Three's Company: Neuroimmune activation, sex, and memory at the tripartite synapse.

The neuroimmune system is required for normal cognitive functions such as learning and memory in addition to its critical role in detecting and responding to invading pathogens and injury. Understanding the functional convergence of neurons, astrocytes, and microglia at the synapse, particularly in the hippocampus, is key to understanding the nuances of such diverse roles. In the healthy brain, communication between all three cells is important for regulating neuronal activation and synaptic plasticity mechanisms, and during neuroinflammation, the activity and functions of all three cells can produce and be modulated by inflammatory cytokines. An important remaining component to this system is the conclusive evidence of sex differences in hippocampal plasticity mechanisms, hormone modulation of synaptic plasticity, functional properties of hippocampal neurons, and in neuroimmune activation. Sex as a biological variable here is necessary to consider given sex differences in the prevalence of memory-related disorders such as Alzheimer's disease and Post-Traumatic Stress disorder, both of which present with neuroimmune dysregulation. To make meaningful progress towards a deeper understanding of sex biases in memory-related disease prevalence, I propose that the next chapter of psychoneuroimmune research must focus on the signal integration and transduction at the synapse between experience-dependent plasticity mechanisms, neuroimmune activation, and the influence of biological sex.