Centre for Neuroscience - Theses
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ItemModels of brain targeted D1 dopamine receptor positive cell ablation( 2012)Dopamine receptor D1a (Drd1a) is one of the most abundant dopamine receptor subtypes in the central nervous system and is implicated in many neurological processes including neuronal growth, development and behavioral responses. Previously, we reported that mice with targeted ablation of Drd1a receptor-positive cells (CamKIIαtox MUT) exhibited behavioral abnormalities similar to those observed in models of Huntington's Disease (HD). In the present study, we focused on identifying the pathological locus for HD-related behavioral deficits by characterizing neurochemical changes within CamKIIαtox MUT mice further, as well as generating a new transgenic line with restricted Drd1a ablation only to the cortex. This novel transgenic line utilized the same Cre-Lox system employed in our previous study but replacing the CamKIIαCre delivery line with an Emx-1Cre line to generate mutant (Emx-1tox MUT) mice that lacked Drd1a-expressing cortical pyramidal cells. Adult Emx-1tox MUT mice with intact Drd1a expression and striatal markers were hyperactive, displayed forelimb dominant clasping, poor rotarod performance, heightened anxiety-like behaviors and impaired memory function. As hypothesized, we found Emx-1tox MUT mice to demonstrate reduced cortical thickness compared to controls in both motor and somatosensory domains, particularly within the deeper cortical layers. This correlated strongly with the loss of DARPP-32-expressing cells in the same region. This study demonstrates a primary role of cortical Drd1a expressing cells in motor control and cognition.