Terry T Takahashi - US grants

The long term goal of this project is to contribute to an understanding neuronal coding and computation. Such information is particularly relevant to the design of neural prosthetic devices (e.g., artificial cochleae) and their interfaces to the nervous system. As a model, the circuitry by which the barn owl's auditory system calculates interaural level difference (ILD), i.e., the difference in the loudness of the sound in the ears, will be analyzed. The barn owl is a species of choice because the significance of ILD to its behavior is clearly understood: ILD signifies the vertical co-ordinate from which a sound emanates. Moreover, its auditory pathways have been traced and characterized. In this project, attention will be focused on a nucleus of the owl's brainstem, VLVp, that is the first site at which ILD is computed. Preliminary studies indicate that the computation requires an inhibition that originates in VLVp of the opposite side. Thus, the central task is to identify and characterize the inhibitory neurons that project to the opposite nucleus. This will be done by a combination of axonal tracing methods and by selectively anesthetizing a subdivision thought to contain the inhibitory neuron. The topography of the projection from this subdivision will be analyzed and compared with a gradient of inhibitory strength that is known to exist in VLVp. Finally, an attempt will be made to study the effects of altering the sensitivity of VLVp neurons to ILD on higher auditory centers. For the latter project, the neurotransmitter that mediates the inhibition will be identified. The study of VLVp's circuitry is essentially a study of a neural system that contrasts the strength of inputs (e.g., from the two ears), and the kind of morphology that underlies this computation. Thus, resulting data will have significance to the study of neural systems in general.

The natural acoustical environment contains many sound sources that are active at the same time. The ears receive the sum of all of these sounds and from this complex waveform, the auditory system manages to determine the location of each source. With age, the ability to assign locations to sound sources deteriorates, and with it, the ability to attend selectively to a single source in a noisy environment. This project will examine how the brain is able to establish the location of multiple, simultaneous, sound sources. The model system is the barn owl, a nocturnal predator renowned for its ability to localize sounds and the fact that its brain contains a retina-like map of auditory space. Like cells of the visual system, these space-mapping cells respond only when stimuli emanate from a discrete location in space and are arrayed so that the spatial relationships of the stimuli are preserved. In this project, neurophysiological experiments will first explore the ability of the space- map to resolve two simultaneously-active sound sources as the similarity between the speaker's sounds and the distance separating the speakers are manipulated. Further neurophysiological tests will explore the possible mechanisms that underlie the ability of the space-map to represent concurrent sound sources. Particular attention is focused on the situation in which two sound sources concomitantly emit broadband noises, an acoustical signal often produced by the owl's prey. Finally, the ability of the barn owl to resolve simultaneously-active sound sources will be tested behaviorally so that neural and behavioral capabilities can be compared.

Our laboratory's long-term goal is to understand how the auditory system allows us to listen selectively to the sound of interest amidst sources of interference. Using the auditory system of the barn owl (Tyto alba), with its topographic maps of space, we have been studying the effects of background noise and echoes on spatial resolution. Auditory events, however, generally unfold in time, and the auditory system must keep track of temporal changes in the features of sounds. In this project, we ask: How well does the auditory system encode time-varying signals in a cluttered environment? Behaviorally salient cues in the owl's environment, such as sounds of prey and many of its vocalizations (e.g, the threat call) consist of broadband signals with complex temporal structure. The neurons of the bran owl's inferior colliculus were recently found to adept at tracking the temporal structure of such complex waveforms in addition to being selective for the source's location. In this project, we examined how this temporal firing pattern is affected by noise. Parallel studies of behavior and neurophysiology are carried out in Aims 1 and 2, and in Aim 3, we combine the two methods in a novel attempt to record neuronal responses from the awake, behaving bird.

[unreadable] DESCRIPTION (provided by applicant): The Systems Physiology Training Grant (STG) will support a program to prepare the most qualified doctoral students for professional research careers in integrative neuroscience through a combination of original, hands-on research, and formal courses. The trainees and their mentors have appointments in the Department of Biology, Department of Human Physiology (formerly Exercise and Movement Science), and Department of Psychology at the University of Oregon. Their research programs span diverse model systems from humans to nematodes and employ a variety of techniques including electrophysiology, neural imaging, molecular biology, psychophysics, and computational modeling. Nevertheless, the trainees, regardless of their departmental affiliations, experience a common set of requirements and activities designed to establish a cohort of students that interact across departmental and disciplinary lines. Our intention is that these students will continue to interact throughout their graduate career, mutually enriching their research efforts with novel ideas and perspectives. The continued funding requested is for 8 predoctoral trainees within a neuroscience graduate program of approximately 50 students, of whom 40 are eligible for training grant support. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Capturing nature's statistical structure in the neural coding is essential for optimal adaptation to the environment. This proposal investigates this issue by asking how the brain can approach statistical optimality in the sound localization system of barn owls. A Bayesian theoretical framework will be used to describe how sensory and a priori information can be combined optimally to guide orienting behavior. Specifically, we seek to demonstrate that sensory reliability and a priori information are represented in the response properties and topography of the neural population that represents auditory space. The first aim studies how sensory cue reliability is represented in the brain. Optimal use of sensory information requires that the statistical reliability of sensory cues is accessible from neural responses. Previous theories have suggested that cue reliability is encoded in the gain of neural responses or alternatively the selectivity of neural responses but how reliability is represented is not known. In the owl, changes in the statistical reliability of spatial cues resultin changes in sound localization behavior consistent with a Bayesian model. Our model predicts that the reliability is encoded in the tuning curve widths of space-specific neurons located in the owl's midbrain. We will manipulate tuning-curve widths and firing rates independently to test this hypothesis and test the model with behavior. The second aim will study whether the integration of spatial cues for sound localization follows the rules of statistical optimality. Perception in natural environments often depends on the integration of multiple cues, both within modalities and across modalities. Here, whether the integration is linear or nonlinear is crucial, as extending a Bayesian model from one to two dimensions indicates that optimal combination of conditionally independent sensory cues should be nonlinear. In the owl's brain, the spatial cues used to determine elevation and azimuth are processed independently and combined nonlinearly in the midbrain to form spatial receptive fields. However, whether or not sound localization cues are conditionally independent is unknown. This aim will demonstrate why nonlinear operations are essential for optimal cue combination and how they arise. We will perform in vivo intracellular recording and behavioral tests to address these questions. This will provide an experimental test of the prediction that optimal combination of conditionally independent cues is nonlinear. The third aim will extend the model to coding dynamic auditory scenes; the time dimension will be incorporated into the Bayesian model of sound localization. We will use a population vector model to determine how a neural system can achieve predictive power in auditory space through Bayesian inference. We will measure receptive fields of midbrain neurons in space and time to test the hypothesis that the owl has a bias for sources moving toward the center of gaze. We will use behavioral tests to measure detection thresholds for moving sound sources. Finally, we will study whether a dynamic gain control in a non-uniform network can account for Bayesian predictive coding of sound motion with a bias for sources moving toward the center of gaze. Broader Impacts: Outstanding open questions of how statistics of natural scenes are captured by neural coding include how reliability of sensory information is represented and combined with prior probabilistic knowledge, and how sensory cues are integrated to optimally guide behavior. This project addresses these questions in the heterogeneous representation of space of the owl's auditory midbrain. Whether non-uniform representations can be decoded using a population vector to perform Bayesian inference and that this mechanism works in multiple dimensions transcends sound localization in barn owls, becoming of general interest to neural coding. The PIs involved in this project, one of them a junior researcher, gather complementary expertise in modeling, physiology and behavioral approaches allowing for a truly interdisciplinary approach. This project will thus consolidate a powerful collaboration while providing groundbreaking information on outstanding questions in Neuroscience. The three institutions involved are committed to the training of underrepresented groups. The location of the Albert Einstein College of Medicine in the Bronx, makes it a pole of development in one of the most diverse and poor counties in the country and provides the potential for direct access to translational research. The inclusion of the Department of Mathematics at Seattle University, ranked among the top ten universities in the West for undergraduate programs, and the University of Oregon will ensure that this project will enhance training from the undergraduate to postdoctoral levels.

DESCRIPTION (provided by applicant): This application aims to demonstrate that Scanning Unnatural Protease Resistant (SUPR) peptides provide a general solution to the problem of targeting traditionally undruggable proteins. To do this, we will use mRNA display with an expanded genetic code to create a new class highly stabilized, membrane-permeant peptides that can block or modulate protein-protein interactions for two of the most important intracellular proteins conferring the oncogenic phenotype-the activated form of Ras and the Stat3 protein. Our three Specific Aims are: 1) To design stabilized SUPR peptides targeting intracellular undruggable proteins involved in cancer transformation or maintenance, 2) To characterize and enhance selected SUPR peptide functions towards cancer drug applications, and 3) To evaluate in vivo characteristics and assess the therapeutic potential of optimized SUPR peptide drug candidates for cancer treatment in mice. Overall, this project is intended to develop novel molecules as well as a general approach to target cancer-relevant proteins that have proved challenging up to this point-so much so that the proteins may be called undruggable. PUBLIC HEALTH RELEVANCE: The development of novel technologies to inhibit undruggable therapeutic cancer targets is an important public health priority. It can expand our abilities to discover new cancer drugs and improve our abilities to manage cancer. Successful completion of the proposed studies will not only offer many new treatment opportunities for cancer, but also provide new tools for cancer drug discovery.

Project Abstract Objects in nature can be better detected or localized by integrating information across multiple senses. Much of the focus in the literature has been on ?facilitation?, the degree to which, for example, an audiovisual (AV) stimulus evokes responses that are faster or more precise than that achieved with the faster or more precise of the two modalities. The project proposed focuses on a different type of facilitation, first reported in humans, in which performance with bimodal stimuli combines the best features of each modality alone. The applicant?s lab demonstrated a similar result in the barn owl (Tyto alba): An owl turns its head toward auditory targets with shorter latencies but lower precision than toward visual targets. Conversely, head-turns to visual targets take longer to initiate, but are more precise. AV-guided head-turns are both fast and precise, but neither faster nor more precise than to audition and vision, respectively. Correspondingly, neuronal latencies in the owl?s optic tectum (OT), an area involved in the direction of gaze, are shorter for auditory stimuli than for visual stimuli. Conversely, visual spatial receptive fields (SRFs) are finer than auditory SRFs. This novel form of multisensory enhancement will be studied neurophysiologically and behaviorally, guided by the hypothesis that auditory information arrives in the OT first, triggering the head turn. The visual information, arriving later, helps to refine the trajectory of the head turn. Each aim is guided by an organizing question: Aim 1. Do owls update only if later arriving information improves localization or does it update to the later arriving information even at the expense of performance? We will blur the visual component of an AV stimulus to determine whether information from the blurred visual component is incorporated or ignored. Aim 2. Auditory and visual input arrives at the OT with different latencies. What is the delay between the auditory and visual streams beyond which updating is no longer observed? We will test two alternative hypotheses: 1.) Updating is limited by a fixed time window that closes during a saccade, or 2.) Updating requires the temporal overlap between the tectal neural responses to auditory and visual stimuli. To distinguish between these ideas, we will vary the duration of sound as we test various time delays between the auditory and visual components of AV stimuli. Aim 3. Is updating exclusive to multimodal stimuli? A sequential pair of unimodal auditory and visual stimuli will be presented in which the localizability of stimuli are altered to determine whether or not information from both senses is necessary.