James C. Houk - US grants

The control of movements and of homeostatic functions represent the major actions of the central nervous system (CNS). The understanding of the CNS mechanisms that underlie these fundamental control systems is of great importance as a basic question in neurobiology and also for the understanding and eventual treatment of diseases such as hypertension, ulcers, obesity, sudden infant death syndrome and for recovery of function following stroke and trauma. In the past decade, neuroscientists have made significant progress in elucidating the cellular and synaptic properties, projections and transmitters of individual nerve cells and systems. The biggest gap in our understanding of the integrative actions of the CNS is the relationship of these properties to function in a behavioral context. The basic question addressed by this program is: How does the CNS integrate single neuron activity to generate actual behavior? Peterson proposes to study the properties and neuronal organization of brainstem pathways that regulate gaze. Baker will study cerebellar mechanisms for the coordination of visual and vestibular information in the control of gaze. Houk will study the properties of cells in the inferior olive, and their participation in controlling limb movements. Gibson will conduct a microelectrode and neuroanatomical analysis of interpositus neurons of the cerebellum. Disterhoft will identify and characterize brainstem premotor neurons that participate in conditioned eye blink responses. Rogers will investigate the direct hypothalamic control over those vagal neurons, both motor and sensory, that control gastric acid secretion. Nelson will examine the development of central neuronal sensitivity to angiotensin II in relation to the development of spontaneous hypertension and in response to captopril treatment. Campfield will study the role of hypothalamic neurons in the descending control of the endocrine pancreas. Feldman will determine the distribution of neurotransmitter receptors among identified brainstem respiratory neuron classes and the pathways that release these transmitters. Rymer will investigate the role of the beta (skeletofusimotor) innervation of muscle spindle receptors in the control of individual limb muscles. Core support is requested for computer, instrumentation, histology and administration, in order to accomplish the scientific goals of this proposal.

The inferior olive, the source of climbing fiber input to cerebellum, is implicated in the control of learned movement, but its specific function remains poorly understood. Recently we initiated microelectrode studies of this nucleus in anesthetized and intact cats. The results indicate that somatosensory information is strongly represented in the olive, and single cells have properties suggestive of a role in somatic event detection. We propose a combination of microelectrode, neuroanatomical and behavioral studies designed to explore further the properties and functions of olivary neurons. Preliminary work suggests that responsiveness of cutaneous neurons is gated on and off during movement. We will study this phenomenon by delivering tactile stimuli during different phases of movement and as a cue for movement. A lesion study will test for gating via a cerebellar pathway. We will evaluate the directional preferences of proprioceptive neurons and determine their topographical distribution in olivary subnuclei. Passive velocity sensitivity will be studied by applying ramp displacements to the limb, and active velocity sensitivity will be evaluated during tracking. We will also evaluate responsiveness to perturbations applied in the course of movement. We will map the face zone of the dorsal accessory olive. Our previous work indicates that other portions of this subnucleus contain detailed cutaneous maps of contralateral body parts. We will study the fine topography of the olivocerebellar connections to and from physiologically identified regions of the olive using small injections of WGA-HRP. Discrete unilateral lesions will be placed at physiologically identified olivary sites using pressure injections of ibotenic acid. The animals will then be tested in a set of tasks designed to demonstrate deficits either in sensorimotor processing or in the adaptive modification of sensorimotor linkages. These studies should improve our understanding of the control of limb movements and their adaptation to new environments. The same adaptive mechanisms are likely to play an important role in the recovery of function following head injury or other types of brain lesions.

The proposed studies are designed to enhance our understanding of the functional role of the primate magnocellular red nucleus (RNm) in sensorimotor integration. Using several experimental conditions chosen to bring out important features of sensorimotor integration, the spatial and temporal properties of the relationship between RNm discharge and forelimb electromyographic (EMG) activity will be measured using time series analysis methods. This information is likely to aid our understanding of motor control in general and our understanding of disorders of movement control in patients suffering from brain trauma, amyolateral sclerosis, Huntington's disease and Parkinson's disease. RNm/EMG relations will be studied first during unloaded tracking movements. Single cell activity in RNm and EMG activity in 16 forelimb muscles will be recorded while the animal operates different tracking devices that elicit movement about finger, wrist, elbow and shoulder joints. Cross-correlation functions for each RNm/EMG pair will be used to identify the spatial patterns of muscle activation that occur in relation to RNm discharge and to quantify the timing relations between the RNm and limb muscles. The neuroanatomical of direct WGA-HRP will be injected into the RNm to demonstrate, via anterograde transport, the locations of direct projections to the ventral horn of the spinal cord. In the same animals, unconjugated HRP will be injected into muscles to demonstrated, via retrograde transport, the locations of specific motor neuron pools. Comparison of terminal and pool locations should reveal the muscles that receive direct input. A functional confirmation will provided by spike triggered averaging. Patterns of direct innervation will be compared with patterns revealed for the same cells by our cross-correlation analysis, which emphasizes the more powerful polysynaptic linkages. Next we will study the dynamical properties of RNm/EMG relations, and their dependence on mechanical load. Unexpected changes in elastic, inertial and torque loads will be applied during tracking movements. Coherence functions and impulse responses will be used to measure the dynamical properties of RN/EMG relations. These studies will test the hypothesis that the RNm codes movement velocity and will reveal the extent to which RNm neurons participate in adaptation to altered loading conditions. We will then determine whether RNm/EMG relations depend on the type of behavioral task. The sensory cue for a give movement will be varied by training the monkey to make tracking movements in tasks will be used to elicit different combinations of limb and digit use. In each case we will use time series analysis to measure the spatial and dynamical properties of RNm/EMG relations. These results will tell us whether RNm neurons are specialized to respond selectively when specific sensory cues, specific muscle activity patterns or other specific situations are encountered.

computational neuroscience; sensory mechanism; proprioception /kinesthesia; sensorimotor system; neural information processing; cerebellum; motor cortex; limb movement; motor neurons; interneurons; sensory feedback; red nucleus; brain regulatory center; cerebellar cortex; cerebellar Purkinje cell; brain electrical activity; visual tracking; psychomotor function; short term memory; electromyography; visual stimulus; electrophysiology; microelectrodes; single cell analysis; Macaca mulatta;

neural information processing; electrophysiology; biomedical facility; biomedical equipment development; electrodes; image processing; brain electrical activity; electromyography; single cell analysis;

This is an application to establish a Center for Neuroscience Research (CNR) on NEURONAL POPULATIONS AND BEHAVIOR. The main thrust of the proposed center would be toward understanding hoe interacting populations of neurons in the cerebral cortex and cerebellum are able to control sensory-motor and perceptual-motor behaviors. We seek understanding at three levels: (1) At the level of representations--we will study how perceptual-motor processes are represented by cellular activity in the cerebral cortex and cerebellum. (2) At the level of operational mechanisms--we will investigate cellular and network mechanisms that the brain uses to regulate patterns of activity in these populations and explore how the spatiotemporal patterns are then harnessed to control the behavior of the organism. (3) At the level of adaptive mechanisms--we will study the mechanisms that the brain uses to update existing representations in interacting neuronal populations and the mechanisms used to learn new representations for dealing with novel perceptual-motor experiences. There will be five project areas: A. Representations of perceptual-motor processes in populations of cerebral cortical neurons will be studied by recording single unit activity in association with cognitive and memory- related behaviors. B. Adaptive network models of sensory-motor and perceptual-motor processes will be developed and used to explore how neuron properties and population activity might cooperate in the control of behavior. C. Operational mechanisms for regulating communication between populations of neurons in motor cortex and cerebellum will be studied with correlational methods and multiple single unit recordings. D. In itro neural networks isolated from the turtle or grown in tissue culture will be used to study celllular and network mechanisms for controlling spatiotemporal patterns in neuronal populations. E. Adaptive mechanisms whereby representations in neuronal populations can be adjusted to novel perceptual-motor experiences will be studied using the cerebellar flocculus as a model system. The proposed CNR addresses the critical question of how populations of neurons are used by the nervous system to translate between mentation and action. This is an important question, the answer to which would greatly enhance our understanding of mental health and mental illmess.

neural transmission; sensorimotor system; biological models; neural information processing; excitatory aminoacid; alternatives to animals in research; neural inhibition; chemical stimulation; synapses; ion transport; brain stem; red nucleus; brain regulatory center; cerebellum; cerebellar Purkinje cell; cerebellar nuclei; neuropharmacology; computational neuroscience; voltage /patch clamp; dyes; Chelonia; microinjections; computer simulation; calcium indicator;

The objective of the proposed studies is to understand the cellular neural events that underlie sensorimotor integration in the red nucleus. Extracellular recordings from red nucleus cells in intact animals have revealed distinct sensory and motor modes of responding. Here we propose in vitro intracellular studies of these neurons to determine the cellular mechanisms that mediate the integration of sensory and motor responses. We will utilize whole-cell and perforated patch recordings from red nucleus neurons, under voltage- and current-clamp conditions. Electrical stimulation will be used to mimic the normal physiological activity in sensory and motor pathways. Most of the experiments will utilize horizontal slices through the mesencephalon of the turtle; this orientation preserves both ascending sensory and cerebellar afferents to the red nucleus. Select experiments will be repeated in brain slices from rodents to assess the generality of the findings. NMDA-, AMPA- and metabotropic-receptor mediated components of excitatory synaptic transmission, and GABAergic and glycinergic components of inhibitory and neuromodulatory transmission will be isolated neuropharmacologically. Using these intracellular data, a biophysically-based computational model of sensorimotor integration will be constructed. This computational model will be developed to the point of predicting how an individual red nucleus neuron contributes to the sensory and motor responses of the rubrocerebellar network. We anticipate that the results of these studies will be relevant to our understanding of the pathophysiology of several neurological diseases that affect the generation of limb motor commands. The spasticity of cerebrovascular disease and dystonia both involve hyperactivity of these circuits. The neuropharmacological and biophysical mechanisms we study here may suggest new therapies for these disorders of muscle tone and voluntary movement control.

DESCRIPTION (provided by applicant): The network of investigators proposed here will explore how problem solving activities engage different loops and circuits that patch together channels through a cognitive map in the dentate nucleus of the cerebellum. Our proposed activities represent a unique focus on developing tasks and methods for cross-species comparisons, bridge building between anatomical and functional data, and joint consideration of both motor and cognitive functions of the cerebellum. Dr. Strick will generate plans for the construction of an unfolded map of the dentate projections to the cerebral cortex in non-human primates. Dr. Miller will generate plans to study how single unit activity is distributed across this map when monkeys engage in cognitive tasks. The PI, Dr. Houk, will explore conceptual and computational models of signal processing in the modular networks in which the dentate channels participate. Our consultant, Dr. Lewis, will work with Dr. Strick to develop correspondences between molecular staining of human and monkey dentate. Dr. Kim will develop high-resolution imaging methods for exploring human dentate. Drs. Fiez and Reber will formulate plans for using this constellation of tools to document the activation patterns that occur in the cerebellar dentate nucleus when humans are executing problem-solving tasks. Interactions with our consultant Dr. Mesulam will help us explore correlations with neurological disorders and the attentional network spread across the cerebral cortex. Similarly, interactions with Dr. Lewis will help us explore correlations with schizophrenia and other psychological disorders.

meeting /conference /symposium; information dissemination; telecommunications; biomedical facility;

DESCRIPTION (provided by applicant) This PPG proposal describes a collaborative effort by five distinguished motor systems groups at five prominent institutions. We will probe the brain's remarkable capacity for the Integration of Motor Programs Across Space and Time. Dr. Scott Grafton, at Dartmouth College, will characterize the neural substrates for the on-line adjustment of errors, for adaptation to persistent perturbations and for skill learning in humans, using functional MRI and transcranial magnetic stimulation. Dr. Emilio Bizzi, at MIT, will develop a new perspective on how the motor cortex solves the problem of transforming a planned hand movement into the intricate set of motor commands needed to carry out this task. Dr. Peter Strick, at the University of Pittsburgh, will characterize how sequences of movements are merged together and adjusted on-line to create skilled actions, using microelectrode recording in non-human primates and 2DG labeling of activity in the motor areas. Dr. James Houk, at Northwestern University, will characterize the regulatory actions of subcortical loops through the basal ganglia and cerebellum in each of the above tasks, using paired microelectrode recordings from subcortical neurons and the cortical neurons to which they project. Dr. Andy Barto, at the University of Massachusetts at Amherst, will explore computation models of each of the motor tasks. Core A support for videoconferencing and administration will facilitate strategic collaborations between the investigators at different institutions, and a Collaborative Core B will fund collaborations between two or more of the PIs to facilitate our ability to compare neurophysiologic data spanning a broad range of both spatial and temporal resolution. The support of these interrelated projects should yield results beyond those achievable if each project were pursued separately, and can be expected to significantly advance our knowledge about how motor programs are integrated across space and time.

The long-term goal of this research is to elucidate the dynamic brain mechanisms underlying spatio-temporally integrated motor and cognitive tasks using magetoencephalography (MEG). The tasks are designed to test hypotheses regarding temporal integration of information as the tasks are being carried out in space. We will focus on praxis, namely complex, purposeful motor actions, such as copying figures from visual templates and finding exist routes in mazes. These tasks are commonly used in clinical neurology underlying these tasks require planning across, and unfold within, space and time, and therefore, exemplify the theme of this program project research application. Data will be acquired using a state-of-the-art whole-head MEG instrument with 248 axial gradiometers. The hypotheses will be tested (a) that specific praxis tasks involve cooperative interactions of specific brain areas, especially in the parietal and frontal cortex, (b) that there is a partial overlap among the dynamic patterns of this activation across tasks, and (c) that this overlap corresponds to the common functional core shared by these tasks. The dynamic processing aspects of the core as well as signal analysis of individual MEG channels and their relations. A 64-processor Linux cluster will be used for these analyses. The results to be obtained will provide novel insights into how the brain deals with dynamic spatiotemporal processes and carries out purposeful eupractic motor actions. It is expected that these insights will lead, in turn, to the generation of specific hypotheses concerning altered neural mechanisms underlying constructional apraxia.