Sickness and the social brain: How the immune system regulates behavior across species

Many instances of sickness critically involve the immune system. The immune system talks to the brain in a bi-directional loop. This discourse affords the immune system immense control, such that it can influence behavior and optimize recovery from illness. These behavioral responses to infection are called sickness behaviors and can manifest in many ways, including changes in mood, motivation, or energy. Fascinatingly, most of these changes are conserved across species, and most organisms demonstrate some form of sickness behaviors. One of the most interesting sickness behaviors, and not immediately obvious, is altered sociability. Here, we discuss how the immune system impacts social behavior, by examining the brain regions and immune mediators involved in this process. We first outline how social behavior changes in response to infection in various species. Next, we explore which brain regions control social behavior and their evolutionary origins. Finally, we describe which immune mediators establish the link between illness and social behavior, in the context of both normal development and infection. Overall, we hope to make clear the striking similarities between the mechanisms that facilitate changes in sociability in derived and ancestral vertebrate, as well as invertebrate, species.

Fevers and the social costs of acute infection in wild vervet monkeys

Fevers are considered an adaptive response by the host to infection. For gregarious animals, however, fever and the associated sickness behaviors may signal a temporary loss of capacity, offering other group members competitive opportunities. We implanted wild vervet monkeys (Chlorocebus pygerythrus) with miniature data loggers to obtain continuous measurements of core body temperature. We detected 128 fevers in 43 monkeys, totaling 776 fever-days over a 6-year period. Fevers were characterized by a persistent elevation in mean and minimum 24-h body temperature of at least 0.5 °C. Corresponding behavioral data indicated that febrile monkeys spent more time resting and less time feeding, consistent with the known sickness behaviors of lethargy and anorexia, respectively. We found no evidence that fevers influenced the time individuals spent socializing with conspecifics, suggesting social transmission of infection within a group is likely. Notably, febrile monkeys were targeted with twice as much aggression from their conspecifics and were six times more likely to become injured compared to afebrile monkeys. Our results suggest that sickness behavior, together with its agonistic consequences, can carry meaningful costs for highly gregarious mammals. The degree to which social factors modulate the welfare of infected animals is an important aspect to consider when attempting to understand the ecological implications of disease.

Differential inflammation-mediated function of prokineticin 2 in the synovial fibroblasts of patients with rheumatoid arthritis compared with osteoarthritis

Prokineticin 2 (PK2) is a secreted protein involved in several pathological and physiological processes, including the regulation of inflammation, sickness behaviors, and circadian rhythms. Recently, it was reported that PK2 is associated with the pathogenesis of collagen-induced arthritis in mice. However, the role of PK2 in the pathogenesis of rheumatoid arthritis (RA) or osteoarthritis (OA) remains unknown. In this study, we collected synovial tissue, plasma, synovial fluid, and synovial fibroblasts (SF) from RA and OA patients to analyze the function of PK2 using immunohistochemistry, enzyme-linked immunosorbent assays, and tissue superfusion studies. PK2 and its receptors prokineticin receptor (PKR) 1 and 2 were expressed in RA and OA synovial tissues. PKR1 expression was downregulated in RA synovial tissue compared with OA synovial tissue. The PK2 concentration was higher in RA synovial fluid than in OA synovial fluid but similar between RA and OA plasma. PK2 suppressed the production of IL-6 from TNFα-prestimulated OA-SF, and this effect was attenuated in TNFα-prestimulated RA-SF. This phenomenon was accompanied by the upregulation of PKR1 in OA-SF. This study provides a new model to explain some aspects underlying the chronicity of inflammation in RA.

Stellate Ganglion Block Successfully Treats Long COVID/PASC: A Case Series

The SARS-CoV-2 pandemic has resulted in a secondary pandemic of individuals suffering from pernicious symptoms termed “Long COVID” or PASC. In spite of significant societal impact, the condition remains mysterious and effective treatment remains elusive. Individuals experience debilitating symptoms including fatigue, “brain fog,” loss or altered smell and/or taste, anxiety and depression. Most of these symptoms are included in the “sickness behavior response” initiated from the brainstem when levels of circulating pro-inflammatory cytokines are high. Ordinarily a feedback loop prevents excessive production of these cytokines, however the SARS-CoV-2 virus has demonstrated the ability to induce the sympathetic nervous system (SNS), likely due to imbalance between ACE1 and ACE2 activity. Persistent sympathetic drive causes increased cytokine release, which interferes with the feedback loop that ends “sickness behaviors.” The stellate ganglion is a paravertebral collection of sympathetic nerves located in the cervical region that provides a convenient entry point to reduce activity of the SNS using local anesthetic blockade. The stellate ganglion block (SGB) has a well-established safety and efficacy profile for a variety of conditions involving the SNS. In this case report series, we treated three consecutive “Long COVID” patients with SGB. All three patients reported significant and durable improvement in symptoms including fatigue, “brain fog,” and smell and taste derangements. Our findings provide evidence implicating dysautonomia as the main etiology of Long COVID/PASC symptoms and suggest that SGB is an effective intervention for this condition with the potential to change the course of the second COVID pandemic, “Long COVID”/PASC.

Automated home-cage monitoring as a potential measure of sickness behaviors and pain-like behaviors in LPS-treated mice

The use of endotoxin, such as lipopolysaccharide (LPS) as a model of sickness behavior, has attracted recent attention. To objectively investigate sickness behavior along with its pain-like behaviors in LPS-treated mice, the behavioral measurement requires accurate methods, which reflects clinical relevance. While reflexive pain response tests have been used for decades for pain assessment, its accuracy and clinical relevance remain problematic. Hence, we used automated home-cage monitoring LABORAS to evaluate spontaneous locomotive behaviors in LPS-induced mice. LPS-treated mice displayed sickness behaviors including pain-like behaviors in automated home-cage monitoring characterized by decreased mobile behaviors (climbing, locomotion, rearing) and increased immobility compared to that of the control group in both short- and long-term locomotive assessments. Here, in short-term measurement, both in the open-field test and automated home-cage monitoring, mice demonstrated impaired locomotive behaviors. We also assessed 24 h long-term locomotor activity in the home-cage system, which profiled the diurnal behaviors of LPS-stimulated mice. The results demonstrated significant behavioral impairment in LPS-stimulated mice compared to the control mice in both light and dark phases. However, the difference is more evident in the dark phase compared to the light phase owing to the nocturnal activity of mice. In addition, the administration of indomethacin as a pharmacological intervention improved sickness behaviors in the open-field test as well as automated home-cage monitoring, confirming that automated home-cage monitoring could be potentially useful in pharmacological screening. Together, our results demonstrate that automated home-cage monitoring could be a feasible alternative to conventional methods, such as the open-field test and combining several behavioral assessments may provide a better understanding of sickness behavior and pain-like behaviors in LPS-treated mice.

Hepatic FGF21 preserves thermoregulation and cardiovascular function during bacterial inflammation

Sickness behaviors, including anorexia, are evolutionarily conserved responses to acute infections. Inflammation-induced anorexia causes dramatic metabolic changes, of which components critical to survival are unique depending on the type of inflammation. Glucose supplementation during the anorectic period induced by bacterial inflammation suppresses adaptive fasting metabolic pathways, including fibroblast growth factor 21 (FGF21), and decreases survival. Consistent with this observation, FGF21-deficient mice are more susceptible to mortality from endotoxemia and polybacterial peritonitis. Here, we report that increased circulating FGF21 during bacterial inflammation is hepatic derived and required for survival through the maintenance of thermogenesis, energy expenditure, and cardiac function. FGF21 signaling downstream of its obligate coreceptor, β-Klotho (KLB), is required in bacterial sepsis. However, FGF21 modulates thermogenesis and chronotropy independent of the adipose, forebrain, and hypothalamus, which are operative in cold adaptation, suggesting that in bacterial inflammation, either FGF21 signals through a novel, undescribed target tissue or concurrent signaling of multiple KLB-expressing tissues is required.

The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging

Precipitous declines in cognitive function can occur in older individuals following a variety of peripheral immune insults, such as surgery, infection, injury, and unhealthy diet. Aging is associated with numerous changes to the immune system that shed some light on why this abrupt cognitive deterioration may occur. Normally, peripheral-to-brain immune signaling is tightly regulated and advantageous; communication between the two systems is bi-directional, via either humoral or neural routes. Following an immune challenge, production, secretion, and translocation of cytokines into the brain is critical to the development of adaptive sickness behaviors. However, aging is normally associated with neuroinflammatory priming, notably microglial sensitization. Microglia are the brain’s innate immune cells and become sensitized with advanced age, such that upon immune stimulation they will mount more exaggerated neuroimmune responses. The resultant elevation of pro-inflammatory cytokine expression, namely IL-1β, has profound effects on synaptic plasticity and, consequentially, cognition. In this review, we (1) investigate the processes which lead to aberrantly elevated inflammatory cytokine expression in the aged brain and (2) examine the impact of the pro-inflammatory cytokine IL-1β on brain plasticity mechanisms, including its effects on BDNF and AMPA and NMDA receptor-mediated long-term potentiation.

Behavior Shapes Infectious Disease Dynamics in Birds

Parasites both affect and are affected by the behavior of birds. Moreover, specific avian behaviors can either suppress or augment parasite spread, depending on context and parasite transmission mode. The chapter focuses on major categories of behavior important for the key steps of the parasite transmission process: first, the likelihood of exposure to parasites; second, host susceptibility to infection and degree of infectiousness reached once exposed; and third, the likelihood of spreading infection to other hosts or vectors. The chapter begins by discussing behaviors that birds use to minimize exposure to parasites (e.g., preening and other ‘antiparasite’ behaviors) and the immediate effects of infection on behavior (e.g., lethargy and other ‘sickness’ behaviors). The focus then truns to foraging and movement, which are specific behaviors that both can increase exposure to parasites and are altered by infection. Finally, the chapter considers how a suite of behaviors including social interactions, individual personality, and mating behaviors can affect and are affected by parasites in ways relevant to all three steps of the parasite transmission process. Throughout, the chapter highlights and integrates areas in which recent advances have been made or for which more data are sorely needed in avian systems, emphasizing directions for future research at the intersection of avian behavior and infectious disease ecology.

Assessing the Use of Biometric Ear Tags as Body Temperature Monitoring Devices in Swine

It is difficult to detect the subtle changes associated with sickness behaviors in individual pigs early enough to prevent disease outbreaks in group housing settings within large production facilities. This failure results in significant losses to the swine industry. Strategies that allow early detection of parameters such as febrile responses could therefore significantly improve herd health and producer profitability. Our objective was to determine if the use of a biometric ear tag capable of measuring temperature could be used to accurately monitor body temperature in swine. To accomplish this, 42-d-old pigs (n = 21) were fitted with biometric ear tags for 35 d. These devices continuously measured auricular skin temperature and allowed data collection via a paired raspberry pi aggregator. During this period, repeated epidermal temperatures were also taken daily on the rump, shoulder, and ear using a clinical grade infrared thermometer. Correlation analysis using the PROC CORR procedure of SAS was then conducted to determine the ability of the biometric device to estimate body temperature relative to estimates from the clinical device. Infrared temperature readings for the ear significantly correlated with those taken at the shoulder (P < 0.0001) and rump (P < 0.0001). Importantly, temperature readings measured by the biometric ear tags also significantly correlated with infrared readings at the ear (P < 0.0001), shoulder (P < 0.0001) and rump (P < 0.0001) with Pearson Correlation coefficients of 0.51, 0.21, and 0.23, respectively. Collectively, these data support the hypothesis that the biometric ear tag device tested during this trial can be used to continuously monitor body temperature in young swine. These results indicate that further efforts to develop these devices as novel herd health monitoring devices is indeed warranted with the next step involving the assessment of their ability to detect physiological changes in body temperature.

Sickness behaviors across vertebrate taxa: proximate and ultimate mechanisms

ABSTRACT There is nothing like a pandemic to get the world thinking about how infectious diseases affect individual behavior. In this respect, sick animals can behave in ways that are dramatically different from healthy animals: altered social interactions and changes to patterns of eating and drinking are all hallmarks of sickness. As a result, behavioral changes associated with inflammatory responses (i.e. sickness behaviors) have important implications for disease spread by affecting contacts with others and with common resources, including water and/or sleeping sites. In this Review, we summarize the behavioral modifications, including changes to thermoregulatory behaviors, known to occur in vertebrates during infection, with an emphasis on non-mammalian taxa, which have historically received less attention. We then outline and discuss our current understanding of the changes in physiology associated with the production of these behaviors and highlight areas where more research is needed, including an exploration of individual and sex differences in the acute phase response and a greater understanding of the ecophysiological implications of sickness behaviors for disease at the population level.