R01NS122969

Title: Multimodal Characterization of Prefrontal and Premotor Circuits Underlying Perceptual Decision Making in Rhesus Monkey

Abstract:
The objective of the proposed research is to understand the diverse lamina-specific neurons and connections between the dorsolateral prefrontal cortex (DLPFC) and the rostral aspect of the dorsal premotor cortex (PMDR) during decision-making. Decision-making refers to our ability to choose and perform appropriate actions based on sensory cues and context to achieve behavioral goals. Disrupted activity in brain areas such as the DLPFC and PMDR contributes to impairments in decision-making observed in mental illness. Our past work and other research have provided some insight into the involvement of DLPFC and PMDR in decision-making and that these areas are strongly interconnected. However, we currently do not understand 1) the relationship between biophysical properties and morphological structure, and in vivo decision-related activity of neurons in different layers of these brain areas, and 2) whether the connections between DLPFC and PMDR are feedforward, feedback, or lateral (both feedforward and feedback).

We address these open questions by using a multimodal approach that combines in vivo neurophysiology in DLPFC and PMDR of behaving monkeys, decoding and Granger causality analysis, optical stimulation of DLPFC inputs to PMDR, tract tracing experiments, and in vitro single neuron electrophysiology and morphometry in slices from the same subjects.

Our first aim uses laminar multi-contact electrodes to investigate neuronal responses across layers of PMDR and DLPFC while monkeys perform a novel decision-making task that separates perceptual decisions from action selection. We will investigate if in vivo differences are related to differences in biophysical and morphological properties of these neurons with in vitro whole-cell patch-clamp recordings of lamina-specific neurons in PMDR slices.

In Aim 2, we examine the Granger causality between the local field potentials recorded simultaneously in DLPFC and PMDR to understand whether DLPFC sends a feedforward driving input or a modulating feedback input. We combine these in vivo experiments with anatomical tracing experiments in DLPFC to understand the bidirectional laminar pattern of DLPFC and PMDR connections.

In Aim 3, we will inject an opsin in DLPFC and stimulate the anterograde fibers in PMDR in vivo to causally investigate whether the pattern of activity induced in PMDR by stimulation of DLPFC is consistent with feedforward, feedback, or lateral connections. To obtain a more detailed understanding of the pattern of inputs from DLPFC to PMDR, we will investigate in vitro synaptic responses of these PMDR neurons in layers 3 and 5 to optical stimulation of afferent DLPFC fibers and localize the morphological compartments of PMDR neurons to which DLPFC afferent fibers provide inputs.

Impact:
This project will elucidate the in vivo and in vitro laminar dynamics within and interactions between two critical, clinically relevant brain areas. Such data is a prerequisite for future development of circuit-level therapeutics for mental illness and brain-machine interfaces for recovery following brain injury.

Trustees Of Boston 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]

Boston, Massachusetts 021182518 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 370% from $658,258 to $3,093,229.