Neurological and psychiatric diseases emerge from pathology and dysfunction of the brain (discussed in Chapter 12 of Principles of Neurobiology). Interestingly, the brain also plays an important role in disease throughout the body, producing associated perceptual and behavioral phenomena. One key example of this is the suite of perceptual and behavioral responses to systemic infection. We have all experienced this—when infected with respiratory viruses that cause the 'common cold,' along with runny noses and coughs, we often are laid low by symptoms like fatigue and 'brain fog.' More clinically important, for certain populations including the elderly, systemic infection can be associated with altered mental status and delirium, sometimes requiring hospital admission.
What is the neural basis of these illness associated effects on perception and behavior? Very little is known about this question, but logically, there are two families of potential mechanisms. On the one hand, it is possible that illness related behavior is adaptive, and the nervous system thus senses infection and associated immune responses, and actively produces illness related percepts and behaviors. On the other hand, it is possible that that illness related behavior emerges from collateral damage to the nervous system associated with the battle between invading pathogens and immune responses. This may occur via occult pathogen invasion of the brain (as has been suggested with the 'respiratory’ virus SARS-CoV-2) or neuroinflammation induced by humoral factors, or other yet-to-be-elucidated mechanisms. These possibilities are not mutually exclusive, but until recently, the evidence for direct sensation and production of illness-associated behavior was scant.
Two recent landmark studies have now identified brain regions and cell types involved with sensing and producing illness behavior (Ilanges et al., 2022; Osterhout et al., 2022). Here, I focus on the more recent paper by Ilanges et al. To probe the neural basis of illness behavior, Ilanges et al. injected mice with lipopolysaccharide (LPS). LPS is a component of the membrane of gram-negative bacteria. Owing to its reliable presence on an important group of pathogens, it is a potent activator of the immune system. Importantly, LPS is not capable of replicating or directly injuring tissue, so any behavioral changes associated with LPS cannot be caused by infection per se. In response to LPS, mice exhibited hypothermia, less locomotion, less food intake, and less water intake.
Having established a rodent model for illness behavior, the authors then employed whole-brain Fos imaging to identify brain areas that may be responsible for mediating these behaviors. Fos is a transcription factor whose expression is upregulated with neuronal depolarization and is thus frequently used as a proxy for neural activity. With whole brain clearing and light sheet microscopic imaging, the investigators were able to identify those regions across the entire brain that were activated by LPS (Fig 1a,b). They found several such activated regions. This finding (that particular brain regions are reliably activated by immunogenic stimuli) suggests that illness behavior may be specifically sensed and produced by the brain. But the authors then go one step further to ask whether reactivating these neurons alone is sufficient to produce illness behavior. To test this idea, they focused on a compelling pair of regions in the brainstem with known roles in the sensation of internal physiological states, the area postrema (AP) and nucleus of the solitary tract (NTS). They used the TRAP2 system to specifically re-activate cells in NTS and AP that were activated by LPS injection (Fig 1c). This recreated the behavioral phenotype of anorexia, adipsia, and decreased locomotion (Fig 1d,e) without any associated immunogenic stimulus! These data strongly argue that the brain senses the immunologic milieu and creates illness behavior. Furthermore, these experiments identify specific neurons that might be involved in this process.
Many interesting and important questions remain. At the organismal level, if sickness behavior is adaptive, it is still rather unclear how it is adaptive. What is the benefit to feeling crummy? We can speculate, but clearer answers to this will be critical to pave the way for therapeutics targeting circuits that promote illness behavior. At the neural level, Ilanges et al. localize illness behavior to a large set of neurons in the AP and NTS. However, the particular role of transcriptomically-defined cell groups in the AP and NTS remains unclear, as do the spiking properties and synaptic architecture of involved neurons. There is much more to learn, but the offering by Ilanges et al., combined with that of Osterhout et al. (which focuses on sickness-regulating neurons in the hypothalamus), is an impressive opening salvo in the endeavor to understand how the brain senses infection and internal disease states to guide behavior.
Figure 1: (a, b) Fos expressing cells in a cleared brains 3 hours after saline (a) or LPS (b) injection. Inset shows numerous Fos-positive cells in the NTS and AP. Scale bars, 1 mm (left) or 250 μm (right). (c) Schematic for TRAP2-based reactivation of LPS activated cells. TRAP2 mice received injections of Cre-dependent excitatory DREADD hM3Dq into the AP-NTS region. 4-HT (4 hydroxytamoxifen, which activates a modified Cre in the TRAP2 strategy) and LPS were simultaneously injected, leading to expression of excitatory DREADDs in cells activated by LPS. (d,e) Re-activation of LPS-TRAPed cells (blue reactivated with CNO, grey controls) results in sickness behaviors including decreased movement (d) and decreased food intake (e). Adapted from Ilanges et al., 2022.
References
Ilanges, A., Shiao, R., Shaked, J., Luo, J.-D., Yu, X., and Friedman, J.M. (2022). Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour. Nature 609, 761–771. 10.1038/s41586-022-05161-7.
Osterhout, J.A., Kapoor, V., Eichhorn, S.W., Vaughn, E., Moore, J.D., Liu, D., Lee, D., DeNardo, L.A., Luo, L., Zhuang, X., et al. (2022). A preoptic neuronal population controls fever and appetite during sickness. Nature 606, 937–944. 10.1038/s41586-022-04793-z.