Nigrostriatal dopamine mechanisms of cognitive control

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Project Summary/Abstract Cognitive impairments, which affect memory, executive functioning, and timing, are experienced by the majority of Parkinson’s disease patients at some point during their disease. For many patients, mild cognitive impairments eventually devolve into Parkinson’s disease dementia. Despite the negative impact on quality of life caused by these symptoms, there are currently no effective therapies to treat cognitive impairment in these patients. Thus, there is an unmet need to develop new treatments for Parkinson’s disease-related cognitive decline. This requires identifying the fundamental neurobiological mechanisms underlying cognitive dysfunction in Parkinson’s disease. Dopamine neuron degeneration in the nigrostriatal pathway is associated not only with the motor symptoms of Parkinson’s disease, but also with cognitive symptoms. Parkinson’s disease patients have reliably impaired performance on interval timing tasks and lesioning or manipulating dopamine neurons in rodents also impairs performance on interval timing tasks. Furthermore, striatal neurons encode temporally relevant information by ramping their activity across timed intervals. The overall goal of my proposed research is to identify how nigrostriatal dopamine signals influence striatal microcircuitry during a cognitive task. My overall hypothesis is that striatal temporal encoding depends on dopamine. I will test this overall hypothesis with two distinct experiments. First, I will test the hypothesis that task- modulated striatal dopamine activity predicts temporal encoding by striatal projection neurons during an interval timing task. I will test this by recording local dopamine dynamics with striatal dLight and fiber photometry while simultaneously recording striatal neuronal ensembles. Second, I will test the hypothesis that dopamine neurons control striatal time-related ramping activity. I will optogenetically silence or stimulate dopamine neurons at key behavioral events during the task while recording striatal neuronal ensemble activity. Together, the proposed experiments will contribute to a model establishing how nigrostriatal dopamine neurons regulate striatal cognitive processing. This knowledge will inform development of novel therapies for cognitive impairments in Parkinson’s disease by identifying where and how to target treatments. This is highly relevant for Parkinson’s disease and other dopamine-linked disorders, as this work will reveal foundational basic science mechanisms of dopamine. Completion of the proposed work will not only expand my technical and research skillset, but also enhance my professional development skills. Therefore, this award will advance me towards my career goal of running an independent laboratory at a competitive research institution, focused on dopamine and basal ganglia circuitry mechanisms of cognitively-guided action.