Neuroimmune Mechanisms and Sex/Gender-Dependent Effects in the Pathophysiology of Mental Disorders

Abstract

Innate and adaptive immune mechanisms have emerged as critical regulators of CNS homeostasis and mental health. A plethora of immunologic factors have been reported to interact with emotion-and behavior-related neuronal circuits, modulating susceptibility and resilience to mental disorders. However, it remains unclear whether immune dysregulation is a cardinal causal factor or an outcome of the pathologies associated with mental disorders. Emerging variations in immune regulatory pathways based on sex differences provide an additional framework for discussion in these psychiatric disorders. In this review, we present the current literature pertaining to the effects that disrupted immune pathways have in mental disorder pathophysiology, including immune dysregulation in CNS and periphery, microglial activation, and disturbances of the blood-brain barrier. In addition, we present the suggested origins of such immune dysregulation and discuss the gender and sex influence of the neuroimmune substrates that contribute to mental disorders. The findings challenge the conventional view of these disorders and open the window to a diverse spectrum of innovative therapeutic targets that focus on the immune-specific pathophenotypes in neuronal circuits and behavior. SIGNIFICANCE STATEMENT The involvement of gender-dependent inflammatory mechanisms on the development of mental pathologies is gaining momentum. This review addresses these novel factors and presents the accumulating evidence introducing microglia and proinflammatory elements as critical components and potential targets for the treatment of mental disorders.

Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior

“…In this study, we observed sex-related disparity in Ucp2 MGKO mice with female mice spared from alterations in network function and behavior. Although these differences may be attributed to divergent effects of steroid hormones on neuronal and microglial functions [ 49 ], there might be other factors that require detailed analysis in the future.…”

Ucp2-dependent microglia-neuronal coupling controls ventral hippocampal circuit function and anxiety-like behavior

“…In this study we observed gender disparity in Ucp2 MGKO mice with female mice spared from alterations in network function and behavior. Although these differences may be attributed to divergent effects of steroid hormones on neuronal and microglial functions (32), there might be other factors that require detailed analysis in the future.…”

Laterality and sex differences in the expression of brain-derived neurotrophic factor in developing rat hippocampus

“…Together with other mechanisms such as endogenous steroid levels, these differences may also underlie sexual dimorphism and left-right asymmetry in the hippocampus. Nevertheless, the hippocampus implicated in the etiology of several mental health disorders, many of which exhibit some degree of sex difference, and there are also subtle sex differences in hippocampal-associated behaviors such as spatial learning strategies and stress responsivity (Exner et al 2008;Frazier et al 2008;Kokkosis and Tsirka 2020;Krolick et al 2018).…”