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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039852-07
Application #
7016316
Study Section
Special Emphasis Panel (ZRG1-IFCN-F (02))
Program Officer
Oliver, Eugene J
Project Start
2000-04-01
Project End
2009-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
7
Fiscal Year
2006
Total Cost
$269,218
Indirect Cost
Name
Emory University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Schultheiss, N W; Edgerton, J R; Jaeger, D (2012) Robustness, variability, phase dependence, and longevity of individual synaptic input effects on spike timing during fluctuating synaptic backgrounds: a modeling study of globus pallidus neuron phase response properties. Neuroscience 219:92-110
Hendrickson, Eric B; Edgerton, Jeremy R; Jaeger, Dieter (2011) The use of automated parameter searches to improve ion channel kinetics for neural modeling. J Comput Neurosci 31:329-46
Edgerton, Jeremy R; Jaeger, Dieter (2011) Dendritic sodium channels promote active decorrelation and reduce phase locking to parkinsonian input oscillations in model globus pallidus neurons. J Neurosci 31:10919-36
Hendrickson, Eric B; Edgerton, Jeremy R; Jaeger, Dieter (2011) The capabilities and limitations of conductance-based compartmental neuron models with reduced branched or unbranched morphologies and active dendrites. J Comput Neurosci 30:301-21
Schultheiss, Nathan W; Edgerton, Jeremy R; Jaeger, Dieter (2010) Phase response curve analysis of a full morphological globus pallidus neuron model reveals distinct perisomatic and dendritic modes of synaptic integration. J Neurosci 30:2767-82
Edgerton, Jeremy R; Hanson, Jesse E; Gunay, Cengiz et al. (2010) Dendritic sodium channels regulate network integration in globus pallidus neurons: a modeling study. J Neurosci 30:15146-59
Günay, Cengiz; Edgerton, Jeremy R; Li, Su et al. (2009) Database analysis of simulated and recorded electrophysiological datasets with PANDORA's toolbox. Neuroinformatics 7:93-111
Gunay, Cengiz; Edgerton, Jeremy R; Jaeger, Dieter (2008) Channel density distributions explain spiking variability in the globus pallidus: a combined physiology and computer simulation database approach. J Neurosci 28:7476-91
Li, S; Arbuthnott, G W; Jutras, M J et al. (2007) Resonant antidromic cortical circuit activation as a consequence of high-frequency subthalamic deep-brain stimulation. J Neurophysiol 98:3525-37
Hanson, Jesse E; Smith, Yoland; Jaeger, Dieter (2004) Sodium channels and dendritic spike initiation at excitatory synapses in globus pallidus neurons. J Neurosci 24:329-40

Showing the most recent 10 out of 12 publications