The objective of the proposed research is to understand the control of neural activity at the output stages of basal ganglia processing. This topic is highly relevant to our understanding of Parkinson's disease as changes in spike rate and pattern of basal ganglia output neurons are directly involved in the generation of dysfunctional neural activity in this disease. Furthermore, deep brain stimulation (DBS) interacts with the generation of spike patterns at this stage, and our work will address important biophysical mechanisms that may mediate the therapeutic effect of this treatment. We will focus our work on how the extensive dendrites of pallidal neurons contribute to signal processing. Recent evidence shows that dendrites make important contributions to signal integration through the activation of complex patterns of voltage-gated currents.
The specific aims of this proposal address the contribution of distinct dendritic mechanisms to synaptic integration in pallidal neurons.
In aim 1 we assess the presence of distinct physiological subtypes of neurons in globus pallidus (GP) and entopeduncular nucleus (EP), and their differential response to dendritic excitatory inputs.
In aim 2 we determine the spatial and temporal processing of excitatory inputs in dendrites of GP and EP neurons, and how this processing is shaped by specific voltage-gated conductances.
In aim 3 we examine how inhibitory and excitatory inputs interact in the control of output spiking. The overall experimental approach primarily relies on whole cell recordings from brain slices. Dendrites are visualized with fluorescent dyes and stimulated at varying distance from the cell body. An important component of the work is given by detailed biophysically realistic computer simulations of pallidal neruons to allow a complete examination of the dynamical interactions of input patterns with intrinsic membrane properties. By determining the details of input/ouput transformations at the single cell level we will be able to make important predictions to how alterations in this process can lead to changes in network processing. ? ?
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