Parkinson?s disease (PD) is the second most common neurodegenerative disorder, characterized by devastating disabilities following the loss of dopamine (DA) neurons in the substantia nigra. Current treatments for PD are limited in efficacy, and no existing treatments are able to alter disease course. The degeneration observed in human PD patients is highly selective, with DA neuron subtypes located ventrally within the substantia nigra pars compacta (SNc) degenerating to a far greater degree than those located dorsally. Importantly, these subtypes appear to be components of entirely different circuits, with distinct inputs, projections and activity patterns. Unfortunately, existing mouse and animal models have not recapitulated the selective vulnerability seen in humans, and instead rely on toxins that can be taken up by all DA neurons. This presents several limitations when trying to understand the circuit-level changes that occur in PD. Since all DA neurons are lost in these models, it has been impossible to study the motor consequences from the selective loss of ventral SNc (i.e. vulnerable) neurons. Conversely, it remains unknown if the dorsal neurons (spared in PD) can compensate for the loss of other DA neurons, or if this surviving circuitry contributes to the efficacy of circuit-based therapies like deep brain stimulation (DBS). My central hypothesis is that selective loss of the ventral SNc alone drives the circuit pathology observed in human PD, while modulation of the surviving dorsal SNc serves as a key cellular substrate for DBS. This proposal will utilize a novel mouse model in which ventral tier SNc neurons have been selectively ablated through an intersectional genetic strategy. In these mice ventral DA neurons, which express the transcription factor Sox6, selectively produce a toxin that causes cell death while leaving the dorsal DA neurons intact.
Aim 1 will determine if ventral tier loss drives Parkinsonian motor deficits. By utilizing multiple behavioral assays, we will show the specific contributions of ventral tier cells to motor deficits.
Aim 2 will then determine the effects of ventral tier loss on surviving dorsal tier neuronal circuitry. By examining activity, projections and effects of subthalamic nucleus stimulation in surviving dorsal tier cells, we will uncover any state-dependent changes that occur after ventral tier loss, with the hopes of establishing subthalamo-nigral circuitry as a key substrate for DBS. This work will provide new insights into the pathophysiology of Parkinsonian motor deficits, and could provide insight into the cellular mechanisms of DBS.
Parkinson?s Disease (PD) is the second most common neurodegenerative disease, causing severe disability following the loss of dopaminergic neurons. The goal of this proposal is to examine behavioral and circuit-level changes in a PD mouse model that recapitulates the selective loss of vulnerable dopamine neurons seen in humans. Successful completion of this project will provide new insight into what drives PD circuit dysfunction and motor deficits, as well as a potential mechanism of deep brain stimulation, opening the door for improving future PD treatments.
