The proposed research will evaluate the hypothesis that spontaneously occurring stereotypy is expressed as a consequence of elevated neuronal activity along cortico-striato-pallidonigro-thalamo-cortical feedback circuits. This hypothesis will be evaluated using Peromyscus maniculatus (deer mice), a mouse species that spontaneously exhibits abnormal repetitive behaviors when reared in standard laboratory cages. A series of in vivo and in vitro manipulations will be performed in these mice. In vivo experiments will consist of site-specific intracerebral pharmacological manipulations, which will be performed in an attempt to modulate the stereotypies emitted in the deer mice. These manipulations will be hypothesis-driven such that, based on existing chemoarchitectural understanding, all ligands will be expected to either exacerbate or attenuate stereotypies via excitation or inhibition, respectively, of activity along the feedback circuit hypothesized to mediate the expression of these abnormal repetitive behaviors. In vitro experiments will consist of immunohistochemical manipulations designed to measure indices of neuronal activity in key loci of the implicated feedback circuit. First, the ratio of striatal neuropeptides dynorphin and enkephalin, which are differentially expressed as a function of activity along the distinct (direct and indirect) pathways of the basal ganglia, will be measured in stereotypic and nonstereotypic mice. This study is expected to reveal shifts in the balance of activity along these pathways, such that stereotypic mice demonstrate greater relative activity along the direct pathway. The final objective of the proposed research is to measure the expression of Fos-related antigen (FRA}, a putative marker of chronic neuronal activity, in the loci comprising the implicated cortico-basal ganglia-cortical circuit. Comparison of the expression levels of FRA will be made between stereotypic and nonstereotypic deer mice, and are expected to reveal elevated FRA expression in the cortico-basal ganglia feedback circuit comprising the direct pathway of stereotypic mice. Taken together, these studies will provide the data needed to critically evaluate the hypothesized involvement of the aforementioned neural circuits in the mediation of abnormal repetitive behaviors.
