Activities within thalamocortical circuits play a critical role in sensory signaling, changes in state, and alterations of excitability such as those that occur in generalized and partial epilepsies. Intrinsic properties of thalamic neurons, modulatory influence of neurotransmitters, and intrathalamic synaptic activities all play a critical role in these normal and abnormal functions.The long- term objective of this project is to understand these interactions and the mechanisms by which alterations in them can lead to disorders such as petit mal epilepsy. Through its synaptic interactions with neurons in the dorsal thalamus, the GABAergic nucleus reticularis (nRt) plays a critical role in regulating intrathalamic excitability. nRt neurons make inhibitory synapses on both neurons in dorsal thalamus and nRt.
One specific aim of the proposed experiments is to define aspects of GABA-A and GABA-B -receptor- mediated inhibition within nRt and its connections with the ventral basal nuclear complex (VB). The circumstances under which OABAa receptors are activated will be studied. The basic properties of spontaneous and evoked GABA-A currents in VB and nRt, and changes in them in response to GABAergic drugs will also be examined to explore potential differences in GABA A receptors in the two structures. A second specific aim deals with the mechanisms of peptidergic modulation of thalamic activities. The thalamus has a rich peptidergic innervation whose function has not been studied. The effects of cholecystokinin, neuropeptide Y and somatostatin on excitatory and inhibitory synaptic activities as well as on calcium and potassium membrane currents in nRt and VB will be examined. The net effect of peptide agonists on intrathalamic oscillatory rhythms will also be explored. Experiments will be done on neurons in thalamic slices maintained in vitro and on acutely dissociated thalamic neurons using whole cell patch clamp techniques for current and voltage clamp recordings, and bath or local applications of agonists and antagonists.
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