Sex Differences in the Neuroimmune Modulation of Learning and Memory

Abstract

The neuroimmune system is a specialized immune system in the brain crucial for both responding to illness and injury as well as regulating normal neural function and behavior. As such, it is perhaps not surprising that activation of the neuroimmune system results in significant impairments in synaptic plasticity and learning and memory mechanisms. In fact, neuroimmune dysregulation has been implicated in memory- and cognitive-related disorders including Alzheimer’s disease, Post-Traumatic Stress disorder, and most recently long-COVID, a series of long-lasting cognitive impairments caused by the virus SARS-CoV-2. There are known sex differences in the neuroimmune response to various pathogens, and because the neuroimmune system is at the convergence of pathological and normal function, the immune cells and signaling mechanisms involved are well-poised to modulate memory processes differently in males and females which may contribute to sex differences in the prevalence or severity of memory-related disorders. Here, we aimed to investigate the interaction of neuroimmune and memory processes in both males and females using central administration of a viral mimic, polyinosinic:polycytidylic acid (poly I:C), in C57BL/6N mice. Poly I:C is synthetic, double-stranded RNA that stimulates several cell types involved in mounting an immune response in the brain including astrocytes, microglia, and neurons, making it an excellent tool for studying broad-based neuroinflammation. Poly I:C treatment induced significant inflammation in the hippocampus of both sexes. Males had a greater magnitude of response than females for cytokines IL-1alpha, IL-1beta, IL-6, IL-10, IFNalpha, TNFalpha, CCL2, and CXCL10. Additionally, while both males and females showed increased expression of the anti-viral Type I interferon beta, only males showed increased anti-viral Type I interferon alpha, highlighting a potentially important sex difference in the anti-viral response to poly I:C. We used a T-maze task and a contextual fear-based memory task to determine the effects of neuroinflammation on learning and memory mechanisms. Pre-training poly I:C did not impair learning in the T-maze task. In contrast, pre-training poly I:C disrupted learning of contextual fear conditioning in both males and females, and analysis of cFos levels revealed significant sex differences in hippocampal activation during context fear conditioning training with poly I:C on board. Together, these findings suggest that a similar behavioral deficit induced by poly I:C in males and females involve sex-specific molecular and signaling mechanisms of learning and memory. To further investigate this, we targeted Type I interferon signaling because of the sex difference in Type I interferon induction we found previously and the capacity for Type I interferons to modulate synaptic plasticity mechanisms. We found that inhibiting Type I interferon receptors prior to treatment with poly I:C attenuated the poly I:C-induced learning deficits in males, and we did not find the same effect in females. This suggests that Type I interferons play a more important role in modulating learning in males compared with females, and Type I interferon signaling is a potential target for understanding sex differences in biological mechanisms of memory impairment induced by neuroimmune activation.