Rebecca A. Code - US grants

Proper functioning of the auditory system requires the integration of incoming sensory stimuli with central feedback information in both the periphery and central auditory centers. Since human cochlear prostheses should incorporate both incoming and descending auditory information, any knowledge regarding the integration of such information should be useful in their design. in this regard, the normal physiology of cochlear hair cells and their ascending projections in the mammalian auditory system have been well characterized; the available data on the descending auditory system, however, are sparse by comparison. For example, relatively little is known about the mechanisms by which olivocochlear (OC) fibers modulate auditory nerve inputs in the cochlea. Similarly, in the cochlear nucleus (CN), the complex interaction between auditory afferents and efferents that results in the modulation of neuronal response properties remains to be elucidated. The avian auditory system might be more useful than the mammalian system in the clarification of the relationship between afferent and efferent inputs because its neuronal architecture and connectivity ace less complex than those in mammals. A first step in understanding the contribution of descending inputs to the normal physiology of the chick auditory system is the neuroanatomical localization of their cells of origin. Identification of efferent neurons and the neurotransmitters that they employ is necessary for elucidating the functional role that efferents play in shaping the response properties of hair cells and auditory neurons. The goals of the proposed investigation are to define the source(s) of efferent projections to the avian cochlea and cochlear nucleus both anatomically and neurochemically. Injections of tritiated gamma-amino butyric acid (GABA) will be made into the chick CN or cochlea and autoradiographic procedures will be used to determine the location of GABAergic cells of origin. Choline acetyltransferase immunocytochemistry and acetylcholinesterase histochemistry will be employed to determine sources of cholinergic input and fiber pathways, respectively, to the cochlea and CN. Additionally, a combination of fluorescent tracers will be used to determine the existence and patterns of axonal collateralization of descending projections.

Recent evidence suggesting that mammalian hair cells are capable of regeneration after noise-induced trauma or exposure to ototoxic drugs lends hope to the possibility of restoring hearing to humans with certain types of sensorineural deafness. The most extensively studied system in terms of regeneration has been the inner ear of the chick. Investigators have focused on the anatomical and functional recovery of auditory nerve fibers that innervate the hair cells of the inner ear; the role that cochlear efferent fibers may play in recovery, however, has not been addressed. In order to understand how cochlear efferent fibers contribute to the recovery of the damaged cochlea, we propose a study of the efferent innervation of the cochlea in the normal chick. Indeed, the contribution that cochlear efferent fibers make to the normal physiology of the inner ear remains to be elucidated. Such information may lead to the improved design of cochlear prostheses by increasing their ability to integrate incoming auditory information with the brain's feedback control via cochlear efferent fibers. A first step toward better understanding the role that cochlear efferents might play in hair cell regeneration and normal functioning of the chick's inner ear is their neurochemical identification. This proposal will determine the distribution of immunocytochemically-distinct cochlear efferent cell bodies in the brainstem as well as the distribution of their terminals in the cochlea. Neurochemically-identified efferent terminals will be examined from normal cochleas and from those exposed to ototoxic drugs. Although the locations of cochlear efferent neurons in the chick brainstem are known, the inputs to these neurons are not. Identifying what controls the activity of cochlear efferent neurons might provide some indication of the functional role that cochlear efferents play in the normal physiology of the cochlea. The superior olive (SO) is a likely source of inputs to cochlear efferent neurons. Although the avian SO receives information on both the timing and intensity of auditory signals, it is not known if these two types of information remain in separate channels within the SO or whether cochlear efferent neurons receive both time-and intensity-coded information from the SO. We will study the types of cells in the SO that project to cochlear efferent neurons and relate them to inputs to the SO from time- and intensity-coded pathways.

DESCRIPTION: (Adapted from the Investigator's Abstract) In the central nervous system, opioid peptides and their receptors appear to modulate a wide variety of physiological processes including attention, drive, mood , reproduction and responses to stress. They have also been found in primary sensory nuclei where they are involved in the filtering and processing of sensory information. Additionally, they have been implicated in the regulation of neuronal development. One means by which opioid peptides (e.g., dynorphin and the enkephalins) or activation of their receptors (kappa- and delta- opioid receptors, respectively) exert their cellular effects is through the regulation of intracellular calcium concentration ([Ca2+]i). An increase in [Ca2+]i can lead to nerve cell death in many parts of the nervous system. For example, in the chick cochlear nucleus, Nucleus Magnocellularis (NM), cessation of excitatory input by unilateral cochlea removal results in a large increase in [Ca2+]i within 1 hr and a subsequent loss of 30% of its neurons compared to the those on the unoperated side of the brain. Understanding the ways that nerve cells can prevent an increase in [Ca2+]i may lead to strategies to prevent neuronal death. In neurons of the chick NM, kappa-opioid receptor (KOR) activation results in a 25% decrease in [Ca2+]i from baseline values. Although pharmacological evidence suggests that KORs exist in NM, anatomical data is lacking. the long-term goals of the research are to investigate the roles of opioid receptor activation in the regulation of calcium homeostasis, neuronal development and sensory processing in the chick N, a relatively simple model system whose physiology and anatomy are well characterized and better understood than its mammalian homologue. As a first step toward those ends, the specific aims of this project are to use immunohistochemical and receptor binding techniques to examine the localization of opioid receptors in the chick NM, to describe their spatial distribution across this nucleus, and to study changes in their expression during development and after deafferentation. This research is significant not only for possibly preventing the nerve cell loss that results in some types of sensorineural deafness, but also in other neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease.