This NRSA application is submitted for support of post-doctoral training involving neuroanatomy/morphology, physiology, neurocircuitry, and use of designer receptors exclusively activated by designer drugs (DREADDs) in Parkinson's disease (PD) and L-DOPA-induced dyskinesias (LIDs). PD results from a progressive loss of dopaminergic neurons in the substantia nigra resulting in dopamine depletion of the striatum, part of the basal ganglia circuitry controlling motor activity and action selection. PD is the most common neurodegenerative movement disorder and is efficaciously treated with L-DOPA. However, chronic L-DOPA therapy leads to uncontrolled motor side effects such as chorea, dystonia, and/or athetosis, i.e. LIDs. The striatum consists primarily of GABAergic spiny projection neurons that can be divided into two subpopulations based on receptor expression and projections. Multiple lines of evidence indicate involvement of direct pathway, D1-expressing striatonigral spiny projection neurons in the neuropathology of LIDs, but less is known about the involvement of indirect pathway, D2 receptor-expressing striatopallidal spiny projection neurons (iSPNs). Our preliminary evidence indicates that in a mouse model of PD, iSPN spine density was decreased and recovered in dyskinetic mice and that this spine deficit reflected a loss of corticostriatal circuitry that rewired with dyskinesias. We seek to complete and expand our preliminary data to better understand iSPN pathology in LIDs. To do so we will use front-wave technologies to assess neuroanatomy/morphology, function, and circuitry. Our working hypothesis is that restoration of iSPN corticostriatal circuitry leads to mis-wiring with inappropriately timed and scaled activity in iSPNs resulting in the failure to suppress unwanted, dyskinetic movements. Moreover we hypothesize that the corticostriatal re-wiring is a homeostatic adaptation resultant from D2-mediated suppression of iSPN activity during L-DOPA therapy and that increasing iSPN excitability (using the hM3D DREADD expressed in iSPNs) during L-DOPA administration will prevent the homeostatic adaptations and decrease LIDs. The planned studies will contribute to my overall NRSA objective to acquire outstanding training in neuroimaging, physiology, optogenetics, and the use of DREADDS and will be used to determine LID-induced changes in iSPN anatomy, morphology and function (aim I), LID-induced circuit dynamics in iSPNs (aim II), and the effect of increasing iSPN excitability (using DREADD technology) on the development and expression of LIDs (aim III). Outcomes from this research will advance our understanding of iSPNs and corticostriatal circuitry in LIDs while expanding my technical abilities and advancing my career objective of becoming an independent academic neuroscientist.
The proposed research is relevant to public health and advances NIH's mission, as it will identify striatopallidal neuropathology associated with Parkinson's disease and L-DOPA-induced dyskinesias. Completion of the proposed studies will move the field vertically by providing novel insights regarding striatopallidal anatomy/morphology, function and circuitry associated with the above disease states as well as a means to attenuate L-DOPA-induced dyskinesias.
|Sebel, Luke E; Graves, Steven M; Chan, C Savio et al. (2017) Haloperidol Selectively Remodels Striatal Indirect Pathway Circuits. Neuropsychopharmacology 42:963-973|
|Surmeier, D James; Graves, Steven M; Shen, Weixing (2014) Dopaminergic modulation of striatal networks in health and Parkinson's disease. Curr Opin Neurobiol 29:109-17|
|Fieblinger, Tim; Graves, Steven M; Sebel, Luke E et al. (2014) Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia. Nat Commun 5:5316|