A Comparative, Developmental, and Clinical Perspective of Neurobehavioral Sexual Dimorphisms

Maria-Paz Viveros,Amy Lehrner,Tomáš Paus,Adriana Mendrek,Hagit Cohen,Rachel Yehuda,Ana Belén López-Rodríguez,Edward J Wagner,Eva Maria Marco

doi:10.3389/fnins.2012.00084

Abstract

Women and men differ in a wide variety of behavioral traits and in their vulnerability to developing certain mental disorders. This review endeavors to explore how recent preclinical and clinical research findings have enhanced our understanding of the factors that underlie these disparities. We start with a brief overview of some of the important genetic, molecular, and hormonal determinants that contribute to the process of sexual differentiation. We then discuss the importance of animal models in studying the mechanisms responsible for sex differences in neuropsychiatric disorders (e.g., drug dependence) – with a special emphasis on experimental models based on the neurodevelopmental and “three hits” hypotheses. Next, we describe the most common brain phenotypes observed in vivo with magnetic resonance imaging. We discuss the challenges in interpreting these phenotypes vis-à-vis the underlying neurobiology and revisit the known sex differences in brain structure from birth, through adolescence, and into adulthood. This is followed by a presentation of pertinent clinical and epidemiological data that point to important sex differences in the prevalence, course, and expression of psychopathologies such as schizophrenia, and mood disorders including major depression and posttraumatic stress disorder. Recent evidence implies that mood disorders and psychosis share some common genetic predispositions and neurobiological bases. Therefore, modern research is emphasizing dimensional representation of mental disorders and conceptualization of schizophrenia and major depression as a continuum of cognitive deficits and neurobiological abnormalities. Herein, we examine available evidence on cerebral sexual dimorphism to verify if sex differences vary quantitatively and/or qualitatively along the psychoses-depression continuum. Finally, sex differences in the prevalence of posttraumatic disorder and drug abuse have been described, and we consider the genomic and molecular data supporting these differences.

Highlights

Psychiatric disorders and drug dependence are very important issues for healthcare systems that affect millions of people each year, and according to the National Institute of Mental Health (NIMH) only a small fraction of those patients receive an adequate treatment
CONCLUDING REMARKS In conclusion, what experimental and epidemiological studies tell us is that sex differences in the brain appear to be predominantly established during developmentally sensitive time intervals
According to the classical view of brain sexual differentiation, organizational effects are permanent structural changes arising from the actions of in utero and perinatal sex hormones, whereas activational effects are direct and temporary influences of circulating gonadal hormones on function and behavior following puberty

Summary

INTRODUCTION

There are sex differences in gene expression occurring in the murine brain as early as 10.5 days post-coitum, which precedes the in utero testosterone surge (Dewing et al, 2003) Many of these genes reside on autosomes, and include Cyp7b (involved in neurosteroid metabolism) and Rorα (implicated in Purkinje cell differentiation). It is clear that the CNS is an organ that, much like the cells and tissues of the gonads, reproductive tract and external genitalia, is targeted by the SRY gene product TDF, MIS, testicular hormones, neurosteroids, and possibly SOX proteins during the in utero and neonatal periods for the development of male patterns of behavior. These include genetic and biological factors, animal strain differences

Animal model

Findings

Arterial spin labeling