Feeling Ill? Blame Your Brain

Reference: Ilanges, A., Shiao, R., Shaked, J., Luo, J.-D., Yu, X., & Friedman, J. M. (2022). Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour. Nature609(7928), 761–771.

The clock read 3:38 AM. I remember the faint light coming in from streetlights by my window illuminating the timepiece as I woke up shivering, my skin clammy with sweat. I hadn’t eaten all day, but I wasn’t hungry for anything. Despite not being thirsty, I forced myself to drink some day-old lukewarm water I had on my nightstand. 

Being sick is not a pleasant experience, but it’s one we all go through at some point or another. The experience itself, however, is an important response to infection, one that has been conserved and improved upon by our evolution. Certain responses show up time and time again, no matter the type of illness, making our lives just a little more miserable. Collectively, these are known as sickness behaviours. I’ve mentioned a few already, such as the lack of appetite or sudden drops in body temperature. 

But what drives these responses?

The role of our immune system in response to infection or disease is a complicated and exhaustive field, full of complex diagrams and more acronyms than you could count. While the immune system is a key player in our health, it’s not the only system that aids in the fight against infections. Sickness behaviours are driven by our brains.

Brains, however, are incredibly confusing, with hundreds of subpopulations of cells important for some part of some behaviour. This is where Anoj Illanges and his labmates at Rockefeller University asked their question: which part of our brain controls our behavioural response to illness?

In order to study sickness behaviours, you need sick animals – like mice with a bacterial infection. However, infections are difficult to control and could lead to unintended circumstances, like prolonged sickness. Fortunately, certain bacterial toxins are enough to cause infection-like symptoms, while remaining manageable in studies. Lipopolysaccharide, or LPS, is a component of the bacterial cell wall pathogens need to survive, and is one of the key foreign signals our immune system recognises to warn us when we’ve been infected. By using LPS, Anoj and her team could induce sickness behaviours in the mice they were studying by making the mice think they were sick, without infecting them with a pathogen.

Using a specialised home-cage, the team could monitor for various changes in behaviour after injecting the mice with LPS. Like many of us battling a fever, the “sick” mice stopped eating food, stopped drinking water, and stopped moving. The loss of appetite was so strong, mice wouldn’t eat even when starving. Additionally, the mice saw a drop in both body temperature and bodyweight. Somewhat predictably, the more LPS that was given to the mice, the more dramatic the illness. About a day after the injection, the mice slowly began recovering. 

To identify which parts of the brain are involved in the suite of sickness behaviours, Anoj used Fos, a gene which signals when neurons are active. By staining thin slices of the brain with antibodies sensitive to Fos, the research team could identify areas where neurons were active following treatment with LPS. Two brain regions stood out – the nucleus tractus solitarius (NTS), and the area postrema (AP) – both found in the brainstem, located at the base of our skull. The NTS is one of the primary relay centres of the brain, communicating with digestive, respiratory, and cardiovascular systems via the vagus nerve (one of the major avenues for regulating many of our unconscious actions, like breathing). The AP, similarly, has a unique function in that it is located outside the blood-brain barrier. While the blood-brain barrier is meant to protect our brain from blood-borne toxins, the AP’s position allows it to detect chemical cues in our bloodstream, such as bacterial toxins.

Exposing mice to LPS activates neuronal populations in the nucleus tractus solitarius (NTS) and the area postrema (AP), visible by fluorescence in the brain. Adapted from Illanges et al (2022) and modified with assets taken from Pixabay.

To confirm the involvement of the NTS and the AP in our sickness behaviours, the team used a genetic “trapping” system. Neurons activated by LPS could be genetically tagged, allowing the same neurons to be chemically reactivated without the use of any bacterial toxins. Reactivating these neurons led to the sickness behaviours the LPS treatment had prompted; less eating, less drinking, and less moving. Using a similar strategy, chemically inhibiting the neurons during LPS treatment resulted in a reduced effect of the bacterial signal; animals ate more, drank more, and moved more. Notably, neuron inhibition did not appear to impact the drops in temperature seen during typical LPS injection or neuron activation. Given infection and LPS treatment affected temperature regulation, these outcomes seemed to indicate that this part of our sickness response is mediated by a different brain region. 

The thing about the brain, you see, is that it’s made up of a diverse mix of cells, all necessary for a range of functions. However, many of these neurons look identical, posing a problem in identifying distinct subpopulations by microscopy alone. To identify the specific neurons involved in our sickness response, Anoj used transcriptomics – a technique that identifies cells by the unique combinatorial expression of their genes. Doing so, he identified a key group of cells whose reactivation led to the suite of sickness behaviours we’re familiar with: neurons characterised by the expression of ADCYAP1, a gene important in the neural response to stress. Activating these neurons, as before, leads to the mice eating less, drinking less, moving less. Their inhibition, on the other hand, largely reduces the effects of LPS on the mice.  

Behaviours, such as anxiety or happiness, are tricky things to study. They’re abstract concepts which don’t frequently lend themselves to simple explanations. What Anoj and his team did here, remarkably, was to connect that collection of behaviours that make our lives miserable to a specific group of neurons deep in our brainstem. The next time that you’re lying in bed at 3am, not hungry despite skipping dinner, not thirsty despite having a full glass of water sitting next to you, shivering despite the duvet covering you – you can blame your brain. 

Additional References:

Ran, C., Boettcher, J.C., Kaye, J.A. et al. A brainstem map for visceral sensations. Nature 609, 320–326 (2022). https://doi.org/10.1038/s41586-022-05139-5

Zhang, C., Kaye, J.A., Cai, Z., Wang, Y., Prescott, S.L. and Liberles, S.D. Area postrema cell types that mediate nausea-associated behaviors. Neuron109, 461-472 (2021). https://doi.org/10.1016/j.neuron.2020.11.010

Cover image sourced from Pixabay in Pexels (https://www.pexels.com/photo/apartment-bed-carpet-chair-269141/)

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