Fig. 1.

Schematic depiction of the multiple levels at which sex influences brain function. Sex is a ubiquitous, context-creating modulator of brain and behavior, accomplished through both organizational effects that program subsequent brain sensitivities and development, and activational effects that acutely impact neural function. Sex influences the internal environment in which brain function occurs (e.g., differential exposure to stress or immune soluble molecules) as well as modulating the impact of the external environment (e.g., diet or stressors, particularly in the prenatal environment, or even social responses from others based on sex). Sex chromosomes impact brain development directly, may impact physiology through differences in exposure to gene products (e.g., sex-linked genes or differences in gene dosage), and alter brain function developmentally and activationally through sex-determined gonadal function and differential exposure to sex hormones. Sex differences in peripheral organs (e.g., adipose, liver) lead to differential exposure of the brain to hormones as well as medications (through effects on metabolism). The sexome refers to the cumulative array of sex-related modulatory effects on intracellular molecular interactions. Sex differences appear at all levels of neural organization, from cell to circuit. Finally, reported sex differences in meta-cognitions may influence perception and processing of environmental stimuli, thus influencing affective generation and regulation (references appear in the text)