TRANSNEURONAL SIGNALS FOR AFFERENT REGULATION

对中枢听觉系统有充分的了解

Adequate understanding of the central auditory system requires characterization of the neurochemical communication between cells. It is well known that afferent neurons release neurotransmitters that regulate the electrical activity of postsynaptic cells. Afferent input, however, also regulates the metabolic activity of postsynaptic neurons and is crucial for cell survival. This proposal investigates the signals regulating the electrical and metabolic activity of neurons. The model system used for these studies is the brain stem auditory system of the chick. Second-order neurons in nucleus magnocellularis (NM, the cochlear nucleus) receive their sole excitatory input from the ipsilateral auditory nerve. Elimination of auditory nerve activity results in death and atrophy of NM neurons. Within hours after eliminating auditory nerve activity, changes in metabolism (e.g., protein synthesis) in NM neurons are observed. These effects of deafferentation are reversible if afferent activity to the neuron is restored and these effects of deafferentation are not observed in adult birds. The necessary signals for maintaining and rescuing neurons are currently unknown. The proposed experiments use a variety of methods to investigate the signals regulating the electrical and metabolic activity of NM neurons. Many of these experiments will examine age-related changes in chickens ranging from embryonic to adult ages. Regulation of electrical activity will be investigated physiologically using an in vitro brain slice preparation of the auditory system. A particular emphasis will be placed on the inhibitory neurotransmitter, GABA. Application of GABA has been shown to produce an unusual electrophysiological response in this system. GABA receptors will also be examined anatomically using both receptor binding and in situ hybridization techniques. Metabotropic glutamate receptors (those linked to second messenger systems) will also be examined. Biochemical assays will determine the types of metabotropic receptors present and their pharmacological profile. Physiological experiments using the slice preparation will determine if this receptor also influences the electrical activity of the neuron. Metabolic regulation of Nm neurons will be investigated by assaying changes in protein synthesis and immunolabeling with a ribosome-specific antibody. Unilateral stimulation of the auditory nerve in vitro has been shown to produce metabolic changes similar to those observed in vivo. Application of specific agonists and antagonists will determine the relative roles of different types of excitatory amino acid receptors in transneuronal metabolic regulation. In summary, these experiments will investigate both electrophysiological and metabolic influences of neurotransmitter systems in the brain stem auditory system. These experiments will provide normative data on neurotransmitter receptors and identify receptors that may be involved in the regulation of neuronal metabolism.