Daniel J. Simons - US grants

[unreadable] DESCRIPTION (provided by applicant): Perception and other cognitive functions such as planning, thought and learning reflect processing of complex information by the cerebral neocortex. The great expanse of brain tissue that comprises the cerebral cortex is composed of iterated, local neuronal circuits that transform afferent information and distribute it to other brain regions, forming large distributed neural systems. An emerging view is that these spatially distributed networks use a minimal number of spikes to perform their functions rapidly and accurately. Neuronal assemblies are readily identified in the rodent somatosensory cortex, which contains groups of synaptically interconnected neurons, called 'barrels', that is related one-to-one to individual whiskers on the contralateral face. Each barrel receives its afferent input from similarly-organized groups of thalamic neurons, called 'barreloids'. Thalamocortical circuits in the rodent somatosensory system are highly sensitive to thalamic response timing. Employing the whisker/barrel cortex of rats and mice as a model system, we will evaluate response timing and firing synchrony in thalamocortical microcircuits. Hypotheses will be evaluated using microelectrodes to record simultaneously the activities of thalamic and cortical neurons that are functionally inter-related. The research plan is based on the premise that abnormalities in the time-critical operations of thalamocortical circuits produce a cascade of events leading to dysfunctions in cortical processing. Understanding the role of local thalamocortical circuitry in promoting adaptive properties of cerebral cortical function is essential for bridging the gap between cellular physiology and the eventual accurate diagnosis and treatment of perceptual/motor and other cognitive dysfunctions due to abnormal cortical development, aging, disease, or trauma. [unreadable] [unreadable] [unreadable]

An important function of the rodent primary somatic sensory cortex (Sml) is to integrate information arising from temporally and spatially patterned deflections of the mystacial vibrissae. An emerging model of this sensory cortex is that it is comprised of 25-30 individual columns, each of which is related principally to a single mystacial vibrissa and each of which contains a central core surrounded by integrative multi-whisker zones where individual columns interface. The purpose of this project is to examine in detail the functional organization and intrinsic connectivity of one of these columns. Neurophysiological techniques will be used to study how individual neurons integrate complicated sensory stimuli produced by an array of independently controllable whisker stimulators. A variety of anatomical techniques will be used to determine a structural counterpart to the interactions among cortical columns revealed by the physiological data. In some experiments intracellular recording and labeling of single neurons will provide a direct correlation between morphological and functional data at the cellular level. The proposed research will thus establish how individual cortical columns operate as basic functional modules underlying cortical information processing. In the long term such knowledge will provide an experimental basis for the clinical diagnosis and treatment of sensory dysfunction and cognitive impairment.

Sensory input often can be enhanced by specific behaviors for looking, listening, sniffing or feeling. Rodents have large facial whiskers, the vibrissae, that are used to investigate objects by touch. Studies on anatomy and physiology of the rodent vibrissal system have examined cellular mechanisms of both sensory integration and the role of experience during development, particularly in relation to the somatosensory cortex of the brain. Sensory capabilities of the vibrissae themselves usually have been inferred from gross deficits seen after whisker removal, but little is known about how well these hairs can detect or discriminate various natural stimuli. This project uses a novel approach to determine how the vibrissae are used in behavior to make sophisticated tactile discriminations. Blindfolded animals will be trained to distinguish between surfaces of calibrated roughness; there is evidence that the rodents can discriminate with vibrissae at least as well as primates using fingertips. Video-based analysis will quantify amplitude, frequency, speed, and relations of whisker movements and head movements. The role of sensory input during development will be tested by trimming rows of whiskers of neonatal rats until they are 45 days old, then allowing whisker growth. This manipulation is known to produce abnormalities in the somatosensory cortex of the brain, and expected to produce discrimination deficits in the adults. Behavioral strategies will be compared between normal and neonatally deprived animals, to see how whisker movements are used to discriminate, and whether new strategies are learned. Finally, the whiskers will be studied as they interact with the surface, and the time patterns of whisking will be compared to the timing of excitation and inhibition seen in nerve cells in the somatosensory cortex. These novel studies will fill a critical gap in our knowledge relating brain function to tactile behavior; results will have a high impact not only on somatosensory science, but on sensory science and neurobiology, and on studies of learning and behavior.

This award provides funds for the establishment of a Research Training Group in Neural Processing in Cognition. The faculty group is a mixture of outstanding senior and junior investigators who come from disciplinary backgrounds as diverse as mathematics, neural science and human behavior, but who share a common interest in the use of mathematics and other analytic tools in the study of relation between neural science and cognition. The research programs in which trainees will participate cross the boundaries of neurophysiology, neuroanatomy, psychology, biophysics and mathematics. The funds will provide stipends for graduate students and postdoctoral fellows, will support research participation by undergraduate students, will defray part of the cost of the trainees' research and will enable the trainees to attend scientific meetings. In addition, funds will be used to purchase specialized research equipment to be used by trainees, and to bring visiting faculty from other research and academic institutions for seminars and workshops. The challenge of relating structural and functional information about the nervous system to behavior is, at once, one of the most exciting and challenging problems of modern science. In recent years, the development of a variety of new techniques for locating individual neurons within the brain and other complex structures, for detection and isolation of hormones and other neuropeptides, and for the analysis of the activity of individual neurons has lead to an extraordinary increase in understanding of the physical structure and functional organization of the brain. Similarly, the development of theoretical paradigms and computational tools for analysis of behavior has significantly increased the sophistication of behavioral analysis. The merging of these disparate areas of research in approaching the underlying physiological basis of cognition requires the training of researchers with diverse expertise in fields not often taught together. The program funded by this award will provide both the formal training and the research experience required for creative work at the forefront of modern cognitive science.

This research is concerned with investigating how the brain recognizes objects in the environment using the somatosensory tactile system. Results obtained will further our understanding of how computations are carried out in complex, cortical information- processing systems, and will contribute to the growing body of knowledge about how the brain is organized to process sensory information. The techniques used are behavioral testing, computer- assisted motion analysis and electrical recordings from single brain cells in order to investigate how mammals acquire, process and use sensory information from facial vibrissae. Previous studies have demonstrated that important similarities exist between this tactile system and use of the fingertips by humans, when they are actively touching textured surfaces.

9421380 Simons The region of the brain called the 'cerebral cortex' is involved in cognitive functions such as learning, recognizing objects, and performing skilled movements. It's function is determined, in part, by the way in which billions of cortical nerve cells are interconnected. Some cortical cells are organized into working clusters called 'columns'. This grant will allow a team headed by Dr. Simons to study how cortical columns make computations about information coming to the cortex from touch receptors. The analysis of the columns will first involve physiological studies of electrical signaling among cells within columns, and these results will be understood by constructing mathematical models of the column circuitry. The results will be important for understanding how the brain constructs flexible representations of the external world. This is likely to advance our ability to design intelligent systems that can perform some of the operations that are normally performed in the cerebral cortex. ***

9413228 Schneider This award renews support of a Research Training Group (RTG) that includes 27 faculty from 13 departments at the University of Pittsburgh and Carnegie Mellon University. Most faculty are affiliated with the Departments of Psychology, Neurobiology, or Mathematics. The RTG provides training for undergraduates, graduates and postdoctoral fellows with a focus on understanding the role of neural processes in cognition through computational and experimental approaches. Research programs of individual faculty involve modeling of individual nerves and other types of excitable cells, characterization of properties of neural networks, localization of metabolic activity in the brain through use of magnetic resonance imaging and other techniques, a variety of in vitro and in vivo physiological studies, and investigations of the effects of disease on cognition in humans and animals. The RTG sponsors about 5 new graduate and 1-2 new postdoctoral students per year, and supports summer research by 3 undergraduates per year. Trainees at all levels are recruited nationally. Graduate trainees are admitted through one of 13 participating departmental Ph.D. programs or through an interdepartmental neuroscience Ph.D. program at the University of Pittsburgh. Graduate training includes required and elective courses in neuroscience, cognition and mathematics. A number of the courses were developed specifically for the RTG. Additional training includes participation in seminars and workshops sponsored by the RTG, as well as individual and collaborative research. ***

We have determined the DNA sequence of one bacteriophage genome and will determine about ten more, and roughly 15 more are available in public databases. We will use PSC facilities to assemble our DNA sequence data to produce finished sequences and then to analyze those sequences. Analysis will include, first, analysis of individual genome sequences to determine the genetic structure of the individual viruses and , second, comparisions among the newly determined sequences and other DNA sequences in the GenBank database In particular, we will focus on comparisons between related bacteriophage sequences, at the level of individual genes and proteins and at the level of the entire genomes. Information from these comparisons will address issues of structure/function relationships in the viral proteins and of genetic mechanisms operating in the evolution of viral genomes.

PI: Land IBN 9603964 A central question in development of the brain is how precise sets of functional connections are made between particular groups of nerve cells. Model systems to study this question often involve a well-defined sensory organ and the target areas in the cortex of the brain that receive the sensory signals. The development of correct central connections and of normal sensitivity by central neurons both often depend on normal sensory experience during development; with deprivation, there often are physiological and biochemical changes in the target neurons in sensory cortex. This study uses the tactile whiskers of rodents and their characteristic "barrel fields" of target nerve cells in the cortex as a model, because the system has a clear anatomical organization that facilitates comparisons between the normal and deprived conditions. The whiskers are easily trimmed at different times to provide a painless and easily reversible form of sensory deprivation in a local area. Physiological, biochemical and anatomical techniques will be used to investigate the effects of deprivation on a particular type of excitatory nerve terminals in developing barrel fields. Results from this model system will be relevant to understanding how specific sets of connections between chemically defined neurons are established during development, and how activity levels in these neurons affect their development. The results will have an important impact on sensory neuroscience as well as developmental neuroscience.

This proposal is a renewal request for 25 service units that will allow us to continue the interplay of physiological experimentation and computer simulation that we've pursued since 1989. Over the past year our efforts at modeling cerebral cortical networks engaged in somatosensory information processing have proven useful in guiding our choice of experiments. We currently are writing a series of three articles concerning the effects on cortical neurons of microiontophoretic application of inhibitory receptor agonists and antagonists, and computer simulations thereof. The first paper deals with cortical layer IV results obtained with the inhibitory neurotransmitter GABA, and bicuculline methiodide, a GABAa receptor subtype antagonist. The second paper deals with a comparison of bicuculline results between layer IV and the layers above and below it, and the third deals with data obtained using the GABAb receptor antagonist, baclofen. Future experiments, and simulations thereof, will include microiontophoretic studies using the excitatory neurotransmitter glutamate, as well as ones proposed in our 1992 request that haven't yet been performed.

Hastings 9801227 The investigator and his colleagues organize an interdisciplinary conference to bring together biologists and mathematicians to discuss wave phenomena from their varying perspectives. The conference aims to give both biologists and mathematicians insights into the types of models that can be used for wave phenomena and the parameter ranges where such behavior can be expected. To this end, the conference includes both general lectures and more technical talks where particular techniques are explored more fully. Of special interest in techniques are continuation methods in models of long range interaction, where integral equation models are involved. One-dimensional traveling waves have long been of interest to biologists, particularly in neurobiology where they describe the propopagation of electrical signals down a nerve axon or as a plane wave across a two-dimensional collection of electrically active cells. Related phenomena include spiral and other patterns, such as those thought to be responsible for some pathogenic behavior in cardiac tissue. Similar patterns in the brain are of current interest as well. Such behavior is not limited to neurobiology, and appears in a wide variety of chemical and biological systems, such as the Belousov-Zhabotinsky reaction, slime molds, and many others. On the other hand, mathematicians have studied basic questions about waves for a variety of models, including biological and chemical settings. One focus of mathematical work has been to prove the existence and stability of traveling waves. In this regard continuation methods have become particularly interesting in models of long range interaction, where integral equations are involved. The conference brings together biologists and mathematicians to discuss wave phenomena from their different perspectives. The meeting fosters interactions between the two areas that should lead to greater understanding of a variety of phenomena important in biology.

DESCRIPTION: (Adapted from the Investigator's Abstract) Synaptically coupled local networks of neurons process and transform sensory inputs and inputs from higher processing levels. These interactions are thought to contribute to adaptive sensorimotor behaviors by responding dynamically to changes in the external environment, and to changes in the brain's internal representation of this environment. In previous studies the applicants used single unit recordings, computer modeling and dynamical system analysis to describe how the interplay between intrinsic membrane properties and local circuit interactions affect processing of thalamic inputs by intracortical circuits in the rat barrel (somatosensory) cortex. They now propose to apply these tools to study the thalamic circuitry itself. This circuitry involves reciprocal interactions between inhibitory neurons in the reticular nucleus of the thalamus (RT) and thalamocortical (TC) neurons. RT neurons receive both TC and corticothalamic inputs, and possess striking non-linear properties. These properties, and interactions among themselves and with TC cells, strategically position RT neurons both for gating and for modulating the transmission of sensory information to the cortex. The proposed experiments will employ single-unit extracellular recordings in conjunction with controlled whisker stimuli or whisker-based behavioral paradigms. Mathematical analyses will be used to characterize the dynamics of the individual neurons and of the circuits in which the are embedded. An understanding of the role of local circuits in generating dynamic properties of distributed neuronal systems in essential for bridging the gap between cellular physiology and eventual diagnosis and treatment of perceptual/motor and other cognitive dysfunctions associated with trauma and disease states of the central nervous system.

[unreadable] DESCRIPTION (provided by applicant): The long-term goal of our research is to understand how experience influences the organization and development of cortical microcircuits Of particular interest is how neonatal tactile experience influences whisker-related barrels in the rat somatosensory cortex. Our previous studies demonstrate that normal tactile experience is essential for the establishment of normal response properties of cortical barrel neurons. Trimming whiskers for the first few postnatal weeks leads to increased excitability of barrel neurons and to a robust and permanent enlargement of their receptive fields. These changes are not, however, accompanied by changes in the topographic pattern or overall morphology of barrels. Instead, available evidence indicates that these physiological abnormalities reflect alterations in local excitatory circuits within individual barrels.The proposed research plan will investigate in detail the development of cortical microcircuits and their alteration by abnormal tactile experience. The research is based on the premise that individual barrels are composed of modular units, and it is at the level of these microcircuits that neonatal experience exerts its influence. These microcircuits are now amenable to analysis using modern cellular-based anatomical and physiological techniques.Experiments are designed to investigate, in normal and whisker-trimmed rats, how cortical microcircuits become matched structurally and functionally to their afferent inputs. Specifically, we will examine in detail 1) the arborization pattern of individual thalamocortical axons, 2) the spatial pattern of locally recurrent intra-barrel connections, and 3) the strength of excitatory synaptic transmission onto individual barrel neurons.Results of the proposed research will provide insight into developmental mechanisms that organize local cortical circuits. By extending, to the somatosensory cortex, important findings from investigations of the visual system, the anticipated results will contribute directly to the identification of general principles of activity-dependent processes underlying cortical development. An understanding of these principles and the cellular mechanisms through which they operate is essential for the eventual diagnosis, treatment and prevention of developmental disorders affecting perception, cognition and other higher cortical functions

[unreadable] DESCRIPTION (provided by applicant): Perception and other cognitive functions such as planning, thought and learning reflect processing of complex information by the cerebral neocortex. The great expanse of brain tissue that comprises the cerebral cortex is composed of iterated, local neuronal circuits that transform afferent information and distribute it to other brain regions, forming large distributed neural systems. An emerging view is that these spatially distributed networks use a minimal number of spikes to perform their functions rapidly and accurately. Neuronal assemblies are readily identified in the rodent somatosensory cortex, which contains groups of synaptically interconnected neurons, called 'barrels', that is related one-to-one to individual whiskers on the contralateral face. Each barrel receives its afferent input from similarly-organized groups of thalamic neurons, called 'barreloids'. Thalamocortical circuits in the rodent somatosensory system are highly sensitive to thalamic response timing. Employing the whisker/barrel cortex of rats and mice as a model system, we will evaluate response timing and firing synchrony in thalamocortical microcircuits. Hypotheses will be evaluated using microelectrodes to record simultaneously the activities of thalamic and cortical neurons that are functionally inter-related. The research plan is based on the premise that abnormalities in the time-critical operations of thalamocortical circuits produce a cascade of events leading to dysfunctions in cortical processing. Understanding the role of local thalamocortical circuitry in promoting adaptive properties of cerebral cortical function is essential for bridging the gap between cellular physiology and the eventual accurate diagnosis and treatment of perceptual/motor and other cognitive dysfunctions due to abnormal cortical development, aging, disease, or trauma. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The provocative finding that there are 10-fold more corticothalamic (CT) than thalamocortical axons reinforces the long-standing view that the cerebral cortex dynamically regulates its own input via CT neurons. However, the role of corticothalamic circuitry remains a deep mystery. This is because a substantial proportion, perhaps even a majority, of CT cells are silent under standard experimental conditions. Recently, we have found in rat primary somatosensory cortex that weakly responsive CT cells, and even some that are otherwise silent, become more responsive to tactile stimulation of facial whiskers during pharmacologically- induced facilitation of the topographically corresponding area of motor cortex. Thus, inputs from other, functionally related neocortical areas can directly influence the excitability of CT neurons in sensory cortex and hence the processing of afferent, sensory signals in thalamocortical circuits. Understanding the nature of information that is potentially transmitted by these strategically located neurons will likely provide new and important insights into cortical function and its regulation during sensorimotor behaviors. The research plan employs a combination of in vivo and in vitro approaches to examine intrinsic electrophysiological properties, synaptic inputs and receptive fields of CT neurons in the rat somatosensory system. Novel findings will be obtained from two different types of corticothalamic projection systems long-postulated to play distinctly different roles in sensory processing during active touch. The research plan should lead to new insights into how - and perhaps, why - the cerebral cortex regulates its own activity during information processing states.

[unreadable] DESCRIPTION (provided by applicant): Effective voluntary, neural control of prosthetic limbs may require sensory feedback that is suitably integrated into sensorimotor systems mediating fine motor skills and discriminative touch. This research plan is based on the assumption that the rational design of artificial sensors incorporated into sensorimotor prosthetic devices depends on an understanding - and exploitation - of the function of central somatosensory circuits that provide relevant, appropriately processed information to motor cortex. In rats, cortically processed somatosensory information is critically important for the control of whisker movements during vibrissal-based active touch. Here we take advantage of the large and growing knowledge base about the organization and function of the rodent whisker system. The principal goal of this research plan is to develop a model system in rats for investigating neural sensorimotor prostheses. Intracranial electrical stimulation keyed to external sensor activity will be used as surrogate sensory stimuli that direct voluntary whisker movements. Rats will be trained to control whisker movements on the basis of surrogate sensory feedback signals delivered into the central nervous system by electrical stimulation of the somatosensory thalamus. Successful outcomes would demonstrate that 1) electrical stimulation of central, somatosensory pathways is an effective signal for regulating voluntary, fine motor behavior, 2) such stimuli can serve as surrogate signals for contact-mediated active touch, and 3) an external, sensory prosthesis can be incorporated into voluntary, sensorimotor control. Future studies could employ similar approaches to investigate motor cortical activity and its use in controlling a prosthetic whisker, analogous to neural control of robotic arms in primates. Combining this with the sensory approaches developed in the present research plan would complete a prosthetic sensorimotor loop that can mediate discriminative active touch. PUBLIC HEALTH RELEVANCE This research plan is based on the assumption that the rational design of artificial sensors incorporated into sensorimotor prosthetic devices depends on an understanding - and exploitation - of the function of central somatosensory circuits that provide relevant, appropriately processed information to motor cortex. The principal goal of this R21 application is to develop an experimental approach in rats for evaluating the use of artificial sensori-neural feedback for fine motor control during active touch. [unreadable] [unreadable] [unreadable]