Our present understanding of several neurological movement disorders relates to pathologies of specific neurotransmitter systems. For example, substantial evidence indicates that the motor deficits associated with Parkinson's Disease result from the degeneration of the dopaminergic nigrostriatal pathway. In Huntington's Disease, motor deficits are associated with degeneration of striatal GABAergic neurons. Our most effective treatments for these disorders rely on agents that are thought to exert their effects on the synaptic signaling mediated by these neurotransmitters. Relating the activities of such neurotransmitter systems and therapeutic agents directly to human behavior, however, poses formidable challenges. The tong-term objective of this research program is to examine interactions between two major neurotransmitters, dopamine (DA) and GABA, in the regulation of feeding behavior. These two """"""""conventional"""""""" neurotransmitters are thought to play key roles in the regulation of appetite, satiation, consummatory behaviors, and food reward in species ranging from invertebrates to man. The proposed studies will use an experimentally favorable model, Aplysia, in which it is possible to identify neurons that exhibit a specific transmitter phenotype, and to relate the activity of those neurons to specific behavior patterns. The three Specific Aims focus on the union of these two neurotransmitter systems in five specific identified interneurons in which DA and GABA are colocalized. The proposed experiments will (1) determine the contributions of colocalized DA and GABA to synaptic signaling, (2) explore the roles of DA and GABA in the modulation of intrinsic synaptic plasticities (metaplasticity), (3) investigate interactions between the cells in which DA and GABA are colocalized and other neurons that converge on common postsynaptic targets (heterosynaptic modulation). Recent advances in our understanding of behaviors related to feeding underscore the utility of this approach. In common with most organisms, the ingestive and egestive behaviors of this system are mediated by a single peripheral """"""""physical plant"""""""" that is differentially activated by a multi-functional central pattern generator (CPG) circuit. The capability of a single CPG to achieve such motor program switching is often attributable to neuromodulatory cotransmitters that produce broad and coordinated reconfiguration of patterned motor output. Consequently, by increasing our understanding of cotransmission in this system, these experiments can be expected to reveal mechanistic and organizational principles that are applicable to the performance and dysfunction of motor behavior in more complex nervous systems.
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