R37NS128416

Control of movements by the cerebellum - cerebellar disease makes ordinary movements extraordinarily difficult, often resulting in endpoint errors. For example, damage to lobule VII of the vermis makes saccadic eye movements dysmetric. These symptoms have suggested that the cerebellum monitors ongoing commands and adjusts them, particularly as the movement nears the target.

Yet, individual Purkinje cells (P-cells) have firing patterns that are modulated much longer than the movement. Thus, it has been difficult to decode the activities of P-cells, and their downstream nucleus neurons, with respect to computations that are necessary for control of movements.

A key to this puzzle is that the inferior olive monitors the output of the cerebellum and returns to it information that appears to encode error [1–4]. This input to the cerebellum organizes P-cells and nucleus neurons into anatomical groups called micro-clusters [5–7]. Cells within a micro-cluster likely have a common feature: they respond similarly to error.

Through a collaboration between Shadmehr, Soetedjo, and Kojima, we used this idea to show that in macaques, if P-cells were organized into groups based on their complex spike response to error, then their simple spikes as a population produced a rate coding that predicted parameters of the ongoing movement [8,9]. The result was a new idea: the fundamental computational unit in the cerebellum may not be an individual cell, but a population of cells that share a common preference for error.

Here, we propose that P-cells that respond similarly to error are part of a network that exhibits a special property: within this network, the P-cells not only coordinate their firing rates, but also temporally align their spikes, especially during the deceleration phase of movements. That is, P-cells transmit information to the nucleus by modulating their firing rates, and synchronizing their spikes. In our hypothesis, P-cells combine disinhibition with synchronization to signal when the movement should be stopped [10].

To pursue this idea, in 2016 we built a marmoset lab, pioneered techniques to train the animals, and then used silicon probes to record from many neurons simultaneously [10,11]. We then built new tools for precise temporal analysis of cerebellar spikes [12].

Here, we propose to record from P-cells, molecular layer interneurons (MLIs), and nucleus neurons, use their error response to organize cells into populations, and then quantify both firing rates and spike timing during movements. Our proposed experiments have the potential to produce simultaneous recordings of P-cells, MLIs, and nucleus neurons, something that is unprecedented in primates.

We will use this neurophysiological approach to test the anatomical basis of our hypothesis, that the inferior olive organizes the cerebellum into cell-assemblies. The data will allow us to determine whether the healthy cerebellum relies on synchronization to encode information, shedding light on conditions such as dysmetria and tremor, pathologies that appear to arise not from mis-modulation of P-cell firing rates, but rather disorganization of spike timing [13–16].

The Johns Hopkins University

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Baltimore, Maryland 212051832 United States

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NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 107% from $1,472,100 to $3,048,473.