Abstract
Immune factors (e.g., cytokines, chemokines) can alter the activity of neuronal circuits to promote “sickness behavior,” a suite of adaptive actions that organisms exhibit in response to infection/injury in order to maximize their chances of recovery (i.e., return to homeostasis). This includes drastic alterations in sleep/wake states, locomotor activity, and food intake, among other behaviors. Despite the ample evidence highlighting interactions between the brain and systemic immunity, studies on how immune challenges alter the activity of genetically defined cell populations controlling arousal states are scarce. As the lateral hypothalamus (LH) serves a major integrative function in behavioral arousal, food intake, and monitoring and responding to changes in systemic physiology, we investigated how GABAergic neurons within this brain region alter their activity across normal sleep/wake states and in response to a peripheral immune challenge with bacterial endotoxin [lipopolysaccharides (LPS)]. Using fiber photometry (GCaMP6s Ca2+ signal) in tandem with electroencephalogram (EEG)/EMG recordings to determine arousal states, we observed that population activity of GABAergic neurons in the lateral hypothalamus (LHGABA) is highest during rapid-eye-movement sleep (REM), and this activity changes drastically across spontaneous arousal state transitions, with the lowest activity observed during non-REM sleep. Upon intraperitoneal LPS challenge, LHGABA neurons rapidly decrease their activity in tandem with elimination of REM sleep behavior (characteristic of cytokine-induced sickness). Together, these data suggest that peripheral immune challenges can rapidly (in < 40 min) alter subcortical neuronal circuits controlling arousal states. Additionally, we demonstrate that fiber photometry offers a sensitive and cell-type specific tool that can be applied to study the neuronal substrates of sickness behavior.
Highlights
Sickness behavior is characterized by acute and protracted changes in sleep/wake states, appetitive, sexual, and social behavior, among other changes (Dantzer and Kelley, 2007; Dantzer et al, 2008; Myers, 2008)
We monitored LHGABA Ca2+ activity during natural arousal state transitions. These neurons exhibited marked changes in GCaMP fluorescence across arousal states, with the highest mean fractional fluorescence change ( F/F or dF/F) during rapid-eye-movement sleep (REM) sleep compared to wakefulness or NREM sleep (Figure 1)
NREM sleep and wakefulness showed similar maximal F/F values, but REM sleep reached upward of 20–30% F/F state (Figure 1E; One-way ANOVA F2,591 = 212.9; p < 0.0001); (Tukey’s post hoc wake vs. REM: q = 27.29, adjusted p < 0.0001; NREM vs. REM: q = 28.45, p < 0.0001). These results indicate that LHGABA Ca2+ activity peaks during REM sleep, suggesting that this heterogenous subset of neurons likely plays a role in REM sleeprelated phenomena
Summary
Sickness behavior is characterized by acute and protracted changes in sleep/wake states, appetitive, sexual, and social behavior, among other changes (Dantzer and Kelley, 2007; Dantzer et al, 2008; Myers, 2008). In response to acute inflammatory challenges, such as bacterial endotoxin [lipopolysaccharides (LPS)] exposure, mice increase their time spent in non-rapid-eye-movement (NREM) sleep at the expense of rapid-eye-movement sleep (REM) sleep, with corresponding decreases in wakefulness. These inflammatory signals in the periphery are partially transduced to the brain via vagal afferent nerve fibers (Opp, 2005; Zielinski et al, 2013; Borniger et al, 2017). Additional work is required to understand how neurons controlling feeding, arousal, and motivational states integrate various inflammatory inputs to induce changes in overt behavior
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