Brain sex differences and hormone influences: a moving experience?

Abstract

Sex differences in the nervous system come in many forms. Although a majority of sexually dimorphic characteristics in the brain have been described in older animals, mechanisms that determine sexually differentiated brain characteristics often operate during critical perinatal periods. Both genetic and hormonal factors likely contribute to physiological mechanisms in development to generate the ontogeny of sexual dimorphisms in brain. Relevant mechanisms may include neurogenesis, cell migration, cell differentiation, cell death, axon guidance and synaptogenesis. On a molecular level, there are several ways to categorize factors that drive brain development. These range from the actions of transcription factors in cell nuclei that regulate the expression of genes that control cell development and differentiation, to effector molecules that directly contribute to signalling from one cell to another. In addition, several peptides or proteins in these and other categories might be referred to as 'biomarkers' of sexual differentiation with undetermined functions in development or adulthood. Although a majority of sex differences are revealed as a direct consequence of hormone actions, some may only be revealed after genetic or environmental disruption. Sex differences in cell positions in the developing hypothalamus, and steroid hormone influences on cell movements in vitro, suggest that cell migration may be one target for early molecular actions that impact brain development and sexual differentiation.

Figure 1

This schematic diagram depicts several signaling systems that may contribute to sexual differentiation of the vertebrate diencephalon. Estradiol (E2) synthesized via the aromatase (Arom) enzyme may bind estrogen receptors (ER’s) located in cell nuclei or estrogen binding proteins (EBP; that may or may not be identified ER’s) found in cell membranes. E2 signaling through ER’s may influence the transcription of genes involved in nitric oxide (nitric oxide synthase; nNOS) or GABA synthesis (glutamic acid decarboxylase; GAD). In turn, the end products, NO and GABA, may diffuse locally to influence neighboring cells or form molecular gradients to impact cells at greater distances. E2 signaling through ER’s may also influence brain derived neurotrophic factor (BDNF). The arrows between cells indicates the hypothesis that cells which synthesize nNOS, BDNF, and GAD may also interact with each other to influence the migration and cell positions of neurons in the developing preoptic area (except BDNF) and hypothalamus (see text for specific evidence). Aromatase may be localized in a separate cell type as depicted in the diagram, or be co-localized in one of the other cell types.