Tom C T Yin - US grants

The long-range objective of this proposed research is to understand the neuronal mechanisms by which sensory information (both visual and acoustic) is used to direct saccadic eye movements. The research focuses on two major areas: the role of the cerebral cortex in the control of visually-guided eye movements and the interaction of visual and accoustic input onto cells in the deep and intermediate layers of the superior colliculus. The primary methodology consists of single-unit microelectrode recordings made in alert cats that have been trained to execute eye movements towards visual and accoustic targets. Eye movements will be monitored using the scleral seach coil technique, and cats will be trained using feedbck of eye position under computer control. The study of visually-guided eye movements will concentrate on three areas in the visual association cortices: the lateral suprasylvian, middle syprasylvian, and frontal eye fields. These areas all receive visual sensory input, but are hypothesized to be involved in different ways in the processing of this sensory input to motor commands. Differences in the response properties of cells in these three cortical regions to identical experimental conditions will help to elucidate the functional properties of these regions. In addition anatomical tracing studies will compare their efferent connections. Studies of the acoustic and visual interactions will examine cells in the deep layers of the superior colliculus. Since visual input is retinotopically coded and acoustic input is coded in a head-coordinate system, the responses of eye movement cells in the SC to these two inputs will provide useful information regarding the coding of saccadic eye movements. These studies are of interest to neurologists who are treating patients with deficits in eye movement control, and they may also prove useful for diagnosing lesions in the auditory pathway.

Auditory information is first processed in the brainstem by neurons in the cochlear nuclear complex, containing several cell types. Output axons of many of these cells project forward in a major pathway forming a structure called the trapezoid body (from its shape). These axons then terminate on neurons at the next higher level called the superior olivary complex. We do not yet understand how the signals from the cochlear nuclei are related to higher aspects of auditory function, such as sound localization or startle responses, which are handled by neurons in the superior olive. This project will determine the signalling and target destinations of the these trapezoid body axons. Intracellular recordings will be used to physiologically characterize the response properties of single axons that extend into the trapezoid body, and intracellular dye filling then will be used to trace the pathways, from cells of origin to target cells, within the cat brainstem. Light and electron microscopy will provide details of location of terminals for each cell, and of detailed morphology of the synaptic endings, to morphologically characterize cell types. This classification then will be correlated to the observed functional responses of these cells. This work will provide a unique integration of information in the central auditory pathway; it will clarify what kinds of signal processing occur at the important level connecting the cochlear nuclei to the superior olivary complex, and will clarify the functional significance of morphological cell classification in the cochlear nucleus.

This research is directed towards understanding how auditory information is processed and coded by nerve cells in the cochlear nucleus, a portion of the brain pathways that are involved in hearing. The auditory environment provides a rich and complex array of information from a myriad of sounds from different sources. Some of this information, such as speech sounds, is highly relevant to us, while much of it is disregarded as extraneous noise. The auditory central nervous system converts auditory information into neural signals which are later analyzed at different levels in the brain. In order to understand how auditory information processing occurs, this research is being conducted to determine what aspects of auditory information are being coded by individual types of nerve cells in the cochlear nucleus as well as where cochlear neurons send this information in the brain. The activity of single nerve cells is recorded and analyzed using microelectrodes inserted into single neurons, the response to auditory stimulation is recorded, and a dye is injected into the nerve cell in order to identify it using histological techniques. By locating and analyzing this labelled neuron using both light and electron microscopy, it is possible to answer a number of basic questions which include: (1) Do certain types of cells encode specific parts of the auditory signal? (2) What part of the brain do these cells relay information to? (3) What are the interactions between individual types of neurons? These studies are essential to understanding how such a complex sensory system provides us with the experience of hearing that is so crucial to perception and cognitive experience.

The long-term objective of this project is a thorough understanding of the behavioral and neural mechanisms of sound localization. The present application will continue our long-standing electrophysiological and anatomical studies of the brainstem circuits thought to underlie sound localization and incorporates our new behavioral techniques to combine physiological recording and behavioral analysis in awake cats. We have three general aims. Aim I continues our studies seeking physiological correlates of the well-known psychophysical phenomenon known as the precedence effect, but now we will record from the interior colliculus of behaving cats. These experiments will explore the effect of behavioral states on the responses to stimuli that are known to evoke the precedence effect in human subjects as well as to resolve differences reported in awake and anesthetized animals. Aim II will study an important source of inhibitory input to the inferior colliculus, the dorsal nucleus of the lateral lemniscus (DNLL). We will study the physiological response properties of the DNLL, focussing on their binaural response and sensitivity to interaural time differences, use intracellular recording and staining of single cells to study structure/function relations, and inactivate the DNLL while recording from cells in the contralateral inferior colliculus to study the function of this bilateral inhibitory input. Aim III will use the virtual acoustic space technique to study responses of cells in the lateral superior olive (LSO) with particular attention to exploring the sensitivity of cells to spectral cues. These studies will provide important information on the neural mechanisms underlying sound localization. Spatial hearing is an important basic function of the auditory system: defects in binaural function in human patients can lead to difficulty in understanding conversations in a noisy room, which is perhaps the most common complaint of the hearing-impaired and can lead to severe social withdrawal.

The long-term objective of this project is a thorough understanding of the behavioral and neural mechanisms of sound localization in the auditory brainstem nuclei. The present application proposes to develop a behavioral preparation for testing sound localization in cats by training them to look at sound sources and to study the physiological responses of cells during this behavior. Previous studies of sound localization have chiefly centered on two areas: human or animal psychophysical work has established the important cues for sound localization and animal physiological work has shown that the nervous system is sensitive to these cues. This application is an effort to link these two approaches by combining animal psychophysics with physiology. There are five general aims. One is to study the psychophysics of sound localization in the cat using normal and spectrally shaped stimuli delivered in free field. Two is to develop a technique for delivering both free field and dichotic stimuli at the same time to determine how the cat hears the "virtual space" stimuli. Three is to determine whether cats exhibit the precedence effect and summing localization, two important psychophysical illusions that enable us to localize sounds in a reverberant environment. Four is to study the role of the cat's external ears, or pinna, in sound localization by measuring pinna movements during localization behavior and by studying the effects of paralyzing the pinna on the ability to localize sounds. Five uses this preparation for physiological studies of single cells in the superior and inferior colliculus in awake, behaving cats. Spatial hearing and sound localization are important basic functions of the auditory system: defects in binaural function in human patients can lead to considerable difficulty in detecting signals embedded in noise, such as understanding conversation in a noisy room, which is perhaps the most common complaint of the hearing-impaired and can lead to severe social withdrawal.

DESCRIPTION: (Adapted from the Investigator's Abstract) The long-term objective of this project is a thorough understanding of the behavioral and neural mechanisms of sound localization. Previous studies of sound localization have chiefly centered on two areas: human and animal psychophysical work has established the important cues for localization while animal physiological work has shown the neural mechanisms by which the auditory system encodes these cues. This application is an effort to link these two approaches by combining animal psychophysics with physiology. This application proposes to extend our present behavioral preparation for testing sound localization in casts by freeing the head of the cat so that it can orient to the sound with unrestrained head and/or eye movements. In addition we will continue our physiological studies of sound localization by recording from cells during this behavior. There are two general specific aims: one directed to behavior and the other to physiology. Specific aim I will develop the head-free preparation by monitoring eye, head and ear movement using the search coil technique and standard operant conditioning. We will compare the accuracy of localization in the head-fixed and head-free conditions, study the effect spectral cues on localization by narrowband pass filtering noise stimuli, and examine the role of pinna muscles by studying the movements of the pinna as well as the effect on localization ability of paralyzing the pinna muscles. Specific aim II is aimed at physiological recordings in these animals while they are actively localizing sounds. We will continue our examination of the motor error hypothesis by recording in the superior colliculus and studying the effect of eye position on auditory responses. Then we propose to move to the auditory cortex where we expect to find cells whose response properties are correlated with the behavioral localization of the stimulus. By progressively narrowband pass filtering the noise stimulus, we expect he cat to gradually mislocalize the sound. At some point the cat will be near threshold, looking half the time at the proper location and the other half to some phantom location. At this point we can deliver the identical stimulus with two different behaviors and correlate the neural activity to one behavior or another. Spatial hearing and sound localization are important basic functions of the auditory system: defects in binaural function in human patients can lead to considerable difficulty in detecting signals embedded in noise, such as understanding conversations in a crowded room, which is perhaps the most common complaint of the hearing-impaired and can lead to severe social withdrawal.

DESCRIPTION (provided by applicant): The Clinical Neuroengineering Training Program (CNTP) will train individuals to use inter-disciplinary approaches from the engineering-neuroscience interface to solve clinical research problems. We define clinical neuroengineering very broadly to encompass clinical and applied aspects of: neural interfacing, neuroelectronics, neuromechanical systems, neuroinformatics, neuroimaging, neuronal prosthetics, neural functions and performance, neural control, neural tissue regeneration, neural signal processing, neural modeling and neurocomputation. The CNTP will be a interdisciplinary program that builds on existing excellence across 5 colleges while providing trainees a common set of cross-disciplinary experiences. CNTP trainees will enter the program with biology or engineering backgrounds and must fulfill the requirements of an existing Ph.D. program at the University of Wisconsin. These graduate programs will provide the disciplinary excellence that trainees need to become future leaders in their respective fields. The trainee will conduct his/her PhD research on a project sponsored by a faculty trainer from the program with the additional requirement that the thesis committee have at least one faculty member from each of the broad subject areas that makeup the program: neuroscience, engineering/physical science and clinical practice. This process will ensure that the trainees will have a truly interdisciplinary research experience with broad exposure to more than one discipline. A common set of cross-disciplinary experiences will distinguish CNTP trainees from their peers; these will include a clinical neuroengineering-oriented minor course program, participation in a CNTP student seminar program. This training will incorporate appropriate clinical exposure and allow them to develop cutting edge engineering technology and incorporate it with leading neuroscience discoveries in real world clinical applications. Students will receive hands-on experience in a variety of clinical, basic neurobiology, and engineering labs. The clinical experiences will include current medical treatments for diseases such as Parkinson's, ALS, spinal cord injury, Alzheimer's, epilepsy, and peripheral nerve injury. The common experiences of CNTP trainees will ensure that all trainees, regardless of their major Ph.D. program, will be conversant in the neuroscience and engineering principles and clinical questions required to function as cross-disciplinary scientists and engineers in the 21st Century.

DESCRIPTION (provided by applicant): The overall aim of this project is to understand the neural mechanisms of sound localization and selective auditory attention. These results will help to understand how the brain integrates auditory information from the two ears and how it can direct attention to one source over others in a noisy environment. This circuitry plays a major role in our ability to detect signals in the presence of background noise, which is the major symptom of elderly people with hearing loss. Understanding the neural mechanisms will help in the design of hearing aids and therapy. There are two major aims. First, we will use two well-known spatial auditory illusions to study the representation of sound sources in space in the inferior colliculus. Experiments will use a combined behavioral and physiological preparation in awake and trained cats. We will continue our on-going experiments on the psychophysics and physiology of the precedence effect and begin a new series of experiments on the Franssen effect. Both of these are robust auditory illusions that can be readily demonstrated in our behaving preparation. Second, we will develop a new psychophysical paradigm for studying selective auditory attention. Cats will be trained to attend to a speaker on one side in order to make frequency discriminations while ignoring sounds from the contralateral side. We hypothesize that attending to one side will enhance the ability to perform the discrimination as compared to trials in which the animal is not cued to attend to one side or the other. We will then make physiological recordings from the auditory cortex using an innovative silicone multichannel probe to look for modulation by attention during this task. Spatial hearing and selective attention are important basic functions of the auditory system: defects in binaural function in human patients can lead to considerable difficulty in understanding conversations in a noisy room, which is the most common complaint of the hearing-impaired and can lead to severe social withdrawal.

DESCRIPTION (provided by applicant): The Clinical Neuroengineering Training Program (CNTP) will train individuals to use inter-disciplinary approaches from the engineering-neuroscience interface to solve clinical research problems. We define clinical neuroengineering very broadly to encompass clinical and applied aspects of: neural interfacing, neuroelectronics, neuromechanical systems, neuroinformatics, neuroimaging, neuronal prosthetics, neural functions and performance, neural control, neural tissue regeneration, neural signal processing, neural modeling and neurocomputation. The CNTP will be a interdisciplinary program that builds on existing excellence across 5 colleges while providing trainees a common set of cross-disciplinary experiences. CNTP trainees will enter the program with biology or engineering backgrounds and must fulfill the requirements of an existing Ph.D. program at the University of Wisconsin. These graduate programs will provide the disciplinary excellence that trainees need to become future leaders in their respective fields. The trainee will conduct his/her PhD research on a project sponsored by a faculty trainer from the program with the additional requirement that the thesis committee have at least one faculty member from each of the broad subject areas that makeup the program: neuroscience, engineering/physical science and clinical practice. This process will ensure that the trainees will have a truly interdisciplinary research experience with broad exposure to more than one discipline. A common set of cross-disciplinary experiences will distinguish CNTP trainees from their peers; these will include a clinical neuroengineering-oriented minor course program, participation in a CNTP student seminar program. This training will incorporate appropriate clinical exposure and allow them to develop cutting edge engineering technology and incorporate it with leading neuroscience discoveries in real world clinical applications. Students will receive hands-on experience in a variety of clinical, basic neurobiology, and engineering labs. The clinical experiences will include current medical treatments for diseases such as Parkinson's, ALS, spinal cord injury, Alzheimer's, epilepsy, and peripheral nerve injury. The common experiences of CNTP trainees will ensure that all trainees, regardless of their major Ph.D. program, will be conversant in the neuroscience and engineering principles and clinical questions required to function as cross-disciplinary scientists and engineers in the 21st Century.

DESCRIPTION (provided by applicant): For more than 35 years, the Neuroscience Training Program has provided nearly all of the graduate training in neuroscience at the University of Wisconsin-Madison. Students are able to engage in research training with faculty in the Program who have research interests that span the breadth of modern neuroscience. The Neuroscience Training Program is designed specifically to allow students to develop research independence within a structured framework. The specific aim of this application is to obtain continued support for this training with a training grant now in its 29th year. The 73 members of the training faculty in the Program draw from 21 departments from across the UW Madison campus. The faculty bring an array of scientific interests and methodologies to student training, ranging from molecular genetics to whole brain imaging. Students are encouraged to combine methods learned in different laboratories in approaching their research questions, and they are required to seek advice from several faculty members in developing and executing their research project. Due to this diversity, the training faculty set an intellectual format for students in the Program that emphasizes conceptual and highly integrative approaches to scientific endeavors. Such interaction provides a context that encourages scientific advances. The primary goal of the Program's training in neuroscience is to enable students to gain experience and knowledge through coursework, seminars, laboratory research, teaching, and community outreach. As has been customary in the Program, the selection of trainees will continue to be based principally upon prior research accomplishments and demonstrated potential for an independent research career as productive neuroscientists. The Program's goal is to attract students to neuroscience and to train them with intellectual breadth necessary for scientific leadership.

This award is funded under the American Recovery and Reinvestment Act of 2009(Public Law 111-5). The project funds a Small Grant for Training and Research in Neuroscience and Public Policy at the University of Wisconsin-Madison (UW-Madison). Three graduate students are supported annually who are engaged in integrated training and research in neuroscience and public policy in the recently established Neuroscience and Public Policy graduate program (N&PP) at UW-Madison. The N&PP is a dual-degree graduate program that leads to a Ph.D. degree in neuroscience, granted by the Neuroscience Training Program (NTP) and a Master of Public Affairs degree (M.P.A.), with an emphasis on Science and Technology Policy, awarded by the La Follette School of Public Affairs. The Program is based on two strongly held beliefs: (1) that sound science and technology policy is essential for the well being of society; and (2) that a step toward ensuring such policy is to train future scientists who are informed about the making of public policy and are prepared to participate in doing so.

The N&PP brings together faculty from the NTP and the La Follette School to train students for a Ph.D. degree in neuroscience and a Masters degree in public affairs (public policy). The training is accomplished in a program that integrates classroom and laboratory research training in neuroscience with a classroom-based education in public policy. In addition to fulfilling all of the requirements that have been established by the NTP and the La Follette School for the Ph.D. degree in neuroscience and the M.P.A. degree, respectively, N&PP students also are required to take the Neuroscience and Public Policy Seminar, which meets monthly, during each of the years that they are enrolled in the N&PP. Thus even after students have completed the requirements for the M.P.A. degree, typically by the end of the third summer, and are working full-time in the last two years of the Program on their doctoral research they maintain an involvement with issues related to public policy. N&PP students also are required to write a critical paper on a topic that bridges neuroscience and public policy as part of the Preliminary Examination for the Ph.D. degree, and complete a summer internship in an agency or organization that is directly involved in science policy.

The N&PP trains future neuroscientists who will have strong research and public policy skills. Currently, there is no other integrated graduate program in the country with goals comparable to those of the N&PP. It is anticipated that one of the major impacts of the N&PP nationwide will be to serve as a model for other institutions who decide to develop similar graduate programs that will integrate training in public policy with neuroscience, genetics or other appropriate biological or physical sciences.

DESCRIPTION (provided by applicant): The overall aim of this project is to understand the neural mechanisms of sound localization. These results will help us understand how the brain integrates auditory information from the two ears and produces orienting movements of the head, eyes, and ears to allow close visual and auditory inspection of targets. The experiments are designed to test the relative roles of two circuits that arise in the auditory brainstem to encode the cues necessary to localize sounds and generate the motor programs that orient the head, eyes and ears to the acoustic target. One circuit involves the midbrain nuclei of the inferior and superior colliculi with outputs to motor circuits in the brainstem from the deep layers of the superior colliculus. The other circuit involves projections from the inferior colliculus to the medial geniculate and primary auditory cortex. By inactivating the cortex or the midbrain, the relative roles of these two circuits in orienting behavior will be determined. The second aim will examine the vestibulo-auricular reflex by testing for the reflex following inactivation of the semicircular canals in the vestibular system. We will plug the semicircular canals and hypothesize that this will greatly attenuate the reflex. In animals with mobile pinnae, it is hypothesized that the reflex serves to stabilize the auditory world just like the vestibulo-ocular reflex stabilizes images on the retina in the presence of head movements. The final aim will study the circuitry that moves the pinna as a model motor system and compare it with the well-known oculomotor circuit. We will also examine the effect of immobilizing the pinna on sound localization performance. PUBLIC HEALTH RELEVANCE: Spatial hearing is an important basic function of the auditory system. Defects in binaural function in human patients can lead to considerable difficulty in understanding conversations in a noisy room, which is the most common complaint of the hearing-impaired and can lead to severe social withdrawal.