Developmental underpinnings of substantia nigra vulnerability

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Abstract: DA neuron degeneration, resulting in deficient DA signaling, underpins the debilitating motor symptoms of Parkinson’s disease (PD). Among DA neurons, those located in ventral tier of the substantia nigra pars compacta (SNc), are particularly vulnerable, compared to those in the dorsal tier of the SNc or ventral tegmental area (VTA). A mechanistic explanation of selective DA neuron vulnerability remains an important goal, that has been hampered in part by a lack of understanding of the intrinsic differences between DA neurons. We hypothesize that even within a single neuroanatomical cluster like the SNc, there exist DA subtypes with distinct developmental histories and intrinsic properties that may influence their vulnerability. Single cell expression profiling based DA neuron classification from our lab revealed the presence of a key SNc population defined by Sox6 and Aldh1a1 - this subtype was located in the ventral tier of the SNc, and was preferentially vulnerable in a toxin model of PD. Our preliminary data indicate that this population exists in human SNc, and is also selectively vulnerable in post-mortem PD samples. To interrogate the basis for selectively vulnerability in the SNc in depth, we next developed a set of intersectional genetic strategies, which strikingly defined a fault-line in the SNc defined by Sox6 expression, with Sox6+ cells being located ventrally and Sox6- cells forming the dorsal tier. Building on these studies, several key questions remain unanswered. Are dorsal and ventral SNc subtypes developmentally distinct? Do these neurons have different anatomical features and DA release characteristics? Is the size of arborizations of these neurons, a property linked to vulnerability, different? Are calcium fluxes and mitochondrial bioenergetic properties distinct? To answer these questions, in Aim 1, we will determine the origin of SNc neuron subtypes. We will use intersectional, subtractive, and inducible genetic approaches, as well as a novel progenitor anchored fate mapping approach (PRISM) to test the hypothesis that the dorsal and ventral tier DA neurons are developmentally distinguished by Sox6. We will then test the potential of Sox6+ medial vs Sox6- lateral floor plate progenitors to give rise to SNc neurons when transplanted into a PD model. In Aim 2, we will examine the arborization of genetically defined SNc neurons, since this feature has been linked to their vulnerability. Using a new sparse labeling tool, we will plot the projections of genetically defined SNc DA neuron subtypes, and determine the size of their arbors, and explore the molecular determinants of extensive arborization. We will also study DA release from axons and dendrites to determine if dorsal and ventral tier neurons are distinguishable by these criteria, also linked to vulnerability. In Aim 3, we will test the hypothesis that the SNc DA neuron subtypes have distinctive physiological properties and that these differences translate into differences in mitochondrial oxidant stress in somatodendritic and axonal compartments. Overall, our studies redefining the SNc based on lineage will provide important insights into selective vulnerability.