Matthew A. Xu-Friedman - US grants

[unreadable] DESCRIPTION (provided by applicant): Project Summary: Like all synapses during normal activity, endbulb synapses formed by auditory nerve fibers onto cochlear nucleus bushy cells show use-dependent changes in synaptic strength. At normal auditory nerve firing rates, endbulb synapses show considerable depression, which can have a major impact on the bushy cell's behavioral role of relaying and improving the timing of auditory nerve spikes for sound localization; however, the kinetics of these changes are not well understood under physiological conditions. The specific aims of this project are to determine the dynamics of use-dependent changes in synaptic strength, as well as the mechanisms underlying them. This work will be carried out using patch-clamp recordings of bushy cells in mouse brain slices. The mechanisms of depression will be considered first, by testing the contributions of presynaptic vesicle depletion and postsynaptic receptor desensitization and saturation. In addition, an unusual form of depression at the endbulb will be examined, which has been proposed to involve reduced presynaptic calcium influx, but has never been directly tested. It will also be determined how depression is mitigated by both recovery processes and facilitation, and how these processes depend on presynaptic calcium levels. In addition, high levels of activity at this synapse can lead to significant delayed release. Current clamp studies will test whether delayed release disrupts the precisely timed responses of bushy cells. The contribution of presynaptic calcium levels to delayed release will also be examined. Taken together, these studies will provide important information about the mechanisms by which timing information is transformed by auditory nerve synapses during realistic activity. Relevance: This work may help to improve the efficiency of cochlear implants, by identifying patterns of auditory nerve stimulation that will be effective, or ineffective, when processed by the cochlear nucleus. This work will also provide information for implants that stimulate the brain directly, for patients who lack a functioning auditory nerve. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Sounds are encoded by the cochlea in the timing of spikes in the auditory nerve. Auditory nerve fibers converge onto bushy cells in the cochlear nucleus, through synapses called "endbulbs of Held". This convergence leads to changes in the timing information passed on by bushy cells to higher auditory centers, which may affect sound localization and processing. Experiments have indicated that the timing of bushy cell spiking is greatly affected by the size of the endbulb synaptic current, which is subject to 2 major influences in vivo. First, endbulb synapses show considerable depression when activated at normal rates. Second, they are subject to a number of neuromodulatory systems. Both these influences can affect the information carried by bushy cells, but neither is well understood. The specific aims of this project are to determine (1) the dynamics and mechanisms of use-dependent changes in the endbulb synaptic current, (2) how the different components of the synaptic current control bushy cell timing, and (3) how neuromodulation changes these relationships. This work will be carried out using patch-clamp recordings of bushy cells in brain slices taken from mice and gerbils. The mechanisms of depression will be considered first, by testing the contributions of presynaptic vesicle depletion and postsynaptic receptor desensitization and saturation. In addition, an unusual form of depression at the endbulb will be examined, which has been proposed to involve reduced presynaptic calcium influx, but has never been directly tested. It will also be determined how depression could be mitigated by both facilitation and the activation of NMDA receptors. In addition, current-and dynamic-clamp studies will test whether delayed release during high levels of activity disrupts the precisely timed responses of bushy cells. Taken together, these studies will provide important information about the mechanisms by which timing information is transformed by convergence of auditory nerve synapses during realistic activity. This work will examine the mechanisms used by cells in the cochlear nucleus to process sound information. It will also provide important insights into the functional role that different receptor types and neuromodulatory systems play in neuronal computation. This work may lead to improvements both in existing cochlear implants and in implants that stimulate the cochlear nucleus directly. [unreadable] [unreadable] [unreadable]

Project Summary Both loud noise and conductive hearing loss can have long-term detrimental effects on hearing. The possible mechanisms have primarily been studied at high-order stages of the auditory pathway, but effects early in the pathway are relatively unknown, despite the likelihood that changes there could have consequences for all downstream processing. We found that sound-driven activity triggers a novel, slow adaptation mechanism that alters the properties of auditory nerve synapses, which are at the very start of the central auditory pathway. Within a week?s exposure to an augmented sound environment, auditory nerve synapses have reduced depression and expanded structure, as well as enhanced spiking in the postsynaptic bushy cells, which combine to enhance fidelity to synaptically-driven activity. By contrast, after one week of occluding the ear canal, auditory nerve synapses have increased depression and reduced size, with reduced spiking and fidelity in bushy cells. These changes are surprising, because it has long been thought that the early auditory pathway was unaffected by sensory experience, except under extreme, pathological conditions. This raises the possibility that this mechanism could be involved in disorders such as tinnitus and otitis media. Therefore, it is important to understand how this mechanism is normally triggered and what mechanisms underlie it. Aim #1 will examine the susceptibility of auditory nerve synapses to abnormal sound levels, in terms of age and duration of exposure. Aim #2 will use in vitro methods to uncover the mechanisms underlying the changes in synaptic function. Aim #3 will examine the functional consequences for synaptic fidelity, both in vitro and in vivo. Studying this mechanism will lead to new understanding of how synapses are normally regulated, as well as new treatments for disorders caused by abnormal activity, including tinnitus and otitis media.