EXPERIENCE AND NEUROCHEMISTRY OF THE SYNAPSE

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The ability of the nervous system to adapt to changes in an animal's environment is essential for survival. Such environmental changes are detected at the level of the single neuron primarily through changes in the cell's neural and humoral inputs. This proposal focuses on the effects of such changes on two aspects of synaptic neurochemistry: the biosynthesis of neurotransmitters and the biosynthesis of their receptors. With regard to transmitter synthesis, emphasis is placed on the factors that regulate both the expression of transmitter phenotypes and the modulation of transmitter synthesis rates. The proposed experiments are designed primarily to investigate the effects of increased nerve activity and of increased exposure to adrenal steroids. The model system chosen for these studies is the superior cervical ganglion, for which a large amount of information is available on its anatomy, biochemistry, and pharmacology. In previous studies in this area, attention has focused solely on the preganglionic and postganglionic neurons in the superior cervical ganglion. One key aspect of the proposed studies is to examine, in addition, the role of non-neuronal cells in these regulatory processes. Use is made of the fact that the ganglion can be readily studied in vivo, in explant cultures and in dissociated cell cultures. Advances, particularly in molecular biology, have greatly increased the tools available for such studies. In the present proposal, both nucleic acid and immunological probes will be used for measuring the expression of transmitter-synthesizing enzymes, neuropeptides and receptors both at the mRNA and protein level. The proposal's six specific aims are as follows:(l) to examine the peptidergic phenotype of preganglionic sympathetic neurons innervating the superior cervical ganglion (2) to examine the effects of increased nerve activity on the expression of peptides in postganglionic neurons in this ganglion, (3) to determine whether increased preganglionic nerve activity leads to the activation and/or proliferation of satellite glial cells, (4) to determine whether satellite glial cells in sympathetic ganglia are involved in the transsynaptic or humoral regulation of transmitter synthesis, (5) to determine whether differentiation factors known to affect the expression of transmitter phenotype in developing sympathetic neurons also affect the regulation of transmitter synthesis in the adult, and (6) to investigate the role of neural and humoral factors in regulating the expression of ganglionic nicotinic receptors. The long-term objective of this research is to understand the molecular and cellular mechanisms underlying neurochemical plasticity. The proposed studies should elucidate mechanisms involved in the development of the nervous system and in its modification during adult life, both under normal conditions and in a variety of neurological and psychiatric disorders. Clinically, the results should be particularly relevant to our understanding of changes that occur in the nervous system in response to increased nerve activity such as that produced by stress, epilepsy, and certain kinds of hypertension.