U01NS126055

A robotic multi-armed two-photon microscope for imaging neural interactions across multiple brain areas - Abstract.

Among the Brain Initiative’s most important achievements are the genetic identification of many new neuron types and the creation of genetic tools to access these cell types. However, uncovering the functional roles of these neuron types and how they cooperate across brain areas to generate mammalian behavior remains an outstanding challenge.

Thus, inventing ways to monitor how large populations of genetically identified neurons interact across multiple regions of the brain is crucial if we are to comprehend global brain dynamics. Today, electrical recording methods can track neural activity across multiple areas but cannot easily target neurons of specific types.

Widefield and two-photon mesoscopes can image the dynamics of identified neuron types across millimeter-scale regions of cortical tissue but cannot access the distributed sets of cortical and subcortical regions that comprise the major nodes of the brain’s sensory, cognitive, or motor circuits.

To clear this impasse, we invented the ‘Octopus’, a robotic imaging system with multiple articulated optical arms, each a two-photon microscope, that can be flexibly positioned around the brain to record neural activity concurrently in multiple superficial or deep areas of a head-restrained behaving rodent or primate.

We designed, built, and tested an initial version of the Octopus with 4 arms, each of which has 5 mechanical degrees of freedom and a micro-optic probe at its tip for two-photon imaging. The design of the arms is based on ideas from surgical robotics and uses remote center-of-motion kinematics to provide a versatile repertoire of robotic arm movements.

Using this system, a visual neuroscientist can concurrently image neural activity in the lateral geniculate nucleus, visual cortex, superior colliculus, and pulvinar, and a motor neurophysiologist can image activity in the motor cortex, basal ganglia, cerebellum, and motor thalamus.

In this project, we will enhance the optical and mechanical design of each Octopus arm and prepare the system for wide dissemination through open-source and commercial routes. Each arm will gain the optical functionality of a state-of-the-art, two-photon microscope for imaging large-scale neural ensemble activity.

Specifically, each arm will incorporate optogenetics and allow dual-color two-photon imaging over an 800-μm-wide field of view. These capabilities will allow neuroscientists to monitor two genetically identified neuron types in each of 4 brain areas, to perturb the dynamics of these cells with optogenetics, and to observe the effects of these manipulations on animal behavior and activity in the other 3 areas.

We will also streamline the mechanical design to simplify the initial assembly of the Octopus for new users and to endow the robot arms with additional dexterity. The new design will also be motorized and will provide users with highly intuitive means of precisely steering the robot arms.

Finally, to iteratively improve the performance and usability of the Octopus and to validate its readiness for dissemination as a groundbreaking new technology, we will work closely with 7 beta-tester labs to implement multi-area neural imaging studies in awake behaving mice and marmosets.

The Leland Stanford Junior 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]

Stanford, California 943052004 United States

Single Zip Code

BRAIN Initiative: Optimization of Transformative Technologies for Large Scale Recording and Modulation in the Nervous System (U01-Clinical Trials Not Allowed) (RFA-NS-18-019)

Amendment Since initial award the total obligations have increased 295% from $767,774 to $3,034,035.