Terry 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.

WPC_ 2 B V P Z Courier 10cpi ? x x x , k x 6 X @ 8 ; X @ HP LaserJet III HPLASEII.PRS x @ , t 0 OpX @ 2 < Z L ! #| x Canon LBP-8III (Letterhead) CALB8IAD.PRS x @ 0 jFX @ Courier 10cpi Courier 10cpi Bold 2 X . ? x x x , l x 6 X @ 8 ; X @ l ? x x x , x ` w ; X > ' 9 >N ( ? 5 6N E 2 D < u | u | t D 5 t$ D E =& t =^ u y r= u t " s r 9320702 Roberts Salmons are well known for their ability to return to the stream in which they were born. The sensory basis for this remarkable behavior is olfactory: during a sensitive developmental period (smolt transformation), salmon imprint to distinctive homestream odors, and adults later use this odorant memory as a migratory cue to guide them back from the open ocean to their natal streams. How salmon imprint to homestream odors has remained an important but perplexing puzzle for over forty years. Proponents of olfactory imprinting have assumed that the olfactory memory for the home stream resides in the central nervous system. Dr. Roberts, however, proposes that olfactory memory is actually retained in the olfactory receptor cells themselves. The basis for his theory rests on two important findings. First, surges in plasma thyroxine levels mediate smolting, and second, olfactory imprinting coincides with this developmental metamorphosis. This small grant for exploratory research enables Dr. Roberts to use state of the art electrophysiological and neuroanatomical techniques to determine whether there are thyroxine induced change s in olfactory receptor neurons to specific odors. This basic research will have direct benefits to Pacific salmon by providing insight into how olfactory imprinting might be artificially manipulated. If thyroxine hormone can influence the ability of fish to imprint during a wider time frame than smolting, this finding could markedly advance conservation efforts aimed at transporting rapidly diminishing endangered salmon runs to healthier river systems. ***

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.

Roberts, William M. IBN 94-10637 The ability to recognize familiar locations by their sights, sounds and smells is a common phenomenon. In salmon, who migrate great distances from fresh water streams to vast salt-water oceans, and ultimately, back to their home streams to reproduce, the ability to identify their home streams is crucial to species survival. But how is it that these fish recognize their home environments? One possible mechanism is the incorporation of familiar smells into memory which occurs during the parr smolt in salmon. During smolting, a physical transformation takes place as does a maturation of olfactory memory. Additionally, smolting is accompanied by a marked increase in thyroid hormone levels. Drs. Roberts and Takahashi will examine the role of thyroid hormones in the development of olfactory memory. Olfactory receptor cells born at the time of the parr smolt will be chemically marked and the effect of exogenous thyroid hormone treatment to enhance their survival will be determined. Moreover, structural changes in the olfactory bulb of the brain at smolting and modulation of those changes by thyroid hormones will be assessed. In addition to examination of the structural changes occurring in the brain at the time of smolting, functional changes in the sensitivity of the olfactory receptor cells to odorants will be examined. These studies have the potential to provide a breakthrough in understanding the physical basis of memory. Further, migration of salmon is of considerable commercial interest. This research has the potential to allow man to devise methods for guiding salmon to their birthplaces following novel pathways that may enhance the survival of the species.

9720334 Krishnaprasad The goal of this research project is to investigate time coding in the central nervous system, specifically the auditory system of the barn owl, the early development of such codes, the learning of associated maps, and the exploitation of such sound codes and maps in source localization and sound separation. The approach consists of electrophysiological and anatomical study, coupled with mathematical modeling of neural circuitry, the rigorous investigation of the structure and performance of relevant learning algorithms and the creation of an experimental robotic testbed. This testbed, a binaural head, is intended to be capable of orienting itself to sound sources in complex acoustic environments through pure auditory servoing, by utilizing the development of control architectures capable of learning maps of the auditory space of the robot, and drawing upon an evolving understanding of barn owl auditory system. The results of this research will provide insights into the design of novel roles for auditory sensing, interpretation and discrimination in autonomous robotic systems. This research could lead to applications in hands-free human-machine communications in acoustically cluttered environments and in monitoring complex environments such as highly automated manufacturing plants.

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): 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.