Larry F. Hoffman - US grants
Affiliations: | University of California, Los Angeles, Los Angeles, CA |
Area:
vestibular codingWe are testing a new system for linking grants to scientists.
The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Larry F. Hoffman is the likely recipient of the following grants.| Years | Recipients | Code | Title / Keywords | Matching score |
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| 2002 — 2004 | Hoffman, Larry F | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Sensory Coding Among Semicircular Canal Afferent Neurons @ University of California Los Angeles DESCRIPTION:(provided by applicant) The present investigation is dedicated to elucidating how head movements are encoded in the discharge characteristics of primary afferent neurons innervating the semicircular canal cristae of the vestibular labyrinth. Its additional objective is to show how this neural code is distributed within the cerebellar cortex. The experiments are designed to determine how dynamic response characteristics, as reflected in broad-band systems transfer functions and in a novel approach to characterizing vestibular afferent receptive fields, are distributed with respect to the entire afferent ensemble. A morphophysiology strategy will show how these systems response characteristics are mapped onto the peripheral crista neuroepithelium. Experiments are also designed to determine how afferent spatial and temporal coding is reflected in the projections of vestibular afferent mossy fibers to the ventral uvula and nodulus of the cerebellar cortex. The results from these studies will elucidate the foundation of sensory coding in the semicircular canal afferent system, and the bases to interpret the contribution of afferent physiologic diversity to processing within the cerebellum. The ensuing maps will also provide the bridge between investigations of the peripheral receptor and the functional coding in the afferent neurons, which will provide a functional context with which to interpret studies of hair cell physiology and pathophysiologic investigations of peripheral vestibular lesions. The experiments to be conducted in this investigation utilize electrophysiologic recording and intracellular labeling methods in a mammalian model to identify the features of sensory coding that are associated with specific morphologic and physiologic characteristics of the afferent neuron. Extensive electrophysiologic recordings will be conducted to elucidate the continuum of afferent response dynamics among the afferent ensemble. These are analyzed in the context of a model of receptive fields for these neurons, in which individual afferents code for a region of head-movement state space. Afferent response dynamics are investigated with respect to the locus of innervation within the crista, and with respect to their terminations within the cerebellar uvula and nodulus. These experiments will reveal new insight regarding the fundamental organization of stimulus coding in this sensory system. |
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| 2003 — 2008 | Hoffman, Larry | N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
@ University of California-Los Angeles 0233337 |
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| 2006 — 2007 | Hoffman, Larry F | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Vestibular Hair Cell Regeneration @ University of California Los Angeles [unreadable] DESCRIPTION (provided by applicant): The objective of this project is to investigate the morphological, physiological and molecular mechanisms of recovery of the horizontal crista vestibularis hair cells following surgical intraotic administration of gentamicin (GM) in the inner ear of adult chinchillas, a well known model for vestibular research. The experimental protocol is designed with the hypothesis that the effect of GM is dose and zone dependent with a threefold difference in the effective ototoxic dose, with type I hair cells being more sensitive than type II hair cells. Among type I hair cells there are also differences related to their location in different crista zones. Spontaneous regeneration of different hair cells takes place when each type is treated with doses that fall within the specific iaotrogenic ototoxic range. The specific aims include the following studies: 1) Investigation of the temporal course of damage and regeneration of the sensory cells and neurons following four pharmaco-kinetically selected doses of GM; 2) Parallel measurements of the changes in the Vestibulo Ocular Reflex (VOR) function and of single vestibular nerve fibers physiological responses to be compared with the anatomical changes; 3) Investigation of the potential protective neurotrophins effect of BDNF, FGF-2, and a combination of both in the VOR and hair cells. The anatomical and physiological changes will be evaluated in the context of a patho-physiological crista model based on anatomical and physiological principles and on the results of the preliminary studies findings. The applied techniques include histology, immunohistochemistry, fluorescence and confocal microscopy, computerized measurements with a new non-invasive animal technique of vestibule oculography for VOR function testing and electrophysiological single fiber recording methods. After more than a decade of research, the control of the anatomical and functional regeneration capacity of vestibular hair cells in mammals remains unresolved. However, our preliminary results have provided evidence of the capacity of spontaneous hair cell regeneration and the research strategies that will place us closer to the era of hair cell medical treatments for the relief of the scourge of presently untreatable diseases that cause disequilibrium and deafness. Advancing the understanding of these processes will precipitate new concepts regarding the normal function of the vestibular organs and lead to methods/treatment preventing complications associated with drugs like GM that are widely used in life saving bacterial infections on other therapeutic otological objectives as in Meniere's. [unreadable] [unreadable] |
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| 2010 — 2011 | Hoffman, Larry F | R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
A New Model For in Vivo Vestibular Pharmacology @ University of California Los Angeles DESCRIPTION (provided by applicant): This application represents an exploratory and development proposal to design, test, and fabricate an experimental model in which acute perfusions of the inner ear labyrinth can be achieved for investigations of vestibular pharmacology. The principal advantage of this new model is that the pharmacologic manipulations can be introduced directly into the labyrinth while recording the discharge of primary afferent neurons, representing the output of vestibular sensory epithelia. Therefore, the effect of the manipulations on spontaneous and stimulus-evoked discharge can be directly determined, enabling future investigations addressing a wide variety of questions for which contemporary pharmacologic tools (e.g. receptor agonists and antagonists, conductance-specific agonists and antagonists, etc.) are applicable. Two hypotheses will be tested through a set of specific aims that will fully test the efficacy of the model. A perfusate delivery system will be constructed that addresses key technical issues, specific to the basic function of the peripheral vestibular system, in its design. Pilot studies have identified potential artifacts in afferent discharge that likely resulted from abrupt changes in perfusate pressure. The perfusate delivery system will be specifically designed and fabricated to eliminate or minimize these artifacts. The design and fabrication of this system will reflect a collaboration between neurobiology and microfluidics engineering, using tools of micro-electro- mechanical systems (MEMS) engineering to construct a microfluidics device (chip) to manage the flow of perfusate directly to the inner ear perilymphatic space of specially prepared chinchillas. A test battery of perfusate solutions will be utilized that address the accessibility of specific solution constituents to hair cells and afferent neurons projecting throughout the crista and utricular neuroepithelia. These experiments have electrophysiologic as well as morphologic components, whereby test solutions will be delivered and the effects monitored through afferent discharge recordings as well as from direct imaging of the incorporation of these solutions by vestibular hair cells. Experiments will be conducted that will test a second hypothesis regarding the presence of transmembrane AMPA-receptor regulatory proteins (TARPs) within the afferent neurons. While providing a detailed direct test of the efficacy of the preparation for pharmacologic manipulations, these experiments will also address the functionality of TARPs in vestibular afferents. These results have the potential to motivate a new line of investigation for sensory processing in the peripheral vestibular system. PUBLIC HEALTH RELEVANCE: The research to be conducted under this exploratory and development proposal will produce a mammalian model system through which direct testing of pharmaceutical agents can be conducted with respect to their influence on the inner ear vestibular system and the signals that are transmitted to the central nervous system. The results from this investigation will lead to future studies ameliorating our understanding of neurochemical and pharmacologic interactions within the inner ear. This system may also provide a test bed for new treatments of inner ear disorders, as well as contribute to the development of new therapies that will assist in neural rehabilitation of damaged inner ear tissues. |
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| 2011 — 2012 | Hoffman, Larry F | R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Engineered Stem Cells For Inner Ear Pharmacotherapy @ University of California Los Angeles DESCRIPTION (provided by applicant): This application represents an exploratory and development research proposal to develop new lines of engineered adult adipose-derived stem cells ASCs, harvested from chinchillas (resulting in chASCs), that can be used for autologous transplantation for the delivery of trophins directly to the inner ear. There is considerable body of evidence demonstrating the limited intrinsic rehabilitative capabilities of the adult inner ear, yet there are numerous conditions in which such capabilities would be extremely valuable. These include cases of otoprotection, in which other systemic life-threatening conditions warrant the use of aggressive therapies that are also ototoxic. Still other conditions abound that would benefit from regenerative capabilities of Scarpa's or spiral ganglion neurons. At the same time, it is clear that inner ear protection and neurorehabilitation is enhanced through the application of neurotrophins, of which brain-derived neurotrophic factor (BDNF) is an important member. Therefore, the development of a strategy to provide BDNF for prolonged periods would be of significant benefit in providing otoprotection and stimulating inner ear rehabilitation. The present application presents a research plan in which we will test the efficacy of using chASCs as a cell-based delivery system to provide BDNF to the inner ear. This work takes advantage of a chronically-prepared chinchilla model in which direct access to the perilymphatic space has been developed. Experiments will be conducted to harvest, characterize, and engineer chASCs via lentiviral transfection to express enhanced green fluorescent protein (GFP) and GFP-tagged BDNF. Strategies will be implemented to produce stable cell lines. These two cell lines will then be transplanted directly to the perilymphatic space in chinchillas. The use of these lines enable the capability to monitor the intrinsic capabilities of transplanted chASCs to secrete BDNF, as well as the enhanced secretion of BDNF resulting from transgene expression. This paracrine function of chASCs will be evaluated through ELISA methodologies. The GFP expression in both transgene systems will enable us to critically evaluate the integration and survival of these cells in vivo through histologic analysis of the recipient temporal bones. Inner ear function of both the peripheral auditory and vestibular systems will be assessed by recording the auditory brainstem response and through single neuron electrophysiology to identify the potential influence of the transplantation on inner ear function. In summary, these experiments represent a direct test of paracrine function of adult engineered stem cells in the inner ear. While the model system incorporates the secretion of neurotrophin, it will serve as a proof-of- concept of a myriad of other otoactive agents. The successful outcome of these experiments can be immediately tested in a model of inner ear neurorehabilitation in the chinchilla developed in the laboratory of the PI. PUBLIC HEALTH RELEVANCE: The research to be conducted under this exploratory and development proposal will test the efficacy of utilizing adult adipose-derived stem cells as a means to deliver trophin therapies directly to the inner ear. We will test the intrinsic paracrine capabilities of these cells as a source of brain-derived neurotrophic factor (BDNF), as well as BDNF resulting from cells that have been engineered via viral transfection. Such a cell-based therapy system takes advantage of the intrinsic and engineered capabilities of stem cells, and if successful will be extremely advantageous in cases requiring neurorehabilitation or neuroprotection of the inner ear. |
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| 2014 — 2016 | Hoffman, Larry F | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Crcns: Bayesian Inference in Spiking Sensory Neurons @ University of California Los Angeles DESCRIPTION (provided by applicant): The Bayesian brain hypothesis asserts that nervous systems in humans and animals transmit and process information as probability distributions, for which there is a growing body of psychophysical evidence. However, few investigations have endeavored to investigate Bayesian inference in early stages of sensory processing. Through this investigation we propose to implement such a test in primary afferent and secondary neurons of the inner ear vestibular system. We will explore afferent circuits of the horizontal semicircular canal, a model sensory system dedicated to coding and processing head kinematic state. The strength and novelty of our approach is that we advance a testable theory about how head state information may be represented by peripheral and central sensory neurons as spike measurement densities (i.e. SMDs) and spike posterior densities (i.e. SPDs) respectively. Furthermore, we submit the hypothesis that the central representation of the Bayesian posterior of head kinematic state is updated with new sense data (i.e. by primary afferent SMDs) via a neural analog of a particle filter. The particle filter provides the computational framework to tes whether the dynamic discharge of second-order vestibular neurons represent discrete loci of head kinematic state space. These experiments will be conducted in late-stage Xenopus larvae, from which the natural distribution of head kinematic states can be explicitly determined from videographic analysis of free-swimming animals. This natural distribution will be used to derive the dynamic prior within the particle filter model, and also serve as the basis of turntable stimul that can be used in the laboratories in the US and Germany to record evoked discharge from primary and second-order neurons, respectively. We will utilize the fictive swimming signals recordable from spinal ventral roots to modify the natural phase relationship between locomotor and head movement states by presenting head movement stimuli that conflict with the fictive motor efference copy. We hypothesize that such anomalous representations will lead to predictable errors in the central representation of the dynam-ic posterior through the collective SPDs, which would render strong support of a computational framework of Bayesian state estimation in spiking sensory neurons. Intellectual Merit: The intellectual merit of this proposal is harbored in the direct testing of Bayesian inference in nervous systems through direct neurophysiologic methods. Our goal is to test whether the Bayesian particle filter model extends well beyond just another way of describing spatial and temporal patterns of activity in vestibular neurons. Rather, we posit that i can predict and explain them, thereby advancing a compelling neurocomputational model of Bayesian inference using natural neuronal components. These experiments will also provide new insights into the role of dynamic heterogeneity among vestibular afferent neurons, which will undoubtedly lead to new research strategies that will ameliorate our understanding of vestibular sensory coding. Broader Impacts: The research encompasses broader impacts that include the integrative electrophysiologic and computational neuroscience training for individuals at the postdoctoral, graduate, and undergraduate levels. The postdoctoral scholar and graduate students will receive an intensely multidisciplinary experiences, with extraordinary opportunities for international collaboration with peers in the US, Germany, and New Zealand. They will receive rigorous exposure to the theoretical and computational aspects of this project. Undergraduate students will be recruited from across the nation as summer research fellows of the Minority Access to Research Careers program. These students, as well as other undergraduate associates participating during the course of the academic year, will have opportunities to engage in laboratory work addressing the multidisciplinary approaches involved in this project. We propose that this will have a significant impact in broadening their perspective of neuroscientific investigation. We have implemented a plan that will enable direct assessments of the undergraduate students' activities in the project, as well as assessments of the research program's impact upon their attitudes and outlook toward creative scientific endeavors and careers. Our goal is that the integrated approach and international friendships fostered by this project will positively impact their confidence and perspective concerning their own scientific creative capabilities. |
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| 2018 — 2019 | Hoffman, Larry F | R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Coding of Head Kinematics During Locomotor Behavior @ University of California Los Angeles Project Summary The vestibular sensory epithelia encode dynamic and static head movements in trains of action potentials that project to the central nervous system along primary afferent neurons. These signals provide the principal drive for behaviors such as the vestibulo-ocular reflex, which functions to stabilize visual gaze during head movements associated with dynamic behaviors, particularly during locomotion. While the response dynamics of vestibular afferents have been widely studied in a variety of animal models, the input/output relations have been limited to preparations that are restrained and/or anesthetized. Recent investigations using lower vertebrates have shown that peripheral vestibular stimulus processing is modulated by centrifugal efferent feedback driven by rostrally-projecting efference copy originating in spinal locomotor pattern generators. Therefore, critical insight into behaviorally-relevant peripheral vestibular stimulus processing would be gleaned under conditions of awake, behaving preparations. At present, data collected under these conditions do not exist. Therefore, such information requires the development of preparations in which the dynamic response characteristics of vestibular afferent neurons are investigated under conditions of natural locomotion. The present proposal aims to achieve this goal through the development of methods to record from individual vestibular afferent neurons in behaving chinchillas, agile rodents commonly used in studies of peripheral vestibular neurophysiology. There are two factors that support the use of this animal model for these studies: 1) the superior vestibular nerve can be accessed from the middle ear, precluding the need for an intracranial approach to the afferents; and 2) these animals tolerate chronic preparations very well. Critical to this project is the availability of a miniature electrophysiology platform that incorporates a 9 degree-of-freedom movement sensor along with a multichannel electrode headstage and on-board data storage. This hardware will enable the direct correlation of afferent discharge during head movements that occur during unrestrained natural locomotion. The successful development of these methods in an agile animal model will provide the foundation for future investigations of vestibular afferent dynamics under a variety of behavioral and treatment conditions, and will transcend the limitations of imposed upon our understanding of head movement coding by the constraints of passive stimulus presentation in restrained and/or anesthetized conditions. In so doing, the research aims of this application address the Functional Connectivity topic of research Priority Area 1 of the NIDCD Strategic Plan. In addition, the methods developed are seminal to understanding the role of vestibular sensory contributions to spatial navigation and orientation behaviors, and as such address other critical research priorities as identified in the Strategic Plan. |
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| 2021 | Hoffman, Larry F | R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Peripheral Vestibular Hypofunction and Neurosensory Coding @ University of California Los Angeles Project Summary The proposed research addresses critical issues of high translational importance concerning the mechanisms and outcomes of partial dysfunction of the vestibular sensory epithelia, referred to as peripheral vestibular hypofunction. The research plan utilizes chemotoxin- induced hypofunction, the foundation for which was identified through recent work from the PI?s laboratory in an animal model enabling precise intraperilymphatic dosing resulting in the production of highly reproducible lesions. This provides the basis for producing lesions of graded magnitudes within the sensory neuroepithelia, documented through histopathologic analyses. The physiologic outcome of these lesions will be evaluated through recordings of single afferent neuron electrophysiology and the vestibulo-ocular reflex, providing the bases for establishing histologic and physiologic correlates to a direct behavioral test of vestibular function. Previous work has demonstrated that the afferent neuron calyx is highly labile to pathologic compromise, and owing to its important contribution to shaping neural dynamics in untreated epithelia it is a focus for assessing pathologic damage. The present research plan will enable the direct correlate of afferent discharge dynamics to critical cellular components of the calyx, including its morphology and expression of KCNQ4 and sodium-potassium ATPase. In addition, we will examine the distribution of synaptic ribbons within hair cells of lesioned epithelia, testing whether a systematic synaptopathy also contributes to the compromised vestibular function. In summary, the present investigation provides critical insight into the histopathologic substrates of vestibular hypofunction and the alterations in sensory coding that underlies the functional compromise. At the same time, however, this investigation will reveal important cellular and physiologic metrics that are required for normal vestibular function, addressing longstanding question in vestibular neurobiology. |
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