Abstract

The objective of the proposed research is to determine how the activity of neurons in the substantia nigra pars reticulata (SNr), one of the major output nuclei of the basal ganglia, is controlled by synaptic input. Simple network models of basal ganglia function and disorders assume that the activity of output neurons is determined by summing the amount of inhibitory and excitatory inputs received. It is clear, however, that single neurons have active intrinsic mechanisms by which synaptic inputs may be integrated in a highly complex non-linear fashion. These complex properties of synaptic integration will be examined in SNr neurons by combining in vitro whole cell recording, extracellular recording and computational modeling. First the passive and then the active properties of these neurons will be catalogued using whole-cell recordings in rat brain slices. These experiments will use current and voltage-clamping in conjunction with pharmacological blockade of various voltage- and ligand gated channels to isolate and characterize purely passive membrane properties and specific voltage-dependent conductances. Recorded neurons will be intracellularly stained and reconstructed histologically with Neurolucida, and the quantitative morphometric data obtained will be used along with the electrophysiological data to construct a compartmental model of SNr neurons. The model will be adjusted and fine tuned by comparing the behavior of the model to that of SNr neurons in whole cell recordings in vitro and in extracellular single unit recordings in vivo, while constraining the parameters to those obtained in the recording experiments. To study the mechanisms by which synaptic input controls activity, the parameters of synaptic inputs including the time courses and amplitudes of excitatory and inhibitory inputs will be measured and used in the model. Finally, realistic sequences of synaptic input, inferred from in vivo and in vitro recordings of SNr neurons will be input to the model to determine the input-output function of SNr neurons.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039852-03
Application #
6540227
Study Section
Special Emphasis Panel (ZRG1-IFCN-5 (01))
Project Start
2000-04-10
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2002
Total Cost
$220,200
Indirect Cost

  Institution

Name
Emory University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

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