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Paul B. Manis, PhD, and his colleagues are studying cellular mechanisms of information processing in the central auditory system. The research has two principal goals. The first goal is to understand the normal cellular mechanisms and the organization and function of neural networks that are responsible for the remarkable sensory abilities of the auditory system. The second goal is to understand how these mechanisms are affected by hearing loss, and how they may contribute to tinnitus. This work is currently supported by 2 NIH R01 grants to Dr. Manis, and grants to Drs. Greg Basura and Joseph Roche.

In the first project, Drs. Manis and Mancilla are studying the physiology of the dorsal cochlear nucleus. The dorsal cochlear nucleus (DCN) is a site for rapid and early processing of spectrally complex acoustic stimuli, and is the first point in the auditory system where auditory and non-auditory information converges. Changes in the DCN following hearing loss has been associated with central tinnitus, which is a perception of a phantom sound. Increased activity of DCN neurons can be caused by increased electrical excitability or decreased inhibition, and thus these are potential mechanisms for tinnitus. While the responses of DCN principal neurons (called pyramidal cells) to sound are strongly molded by inhibition, little is known about the functional operation of the major inhibitory networks. The goals of this project are to investigate inhibitory circuits in the DCN, and to elucidate their roles in normal sensory processing as well as in auditory dysfunction. In the first aim, we are studying the organization and synaptic dynamics of the two major inhibitory circuits in the DCN, using paired whole-cell recording. We are examining whether the synaptic influence of the most populous inhibitory interneurons, the cartwheel cells, depends on the target cell type, and whether cartwheel cells can fire in a synchronized manner as predicted from their physiology and connections. We are studying the spatial organization of cartwheel cell axons to determine whether and how this system, which receives non-tonotopic inputs, might operate in a tonotopic fashion. These experiments include morphological reconstruction of cell pairs to determine the spatial organization of local connections. In the second aim, we are investigating short (seconds) and long-term (hours) synaptic plasticity at inhibitory synapses in the DCN. We will test whether cartwheel cells utilize glycine and GABA as co-transmitters onto the pyramidal cells and other cartwheel cells, and whether there is activity-dependent short-term modulation of inhibitory synapses. We are also testing whether the inhibitory synapses from cartwheel to pyramidal cells, and the synapses between cartwheel cells, can undergo similar activity-dependent plastic changes. In the third aim, we are using our data on electrical excitability and synaptic function to create a biologically accurate circuit model of the DCN. We will use this model to test predictions about how changes in synaptic function associated with hearing loss can affect the output of the nucleus. In the fourth aim, we are testing (using a rat model system) whether noise-induced central tinnitus is associated with decreases in inhibitory synaptic strength, or with increased intrinsic electrical excitability. These experiments will test whether changes in intracellular chloride regulation, consequent to changes in activity after hearing loss, will alter the behavior of inhibitory networks and the strength of inhibition, thus leading to abnormal activity and the perception of a phantom sound. Tinnitus is a phenomenon that affects nearly 20% of people in the U.S., and which is debilitating to nearly 2 million citizens. There is a significant unmet need for effective treatments. Our experiments will directly evaluate specific synaptic systems and receptors that can be targeted for pharmacological intervention for treatment and cure of this persistent problem. This project is funded by NIH through 2011.

In a second research project, Dr. Manis, along with Dr. Ruili Xie, Mr. Luke Campagnola (Neurobiology graduate student) and Mr. Alexander Rich (MS4 at UNC), are investigating the integrative mechanisms of anterior ventral cochlear nucleus (AVCN) bushy and stellate neurons in normal animals, and in animals experiencing acute and chronic hearing loss. These cells are part of a major set of pathways that are important in both speech perception and for sound localization. Central processing of the auditory environment begins with the generation of diverse, parallel, streams of information processing at the level of the first auditory center of the brain, the cochlear nucleus. These streams are created by populations of neurons with distinct patterns of synaptic inputs and projections. Recent studies have shown that inhibition plays a much more important role in sculpting the responses of ventral cochlear nucleus (VCN) neurons to sound than previously appreciated. Inhibition can serve to enhance both the spectral and temporal processing of sound attributes that are important for sound identification and localization as well as speech processing. Our studies have revealed that the time course of inhibition, even from a single source, is different in the two principal cell types, the bushy and stellate cells. The first aim of this proposal is to clarify the functional synaptic organization of two local inhibitory synaptic circuits in the VCN. The second aim is to test the hypothesis that the synaptic currents on different cell types are mediated by different glycine receptor subunits. We are also investigating the presynaptic mechanisms that regulate the time course of release during sustained activity. A third aim is to incorporate this information into a detailed computational model, which will be used to explore the importance of different aspects of inhibition in temporal and spectral processing in the VCN. The fourth aim is to determine how the function of these inhibitory circuits, as well as their excitatory counterparts, is affected by hearing loss. All of these experiments will be performed in brain slices of adult mice. Overall, our studies will identify critical mechanisms in early auditory information processing, and determine how those mechanisms contribute to the analysis of complex sounds. We will then determine how these mechanisms are affected by hearing loss, which will provide insights for alternative stimulation strategies for the hard-of-hearing and for cochlear implant users. This project received renewed funding from NIH this year, and will continue through 2013.

Auditory information processed by the brainstem and midbrain auditory nuclei is ultimately analyzed in the auditory cortex, which consists of a core or primary region and several highly interconnected surrounding areas defined by their tonotopic organization and acoustic responsiveness. Recent studies have shown that the primary auditory cortex is highly plastic, and that the properties of the cells can be modified by relevant interactions between the organism and its environment. Furthermore, it has become evident that sensory cortex not only processes sensory information, but also plays an active role in the recall of prior sensory experience. This has led to a new line of research in the laboratory that has now received additional funding from the NIH to Dr. Greg Basura, a resident in the laboratory, and AAO-HNS/ANS to Dr. Joseph Roche. Dr. Basura is studing the consequences of hearing loss on cellular processing in auditory cortex, and to study the potential role of serotonergic receptors in modulating hearing-loss induced plasticity. Ms. Deepti Rao, a graduate student from Cell and Molecular Physiology, is also working on this project. The lab is also interested in investigating synaptic changes that are associated with learning and memory in the auditory cortex. Ms. Rao, Ms. Megan Kratz (a graudate student in the Curriculum in Neurobiology) and Dr. Joe Roche are also investigating the mechanisms and functional significance of spike timing dependent plasticity, which is thought to be a learning rule that maximizes mutual information between inputs and outputs of simple neural networks. Dr. Joe Roche along with Dr. Manis will also be studying the development of spike timing dependent plasticity and how it is affected by sensorineural hearing loss.

Lastly, a collaborative project with Dr. Patricia Maness (Department of Biochemistry and Biophysics) is examining inhibitory circuits and their role in regulating gamma rhythms in the auditory cortex in a mouse model of schizophrenia is supported through the UNC Conte Center (Dr. John Gilmore, PI).