Friday, June 6, 2025
6/6/2025
The Neural Basis of Dopamine-Driven Deficits in Cognition and Perception - PROJECT SUMMARY/ABSTRACT Dopamine dysfunction is implicated in a wide range of neuropsychiatric diseases, but how changes in dopamine signaling modulate downstream neural circuits to cause the symptoms of these diseases is not well understood. Using in vivo imaging, we have determined how excess dopamine changes activity in D1 and D2 dopamine receptor-expressing spiny projection neurons (SPNs) in the dorsal striatum (Yun et al., Nat Neurosci, 2023). In parallel, we developed a genetic approach to selectively activate the substantia nigra pars compacta (SNc) dopamine neurons that innervate the dorsal striatum (Moya et al, Neuropsychopharmacology 2023). This proposal combines these approaches and their insights to inform our understanding of dopamine-associated diseases and therapeutic strategies for treating them. Specifically, we have shown that selectively activating SNc dopamine neurons in mice disrupts spatial working memory and misconstrues perception in an assay of auditory perception confidence. These findings are relevant to dopamine-associated diseases with deficits in cognition and perception such as schizophrenia. To determine the neural substrates underlying these symptoms, we will use miniature microscopes to image calcium activity in D1 and D2 dopamine receptor-expressing spiny projection neurons (SPNs) in the dorsal striatum, under normal and hyperdopaminergic conditions (by selectively activating SNc dopamine neurons). Based on their distinct anatomical connections and implications in behavior, we will image D1- and D2-SPN activity in the dorsomedial striatum (DMS) during working memory and caudal tail of the dorsal striatum (TS) during auditory perception. After determining how activating SNc dopamine projections to the dorsal striatum alter task-related D1- and D2-SPN activity in each sub-region and behavioral process, we will use chemogenetics (i.e., DREADD manipulations) to counteract the effects of nigrostriatal dopamine on D1- and D2-SPN activity levels. We will do this in each striatal subregion to determine whether dopamine-driven alterations in the activity of each cell type are preferentially involved in working memory or perceptual deficits. Because existing antipsychotic drugs preferentially block D2 dopamine receptors and are more effective for abnormal perception than cognitive deficits, our overarching hypothesis is that dopamine driven-changes in D2-SPN activity are more associated with faulty perception and those in D1-SPN activity with working memory deficits. However, our recent discovery that antipsychotics also affect the activity of D1-SPNs (Yun et al., Nat Neurosci, 2023) requires the rigorous adjudication of this hypothesis. Our work will inform our understanding subcortical dopamine’s role in working memory and perception and constrain therapeutic strategies for normalizing the symptoms associated with these processes when the dopamine system goes awry.
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