Dopamine modulation of the neostriatal feedback circuitry

Project Details

Description

GABAergic inhibition is a primary determinant of the activity of neostriatal projection neurons and recent
evidence demonstrates that a significant fraction of this inhibitory control originates from the axon collaterals
of the projection neurons themselves. The existence of a functional synaptic circuitry among projection
neurons suggests a critical role in the regulation of the spatial and temporal pattern of activity of the
neostriatum, and in particular in the control of the balance of activity between the functionally segregated
output pathways (the"direct" and "indirect" pathways) of the neostriatum. To extend the understanding of
the inhibitory circuitry of neostriatal projection neurons the first objective of the present proposal will be to
investigate the connectivity and the biophysical properties of synaptic communication between the striato-
nigral (direct) and striato-pallidal (indirect) neostriatal projection neurons with paired whole cell voltage and
current clamp recordings in acute brain slices .
The second major objective is to test the hypothesis that dopamine regulates synaptic transmission
among projection neurons in a circuit dependent manner through two different receptor mechanisms. Our
preliminary data demonstrate that synaptic transmission between a subset of pairs of projection neurons is
enhanced by dopamine through DHike receptors while D2-like receptors suppress transmission between a
complementary population of pairs. Considering the strict segregation of the two mechanisms demonstrated
by our preliminary data, and the known projection pathway selective distribution of dopamine receptors, we
hypothesize that the feedback circuitry of projection neurons contributes to the dopaminergic control of the
relative activity of the direct and indirect pathways through differential modulation of synaptic connections of
projection neurons of the two neostriatal output pathways. These questions will be investigated in
electrophysiological and pharmacological experiments by obtaining in vitro paired recordings from projection
neurons identified using single-cell RT-PCR profiling of the expression of enkephalin, substance P and the 5
main dopamine receptor subtypes.
The basic cellular mechanisms responsible for the differential regulation of activity of the opponent output
pathways of the neostriatum has important implications for the understanding of the pathophysiology of
several neurological and psychiatric disorders including Parkinson's and Huntington's disease, schizophrenia
and drug addiction. In particular, understanding the dopaminergic modulation of the neostriatal circuitry may
facilitate the identification of novel, non-dopaminergic primary or adjunctive pharmacotherapies of
Parkinson's disease and contribute to the improvement of non-pharmacological treatment modalities of the
disorder.
StatusFinished
Effective start/end date3/1/062/28/11

Funding

  • National Institute of Neurological Disorders and Stroke: $300,753.00
  • National Institute of Neurological Disorders and Stroke: $303,790.00
  • National Institute of Neurological Disorders and Stroke: $325,602.00
  • National Institute of Neurological Disorders and Stroke: $316,763.00
  • National Institute of Neurological Disorders and Stroke: $303,790.00

ASJC

  • Clinical Neurology
  • Psychiatry and Mental health
  • Neuroscience(all)

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