Epigenetic entrainment of striatal engram-like neurons across the time course of LID development - Project Summary/Abstract Levodopa (L-DOPA)-induced dyskinesia (LID) is a debilitating motor side effect of long-term use of Parkinson disease (PD) medication. Proportionally higher output of the basal ganglia direct pathway compared to the indirect pathway, resulting in hyperkinetic abnormal involuntary movements, is a circuit-level hallmark of LID. Once developed, LID is difficult to mitigate and grows in severity with each successive dose. Our work indicates that a subpopulation of D1 receptor-expressing medium spiny output neurons (D1-MSNs) are transcriptionally altered by the development and stable expression of LID in animal models. This transcriptional profile is reminiscent of that of hippocampal engram cells upon recall of an entrained stimulus. In addition, manipulation of these specific D1-MSNs has been shown to bidirectionally mediate LID expression. THese characteristics suggest that a specific subset of D1-MSNs may serve as engram cells for LID. However, the evolution of cellular and molecular changes that uniquely occur in these engram-like D1-MSNs in response to L- DOPA treatment across the time course of LID development have not been established to date. We have previously observed that epigenetic processes play a key role in the development of LID, though these processes have never been investigated in a cell type-specific manner. The critical next steps are identifying the unique transcriptional, physical, and physiological characteristics of L-DOPA-responsive D1-MSNs upon both acute and chronic L-DOPA exposure and determining the epigenetic mechanisms that may spur this process. The overall goal of the work proposed in this application is to utilize genetic approaches to establish an engram-like population of D1-MSNs utilizing a well-established preclinical model of LID in combination with a novel mouse model, allowing us to specifically target the cells which underlie LID. We will utilize a transcription-to-behavior approach to investigate cellular connectivity at the level of chromatin remodeling, transcription, cellular morphology and physiology, and behavior. Our hypothesis is that LID development is associated with remodeling of L-DOPA-responsive D1-MSNs (Aim 1), mediated by a shift in chromatin availability and corresponding transcriptional networks (Aim 2), that underlies the transition from the acute to chronic LID state. To date, there are no available therapies to halt LID development. The results from this research will indicate targets for LID- mitigating therapies to prolong the usefulness of L-DOPA, the gold standard of PD therapy for over 50 years.
