Sensory hyper- and hyposensitivity is a feature of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). It can cause significant quality of life deficits through maladaptive sensory seeking and avoiding behaviors. Foxp2 is a transcription factor expressed in the developing and mature brain. Mutations in human FOXP2 have been linked to NDDs, ASD, and most notably speech and language disorders. Foxp2 has selective expression in the brain including several areas involved in the auditory processing pathway including layer VI corticothalamic projection neurons (CThPNs), in the cells in auditory cortex (AC) and cells in the inferior colliculi (IC), a midbrain region crucial in auditory processing. Preliminary studies of the loss of Foxp2 in the mouse IC show sensory gating deficits and cell population changes. However, the role for Foxp2 in the developing and mature auditory sensory areas of the neocortex and brainstem, remains to be fully elucidated. This proposal will address the role of Foxp2 in the developing AC and IC at single nuclei resolution to identify downstream targets of and chromatin accessibility changes by Foxp2. With two regions, single nuclei transcriptomic (snRNA-seq) and chromatin accessibility data (snATAC-seq) can identify unique and overlapping genes and regulatory pathways which will help elucidate the role of Foxp2 in each region and region-specific cell types in sensory processing. Ex vivo recordings will also identify changes in cell and circuit function with electrophysiological recordings of single and paired cells to find circuit and synapse dysregulation and cellular excitability alterations caused by the loss of Foxp2. I hypothesize that Foxp2 has a critical role in sensory processing mediated through proper cortical and IC neural development. I predict Foxp2 regulates cell type-specific transcriptional networks with both cell autonomous and non-cell autonomous effects in gene regulation, chromatin accessibility, and influences cell and circuit dysfunction underlying the sensory processing deficits seen in ASD and other NDDs as a risk gene. Aim 1 will utilize paired snRNA-seq and snATAC-seq to determine how conditional deletion of Foxp2 affects cellular expression profiles of the AC and IC across development. I hypothesize that Foxp2-cKO will have ASD-related gene dysregulation, chromatin accessibility patterns, and cell type imbalances in cortical and IC neurons. Aim 2 will assess the cortical and IC cell and circuit electrophysiology regulated by Foxp2. I hypothesize that the loss of Foxp2 expression in the cortex and IC will have circuit and cellular level changes that will result in changes in intrinsic excitability, interfering with thalamic signaling. These data will be generated through whole cell recordings to determine the intrinsic electrophysiologic properties of both AC Layer VI CThPNs and IC excitatory neurons as well as paired stimulation and recording of IC and AC projections and ...