The long term goal of the proposed work is to elucidate the mechanism of neurotransmitter release at synapses. Synapses form the communications link between neurons in the brain, so their function is central to understanding how the brain carries out its computations. Also, most neurobiologists believe that memories are stored as patterns of synaptic effectiveness, a property of synapses that can be modified by neuronal activity. Furthermore, many pharmacological agents that affect the brain do so by modifying, directly or indirectly, synaptic function. Thus, increased understanding of synaptic function has potential health implications as well as a significance for appreciating how the brain operates. The specific goals of the proposed work are to investigate essential details of synaptic structure and function. Neurotransmitter is released in a probabilistic manner in integral multiples of a fundamental unit -- the neurotransmitter quantum -- and this quantum is thought to correspond to small spherical structures known as synaptic vesicles that are filled with the chemicals used to carry information from one neuron to another. The proposed experiments are designed to follow the life history of synaptic vesicles as they move from a reserve pool to the specialized sites at which they release their contained neurotransmitter and send a signal to a receiving neuron. Additional experiments are aimed at examining the reliability of synaptic transmission. Synapses seem to be very unreliable, randomly failing many times to pass on the information that arrives at them as nerve impulses. The proposed experiments are designed to assess the extent of unreliability in a major part of the brain, the neocortex, and to discover the range of reliability that synapses exhibit.
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