Sex differences in the neuroimmune system
Introduction
Sex is a biological variable that significantly affects all aspects of an organism, including the immune system. An individual’s biological sex is determined as male or female by the differential presence of the sex chromosomes in each cell, the differentiation of the reproductive organs, and the subsequent production of sex-specific steroid hormones that organize the brain as male or female. Every cell has a sex; thus, biological sex differences can influence the physiological characteristics of the immune response that determine recognition, clearance, and transmission of pathogens, as well as the neuroimmune response to environmental insults. Gender, on the other hand, is an individual’s identity as male or female with reference to social and cultural differences, rather than biological differences, per se. Gender differences can influence behaviors that impact the risk of exposure to pathogens, can restrict or promote access to healthcare, and can influence other behaviors that affect the course or duration of an infection in men and women. While both sex and gender have a critical role in determining the neuroimmune response in males and females, the focus of this review will be on biological sex differences in the neuroimmune response and their influence on the brain and behavior throughout the lifespan.
Section snippets
Sex differences in microglia number and function in the developing brain influence sex differences in neural circuit formation
A critical period is defined as a period of development wherein a system maintains a heightened sensitivity to particular stimuli in order to develop in a specific manner. Some of the most compelling evidence for critical periods comes from the early studies of sexual differentiation of the brain and behavior [1]. These studies elegantly demonstrate the powerful role of sex steroid hormones during perinatal development in organizing the brain and behavior as either male or female. These
Sex differences in microglia: how is risk conferred following early-life immune activation?
During the early neonatal period (P4), males have more microglia with an amoeboid morphology than females in a number of brain regions important for cognition, memory, and emotion processing [3]. But, compared to males, female microglia show significant increases in the expression of a number of cytokines and chemokines including IL-10, IL-1f5, CCL22, CCR4, CXCL9, and IL-1β protein in many of these same regions at this same age [3]. These findings suggest that males and females have fundamental
Age as a determinant of sex differences in the neuroimmune response: what do we know about the role of microglia?
Age, much like sex, is a critical determinant for how immune activation influences sex differences in the immune response. As previously mentioned, Bilbo and colleagues found that neonatally infected male rats showed cognitive deficits in adulthood following an immune challenge that occurred around the time of learning, an effect that is not seen in females [15]. Using this same model, Osborne and colleagues [30••] determined that juvenile males and females do not yet show these cognitive
Conclusions
The recent data summarized here only begin to elucidate the diverse mechanisms by which sex differences in microglia number and function may influence the establishment and maintenance of sex differences in the brain. What has been discovered to-date has been enormously instrumental in our understanding of how sex differences in the neuroimmune system can affect sexual differentiation of the brain and behavior and the vulnerability to early-life immune challenges, which increases the risk for
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
•• of outstanding interest
Acknowledgements
This work was supported by the National Institutes of Health [NIH R21MH104280, R01MH106553 and R21MH101663 to JMS] as well as a Brain and Behavior Research Foundation NARSAD Young Investigator Award to JMS.
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