Kevin D. Alloway - US grants

DESCRIPTION: (Investigator's abstract): The studies will use cross-correlation analysis to examine neural interactions between the somatosensory thalamus and cortex during controlled cutaneous stimulation. The first experiment will test the hypothesis that thalamocortical cells elicit responses more effectively from middle cortical layers than from supra- or infragranular layers. Laminar differences in thalamocortical efficacy will have an important bearing on hypotheses regarding the sequence of information transmission between cortical layers. A related hypothesis concerns the strength of thalamocortical interactions in the horizontal cortical dimension. Studies will measure changes in this parameter as a function of somatotopic similarity/disparity between the thalamus and cortex. The last set of studies is designed to test the hypothesis that thalamic activity causes recipient cortical areas to inhibit neighboring cortical columns. Finally, in each of the experiments, special attention will be given to detecting the presence of corticothalamic interactions and determining whether these connections function to enhance or inhibit thalamic responsiveness.

DESCRIPTION (Adapted from the Investigator's Abstract): The aim of this project is to understand thalamocortical and corticocortical connections. Although many details concerning the anatomy of thalamocortical and corticocortical neurons are known, few physiological experiments have studied the dynamic properties of thalamocortical networks. This project is a continuation of studies that have successfully measured the functional strength of connections between anatomically-connected brain neurons using basic sensory stimulation techniques. In this project we propose experiments to elucidate the behavior of a network of thalamic and cortical neurons during more naturalistic stimulation and determine how selective loss of sensory input alters neuronal interactions in these regions. We will test the hypothesis that a moving cutaneous stimulus enhances thalamocortical and corticocortical synchrony in the somatosensory system as measured by cross-correlation analysis. They will accomplish this aim by measuring and comparing the strength of thalamocortical and corticocortical interactions produced by cutaneous RFs with stationary and moving stimuli. They will test the hypothesis that plasticity of thalamocortical circuits contribute towards cortical reorganization following temporary or permanent loss of cutaneous inputs. This will be accomplished by chronically implanting arrays of microwire electrodes into thalamus and measuring changes in the topographical organization of thalamus produced by cutaneous anesthesia or by transection of the digital nerves. They will test the hypothesis that corticocortical interactions between sensory-deprived and surrounding cortical regions become stronger during the process of cortical reorganization. This will be accomplished by inserting recording electrodes at regular intervals in the transition from innervated to sensory deprived cortical representations and using cross-correlation analysis and electrical microstimulation to measure the horizontal spread of neuronal activity. This project is concerned with uncovering fundamental principles of governing corticocortical interactions and may shed light on the mechanisms of cortical recruitment and other phenomenon involved in the etiology and development of cortical seizures. Furthermore, experiments in this project will examine changes in neuronal communication following sensory deprivation and will advance our understanding of functional recovery from nerve injury or other forms of damage to the peripheral or central nervous system.

[unreadable] DESCRIPTION (provided by applicant): The neostriatum and related parts of the basal ganglia contain functional channels that separately process prefrontal, limbic, oculomotor, and sensorimotor information received from the cerebral cortex. Although the specific cortical areas that activate each functional channel are different, each channel contains the same basic input-output pattern of connections. By using cutaneous stimuli to activate corticostriatal projections from somatosensory cortex, we can characterize the pattern recognition properties of neostriatal neurons and determine how neural activity in the sensorimotor channel is coordinated during sensory stimulation. Hence, this paradigm presents a unique opportunity for understanding the rules that govern the dynamic operation of corticostriatal circuits across all functional channels because there are no accepted methods for directly activating limbic or prefrontal channels in a controlled, naturalistic manner. [unreadable] [unreadable] The anatomic and physiologic properties of the neostriatum represent a significant issue in contemporary neuroscience because this brain region has been implicated in Parkinson's disease, Huntington's chorea, Tourette's syndrome, and schizophrenia. In this project we will use anterograde tracing methods to test the hypothesis that corresponding representations in the primary and secondary somatosensory cortical areas send convergent projections to the neostriatum. We will also use retrograde tracing techniques to verify previous results indicating that corticostriatal projections from somatosensory cortex have an anisostropic organization. We will also compare corticostriatal and corticopontine projections to determine if the corticopontine projections follow the same principles of organization that have been identified in the corticostriatal system (ie. Principles of Cortical Proximity, Somatotopic Homology, and Behavioral Cooperativity). Finally, we will record neuronal activity in multiple parts of the cerebral cortex and neostriatum so that we may analyze neuronal interactions between the cortex and neostriatum. These physiology studies will determine whether a primary function of neostriatal neurons is to detect synchronized activity among functionally-related cortical areas.

Individual neurons in the nervous system use electrical impulses or action
potentials to communicate sensory information from one region of the brain
to another region. This project is concerned with determining how neurons
in the somatosensory part of the thalamus communicate with neurons in the
somatosensory part of the cerebral cortex during tactile stimulation. More
specifically, we wish to measure how the relative timing of action
potentials among neighboring thalamic neurons might alter the
responsiveness of neurons in the cerebral cortex. Many neuroscientists
believe that cortical neurons are likely to respond with an action
potential when they receive communication from multiple thalamic neurons at
the same time but are less likely to respond if they receive communication
from only one thalamic neuron. We will directly test this hypothesis by
inserting multiple electrodes into both brain regions and recording the
precise times of their neuronal action potentials when the skin is touched
by a computer controlled air puff. We will use statistical analysis to
determine if the probability of a cortical action potential is highest when
pairs of thalamic neurons discharge at the same time (in synchrony) or at
different times (asynchronously). We will also use our computer controlled
air puffer to stimulate the skin in a variety of spatiotemporal
configurations to determine which types of tactile stimuli are best for
activating pairs of thalamic neurons at the same time. We will also use
this method to determine which tactile stimuli activate pairs of cortical
neurons at the same time. This research project is important because it
will determine if neuronal synchronization is a mechanism used by the brain
to communicate information from one brain region to the next. This project
will also provide evidence suggesting whether neuronal synchronization
could be used by the brain to represent certain types of sensory
stimuli. Hence, when this project is completed, we will know how
individual cortical neurons respond to simultaneous inputs and this will
greatly increase our understanding of how neuronal circuits operate in the
mammalian brain.

DESCRIPTION (provided by applicant): The overall goal of this project is to understand how neuronal responses to sensory stimuli are coordinated in the cerebral cortex, both locally and across connnected cortical areas. Somatosensory information is important for guiding many motor behaviors, and this is mediated by projections from somatosensory cortex to brain regions involved in controlling motor output. Hence, increased knowledge of these pathways and the mechanisms that govern long-range interactions between the primary somatosensory (SI) cortex and the primary motor (Ml) cortex should facilitate the development of new strategies and techniques for rehabilitating brain-damaged individuals that suffer sensory impairment: We will use the rodent SI barrel cortex as an animal model to test several hypotheses concerning the corticocortical projections from SI to MI. For Specific Aim 1, the distribution of retrogradely-labled neurons in the barrel field of SI will be characterized following discrete deposits of two tracers into neighboring focal sites of MI. By using a dual tracing paradigm, we will determine the topography of SI neurons that converge on focal sites in MI cortex. For Specific Aim 2, we will simultaneously record multiple neurons in SI barrel cortex to characterize how different types of neurons are coordinated with each other during sensory stimulation. Thus, we will characterize the coordination or relative timing of discharges among: a) pairs of SI neurons that project to MI, b) pairs of SI neurons that do not project to Ml, and c) heterogeneous pairs of projection and non-projection neurons. For Specific Aim 3 we will simultaneously record multiple neurons in connected parts of SI and MI to test the hypothesis that neighboring pairs of projection neurons in SI cooperate with each other to activate common neuronal targets in MI cortex. To address this issue, conditional cross-correlation analysis will be used to quantify the impact of synchronized activity in SI on the probability of neuronal responsiveness in corresponding parts of the MI whisker representation.

The basal ganglia and pontocerebellar systems are both involved in sensorimotor and cognitive behaviors. While it is often difficult to activate cognitive processes in animals in a controlled manner, the somatosensory system and its targets are easily activated by controlled stimulation. Hence, the structural and functional principles that govern sensory integration in these brain regions are likely to apply to the integration of cognitive information as well. Using the somatosensory system as a model system, we plan to analyze and compare the integration of cortical inputs in both the neostriatum and the pons. The potential clinical importance of this work is underscored by the fact that the basal ganglia have been implicated in several neurologic disorders including Parkinson's disease, Huntington's chorea, and Tourette's syndrome, while the pontocerebellar system is associated with several clinical sensorimotor problems. This project has four aims: Aim 1. Support or refute the hypothesis that bilateral corticostriatal and corticopontine overlap is greatest for projections from Ml sites representing proximal body parts that are bilaterally coordinated. Aim 2. Support or refute the hypothesis that corticopontine projections from SI and SI I enable more integration than corticostriatal projections from the same sites or than projections from SI and ML Aim 3. Support or refute the hypothesis that neostriatal neurons discharge mainly when they receive synchronous inputs from related (ie., interconnected) cortical areas in somatosensory cortex. Aim 4. Support or refute the hypothesis that stimulus-induced neuronal activity in SI barrel cortex and the pons are more strongly correlated than stimulus-induced activity in SI cortex and the neostriatum.

[unreadable] DESCRIPTION (provided by applicant): The aim of this proposal is to perform non-invasive, simultaneous functional magnetic resonance imaging (fMRI) and diffuse optical tomography (DOT) in rodent models of neural plasticity. The technique will develop an integrated MRI/optical probe, designed specifically for imaging the rat cortex. This probe will enable dual-wavelength multiple source/detector nearinfrared DOT and phased-array fMRI. This system will be used to measure the plasticity of neural responses at high spatial and temporal resolution using well-characterized whisker-clipping paradigms. We hypothesize that fMRI and DOT will detect spatial and temporal differences in stimulus-induced neural responses evoked in control and sensory-deprived (selective whisker clipping) rats. Finally, we will add a third wavelength to the DOT system to elucidate a fundamental question in optical imaging, namely the extent of the large-vessel contribution to the optical signal in brain activation. We will test the hypothesis that changes in the absorption coefficient in large veins do not contribute significantly to changes in the optical signal, and provide an accurate estimation of the relative signal changes from the capillary bed and small vessels. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Sleep is a fundamental biological cycle that is coupled into every aspect of body function from behavior and information processing to metabolic storage and release. Sleep-wake patterns correlate with, and sleep disruptions are comorbid with, many neurological and mental health disease dynamics including epilepsy. Abnormal sleep can be disruptive to quality of life and further exacerbate the primary disorders. Within the past decade a number of groups have developed mathematical and computational dynamical models for the network of brain nuclei and cell groups that regulate sleep-wake dynamics. But their validation to date has been substantially limited to reproduction of statistic of cycle time and dwell time durations, and their application to understanding and control of diseases limited. The first objective of this project is to validate and optimize these models for reconstruction, forecasting, and control of sleep-wake regulation. This involves experimentally recording activity from select cell groups of the sleep-wake regulatory system (SWRS) along with cortical, hippocampal, and behavioral activity. The mathematical models will be incorporated into model-based data assimilation (DA). The parameters and models will be optimized for reconstruction and forecasting, and performance will be used to establish the 'best' model. Experimental perturbation of sleep state and sleep cycle dynamics will be done with both sensory and direct neural stimulation. The models will then be modified to account for and predict changed dynamics from such perturbations. The second objective of this project is to apply these models and framework to understand and control sleep-cycle dis-regulation in a model of temporal lobe epilepsy. This involves experimentally recording activity from the SWRS in epileptic animals, modifying and optimizing the models to reconstruct and forecast the observed sleep cycle dynamics. The models will then be used in closed feedback form to prescribe control perturbations to regularize the sleep cycles of the epileptic animals. The project embodies a paradigm shift for neuroscience and neural-engineering in which computational models are validated and optimized through their capacity to reconstruct and forecast detailed time series from real neurological measurements, that such model-based reconstruction is used to observe detailed state dynamics from less costly (invasive or damaging) measurements, and in which such biologically based models are used to control neurological systems and treat neurological disorders. The approach of this proposed research will have a major impact in diagnosing, monitoring, and controlling neurological disorders by both incorporating detailed biologically based models into the measurement or observation process, and by allowing remote observation through measurement of identified less costly measurements. The specific validation and improvement of computational models and observation methodology of the sleep-wake regulatory system will allow detailed investigation of its role in a host of neurological diseases in which sleep regulatin is implicated either as a cause or consequence, such as epilepsy and schizophrenia, and thereby the development of interventions or therapy. In addition to the theoretical and experimental advances, educational and outreach will be served through this project, including development of new course materials and enhancing underrepresented participation in research.