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

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.

Neurocognitive Growth Charting in Psychosis Spectrum Youths

“…Females with schizophrenia have a later onset and less severe symptoms, reflecting less vulnerability; perhaps greater neurocognitive dysfunction is needed for psychosis to occur. [37][38][39][40] While our ascertainment procedures differ from current clinical high-risk studies that recruit help seekers, we nonetheless capture an at-risk sample. The WRAT scores and parental education are lower in the psychosis groups, consistent with clinical high-risk samples and population-based studies of psychosis in adults.…”

Emergence of sex differences in the development of substance use and abuse during adolescence

“…Males and females receive their complement of X and Y chromosomes at fertilization, which dictate whether a fetus will be male (XY) or female (XX). A rapidly expanding literature shows that sex-specific gene expression occurs in the brain even before ovaries and testes form (Viveros et al, 2012). XX genotype alone accelerates habit formation, a critical component in the transition from reinforced to compulsive responding (Quinn, Hitchcott, Umeda, Arnold, & Taylor, 2007), and also influences nociception, aggression and maternal behavior (Arnold & Chen, 2009) The testis-determining gene sry exerts direct effects on brain development independent of the production of testosterone (De Vries et al, 2002; Dewing et al, 2006; Gatewood et al, 2006; Quinn et al, 2007).…”

“…There are conflicting data, but some studies suggest that females attain higher final volume than males (reviewed in Giedd (Giedd et al, 2012). In amygdala, changes are nucleus specific, but size of the important basolateral amygdala that is crucial for stress systems attains adult dimensions in childhood in girls, but it continues to grow during adolescence in boys to a greater final volume (Juraska et al, 2013; Viveros et al, 2012). Finally, while thinning of the cortex occurs in both boys and girls, the sex difference (thickness greater in boys than girls) diminishes in critical prefrontal areas during adolescence, and girls attain adult thickness in these areas related to executive function and behavioral inhibition before boys (Raznahan et al, 2010).…”

Epigenetic Regulation of Infant Neurobehavioral Outcomes

“…A number of neurobehavioral diseases exhibit sex-differences in their prevalence and onset including autism, ADHD, and affective disorders [58]. Placental epigenetic marks also exhibit sexual-dimorphism [59-61] [47] which could influence these neurobehavioral differences.…”