Paul B. Manis, PhD

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, Dr. Manis and Dr. Jaime 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. Increased spontaneous activity in the DCN after hearing loss has also been associated with central tinnitus (perception of a phantom sound) after noise-induced hearing loss. 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.

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 chronic hearing loss. These cells are part of a major set of pathways that are important in both speech perception and for sound localization. There are 3 sets of experiments. In the first aim, we are testing explicit hypotheses about the subthreshold integrative mechanisms of AVCN bushy neurons using in vitro methods and dynamic clamp to apply realistic patterns of synaptic conductance changes that represent the activity expected with acoustic stimulation. We are examining ideas about how the specialized potassium conductances found in auditory neurons contributes to integration of synaptic inputs using a new method called “dynamic clamp”. In the second aim, we are testing the hypothesis that the two primary sources of inhibition to bushy cells utilize synapses with different release properties and temporal dynamics. We are also testing whether inhibition is necessary to improve temporal fidelity of timing information, and whether inhibition helps to provide a sparse code to more central synapses. We are documenting the organization of the functional circuitry within the AVCN through paired recordings between inhibitory interneurons and principal neurons. In the third aim, we are examining the effects of hearing loss on synaptic transmission at both excitatory and inhibitory synaptic inputs in a mouse model. We are testing the hypothesis that hearing loss causes the postsynaptic receptors to return to an immature state, e.g., similar to the receptor expression pattern seen during early development. With Ms. Eveleen Randall (MS2 at UNC) and Ms. Heather O’Donohue, we are also investigating the more speculative hypothesis that there are compensatory changes in nicotinic cholinergic receptor function in the AVCN, since there is evidence that innervation of the cochlear nucleus by cholinergic afferents may be increased after profound hearing loss that includes loss of spiral ganglion cells. This work is also dovetailing with the UNC Proteomics Core and Dr. Xian Chen, to look at other proteins that may change in the cochlear nucleus and inferior colliculus with hearing loss. These experiments will help us understand how information is processed in the central auditory system under normal hearing conditions, and will shed light on functional and cellular changes in central processing that occur in hearing loss and deafness. Understanding these dynamic changes is an essential step toward developing compensatory or corrective strategies to restore hearing and optimize auditory communication in the face of hair cell and ganglion cell loss.

In a related set of experiments, Dr. Manis’ lab is examining the effects of age-related hearing loss on central processing in mice. The DBA strain of mice exhibits a highly reproducible early-onset high frequency hearing loss of peripheral origin. Dr. Yong Wang, a past member of the lab, found that cells in the high frequency regions of the cochlear nuclei of these mice undergo changes in their synaptic communication with the auditory nerve. We are excited about these results, and the experiments may have implications for understanding how best to treat patients with significant hearing loss. Dr. Wang has recently moved on to take a faculty position in the department of Otolaryngology/HNS at the University of Utah.

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 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 Deafness Research Foundation (to Dr. Greg Basura, a resident in the laboratory), to study 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. Deepti Rao 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 (Dr. Roche has been awarded the AAO-HNS/ANS Herbert Silverstein Otology and Neurotology Research Award).

Lastly, a project 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.