1985 — 2007 |
Knudsen, Eric |
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. |
Analysis of Space by the Auditory System
Experience plays a critical role in shaping the structural and functional properties of the developing central nervous system. When experience is rich and normal, it leads to a brain that is optimized for the individual. When experience is chronically abnormal, however, as a consequence of disease, defects, injury or dysfunction, for example, experience can lead to abnormal structure and function. For the many pathways that are subject to sensitive periods, these effects result in permanent neurological disability. The proposed research investigates, at the systems, cellular and molecular levels, the effects of experience on the developing central auditory system. The research focuses on the pathways that process spatial information, pathways that are known in relative detail. The effects of experience on these pathways are dramatic and readily quantified. The barn owl is studied because the space processing pathways are particularly well developed in this species, and the sensitive periods have been established. Extracellular neurophysiological, pharmacological and anatomical techniques will be combined with dichotic sound stimulation to characterize both the effects of abnormal sensory experience and the ability of the auditory system to recover normal function following restoration of normal experience. The effects of two different sensory challenges will be compared: abnormal vision and abnormal hearing. In the midbrain space processing pathway, where sites of plasticity are already known, the research emphasizes the cellular and molecular mechanisms of plasticity and sensitive periods (the roles of anatomical reorganization, specific neurotransmitter receptors, neurotrophins, and sex steroids). Also, the anatomical source and nature of the instructive signal that governs this plasticity will be explored. In the forebrain space processing pathway, the research concentrates on identifying sites of plasticity and characterizing the properties of the plasticity. This research aims to provide a mechanistic understanding of the effects of experience on the developing central auditory system. Knowledge of the aspects of neuronal connectivity that are altered by experience and how these alterations are implemented may lead to improved therapeutic strategies for the many individuals who suffer from or have suffered from prolonged periods of abnormal sensory experience. In addition, the results should teach us much about the normal structure, function and development of the central auditory system.
|
0.915 |
1986 — 1987 |
Knudsen, Eric |
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. |
Analysia of Space by the Auditory System
The auditory system derives the location of a sound source from multiple acoustic cues. The strategies of information processing used by the auditory system to evaluate and integrate these cues will be studied with extracellular recording techniques in the barn owl. Neuronal activity that reflects auditory spatial analysis is found in the optic tectum, where neurons are sharply tuned for sound source location and are organized according to their spatial tuning to form a physiological map of space. Digitally synthesized sounds delivered dichotically and in a free-field will be used to elucidate the integrative basis of their spatial tuning and of the space map. The underlying processes involve the real-time analysis of time-varying complex signals, the comparison and exact evaluation of differences in signals at the two ears, and the detection of particular sets of cues that are associated with appropriate locations in space. Revealing the mechanisms by which these functions are carried out will broaden substantially our understanding of information processing in the nervous system. Auditory experience during early life shapes sound localization behavior and the spatial tuning of neurons in the optic tectum; pilot studies indicate that early visual experience has a similar influence on these auditory functions. Behavioral experiments will investigate the role of vision in the development of sound localization. The sensitive and critical periods will be elucidated and the neural basis of this developmental plasticity will be sought. Answers to questions such as how and where experience exerts its influence on brain development and what causes the brain to become refractory to this influence after the end of the critical period will provide a foundation for formulating optimal therapeutic procedures for the prevention of perceptual handicaps (such as language impairment and learning disorders) and the recovery of mental function, especially among individuals who have suffered sensory losses early in life.
|
0.915 |
1990 — 2004 |
Knudsen, Eric |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Nervous System Regeneration and Plasticity |
0.915 |
1990 |
Knudsen, Eric |
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. |
Neural Control of Saccadic Head Movement
Brain mechanisms that program head movements will be studied in the barn owl as a model system for understanding principles of motor system organization and sensorimotor integration. The owl's optic nerve tectum (superior colliculus) issues commands that redirect the head to stimulus sources; the site activity in the tectum represents the direction and magnitude of the desired movement. The motor code is "high-order" in that it specifies a change in orientation, but not the forces that must be generated in particular muscles to accomplish the movement. This place code for movement is subsequently transformed into an intermediate code by 4 independent saccade generators which represent orthoganal (up, down, left and right) vector components if the desired movement. This transformation of motor command signals will be studied using microstimulation, neurophysiological, anatomical, and behavioral techniques; barn owls are chosen because they make extremely accurate, rapid head movements. Specifically, we will determine which nuclei in the brainstem are responsible for transforming the place code into vector component code, and the physiological and anatomical mechanisms by which the transformation is accomplished. In addition, we will address such fundamental issues as how the motor command signals are calibrated by visual experience and whether the commands for head movement are issued in a head-centered or a body-centered frame of reference. The results of these studies will elucidate the computational strategies that underlie motor control in a complex, multi-articulated system. In addition, these studies will teach us about how the brain represents desired movements, how and what components of movement are processed in parallel, and how information is translated from one code to another and from one reference system to another. Knowledge of how the brain programs and executes movements will be important to the development of prosthetics, robotics and computational theory, and to our understanding and appreciation of principles of brain function. Such information will also provide a foundation for accurate interpretation of clinical signs relating to head movement control (such as spasmodic torticollis, supranuclear palsy, etc.), for diagnosis of movement disorders of central origin, and for designing optimal therapies and corrective procedures for certain classes of motor dysfunction.
|
0.915 |
1991 — 1992 |
Knudsen, Eric |
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. |
Neural Control of Goal Directed Head Movement
Brain mechanisms that program head movements will be studied in the barn owl as a model system for understanding principles of motor system organization and sensorimotor integration. The owl's optic nerve tectum (superior colliculus) issues commands that redirect the head to stimulus sources; the site activity in the tectum represents the direction and magnitude of the desired movement. The motor code is "high-order" in that it specifies a change in orientation, but not the forces that must be generated in particular muscles to accomplish the movement. This place code for movement is subsequently transformed into an intermediate code by 4 independent saccade generators which represent orthoganal (up, down, left and right) vector components if the desired movement. This transformation of motor command signals will be studied using microstimulation, neurophysiological, anatomical, and behavioral techniques; barn owls are chosen because they make extremely accurate, rapid head movements. Specifically, we will determine which nuclei in the brainstem are responsible for transforming the place code into vector component code, and the physiological and anatomical mechanisms by which the transformation is accomplished. In addition, we will address such fundamental issues as how the motor command signals are calibrated by visual experience and whether the commands for head movement are issued in a head-centered or a body-centered frame of reference. The results of these studies will elucidate the computational strategies that underlie motor control in a complex, multi-articulated system. In addition, these studies will teach us about how the brain represents desired movements, how and what components of movement are processed in parallel, and how information is translated from one code to another and from one reference system to another. Knowledge of how the brain programs and executes movements will be important to the development of prosthetics, robotics and computational theory, and to our understanding and appreciation of principles of brain function. Such information will also provide a foundation for accurate interpretation of clinical signs relating to head movement control (such as spasmodic torticollis, supranuclear palsy, etc.), for diagnosis of movement disorders of central origin, and for designing optimal therapies and corrective procedures for certain classes of motor dysfunction.
|
0.915 |
1994 — 1998 |
Knudsen, Eric |
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. |
Space by the Auditory System
Experience plays a critical role in shaping the structural and functional properties of the developing central nervous system. When experience is rich and normal, it leads to a brain that is optimized for the individual. When experience is chronically abnormal, however, as a consequence of disease, defects, injury or dysfunction, for example, experience can lead to abnormal structure and function. For the many pathways that are subject to sensitive periods, these effects result in permanent neurological disability. The proposed research investigates, at the systems, cellular and molecular levels, the effects of experience on the developing central auditory system. The research focuses on the pathways that process spatial information, pathways that are known in relative detail. The effects of experience on these pathways are dramatic and readily quantified. The barn owl is studied because the space processing pathways are particularly well developed in this species, and the sensitive periods have been established. Extracellular neurophysiological, pharmacological and anatomical techniques will be combined with dichotic sound stimulation to characterize both the effects of abnormal sensory experience and the ability of the auditory system to recover normal function following restoration of normal experience. The effects of two different sensory challenges will be compared: abnormal vision and abnormal hearing. In the midbrain space processing pathway, where sites of plasticity are already known, the research emphasizes the cellular and molecular mechanisms of plasticity and sensitive periods (the roles of anatomical reorganization, specific neurotransmitter receptors, neurotrophins, and sex steroids). Also, the anatomical source and nature of the instructive signal that governs this plasticity will be explored. In the forebrain space processing pathway, the research concentrates on identifying sites of plasticity and characterizing the properties of the plasticity. This research aims to provide a mechanistic understanding of the effects of experience on the developing central auditory system. Knowledge of the aspects of neuronal connectivity that are altered by experience and how these alterations are implemented may lead to improved therapeutic strategies for the many individuals who suffer from or have suffered from prolonged periods of abnormal sensory experience. In addition, the results should teach us much about the normal structure, function and development of the central auditory system.
|
0.915 |
2002 — 2006 |
Knudsen, Eric |
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. |
Mechanisms of Instructed Learning in the Auditory System
DESCRIPTION (provided by applicant): Much of what the brain learns from experience, including language and sound identification and localization, is acquired through the mechanisms of supervised learning. In supervised learning, plasticity in one network of neurons is regulated or guided by information from another network. Our knowledge of the mechanisms of plasticity has increased tremendously over the past decade. In contrast, our knowledge of the mechanisms that regulate and instruct plasticity remains primitive.The calibration of the auditory system's map of space by the visual system is a well-characterized example of supervised learning. In the barn owl, the site in the auditory pathway where visual signals exert there effects, and the structural and functional changes they cause, have been determined. However, the properties of the instructive signals themselves, and the mechanisms by which they exert their effects, remain a mystery.The proposed research will study the instructive signals that calibrate the auditory space map in the owl. Extracellular electrophysiological techniques will be used to measure responses of instructive neural activity to visual, auditory and cross-modal parameters of stimulation. Pharmacological techniques will be used to determine the neurotransmitters that mediate the instructive signals, and the contribution of neuromodulators to the regulation of auditory plasticity. Anatomical techniques will be used to identify the source of input that gates the instructive activity. Behavioral techniques will be used to study the properties of the instructive signal as it occurs naturally in trained animals. Finally, we will manipulate the instructive signal in an attempt to train neural responses to specific auditory stimuli.This research aims at understanding, in detail, mechanisms that instruct neural plasticity. A thorough knowledge of these instructive mechanisms and the principles by which they operate will add substantially to our understanding of how the nervous system learns from experience. This, in turn, may lead to improved methods for teaching both normal and learning disabled children, as well as to improved therapeutic strategies for maximizing the restoration of function to patients following neurological injury or disease.
|
0.915 |
2008 — 2013 |
Knudsen, Eric |
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. |
Neural Mechanisms of Visual and Auditory Stimulus Selection
DESCRIPTION: Understanding the cellular mechanisms that underlie attention is crucial for developing effective treatments for the many psychiatric and learning disorders that affect attention. We have developed experimental protocols in the barn owl that allow us to study the cellular basis of a fundamental component of attention, stimulus selection, in quantitative detail. The aim of the proposed research is to analyze characteristics of bottom-up (automatic) and top-down stimulus selection at the neuronal level and to elucidate mechanisms that underlie these processes. The properties of bottom-up and top-down stimulus selection will be studied in the optic tectum, a structure known to be involved in spatial attention. The effects of multiple, simultaneous sensory stimuli on neuronal responses will be measured as the salience and location of competing stimuli are varied parametrically. Top-down signals (originating in the forebrain) that bias stimulus selection will be activated by electrical microstimulation. Finally, the respective roles of specialized cholinergic and GABAergic nuclei in bottom-up and top-down stimulus selection will be explored with electrophysiology and pharmacological inactivation experiments. The mechanisms by which the brain selects stimuli for attention are not known. In addition, the effects of cholinergic input on information processing in the brain are not understood. Many debilitating conditions (e.g., Schizophrenia, Autism, ADHD) include dysfunctions of stimulus selection, and others (e.g., Alzheimer's, Parkinson's, Down's) are associated with dysregulation of cholinergic transmission. An understanding of the cellular mechanisms of stimulus selection and the function of cholinergic circuits is crucial for developing treatments that can mitigate or remediate the devastating effects of these conditions. PUBLIC HEALTH RELEVANCE Many debilitating, psychiatric conditions (such as Schizophrenia, Autism and Attention Disorder) include dysfunctions of attention, and others (such as Alzheimer's, Parkinson's and Down's Syndrome) are associated with dysregulation of cholinergic circuitry in the brain. The proposed research will explore the cellular mechanisms of attention and the functional properties of cholinergic circuits. The results from this research will provide crucial information that may help in the development of treatments that can mitigate or remediate the devastating effects of these psychiatric conditions.
|
0.915 |
2012 — 2013 |
Knudsen, Eric |
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.) |
Mechanisms of Bottom-Up and Top-Down Control of Spatial Attention
DESCRIPTION (provided by applicant): How does competitive stimulus selection work, at the level of cells and circuits? In primates, stimulus selection is controlled in two fundamentally different ways: bottom-up and top- down. We have developed automated behavioral tasks that demonstrate both kinds of control of stimulus selection in chickens. In primates, a midbrain network is essential to competitive selection. What are the circuits that cause the selection of one stimulus and the suppression of all others, and how do they work? The midbrain network is highly conserved across vertebrate species, from fish to mammals, and it is most differentiated in birds. The highly differentiated avian network provides the opportunity to test the effects of inactivating specific, specialized circuits on stimulus selection behavior. Preliminary studies in birds indicate that a specific cholinergic circuit contributes to the bottom-up control of stimulus selection, and that a specific GABAergic circuit participates in the suppression of competing stimuli. In Aims #1 and 2 we analyze quantitatively the properties of bottom-up and top-down control of competitive stimulus selection in chickens. In Aim #3, we test the respective contributions of the specialized cholinergic and GABAergic circuits to bottom-up and top-down control of stimulus selection. Understanding the role of these circuits in selection behavior will greatly advance our understanding of how the midbrain network performs these essential functions. The results will lay the foundation for future recording, inactivation, microstimulation, and optogenetic studies into mechanisms of attention control, how to identify dysfunction of specific attention-related circuits, and how to restore function to damaged networks. PUBLIC HEALTH RELEVANCE: Dysfunctional control of stimulus selection for attention is a core component of many, prevalent neurological diseases, including Schizophrenia and ADHD, for which no cures are currently available. We will test the hypothesis that fundamental characteristics of competitive stimulus selection are shared between chickens and humans, and we will test the roles of specific neural circuits in attention-related behaviors. The unique advantages of this species are its well characterized and highly differentiated midbrain network and its availability, trainability, availability, and robust selection behavior. These unique advantages will vastly accelerate the discovery of cellular and circuit mechanisms of stimulus selection, and the discovery of therapeutic remedies this knowledge will provide.
|
0.915 |
2014 — 2017 |
Knudsen, Eric |
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. |
Cholinergic Control of Spatial Attention: Cellular and Circuit Mechanisms
DESCRIPTION (provided by applicant): The purpose of this research is to explore the cellular and circuit mechanisms that underlie cholinergic control of spatial attention. Patients with various psychiatric disorders, including schizophrenia and ADHD, typically exhibit dysregulation of attention and gaze control, abnormal modulation of gamma (25-60 Hz) oscillations in local field potentials, and dysfunction of cholinergic signaling. We hypothesize that the co- occurrence of these four symptomatic phenomena reflects that they are mechanistically related. We will test this hypothesis by studying the properties of cholinergic neurons that lie at the heart of the midbrain stimulus selection network, where these four phenomena converge. We will use a combination of sophisticated behavioral, in vivo electrophysiological, and in vitro slice approaches. In Aim #1, we characterize quantitatively the causal role of these cholinergic neurons in the control of attention and gaze in chickens trained to perform selective attention tasks; in Aim #2, we parameterize and quantify the information they encode in the context of these attention-demanding tasks; and in Aim #3, we use in vitro slice techniques to reveal the synaptic mechanisms they employ to control the power and duration of gamma oscillations. This critical, cholinergic circuit element is spatially segregated from other circuit components in bird (uniquely). Our experiments take advantage of this spatial segregation in birds, to selectively record from and manipulate this critical circuit element in vivo and in vitro. We hypothesize that the action of these neurons is essential to the generation of selection signals that are issued by the midbrain for controlling spatial attention and gaze; preliminary data support this hypothesis. The results from our experiments will illuminate the role of cholinergic mechanisms in the generation of selection signals. Discovering these mechanisms will give insight into the symptoms and causes of diseases that involve these four phenomena, as well as suggest avenues for improved diagnosis and rational treatments of those symptoms.
|
0.915 |