Dopamine neurotransmission plays a central role in both human psychiatric disorders and drug addiction. The physiological functions of dopamine are mediated by five known receptors. Due to limited specificity of all known dopamine receptor ligands, the functions of individual dopamine receptor subtypes remain to be clarified. Genetic ablation by knocking out dopamine D1 gene provides valuable insight in our understanding of the D1 receptor function. However, this approach is limited due to the potential of developmental complications. No conditional D1 knockout mice have been reported to address the roles of different brain regions in the modulation of behavior. Therefore, the central focus of this proposal is to develop AAV (adenovirus-associated virus) mediated D1R shRNAs (small hairpin RNA) to silence D1R expression in mouse striatum to examine D1R effects at the behavioral level. We hypothesize that D1R silencing in mouse striatum will reduce the deficit of prepulse inhibition (PPI) caused by dopamine agonists. The successful development of the D1 shRNAs will help examine the role of D1R neurotransmission in other brain regions such as prefrontal cortex in the modulation of PPI and other behavioral activities in future studies. To initiate the investigation of this hypothesis, the following specific aims are proposed.
SPECIFIC AIM 1 : The development of scAAV-D1shRNA.
SPECIFIC AIM 2 : To examine the contribution of the striatal dopamine D1R-expressing neurons in the modulation of mouse prepulse inhibition (PPI) and locomotor activity.
Current medications for schizophrenia are relatively ineffective in treating cognitive disruptions, which incur a substantial burden on the quality of life of these patients (e.g. low employment rates). Dopamine neurotransmission mediated by the D1 receptor is critical for normal cognitive functions and is aberrant in the prefrontal cortex of schizophrenia patients. Understanding of the regional mechanisms of D1 neurotransmission will help identify the neural pathways for D1 effects on cognition, as well as guide the development of pro-cognitive drugs with minimal side effects.
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