Xiaoqin Wang - US grants

The long-term goal of our research is to understand the neural basis for the perception of species-specific vocalizations in the auditory cortex and the fundamental cortical mechanisms that subserve neural representations of these biologically important communication sounds. Currently such mechanisms are poorly understood and there are no adequate models available to address these issues. In the present proposal, we will approach these problems using a vocal primate model, the common marmoset (Callithrix jacchus jacchus), which provides several important advantages, namely, a rich vocal repertoire, a primary auditory cortex that lies on the lateral surface of the cerebral cortex, thereby making it accessible for electrophysiological recordings and anatomical tracer placements (the primary auditory cortex of most primates is tucked into the depths of the lateral fissure) and an extremely high reproductive rate while in captivity. The specific aims of this application are to investigate the nature of the cortical representation of species-specific vocalizations in the primary and secondary auditory cortex, to analyze how cortex treats natural and unnatural sounds, and to determine the acoustic elements in marmoset vocalizations that not only characterize the sounds but also effectively evoke cortical responses. These studies are a natural extension of the P.I.'s previous work. The investigations will emphasize the systematic and quantitative characterization of marmoset vocalizations, and standard extracellular single-unit recording and analytic techniques with a focus on populations of neurons whose responses may reflect the detection of vocalization features. Findings of the present study will contribute to our basic understanding of the cortical representation of complex acoustic stimuli, and will have implications for the neural b~is of human speech perception, clinical management of speech- and hearing related disorders, and for designing better hearing aids and prosthetic devices for the deaf and hearing- impaired.

DESCRIPTION (provided by applicant): The objective of the proposed research is to understand physiological mechanisms underlying auditory-vocal interaction in primates. Currently such mechanisms are poorly understood, and there are no adequate primate models available to address these issues. In this application, we will examine our research questions in a highly vocal primate, the common marmoset (Callithrix jacchus). The marmoset provides several important advantages for our studies over other primate species: a rich vocal repertoire and a high reproductive rate while in captivity. In the proposed research, we will examine two fundamental questions concerning auditory-vocal interaction in primates: 1) Does the vocal production system influence cortical processing of auditory information? 2) Is auditory input necessary to maintain normal vocal production? Specifically, we will test the hypothesis that the vocal production system modulates neural responses in the auditory cortex in primates. Furthermore, we will determine spatial distributions of neurons exhibiting vocalization-related modulated in the auditory cortex. Our preliminary data indicates that neural responses in the auditory cortex are modulated by the vocal production system, with the modulation starting prior to the vocal onset. In the second series of experiments, we will study developmental changes in marmoset vocalizations and its dependence on the auditory experience. Our hypothesis is that marmoset vocalizations undergo postnatal changes under the normal auditory environment. We will further test the hypothesis that auditory feedback is necessary for maintaining normal vocal productions. The proposed research will approach the issues related to auditory-vocal interaction in an integrated manner. Aims 1-2 and 3-4 represent intellectually linked efforts to study auditory-vocal interaction from two directions: Aims 1-2 investigate modulation of auditory processing by the vocal system, whereas Aims 3-4 investigate modulation of vocal production by the auditory system. Findings of this research will provide insight into speech production and perception mechanisms in humans and establish a parallel non-haman primate model to investigate disease-related issues in speech and hearing.

The overall objective of the proposed research is to reveal physiological mechanisms underlying auditory-vocal interaction in non-human primates. Such mechanisms have fundamental importance to our understanding of human speech production and perception mechanisms but are poorly understood, and there are no adequate non-human primate models available to address these issues at the cellular level. In this application, we will examine our research questions in a highly vocal primate, the common marmoset (Callithrix jacchus). The marmoset provides several important advantages over other non-human primate species: a rich vocal repertoire, a high reproductive rate while in captivity, and a smooth brain allowing easy access to all parts of the cerebral cortex. In the proposed experiments, we will focus on neural substrates of auditory-vocal interactions in marmoset auditory cortex. In Aim 1, we will develop a behavioral paradigm to experimentally induce vocalizations in the common marmoset. The ability to behaviorally (not electrically) elicit vocalizations in monkeys has long been sought by researchers and remains a significant obstacle in the study of vocal control mechanisms in non-human primates. We will study in Aim 2 how various areas of the auditory cortex are involved in auditory-vocal interactions. Findings from this aim will reveal functional and anatomical properties of neurons involved in auditory-vocal interactions in marmoset auditory cortex, and pave the way for future studies of their connectivity with the brain structures involved in vocal production. In Aim 3, we will study the role of behavioral context in auditory-vocal interactions within auditory cortex. Marmosets produce a wide range of vocalizations in different behavioral contexts. We will investigate whether different types of vocalizations produce different modulatory effects in individual auditory cortical neurons. Findings of this research will provide important insight into speech perception mechanisms in humans and establish a non-human primate model to investigate issues related to diseases and dysfunctions in speech and hearing.

Many neurons in the auditory system respond to sounds nonlinearly; that is, its response to two sounds played simultaneously differs from the sum of its responses to each sound played alone. Nonlinearities are necessary for many computational functions, but unlike nonlinear models that allow closed-form solutions, nonlinear models are often too hard to characterize in practice. To make nonlinear models tractable, this project will combine single-unit recording in awake marmoset monkey with automated online stimulus design by parallel computing. The goal of this stimulus design is not to maximize the firing rate of a neuron, but to extract the most information about the global stimulus-response relationship. Optimal sounds will be designed "on the fly" according to a neuron's response history, with the help of a fast parallel computer whose running time is compatible with the single-unit recording experiment. The proposed research is expected to produce practical and widely applicable methods for characterizing nonlinear sensory neurons. The auditory system is an ideal system for this type of online experiment because sound space is of lower dimensions and allows faster computations. The methods developed here are expected to generalize to nonlinear problems in other sensory modalities.

Theory and algorithm development will focus on generating sound stimuli which can either most accurately estimate a given model, or maximally distinguish competing models. Nonlinear models with various degrees of complexity, including neural network models, will be used simultaneously, and contrasted against one another in the automated experiment. The model-based sound design method will be used to characterize complex response properties of neurons in auditory cortex and inferior colliculus of awake marmoset monkey, a vocal primate. This project focuses on the auditory cortex because studies of its pronounced nonlinearities may potentially benefit most from the new method. For comparison the same method will also be applied to the inferior colliculus, the inputs to which are better known, allowing more realistic hierarchical models to be developed. The models obtained from this method should provide a concise summary of the global stimulus-response relationship of a neuron that generalizes across all types of stimuli. Neural network models may also help extract additional information about the connectivity between different neuronal types, thus providing a link between the stimulus-response function and the structure of the underlying neural circuits.

DESCRIPTION (provided by applicant): The objective of the proposed research is to understand neural mechanisms underlying vocal production in the primate brain and their implications for human speech processing mechanisms in normal and pathological conditions. Earlier studies concluded that the cerebral cortex plays little role in vocal production in non-human primates, which is in sharp contrast to the role of human cortex in speech production and inconsistent with accumulating evidence from the past two decades. In this application, we will re-examine this important question using a highly vocal primate, the common marmoset (Callithrix jacchus), as our experimental model. The marmoset provides a unique advantage over other non-human primate species typically used in laboratory studies in that it as a rich vocal repertoire and interesting vocal behaviors that are readily studied in laboratory conditions. In Aim 1, we will identify frontal cortex areas associated with vocal production in marmosets. The proposed experiments in this aim will take the advantage of a unique vocal behavior (antiphonal calling) and a well-developed chronic recording technique to identify specific cortical areas in the marmoset brain involved in vocal production. Aim 2 will study physiological properties of neurons in the frontal cortex during vocal exchanges in freely roaming marmosets using a wireless recording technique. Experiments in this aim will help identify the network of cortical areas in the marmoset brain that are responsible for generating and controlling vocalizations. Aim 3 will examine the roles of specific frontal cortex areas in controlling vocal production using reversible inactivation methods. Findings from the proposed study will shed lights on neural mechanisms responsible for vocal production in the primate brain and have implications for understanding how the brain operates during speaking and hearing. PUBLIC HEALTH RELEVANCE: How the brain processes speech is of the fundamental importance to the well-being of everyone in the society, but remains largely unknown to date. Findings of the present study will contribute to our understanding of neural mechanisms underlying vocal production in the primate brain. They will have important implications for understanding human speech production mechanisms in normal and pathological conditions. .

DESCRIPTION (provided by applicant): The long-term objective of this research is to understand both neural mechanisms for processing communication sounds and fundamental neural coding mechanisms in auditory cortex that subserve cortical representations of biologically relevant sounds. We will use the common marmoset (Callithrix jacchus) as our experimental model to address these questions. This model system provides several important advantages over other species, namely, a hearing range similar to that of humans, a rich vocal repertoire, an auditory cortex that lies largely on the lateral surface of the cerebral cortex and a high reproductive rate while in captivity. In this application, we will focus on elucidating information processing mechanisms in the rostral areas outside the primary auditory cortex (A1). Aim 1 will study neural representations of marmoset vocalizations in the rostral areas using "virtual vocalization" stimuli that we have recently developed in our laboratory. These stimuli are based on the statistics of marmoset vocalizations and can be easily manipulated in both spectral and temporal domains to probe cortical responses with great flexibility. Aim 2 will investigate the roles of spectral and temporal pitch mechanisms in generating pitch-selective neural responses in a "pitch- region" located in the rostral areas. Results of this aim will pave the way for further studies to investigate anatomical connectivity of pitch-selective neurons in auditory cortex. Aim 3 will use sleep as a unique behavior state to study the state-dependent processing in the rostral areas. We will quantitatively evaluate neural responses in the rostral areas to external sounds during sleep. The transformation of cortical representations of sound-evoked responses during sleep from A1 to the rostral areas will provide further insight into information processing streams within the superior temporal gyrus. PUBLIC HEALTH RELEVANCE: The auditory cortex, the part of the brain being studied in this application, is a crucial for our hearing and speech and language. Findings of the present study will contribute to our basic understanding of the cortical representation of complex acoustic stimuli, and will have implications for the neural basis of human speech perception and for designing better hearing aids and prosthetic devices for the deaf and hearing-impaired.

? DESCRIPTION (provided by applicant): Johns Hopkins University, and its various divisions and departments, have joined hands to put together one of the first predoctoral training programs in Neuroengineering. The Neuroengineering Training Program at JHU involves Departments of Biomedical Engineering, Electrical and Computer Engineering, Neuroscience, Materials Science and Engineering, Cognitive Sciences, Neurology, Neurosurgery and Radiology, Mind-Brain Institute and Kennedy-Krieger Institute. An explosive growth of the field of Neuroengineering is backed by an impressive level of interest by top students with outstanding credentials. The central mission of this training program is to produce the next generation of engineers, scientists and educators and to groom the trainees into scientific and engineering leaders. The training program selects outstanding trainees through multi- departmental recruiting efforts and an institution-wide effort to recruit under-represented minority. The training program is structured to provide introductions to select laboratories, mentors and projects, including expanded internship opportunities to industry and the medical school, provide mentoring for career development and eventual career transition. The program has now expanded to now include six theme areas (Neurotechnology, Neuroimaging, Computational Neuroengineering, Systems Neuroscience, Neural Tissue Engineering, and Clinical Neuroengineering) and embraced a number of additional faculty preceptors across eight departments and two divisions. A number of innovations and initiatives have been incorporated, including integrating clinical and translational problems and their solutions, tapping into major institutional initiatives to modernize PhD education, introducing international training opportunities, and mentoring career paths to produce future scientists and leaders in academia and beyond.

? DESCRIPTION (provided by applicant): The long-term goal of our research is to elucidate neural coding and plasticity mechanisms underlying cortical processing of cochlear implant (CI) signals in the context of vocal communication. We have established a new CI model (the common marmoset) to pursue these questions. The present application builds on that foundation and represents the next key steps towards our long-term objectives. Marmosets have a rich vocal repertoire, are highly communicative, and can potentially be used to study vocal production and auditory feedback mechanisms related to speech processing in CI subjects, which is an area that lacks suitable animal models. The hearing range of the marmoset is similar to that of humans and its auditory cortex shares similar organizations as humans. These similarities make it a highly valuable animal model to address issues in CI research pertaining to human users. The PI's laboratory is a pioneer in marmoset research, and the proposed research will benefit from techniques we developed over the past two decades to study marmoset auditory cortex in awake and behaving conditions. Aim 1 will compare auditory cortex neuron selectivity for acute and chronic CI stimuli. Our preliminary studies showed that primary auditory cortex (A1) neurons that are acoustically selective to both frequency and sound level are often unresponsive to electrical stimulation of the cochlea. It is not clear how these highly selective cortical neurons behave in the chronic CI stimulation condition. Aim 2 will define cortical representations of time-varying cochlear implant stimuli in alert primates. Temporally modulated signals are critical components of vocal communication sounds of humans and animals. Previous CI studies in anesthetized animals have encountered limits of cortical phase locking between 20-60 Hz, leaving unanswered the question of how higher frequency envelope modulations, which can be perceived by CI users, are represented in auditory cortex. Aim 3 will characterize neural responses to CI stimulation in non-primary auditory cortex. Currently, our knowledge on how the auditory cortex processes CI input has almost exclusively relied on studies of A1. Little is known about how cortical areas outside A1 are engaged by CI stimulation at the single neuron level. The results of these aims will help elucidate cortical processes involved in electric hearing and provide insights for improving current cochlear implant designs.

Project Summary The common marmoset (Callithrix jacchus) has experienced unprecedented growth in research across the United States and is rapidly emerging as a likely keystone biomedical model system in the next chapter of scientific discovery. Over the past decade, the number of marmoset laboratories in the US has quadrupled. There are now over 40 Principal Investigators who use marmoset as the model system in their research. Neuroscience is the primary engine driving marmoset research today, as nearly three quarters of marmoset researchers in the US use this model species to examine molecular, systems or cognitive functions in normal and diseased brains. Although these grassroots have been successfully forged new paths of scientific inquiry using marmosets in the U.S., critical bottlenecks have emerged that threaten to thwart the continued growth of this emerging model system. We propose to establish a Bicoastal Marmoset Breeding center, with two breeding colonies, one on the East Coast at Johns Hopkins University (JHU) and the other on the West Coast at University of California at San Diego (UCSD). The Center aims to produce a large number of marmosets to supply the marmoset research community in the U.S. Because of the non-availability of air transport of NHP in U.S. and prohibitively expensive ground transportation of NHP between the east and west coast, these two breeding colonies are strategically located to support the marmoset community in regions near each colony. We believe such a center is needed to address the national shortage of marmosets in order for the marmoset model to realize its full potential as a keystone species in the next chapter of neuroscience that serves to accelerate the rate of discovery and better understand human neurological disease.