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Project #1 (PI: Dieter Jaeger, PhD): Synaptic Integration of Cortical and Nigral Input in Parkinsonian Mouse Motor Thalamus

Overview

In this project we are studying how the communication between brain structures is changed in a mouse model of Parkinson’s disease, compared to normal control mice. In particular, an important pathway of the output from the basal ganglia is to the motor cortex. This pathway passes through the ventral motor thalamus before it reaches cortex. The main hypothesis of this research is that processing of basal ganglia signals in motor thalamus is altered in the parkinsonian state. We will address this hypothesis in three specific aims that examine changes in the cellular and signal processing properties of neurons in the motor thalamus in the parkinsonian condition, using the 6-hydroxydopamine lesion model of dopamine depletion in mice.  In aim 1 we will analyze in a brain slice preparation which properties of thalamic neurons and synaptic inputs are changed in the parkinsonian condition using electrophysiological intracellular recordings.  In aim 2 (see figures below) we will examine with electrophysiological recordings from neurons in the motor thalamus of awake behaving mice whether electrical activity patterns in parkinsonian mice differ from those in control animals during motor behavior.  We will also use optogenetic stimulation techniques to trace specific signals along the basal ganglia-thalamocortical route. These stimulation techniques will also be studied with respect to their potential use as counteracting pathological patterns of activity seen in the parkinsonian animals.  Finally, in aim 3, we will synthesize our understanding resulting from aims 1 and aim 2 by building a detailed computer model of how neurons in the motor thalamus of parkinsonian mice process input from the basal ganglia and how this differs from the normal condition. We will test the validity of this model with accompanying brain slice experiments, in which real neurons are subjected to the same synaptic input patterns that are used in the computer simulations. This allows for a direct comparison between spiking activity patterns generated by the computer model and those seen in recordings.

This research will result in new insights concerning the mechanisms that lead to the expression of pathological neural activity patterns in the parkinsonian state. In particular little is known about the involvement of the motor thalamus in the pathophysiology of parkinsonism, and our results will make a substantial contribution to filling this knowledge gap. Further, our research results are expected to inform us about potential new techniques of optical deep brain stimulation with a positive effect on thalamic signal integration that could ameliorate parkinsonian signs and symptoms. Finally, our computer model will be made available to the public and will allow other researchers to construct better brain network models of how different interventions (such as deep brain stimulation treatment) affect activity in the thalamus and cerebral cortex.  Such modeling is increasingly used as a tool to predict the effect of novel deep brain stimulation treatments.

Proj 1 Behavioral Task

Proj 1 Mouse electrophysiology

Dr. Jaeger's Recent Publications