AFFERENT REGULATION OF CHOLINERGIC FOREBRAIN NEURONS

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The goal of the proposed research is to understand how the basal foebrain (BF) is organized to modulate distributed neuronal processes within sensory, motor and higher order cognitive systems in the cerebral cortex. Pharmacological studies have shown that dopaminergic and glutamatergic stimulation have a profound effect on cortical acetylcholine release, suggesting a critical role for these afferents in mediating increased cholinergic tone in behavioral states of attention, arousal and reward mechanisms. The proposed experiments will test various hypotheses about the ways in which corticipetal cholinergic and associated non-cholinergic neurons in specific basal forebrain circuits are influenced by dopaminergic and glutamatergic afferents. The following specific hypothesis will be tested: 1) Prefrontal glutamatergic axons terminate on different type of GABAergic neurons in the basal forebrain. 2) Different types of BF GABAergic neurons, identified by the presence of different calcium binding proteins (i.e., parvalbumin, calbindin D28, calretinin), contract BF cholinergic projection neurons. The number of and topography of synapses on the cholinergic neurons will vary according to the location and/or the type of GABAergic neuron. 3) Glutamate and dopamine influence the cholinergic output neurons through different pre- and postsynaptic mechanisms. To accomplish these goals e will undertake on a combined anatomical and electrophysiological study. The following major lines of research will be pursued: 1) Identification of the sources and site of termination of dopaminergic and glutamatergic terminals on basal forebrain neurons. 2) Electrophysiological characterization of thee effect of the stimulation of the substantia nigra or putative glutamatergic sources on identified BF neurons, recorded extracellularly in vivo. 3) Reconstruction of biocytin labeled BF GABAergic neurons to identify their synapses with cholinergic neurons. 4) Cellular characterization of dopaminergic and glutamatergic receptors. These studies will be aided by using in vivo juxtacellular recording, anterograde tracing of afferent pathways and double immunolabeling methods in various combinations at both the light and electron microscopic level, supplemented by computerized 3-D reconstruction of identified neurons and their synapses.