Project Abstract
Many children with autism spectrum disorder (ASD) exhibit enlargement of the dorsal striatum, a brain
structure within the basal ganglia that is known for its roles in automation of motor behavior and habit
formation. It is postulated that abnormalities in the dorsal striatum contribute to restrictive, repetitive behavior
(RRB), a diagnostic criterion for ASD and a component of other neurodevelopmental impairments
encompassing repetitive motor behavior, inflexibility in routine, and fixated interests. Our laboratory has
previously demonstrated that prenatal stress, which is a known environmental risk factor for
neurodevelopmental disorders, leads to enlargement of the dorsal striatum in mouse offspring. These offspring
also display deficits in striatal-dependent learning. So far, the neurobiology of the enlarged dorsal striatum has
not been investigated beyond total volume and medium spiny neuron (MSN) density. MSNs, which comprise
the majority of the dorsal striatum, form two opposing pathways: direct and indirect. In order to better
understand striatal developmental dysfunction, further molecular and cellular investigations of striatal
enlargement are necessary. In Aim 1, prenatal stress will be used as a model of neurodevelopmental risk and
striatal enlargement. Prenatally-stressed mice will be evaluated on striatal-dependent learning behaviors, in
order to confirm the previously-observed effects of prenatal stress. The ratio of direct to indirect MSNs will be
measured using immunohistochemistry, revealing whether striatal enlargement is driven by one subtype.
Additionally, single-cell RNA sequencing analysis will identify genes and biological pathways that are altered in
the enlarged striatum in a cell subtype-specific manner. In Aim 2, to test the sufficiency of prenatal striatal
overgrowth on behavioral deficits, the metabotropic glutamate receptor agonist CHPG will be introduced
intracerebroventricularly to the brains of developing mouse embryos. This will specifically promote cellular
proliferation in the lateral ganglionic eminence, the transient embryonic structure from which the dorsal striatum
primarily arises. Together, these studies will shed light on how overgrowth of the striatum during development
plays a crucial role in RRB. The findings from these experiments will aid the design of new methods of
prevention and therapeutic treatment for ASD and other related neurodevelopmental disorders.