Neuroimmune Activation Drives Multiple Brain States

Abstract

Neuroimmune signaling is increasingly identified as a critical component of neuronal processes underlying memory, emotion and cognition. The interactions of microglia and astrocytes with neurons and synapses, and the individual cytokines and immune signaling molecules that mediate these interactions are a current focus of much research. Here, we discuss neuroimmune activation as a mechanism triggering different states that modulate cognitive and affective processes to allow for appropriate behavior during and after illness or injury. We propose that these states lie on a continuum from a naïve homeostatic baseline state in the absence of stimulation, to acute neuroimmune activity and chronic activation. Importantly, consequences of illness or injury including cognitive deficits and mood impairments can persist long after resolution of immune signaling. This suggests that neuroimmune activation also results in an enduring shift in the homeostatic baseline state with long lasting consequences for neural function and behavior. Such different states can be identified in a multidimensional way, using patterns of cytokine and glial activation, behavioral and cognitive changes, and epigenetic signatures. Identifying distinct neuroimmune states and their consequences for neural function will provide a framework for predicting vulnerability to disorders of memory, cognition and emotion both during and long after recovery from illness.

Memory deficits in males and females long after subchronic immune challenge

“…Although we did not observe microglial activation, it is likely that more subtle neuroimmune changes persist long after a subchronic immune challenge (Tchessalova et al, 2018). For example, persistent microglial priming persists to adulthood after early life immune challenge (Hoeijmakers, Heinen, van Dam, Lucassen, & Korosi, 2016;Williamson & Bilbo, 2013).…”

“…Together, these findings demonstrate progressive changes in neural function and sex-specific patterns of memory deficits emerging over the weeks and months following a mild, subchronic immune challenge. The delayed emergence of memory deficits in the absence of ongoing overt microglial activation suggests that the transient immune response exerts lasting indirect effects on neural function (Tchessalova, Posillico, & Tronson, 2018).…”

Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge

“…In contrast, females previously exposed to a subchronic immune challenge showed markedly different patterns of gene expression after an acute injection compared with previously naïve mice. Together with the sexspecific changes in baseline gene expression, where males but not females showed changes 12 weeks later, these findings suggest that males and females have different patterns of vulnerability and resilience to future stressors, immune challenge, and other environmental events (Tchessalova et al, 2018).…”

“…Here, females previously exposed to a subchronic immune challenge showed greater dysregulation of transcriptional response after an acute LPS injection, whereas males showed similar patterns of gene expression whether or not they had previously experienced a subchronic challenge. Thus both males and females show changes in transcriptional processes in the brain that persist long after a subchronic immune challenge, but the patterns of dysregulation show striking sex specificity, and suggest that males and females have different patterns of vulnerability and resilience to future stressors, including immune challenge, and other environmental events (Tchessalova et al, 2018).…”

“…The neuroimmune system, and its regulation by peripheral immune states, plays an important regulatory role for behavioral, affective, and cognitive functions (Raison et al, 2006;Tchessalova et al, 2018). In addition to their central role in behavioral and physiological changes during illness and injury (Dantzer et al, 1998), neuroimmune cells and cytokines are activated as a consequence of physical and psychological stressors (Bekhbat and Neigh, 2017), and are critical for normal neural functions including synaptic plasticity and memory (Avital et al, 2003;Yirmiya and Goshen, 2011;del Rey et al, 2013;Adamsky et al, 2018).…”