of both.

However I don’t think it has been clearly demonstrated that there is a distinct sickness response rather than as @duncan suggested symptoms arising from being ill. If it was a distinct sickness response you might expect it to be the same regardless of the triggering illness and I am not sure that it is always the case. Certainly I behave very differently when I have a cold to when I have a migraine. Also do you see the same response across different animals? I suspect that a sick gazelle will behave very differently to a sick lion.

Also I worry that the phrase ‘sickness behaviour’ in relation to such as ME risks introducing the idea that we are indulging a voluntary behaviour that is maladaptive in our situation and so contains an element of moral judgement. I suspect most people with ME after any initial acute phase rather have tried ignoring feeling sick and pushed on through, but only over time learn that this worsens symptoms (ie PEM).

 

Sickness behavior is at least one step removed from symptoms. It's diagnosing from the outside. Veterinarians like it, and coined it, because, well, horses and cows cannot speak or sign.

When applied to humans, at best it is a social construct. On a darker level, the term can devalue symptoms as reported by the sick.