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The overall goal of my research is to understand the
mechanisms by which the activation of cortical inhibitory
and excitatory circuits by incoming sensory information is
modulated. The central hypothesis of this proposal is that
presynaptic GABAB adenosine, and metabotropic glutamate
receptors modulate thalamocortical stimulation of cortical
inhibition. It is becoming increasingly clear that cortical
inhibitory circuits play very important roles in sensory
processing and cortical reorganization. Therefore,
understanding how the activation of these inhibitory
cortical circuits is regulated will provide important
insights into how sensory processing can be altered
pharmacologically. Perhaps in the future one would have the
ability to alter sensory processing via receptor agonists or
antagonists in order to assist in new skill learning,
relearning after an accident of stroke, or treatment of
conditions like phantom limb pain which have aberrant
cortical reorganization. However, before any such
interventions can be done we need more detailed information
on the types and subtypes of receptors that regulate the
activation of inhibitory cortical circuits via incoming
sensory information. To begin to address this deficit in our
knowledge and extend the initial observations found during
the first three years of this grant, the following aims are
proposed. Specific aim I: To test the hypothesis that
metabotropic glutamate receptors modulate thalamocortical
excitation of inhibitory neurons. Specific Aim 2: To test
the hypothesis that endogenously released GABA, adenosine,
and glutamate can modulate thalamocortical excitation of
inhibitory neurons. Specific Aim 3: To test the hypothesis
that presynaptic GABAB adenosine Al and metabotropic
glutamate receptors modulate thalamocortical stimulation in
adult animals. Specific Aim 4: To test the hypothesis that
intracortical and thalamocortical synapses are
differentially regulated by GABAB, adenosine and
metabotropic glutamate receptors. Detailed knowledge of the
pharmacology and physiology of the mechanisms which regulate
the thalamic activation of cortical inhibitory circuits
could improve treatments for people recovering from strokes
or accidents.
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