ANATOMY AND PHYSIOLOGY OF SUBSTANTIA NIGRA AFFERENTS

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DESCRIPTION: (Adapted from the applicant's abstract) The experiments in this proposal are designed to describe the anatomy and physiology of afferents that control the activity of substantia nigra dopamine neurons. In particular, various aspects of a GABAergic pathway to dopaminergic neurons originating from the axon collaterals of non-dopaminergic substantia nigra pars reticulata projection neurons will be studied. The central hypothesis is that many of the important inputs to dopaminergic neurons that control the rate of firing and spontaneous activity are filtered through pars reticulata neurons. Six specific aims are proposed. Aim 1. To test the hypothesis that there is a physiologically functional monosynaptic connection between substantia nigra pars reticulata GABAergic projections neurons and pars compacta nigrostriatal dopaminergic neurons with electrophysiological means. Aim 2. To determine the subtype of the GABA receptor on the dopaminergic nigrostriatal neuron that mediates the inhibitory influence of GABAergic afferents arising from neostriatum, globus pallidus and substantia nigra par reticulata with in vivo neuropharmacological studies. Aim 3. To determine the relative influences of GABA-A and GABA-B synaptic inputs on the firing pattern of nigrostriatal neurons in vivo. Aim 4. To look for anatomical evidence of a direct monosynaptic connection between substantia nigra pars reticulata projection neurons and nigrostriatal dopaminergic neurons by light and electron microscopic analysis of the axon collaterals of electrophysiologically characterized pars reticulata neurons that were intracellularly or juxtacellularly labeled with biocytin. Aim 5. To test the hypothesis that activation of GABAergic pars reticulata neuron axon collaterals and/or pallidonigral inputs are responsible for the inhibitory responses seen in pars compacta dopaminergic neurons after stimulation of presumed excitatory inputs. Aim 6. To test the hypothesis that individual striatonigral and pallidonigral afferents synapse with either dopaminergic or non-dopaminergic neurons in substantia nigra by intracellular or juxtacellular labeling and tracing axons to nigra and performing double label electron microscopy.