VTA dopamine neurons and cognitive symptoms of Parkinson’s disease

Abstract Cognitive symptoms of Parkinson’s disease (PD) can affect up to 80% of PD patients and lead to enormous societal cost. These symptoms involve impaired executive functions such as working memory, attention, behavioral flexibility, and timing, and can progress to psychosis, hallucinations, and dementia. There are few therapies that improve cognitive function in PD. Thus, there is a critical need to better understand the fundamental mechanisms of cognitive dysfunction that occurs in PD. Our long-term goal is to elucidate the mechanisms by which cognitive dysfunction occurs in PD patients in order to develop new targeted treatments. PD involves death of midbrain dopaminergic neurons in ventral tegmental area (VTA). These neurons send mesocortical projections to key cognitive cortical areas such as the prefrontal cortex. It is unknown how VTA dopamine neurons are involved in cognitive processes that malfunction in human PD patients. Our goal in this proposal is to harness cell-type specific rodent models to characterize VTA dopamine neuronal function in cognitive processes relevant to PD. Our preliminary data demonstrates interval- timing variability correlates with PD-related cognitive dysfunction. Our rodent research demonstrates that VTA dopamine is necessary for interval timing, prefrontal timing-related modulations and prefrontal 4 Hz rhythms. Here, we will combine optogenetics, fiber photometry, and neuronal ensemble recordings in transgenic mice to interrogate VTA dopamine projections with cell-type-specificity and millisecond resolution. We will test the overall hypothesis that VTA dopamine neurons engage cognitive processing in the prefrontal cortex. In Aim 1 we will determine how silencing VTA dopamine neurons impacts cognitive processing. In Aim 2 we will define how VTA dopamine neuron dynamics predict cognitive processing. In Aim 3 we will determine how stimulating VTA dopamine neurons impacts cognitive processing. This proposal is broadly significant in determining when and how VTA dopamine engages prefrontal cognitive processing. Although this is a basic-science proposal focused on VTA dopamine neurons, our results will guide new therapies for human PD. This work could contribute to biomarkers for PD and for other Alzheimer’s disease and related dementias (ADRDs) such as dementia with Lewy bodies (DLB).