Sex differences in the brain are established by the differential gonadal steroid hormonal milieu experienced by developing male and female fetuses and newborns. Androgen production by the testis starts in males prior to birth resulting in a brief developmental window during which the brain is exposed to high levels of steroid. Androgens and aromatized estrogens program the developing brain toward masculinized physiology and behavior that is then manifest in adulthood. In rodents, the perinatal programming of sex-specific adult mating behavior provides a model system for exploring the mechanistic origins of brain sex differences. Microglia are resident in the brain and provide innate immunity. Previously considered restricted to response to injury, these cells are now thought to be major contributors to the sculpting of developing neural circuits. This role extends to being an important component of the sexual differentiation process and has opened the door for exploration into myriad other aspects of neuroimmunity and inflammation as possible determinants of sex differences. In humans, males are at greater risk for more frequent and/or more severe neuropsychiatric and neurological disorders of development, many of which include prenatal inflammation as an additional risk factor. Emerging clinical and preclinical evidence suggests male brains experience a higher inflammatory tone early in development, and this may have its origins in the maternal immune system. Collectively, these disparate observations coalesce into a coherent picture in which brain development diverges in males versus females due to a combination of gonadal steroid action and neuroinflammation, and the latter increases the risk to males of developmental disorders.
Margaret M. McCarthy
Danielle S. Stolzenberg, Kimberly L. Hernandez-D'Anna, Oliver J. Bosch, and Joseph S. Lonstein
For female mammals, caring for young until weaning or even longer is an extension of the reproductive burden that begins at insemination. Given the high price females potentially pay for failing to transmit genetic material to future generations, a multitude of interacting endocrine, neuroendocrine, and other neurochemical determinants are in place to ensure competent maternal caregiving by the time the offspring are born. Achieving this high maternal competency at parturition seems effortless but is quite a feat given that many nulliparous and parentally inexperienced female mammals are more prone to ignore, if not outright harm, conspecific neonates. There are important roles for ovarian steroids (e.g., estradiol and progesterone), adrenal steroids (e.g., glucocorticoids), and neuropeptide hormones (e.g., prolactin, oxytocin, arginine-vasopressin, and corticotropin-releasing factor) released during pregnancy, parturition, and postpartum in the onset and maintenance of caregiving behaviors in a broad range of commonly studied animals including rats, mice, rabbits, sheep, and primates. It is especially remarkable that the same collection of hormones influences caregiving similarly across these diverse animals, although to varying degrees. In addition to the well-known effects of hormones and neuropeptides on motherhood, more recent research indicates that experience-dependent epigenetic effects are also powerful modulators of the same neural substrates that can influence maternal responding.
Jacques Balthazart and Gregory F. Ball
It is well established that testosterone from testicular origin plays a critical role in the activation of male sexual behavior in most, if not all, vertebrate species. These effects take place to a large extent in the preoptic area although other brain sites are obviously also implicated. In its target areas, testosterone is actively metabolized either into estrogenic and androgenic steroids that have specific behavioral effects or into inactive metabolites. These transformations either amplify the behavioral activity of testosterone or, alternatively, metabolism to an inactive compound dissipates any biological effect. Androgens and estrogens then bind to nuclear receptors that modulate the transcription of specific genes. This process is controlled by a variety of co-activators and co-repressors that, respectively, enhance or inhibit these transcriptional processes. In addition, recent work has shown that the production of estrogens by brain aromatase can be modulated within minutes by changes in neural activity and that these rapid changes in neuroestrogen production impact sexual behavior, in particular sexual motivation within the same time frame. Estrogens thus affect specific aspects of male sexual behavior in two different time frames via two types of mechanisms that are completely different. Multiple questions remain open concerning the cellular brain mechanisms that mediate testosterone action on male sexual behavior.