R01NS122742

Cell type and circuit mechanisms of non-invasive brain stimulation by sensory entrainment

Patterned sensory stimulation (PSS) is a non-invasive technique for manipulating brain activity and states, typically employing periodic light flicker or auditory tones presented at regular intervals. We and others have recently shown that PSS at certain frequencies (centered at 40 Hz) causes widespread neural entrainment and state changes in non-neuronal cell populations (including, e.g., effects on the activity of microglia and on vasomotion), improvements in memory and cognitive function, and clearance of markers of neurodegeneration in animal models of brain disease. These observations suggest a strong potential of PSS for non-invasive brain stimulation applications in basic science and as a therapeutic tool.

To enable such applications, however, it is important to know the mechanisms mediating the complex effects of PSS on neurons and non-neuronal cells. These mechanisms are poorly understood. In this project, we systematically investigate mechanisms of PSS by dissecting how cell types and circuit properties in the brain mediate the entrainment of neural activity and modifications of the states of neuronal and non-neuronal cell populations, with the focus on the mouse cortex as a model system.

The central component of this project is a systematic modeling effort, relying on our recent progress in integrating diverse structural and functional data into highly detailed, bio-realistic models of the mouse cortical circuits. These models will be applied and refined to simulate the effects of PSS at the level of a single cortical area (primary visual cortex) and the whole mouse cortex. We will also develop models of coupling from the activity of different neuron types to non-neuronal cells, providing insights into the effects of neuronal entrainment to PSS on, e.g., microglia and vasculature.

These modeling efforts will go hand-in-hand with electrophysiology recordings in awake mice, accompanied by chronic and acute perturbations (using chemogenetics and optogenetics). In multiple iterative stages, modeling predictions regarding the roles of excitatory and inhibitory (e.g., PV, SST, VIP) cell types in different cortical layers on the entrainment to PSS will be tested experimentally, and models will be refined to match data.

The project will also characterize transcriptomic and epigenetic responses to PSS in different cell types, which will be correlated with circuit effects revealed by simulations and perturbative experiments in vivo. The results of these studies will provide a rich description of molecular, cell type, and circuit mechanisms mediating the PSS effects, which will be crucial for future rational development of applications of this brain stimulation technique.

Besides the knowledge, this project will also provide highly biologically realistic, ready-to-use computational models applicable for studies of PSS and other phenomena, which we will freely share with the community.

Allen Institute

(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.

93.372 - 21st Century Cures Act - Brain Research through Advancing Innovative Neurotechnologies

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

Washington United States

State-Wide

BRAIN Initiative: Biology and Biophysics of Neural Stimulation and Recording Technologies (R01 Clinical Trials Optional) (RFA-NS-20-006)

Amendment Since initial award the End Date has been extended from 08/31/24 to 08/31/27 and the total obligations have increased 740% from $394,619 to $3,316,143.