Defining the cellular and anatomic identity and developmental trajectory of sex-differential subcortical cells and circuits in ASD

The biological basis of the sex bias in autism (ASD) remains unclear. This project hypothesizes that sex-differential subcortical regions mediate a female protective effect, either by modifying cortical function or by directly disrupting subcortical circuitry. To address this hypothesis, the project aims to define how sex differences in neural development and function intersect with ASD-related genetic vulnerability within three key subcortical structures – the bed nucleus of the stria terminalis (BNST), medial amygdala (MeA), and ventromedial hypothalamus (VMH) – and the interaction of these regions with the medial prefrontal cortex (mPFC).

First, the team seeks to characterize subcortical cell populations that are sex-differential and/or impacted by ASD-associated genes. Building on their previous discovery of sex-specific neurons in these regions in mouse and vole, the focus will be to determine their molecular identity, developmental timing, and conservation across species. Additionally, studies will assess their connectivity within subcortical circuits and to the mPFC. Second, efforts will focus on examining how mutations in ASD-associated genes (SCN2A, SHANK3, ARID1B, ADNP) affect subcortical neuronal function and circuit connectivity across development. Studies will test the hypothesis that a critical period, during which sex differences in subcortical physiology emerges, increases male susceptibility to ASD-associated mutations. The group will map connectivity within estrogen-sensitive (Esr1+) circuits and employ genetically encoded voltage indicators to identify sex-specific neural dynamics, uncovering novel biomarkers and mechanisms of circuit dysfunction.

By integrating molecular, developmental, and systems-level approaches across species, this research will reveal mechanisms linking sex, subcortical circuits, and ASD risk — providing a foundation for novel, circuit-targeted interventions that address sex bias in ASD.