Sex differences in the neuroimmune system

https://doi.org/10.1016/j.cobeha.2018.05.007Get rights and content

Highlights

  • Sex differences in microglia number and function are evident early in the neonatal brain.

  • Microglia have an important role in establishing sex-specific behaviors later in life.

  • Vulnerability to perinatal immune activation is dependent on sex difference in microglia.

  • Age significantly influences sex differences in the expression of the neuroimmune response.

While sex differences in the peripheral immune response have been studied extensively, sex differences in the neuroimmune response, including glial activation and associated cytokine production in the brain, is a recently emerging field. Advances in our understanding of sex differences in the neuroimmune response have important implications for understanding how neural circuits are shaped during early brain development, how activation of the immune system may impact cognitive function and behavior, and how inflammation may be associated with the risk of mental health disorders that have strong sex-biases. The goal of this mini review is to highlight recent work in the field of sex differences in neuroimmune function, with a particular focus on how microglia function is influenced by age and sex hormone exposure.

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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