Cellular and molecular investigations of striatal enlargement in prenatal stress model of neurodevelopmental risk

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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.