Synaptic, cellular, and circuit mechanisms underlying sex differences in behaviors

Biol Sex Differ. 2026 May 29. doi: 10.1186/s13293-026-00931-8. Online ahead of print.

ABSTRACT

Consistent with differences in behaviors between sexes, studies reveal sex differences in the organization of neural circuits, synaptic function, and neuronal excitability, as well as sex-dependent recruitment of specific neuronal subtypes during behavior. These studies demonstrate sex differences in cell numbers, brain region volumes, cellular composition of brain areas, and density and strength of synapses in many brain regions, innervation of neuronal subtypes, receptor-mediated transduction mechanisms, neurotransmitter and neuropeptide release, and the influence of neuronal growth factors. Beyond insights into the mechanisms of sex differences in behaviors, understanding sex-typical circuit, cellular, and synaptic processes is crucial for identifying the causes of sex-typical vulnerabilities to nervous system disorders, such as the high prevalence of autism spectrum disorders and attention deficit hyperactivity disorder in males, and the higher incidence of affective, anxiety, and trauma-related disorders in females. Because these disorders often emerge during various developmental stages, it is essential to understand how development interacts with genetic, epigenetic, metabolic, hormonal, and environmental factors to affect the nervous system across sexes. Consequently, future research that examines the interaction between the nervous system and these critical factors is expected to elucidate the mechanisms underlying nervous system disorders. Additionally, targeting sex-specific mechanisms involved in these disorders could open new opportunities for more effective treatments in both sexes.

PMID:42216105 | DOI:10.1186/s13293-026-00931-8