Nicotinic acetylcholine receptors (nAChRs) are located in many brain regions and are known to participate in critical tasks including learning, memory, and vision. Activation of nAChRs by exogenous application of acetylcholine (ACh) or nicotine produces diverse functional responses. Presynaptic nAChRs mediate enhanced release of several neurotransmitters. Activation of postsynaptic nAChRs produces excitatory responses that can be sufficient to elicit action potentials in neurons. Although these findings are critically important, relatively little is known concerning the functional effects of endogenously released acetylcholine and the cholinergic modulation of physiologically important pathways in the visual system and basal ganglia. The major goal of this proposal is to enhance our understanding of the overall impact of nicotinic receptor activation by endogenous ACh on synaptic transmission at defined sites within brain slices. Key featuresof our approach include the use of well-characterized model systems (ventral lateral geniculate and lateral spiriform nucleus) with robust presynaptic and postsynaptic nicotinic responses, and our ability to examine the physiological significance of nicotinic modulation resulting from the electrically stimulated release of endogenous ACh. Localization of nAChR subtypes within the circuitry of these brain regions will allow us to construct a model for their roles in the processing of incoming information and the output of projection neurons. Functional studies will be done using whole cell patch-clamp electrophysiological recordingsof single neuron activity in brain slices. The impact of cholinergic transmission at both nicotinic and muscarinic receptors will be evaluated in relationship to glutamatergic and GABAergic transmission. We will examine both short term and long term effects of activation of nicotinic receptors, and study developmental regulation of cholinergic modulation. Cigarette smoking causes over 400,000 premature deaths per year in the USA. Nicotine is the addictive principle in tobacco, and acts at central nAChRs to create dependence. Nicotinic receptors also mediate enhanced cognition and visual attention, and are reduced in number in several neurodegenerative diseases. They are present at high densities in the visual system and basal ganglia, but their functional roles in these systems are poorly understood. This project will expand our knowledge of the roles of these receptors.
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