Winifred Masterson Burke Medical Research

MITOCHONDRIAL DYSFUNCTION IN NEUROGEGENERATION OF AGING

NEURAL PREDICTORS OF HAND THERAPY EFFICACY IN CHILDREN WITH CEREBRAL PALSY

PLASTICITY IN THE AGING OLFACTORY SYSTEM

SYNAPSE ELIMINATION IN THE CENTRAL NERVOUS SYSTEM

ELECTROPHYSIOLOGICAL EVALUATION OF BRAIN REGIONS VULNERABLE TO ALZHEIMERS DISEASE

THE ROLE OF CD36 IN ISCHEMIC INFLAMMATION AND INJURY

CORTICOSPINAL NEURON DYSFUNCTION AND DEGENERATION IN ALS: TESTING THE ROLE OF CORTICOMOTOR CONNECTIVITY IN MOTOR NEURON DISEASE - ABSTRACT (SUMMARY): IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS (ALS) AND THE RELATED MOTOR NEURON DISEASE (MND) PRIMARY LATERAL SCLEROSIS (PLS), DEFICITS IN MOTOR CONTROL OCCUR AS A CONSEQUENCE OF THE DEGENERATION OF CORTICOSPINAL NEURONS (CSNS). ALS IS MORE COMMON THAN PLS, AND GENETICALLY MORE COMPLEX, WITH FAMILIAL FORMS ASSOCIATED WITH CAUSAL MUTATIONS IN OVER 30 ALS-RELATED GENES. IN THESE ALS MICE, HOWEVER, DYSFUNCTION AND DEGENERATION OF CSNS HAVE NOT BEEN CAREFULLY EXAMINED, AND DATA IMPLICATING CORTICOSPINAL (CS) CIRCUITS IN THESE MODEL SYSTEMS OF ALS IS SURPRISINGLY LIMITED. ONE REASON FOR THIS MAY BE THE VERY DIFFERENT PATTERN OF CONNECTIVITY BETWEEN CSNS AND SPINAL MNS IN HUMANS VS. MICE. IN HUMANS, CS AXONS LOCATED IN THE VENTRAL AND LATERAL FUNICULI FORM DIRECT CONNECTIONS WITH BOTH MNS (CORTICO-MOTONEURONAL (CM) CONNECTIONS) AND INTERNEURONS. IN CONTRAST, CS AXONS IN MICE ARE LOCATED MAINLY IN THE DORSAL FUNICULUS AND ONLY FORM INDIRECT CONNECTIONS WITH MNS THROUGH PRE-MOTOR INTERNEURONS. THEREFORE, WE WILL USE PLEXINA1 MUTANT MICE WHICH HAVE CM CONNECTIONS TOGETHER WITH ALS MOUSE MODELS TO ANALYZE CS CIRCUITS. OUR CENTRAL HYPOTHESIS IS THAT PROGRESSIVE DEFECTS IN CS CIRCUITRY IN ALS MICE WILL BE EXACERBATED BY THE ESTABLISHMENT OF CM CONNECTIONS. IN AIM 1, WE WILL DETERMINE FORMATION OF CS CIRCUITS IN ALS MOUSE MODELS WITH CM CONNECTIONS. IN AIM 2, WE WILL DETERMINE FUNCTION OF CS CIRCUITS IN ALS MOUSE MODELS WITH CM CONNECTIONS. IN AIM 3, WE WILL EXAMINE SKILLED MOVEMENTS IN ALS MOUSE MODELS WITH CM CONNECTIONS. THESE STUDIES WILL PROVIDE A MODEL SYSTEM TO STUDY MECHANISMS OF CS DEGENERATION IN ALS/PLS, AND TO TEST NOVEL THERAPEUTICS TARGETING UPPER MOTOR NEURON DYSFUNCTION IN THESE DISORDERS.

TRANSCRANIAL DIRECT CURRENT STIMULATION AND ROBOTIC TRAINING IN CHRONIC STROKE

ENGAGING NEURON-INTRINSIC SIGNALING FOR AXON GROWTH AFTER SPINAL CORD INJURY

GRADING VISUAL IMPAIRMENT IN CHILDREN WITH BRAIN INJURY

MODULATION OF CORTICAL NETWORKS, A NEW APPROACH TO SPINAL CORD INJURY REHABILITATION

IMMUNE-MEDIATED MECHANISMS UNDERLYING CONDITIONING-INDUCED STROKE RECOVERY

VASCULAR CONTROL IN DIABETIC RETINOPATHY

B-RAF DRIVES REGENERATIVE AXON GROWTH IN THE OPTIC NERVE IN VIVO

RETINAL NEURAL PROCESSING DURING RETINAL DEGENERATIVE DISEASES

OPTICAL DISSECTION OF INTRACORTICAL CIRCUITS SUPPORTING MOTOR RECOVERY AFTER SPINAL CORD INJURY

TRANSCRIPTIONAL REGULATION OVER NEUROGENESIS OF CORTICAL OUTPUT NEURON SEGMENTAL IDENTITY AND DIVERSITY - SUBCEREBRAL PROJECTION NEURONS (SCPN) RESIDE IN THE NEOCORTEX, AND EXTEND AXONS TO SUBCEREBRAL TARGETS IN THE BRAINSTEM AND SPINAL CORD. CORTICOSPINAL NEURONS (CSN), A SUBCLASS OF SCPN, PROJECT TO THE SPINAL CORD AND THEIR AXONS FORM THE CORTICOSPINAL TRACT (CST), A CRITICAL CIRCUIT FOR VOLUNTARY MOTOR CONTROL. IN ADDITION, PROJECTIONS FROM THE NEOCORTEX TO BRAINSTEM TARGETS FUNCTION IN PARALLEL WITH CSN TO EXERT MOTOR CONTROL. DEGENERATION OF THESE PROJECTION NEURONS IN AMYOTROPHIC LATERAL SCLEROSIS (ALS), ALONG WITH DEGENERATION OF SPINAL MOTOR NEURONS, CAUSES SPASTICITY AND PARALYSIS. IN HUMANS, DAMAGE TO THE CST AFTER SPINAL CORD INJURY IS A PRINCIPAL CAUSE OF LOSS OF VOLUNTARY MOTOR CONTROL. FURTHER, INTEGRITY OF CORTICOSPINAL CONNECTIVITY IS CENTRALLY LINKED TO RECOVERY FROM STROKE AND CEREBRAL PALSY. THERE HAVE BEEN MULTIPLE INVESTIGATIONS DETAILING THE ROLE OF CORTICO-BRAINSTEM VS. CORTICOSPINAL PROJECTIONS IN BOTH MOTOR CONTROL, AS WELL AS THEIR DISTINCT CONTRIBUTIONS TO FUNCTIONAL RECOVERY IN THESE DISTINCT CAUSES OF PARALYSIS. HOWEVER, IT REMAINS UNCLEAR WHEN AND HOW THESE DISTINCT PROJECTIONS ARE ESTABLISHED DURING DEVELOPMENT. UNDERSTANDING THE MOLECULAR BASIS OF THIS SPECIFICATION AND DIFFERENTIATION DURING DEVELOPMENT THEREFORE HOLDS SIGNIFICANT PROMISE IN ESTABLISHING APPROACHES THAT ARE TAILORED TO ENHANCING PLASTICITY OF THESE RELATED, YET DISTINCT CIRCUITS. A NECESSARY FIRST STEP TOWARD THIS ULTIMATE GOAL IS TO IDENTIFY THE MOLECULAR MECHANISMS DIRECTING SCPN AXONS TO BRAINSTEM (CORTICO-BRAINSTEM NEURONS) VERSUS SPINAL CORD (CSN). ONGOING WORK IN OUR LAB HAS IDENTIFIED THAT SUCH PROJECTIONS ARE INITIALLY SPECIFIED DURING THE PROCESS OF AXON EXTENSION DURING DEVELOPMENT. WE HAVE IDENTIFIED THAT CORTICO-BRAINSTEM AND CORTICOSPINAL NEURONS EXPRESS DISTINCT GENES AND CAN BE MOLECULARLY DISTINGUISHED IN MICE BY BIRTH. FURTHER OUR DATA SUGGEST THAT THE TRANSCRIPTIONAL REGULATOR SATB2 ACTS, IN PART, TO SPECIFY CORTICO-BRAINSTEM NEURONS. THIS PROPOSAL INVESTIGATES THE HYPOTHESIS THAT TRANSCRIPTIONAL REGULATION CONTROLS THE DEVELOPMENT OF CORTICO-BRAINSTEM VS. CORTICOSPINAL PROJECTIONS BY LATE EMBRYONIC DEVELOPMENT IN MICE. BUILDING ON THIS FOUNDATION, WE WILL FIRST IDENTIFY THE TIME POINT IN DEVELOPMENT WHEN THESE PROJECTIONS ARE SPECIFIED USING KNOCK-IN CRE REPORTER MICE (AIM 1). THIS WILL BE TESTED USING INTRACEREBRAL INJECTIONS OF AAV-REPORTERS AT DISTINCT DEVELOPMENTAL TIMES IN UTERO WITH ADULT ANALYSIS OF AXONAL PROJECTIONS. IN AIM 2, WE WILL INVESTIGATE THE TRANSCRIPTIONAL TARGETS OF SATB2 IN SCPN AT LATER DEVELOPMENTAL TIMES BY PROFILING ALL SCPN IN SATB2 WT AND CONDITIONAL KO MICE, AS WELL AS BY SATB2 OVEREXPRESSION, AT SINGLE CELL RESOLUTION. FINALLY, IN AIM 3 USING SUBPOPULATION-SPECIFIC TRANSGENIC CRE LINES, WE WILL INVESTIGATE SCPN AXON TARGETING IN BOTH SATB2 LOSS- AND GAIN-OF-FUNCTION. IN ADDITION, WE WILL INVESTIGATE WHETHER MISEXPRESSION OF SATB2 TARGET GENES CAN ALTER SCPN TARGETING TO THE BRAINSTEM VS. SPINAL TARGETS. TOGETHER, OUR WORK WILL DISCERN IN-DEPTH, THE MECHANISMS OF WHEN AND HOW TRANSCRIPTIONAL REGULATION CONTROLS SCPN SEGMENTAL “IDENTITY” THEREBY PROVIDING A MECHANISTIC FRAMEWORK FOR SUBSEQUENT IDENTIFICATION OF MOLECULES CONTROLLING SEGMENTALLY APPROPRIATE SCPN CONNECTIVITY WITH SUBCEREBRAL TARGETS.

ROLE OF CD36 IN FUNCTIONAL RECOVERY IN CHRONIC STROKE

USING TRANSCRIPTION FACTORS TO ENHANCE TRANSPLANTED CELL SURVIVAL FOR SCI REPAIR

TARGETING STROKE-INDUCED BRAIN SWELLING IN OBESE SUBJECTS: ROLE OF VEGF

IMPACT OF SENSORY IMPAIRMENTS ON MOVEMENT IN CHILDREN WITH CEREBRAL PALSY

IMPACT OF BDNF SNP ON STROKE-INDUCED PLASTICITY AND MOTOR FUNCTION

ALLELIC CHOICE IN RETT SYNDROME

HDAC6: A TARGET FOR REGENERATION FOLLOWING INJURY IN THE NERVOUS SYSTEM

A NOVEL COMBINATORIAL APPROACH TO RESTORE MOTOR FUNCTION AFTER SPINAL CORD INJURY

MOTOR CORTEX ELECTRICAL STIMULATION TO AUGMENT SPONTANEOUS RECOVERY AFTER CHRONIC SUBCORTICAL STROKE

BENFOTIAMINE IN ALZHEIMER'S DISEASE: A PILOT STUDY

STUDYING THE MOLECULAR REGULATION OF MGE PROJECTION NEURON IDENTITY BY ST18 - PROJECT SUMMARY: THE MEDIAL GANGLIONIC EMINENCE (MGE) IS A NEURAL PROGENITOR DOMAIN LOCATED IN THE VENTRAL TELENCEPHALON. IT IS WELL-STUDIED FOR ITS PRODUCTION OF CORTICAL INTERNEURONS, A BROADLY DISTRIBUTED POPULATION OF LOCALLY-PRO- JECTING NEURONS THAT REGULATE CORTICAL RHYTHMICITY. THE MGE ALSO PRODUCES PROJECTION NEURONS THAT REMAIN IN THE VENTRAL FOREBRAIN, ARRANGED IN DISCRETE NUCLEI THAT PROJECT DISTALLY POINT-TO-POINT. INTERNEURON AND PROJECTION NEURON IDENTITY REPRESENT TWO FUNDAMENTALLY-DISTINCT POPULATIONS, WITH DISTINCT FUNCTIONS. HOW THE MGE DELINEATES BETWEEN THE PRODUCTION OF IN AND PN, HOWEVER, IS NOT UNDERSTOOD. WE HAVE IDENTIFIED A TRANSCRIPTION FACTOR, ST18 THAT APPEARS TO REGULATE THIS FUNDAMENTAL DELINEATION. WE PREVIOUSLY DESCRIBED A MODEL SYSTEM TO STUDY MGE DEVELOPMENT USING INDUCED EXPRESSION OF CANDIDATE FACTORS. WHEN ST18 WAS INTRO- DUCED IN THIS SYSTEM, THE CELLS LARGELY ADOPTED A PROJECTION NEURON IDENTITY. FURTHER, WHEN THESE CELLS WERE TRANSPLANTED IN UTERO, THEY REMAINED IN THE VENTRAL FOREBRAIN AND ADOPTED LONG-RANGE AXONAL PROJECTIONS REMINISCENT OF GLOBUS PALLIDUS PARS EXTERNA (GPE). MOREOVER, IN OUR INITIAL ANALYSIS OF THE ST18 CONDITIONAL LOSS-OF-FUNCTION MUTANT MOUSE, WE OBSERVED A SPE- CIFIC LOSS OF GPE NEURONS, WHILE ALL OTHER MGE LINEAGES APPEAR SPARED. IN THIS PROPOSAL, WE WILL; AIM 1) DETERMINE WHETHER ST18 INDUCED EXPRESSION IS SUFFICIENT TO DIRECT MGE PROGENITORS TOWARDS PROJECTION NEURON IDENTITY (TECHNIQUES: ESC DIRECTED DIFFERENTIATION, NEURONAL CULTURE, IN VITRO MIGRATION ASSAYS, UBM TRANSPLANTATION, RNA-SEQ). AIM 2) TEST WHETHER ST18 IS NECESSARY FOR MGE PROJECTION NEURON FATE BY ANALYSIS OF ST18 CONDITIONAL LOSS-OF-FUNCTION MOUSE (TECHNIQUES: MOUSE GENETICS, VIRAL AND DYE TRACING OF AXON PROJECTIONS, SCRNA- SEQ). AIM 3) MANIPULATE ST18 DURING MGE PROGENITOR DIFFERENTIATION TO PROBE THE TIME WINDOW OF ITS ACTION AND TEST HOW IT REGULATES GENE EXPRESSION IN DIRECTING PROJECTION NEURON IDENTITY (TECHNIQUES: ESC DIRECTED DIFFERENTIATION, IN VITRO MOR- PHOLOGY AND MIGRATION ASSAYS, CHIP-SEQ). IMPORTANTLY, IN THE COURSE OF OUR STUDY, WE WILL PERFORM A MULTI-LEVEL EXPRESSION AND CHIP-SEQ ANALYSIS TO UNCOVER THE GENE NETWORKS AND CELLULAR PATHWAYS UNDER THE REGULATION OF ST18 THAT COLLECTIVELY GOVERN ASPECTS OF PROJECTION NEURON IDENTITY: NEURONAL MIGRATION, POLARITY, PROCESS MORPHOGENESIS. IN SUMMARY, WE ARE UNIQUELY POSITIONED TO ADDRESS HOW MGE PROGENITORS REGULATE PROJECTION NEURON VERSUS INTERNEURON IDENTITY IN THE MGE LINEAGE. THROUGH THESE EFFORTS, WE AIM TO INFORM MORE BROADLY AS TO HOW PROJECTION AND INTERNEURON IDENTITY IS ASSIGNED THROUGHOUT THE NERVOUS SYSTEM.

MOLECULAR REGULATION OVER THE DECLINE IN LONG-DISTANCE CORTICOSPINAL AXON REGENERATIVE ABILITY DURING DEVELOPMENT - CORTICOSPINAL NEURONS (CSN) RESIDE IN THE NEOCORTEX, AND EXTEND AXONS TO SPECIFIC SEGMENTAL TARGETS IN THE SPINAL CORD FORMING THE CORTICOSPINAL TRACT (CST). CSN CRITICALLY CONTROL VOLUNTARY MOVEMENT AND ARE CENTRALLY INVOLVED IN RECOVERY FROM PARALYSIS ORIGINATING FROM MULTIPLE CAUSES, E.G., STROKE, SPINAL CORD INJURY (SCI), CEREBRAL PALSY, ETC.. CSN DEGENERATION IN AMYOTROPHIC LATERAL SCLEROSIS (ALS), ALONG WITH DEGENERATION OF SPINAL MOTOR NEURONS, CAUSES SPASTICITY AND PARALYSIS. RECOVERY IN ALL THESE DISTINCT CAUSES OF PARALYSIS WOULD ULTIMATELY REQUIRE LONG-DISTANCE CST REGENERATION, WHICH REMAINS AN UNATTAINED GOAL IN REGENERATIVE NEUROSCIENCE. PREVIOUS WORK USING NEONATAL LESIONS HAS ESTABLISHED CST REGENERATIVE ABILITY DECLINES FROM DEVELOPMENT INTO ADULTHOOD. WHEN THE CST IS DAMAGED IN EARLY LIFE, THERE IS GREATER PLASTICITY AND REGENERATION AS COMPARED TO SIMILAR LESIONS IN THE ADULT. HOWEVER, DESPITE THIS WORK, WE STILL DO NOT KNOW WHEN LONG-DISTANCE REGENERATIVE ABILITY IS LOST DURING DEVELOPMENT. THIS IS BECAUSE A KEY LIMITATION OF THESE ESTABLISHED NEONATAL LESION MODELS IS THAT THEY MASSIVELY DISRUPT THE SPINAL ENVIRONMENT AND THEREBY INTERFERE WITH THE NORMAL PROCESS OF LONG- DISTANCE CSN AXON EXTENSION DURING DEVELOPMENT. THIS LIMITS THE ABILITY OF THESE LESION PARADIGMS TO ASSESS THE ABILITY OF THE CNS TO SUPPORT LONG-DISTANCE REGENERATION. WE RECENTLY ESTABLISHED A NOVEL MICROSURGICAL APPROACH TO AXOTOMIZE THE CST DURING DEVELOPMENT, WHILE LEAVING THE SPINAL ENVIRONMENT RELATIVELY INTACT. WE IDENTIFIED THAT LONG-DISTANCE CST REGENERATIVE ABILITY IS LOST AT DIFFERENT TIMES AT DISTINCT SPINAL LEVELS– AT POSTNATAL DAY 4 (P4) THE CST CAN FULLY REGENERATE WHEN LESIONED AT THORACIC T11, BUT FAILS TO DO SO WHEN LESIONED AT CERVICAL C2. OUR RESULTS INDICATE THAT THE LOSS OF LONG-DISTANCE CST REGENERATIVE ABILITY CLOSELY PARALLELS THE DEVELOPMENTAL TIMELINE OF NORMAL CST GROWTH INTO THE SPINAL CORD, WHICH SUGGESTS THAT THE NORMAL PROCESS OF DIFFERENTIATION, BOTH IN CSN AND IN THE SPINAL CORD, RESULTS IN THE LOSS OF LONG-DISTANCE REGENERATIVE ABILITY. THIS PROPOSAL INVESTIGATES THE HYPOTHESIS THAT INHIBITION OF DIFFERENTIATION TO PROLONG THE IMMATURE DEVELOPMENTAL STATE WILL EXTEND THE TIME WINDOW WHEN LONG-DISTANCE REGENERATION IS POSSIBLE. SPECIFICALLY, WE WILL MANIPULATE THE FUNCTION OF RE1 SILENCING TRANSCRIPTION FACTOR (REST), A GLOBAL REPRESSOR OF NEURAL DIFFERENTIATION, TO TEST THIS HYPOTHESIS. BUILDING ON THIS FOUNDATION, WE WILL FIRST MANIPULATE REST FUNCTION (BOTH GAIN- AND LOSS-OF FUNCTION) AT DISTINCT SPINAL LEVELS TO INVESTIGATE WHETHER THIS AFFECTS THE ABILITY OF THESE SPINAL SEGMENTS TO SUPPORT LONG-DISTANCE CST REGENERATION (AIM1). WE WILL MANIPULATE REST FUNCTION IN CSN TO SIMILARLY INVESTIGATE LONG-DISTANCE CST REGENERATION (AIM 2). FINALLY, WE WILL USE SINGLE CELL PROFILING TO INVESTIGATE POTENTIALLY DISTINCT MOLECULAR EFFECTS OF MICROLESIONS AT DISTINCT SPINAL LEVELS ON DISTINCT CSN SUBSETS DEPENDING ON THEIR DEVELOPMENTAL STATE (AIM 3). TOGETHER, OUR WORK WILL DISCERN NOVEL MOLECULAR MECHANISMS OF HOW LONG-DISTANCE CST REGENERATION IS REGULATED DURING DEVELOPMENT, THEREBY PROVIDING A MECHANISTIC FRAMEWORK FOR SUBSEQUENT IDENTIFICATION OF MOLECULES THAT CAN BE USED TO EFFECT LONG-DISTANCE CST REGENERATION IN THE ADULT CNS.

INJURY AND ADAPTATION IN THE DEVELOPING RAT CORTICOSPINAL AND RUBROSPINAL TRACTS

AXONAL TRANSPORT AND LOCAL TRANSLATION IN NEUROPATHIC PAIN

AUTOMATED ASSESSMENT OF VISUOMOTOR FUNCTION IN CHILDREN WITH BRAIN INJURY

ADVANCED, MULTI-FUNCTION, INVERTED CONFOCAL MICROSCOPE FOR BNI STRUCTURAL AND FUNCTIONAL IMAGING CORE

NON-INVASIVE STIMULATION FOR IMPROVING MOTOR FUNCTION IN SPINAL CORD INJURY

ADVANCED MATERIALS FOR SAFE AND EFFECTIVE STIMULATION OF THE RAT CERVICAL SPINAL CORD

USING NATURAL MOUSE MOVEMENT TO ESTABLISH A DEVELOPMENTAL "BIOMARKER" FOR CORTICOSPINAL DAMAGE - THE CORTICOSPINAL TRACT (CST) IS A CRITICAL CIRCUIT UNDERLYING SKILLED VOLUNTARY MOVEMENTS. DAMAGE TO THIS CIRCUIT DURING DEVELOPMENT CAN CAUSE PERMANENT, LONG-TERM MOVEMENT DISABILITY IN HUMANS. RECOGNIZING AND TREATING SUCH DEVELOPMENTAL CST DAMAGE IS CHALLENGING, LARGELY BECAUSE IMMEDIATELY AFTER THE LESION, THERE ARE LIMITED OR ALMOST NO FUNCTIONAL DEFICITS. HOWEVER, EARLY RECOGNITION AND INTERVENTION WITH THE APPROPRIATE TREATMENT MEASURES IS KEY TO REDUCING LONG-TERM DISABILITY. THE USE OF PRECLINICAL MOUSE MODELS, WHICH HAVE OTHERWISE PROVEN TO BE HIGHLY USEFUL IN FUNCTIONAL INVESTIGATIONS OF NERVOUS SYSTEM DEVELOPMENT, HAS BEEN LIMITED IN THIS REGARD. SINCE THE CST IS KNOWN TO CONTROL SKILLED MOVEMENTS, ESTABLISHED BEHAVIORAL TESTS IN MICE THAT INVESTIGATE CST FUNCTION REQUIRE TRAINING MICE IN SKILLED TASKS. THIS PRECLUDES THEIR APPLICATION IN NEONATAL MICE. FURTHER, MOUSE MODELS USED TO INVESTIGATE DEVELOPMENTAL CST DAMAGE, E.G. NEONATAL HYPOXIA OR SPINAL INJURIES, DO NOT ONLY DAMAGE THE CST; RATHER THEY DISRUPT MULTIPLE NEURAL PATHWAYS. IT THEREFORE REMAINS COMPLETELY UNKNOWN WHETHER THE CST CONTRIBUTES ONLY TO SKILLED MOVEMENTS IN ADULT MICE, OR WHETHER IT ALSO CONTRIBUTES TO THE DEVELOPMENT OF NATURAL, INNATE MOTOR ABILITY DURING DEVELOPMENT, BEGINNING IN NEONATAL MICE. THIS LATTER POSSIBILITY WOULD SUGGEST THAT THERE ARE EARLY, ALBEIT SUBTLE, BEHAVIORAL CORRELATES OF DEVELOPMENTAL CST INJURY IN MICE. WE RECENTLY DEVELOPED A NEW MICROSURGICAL APPROACH TO SPECIFICALLY DISRUPT THE DEVELOPING CST IN NEONATAL MICE. IN ADDITION, WE HAVE ALSO ESTABLISHED THE USE OF MOTION SEQUENCING (MOSEQ), A NEW MACHINE LEARNING AND ARTIFICIAL INTELLIGENCE PLATFORM, TO LONGITUDINALLY INVESTIGATE THE DEVELOPMENT OF NATURAL MOVEMENTS IN NEONATAL MICE. OUR PRELIMINARY RESULTS USING MOSEQ SUGGEST THAT DEVELOPMENTAL DAMAGE TO THE CST RESULTS IN SPECIFIC CHANGES TO MOVEMENT STRUCTURES IN MICE, AS EARLY AS P12; THESE EXTEND INTO MATURITY AT P35. FURTHER, ANALYSIS OF THESE P35 MICE USING CONVENTIONAL METRICS OF LOCOMOTION SUCH AS THE CATWALK, DID NOT IDENTIFY ANY DEFICITS, HIGHLIGHTING THE SENSITIVITY OF MOSEQ IN IDENTIFYING CHANGES IN MOUSE MOVEMENTS. THIS PROPOSAL INVESTIGATES THE HYPOTHESIS THAT THE CST CONTROLS DEVELOPMENT OF NATURAL MOUSE MOVEMENTS, AND NOT ONLY SKILLED MOVEMENTS AT MATURITY. WE WILL USE MOSEQ TO ANALYZE FEZF2 KNOCK OUT (FEZF2 KO) MICE IN WHICH THE CST IS NEVER ESTABLISHED DURING DEVELOPMENT (AIM1), AS WELL AS MICE THAT UNDERGO MICROSURGICAL LESIONS TO DISRUPT SPINAL CONNECTIVITY OF THE CST AT DISTINCT DEVELOPMENTAL TIMES (AIM2). TOGETHER, OUR WORK WILL IDENTIFY NOVEL FUNCTIONAL READOUTS OF DEVELOPMENTAL DAMAGE TO THE CST USING NATURAL MOUSE MOVEMENTS. THIS NEW UNBIASED QUANTITATIVE APPROACH TOWARD INVESTIGATING THE EARLIEST BEHAVIORAL SIGNS OF CORTICOSPINAL DYSFUNCTION IN MICE WHICH WILL HAVE EVENTUAL APPLICATION IN INVESTIGATIONS OF DESCENDING CIRCUITS OF MOTOR CONTROL, AS WELL AS MULTIPLE PRECLINICAL MODELS OF DEVELOPMENTAL DAMAGE SUCH AS NEONATAL HYPOXIA OR SPINAL INJURIES.

LOSS OF A COHORT OF AXONAL MRNAS AS A RESULT OF REDUCED SMN LEVELS.

DISSECTING MOTOR CORTEX MODULATION OF NOCICEPTION DURING CHRONIC PAIN - PROJECT SUMMARY (SEE INSTRUCTIONS): THE HEAVY BURDEN OF CHRONIC PAIN AND THE OPIOID EPIDEMIC HAS PROMPTED AN URGENT, WORLDWIDE SEARCH FOR ALTERNATIVE, NON-ADDICTIVE METHODS OF ANALGESIA. ONE PROMISING ALTERNATIVE IS NON-INVASIVE ELECTRICAL OR MAGNETIC STIMULATION OF THE MOTOR CORTEX (MC). WHILE MC STIMULATION (MCS) HAS REPEATEDLY BEEN FOUND TO REDUCE CHRONIC PAIN IN HUMAN SUBJECTS AND DECREASE NOCICEPTIVE BEHAVIORS IN RODENT MODELS, MAJOR QUESTIONS REMAIN ABOUT ITS MECHANISM OF ACTION AND HOW TO IMPROVE MCS EFFICACY. EVIDENCE SUGGESTS THAT MCS ANTINOCICEPTIVE EFFICACY INCREASES WHEN THE STIMULATION TARGETS THE REGION IN MOTOR CORTEX THAT CORRESPONDS TO THE BODY PART FROM WHICH PAIN ORIGINATES (SOMATOTOPICALLY MATCHING MCS) AND THAT MCS ANALGESIA REQUIRES ENDOGENOUS OPIOID ACTIVITY. HERE, I PROPOSE TO USE A RODENT MODEL OF TRIGEMINAL NEUROPATHIC PAIN TO ELUCIDATE THE UNDERLYING MECHANISM OF MCS ANTINOCICEPTION AND TO DEFINE KEY MCS FEATURES THAT PAIN CLINICIANS CAN USE TO IMPROVE MCS EFFICACY. TO CHARACTERIZE THE MCS MECHANISM, I WILL 1) QUANTIFY THE EFFICACY OF SOMATOTOPICALLY MATCHED MCS (SSMCS), 2) DETERMINE WHAT OPIOID RECEPTOR SUBTYPES ARE REQUIRED FOR MCS ANTINOCICEPTION, AND 3) IDENTIFY HOW ENDOGENOUS OPIOIDS MODULATE AN OPIOID-SENSITIVE MC DESCENDING CIRCUIT TO THE DESCENDING PAIN CONTROL PATHWAYS DURING SSMCS. TO DETERMINE THE EFFICACY OF MCS BETWEEN MATCHED AND OFF-TARGET MCS IN TWO DIFFERENT NERVE CONSTRICTION MODELS, I WILL USE CLASSIC BEHAVIORAL PARADIGMS ALONG WITH CUTTING-EDGE MACHINE LEARNING ALGORITHMS TO ANALYZE MOUSE BEHAVIORAL RESPONSES. I WILL THEN USE COMPLEMENTARY PHARMACOLOGICAL AND GENETIC MOUSE LINES TO DETERMINE HOW SSMCS IS IMPACTED BY DISTINCT OPIOID RECEPTOR TYPES. TO INTERROGATE THE COMBINED IMPACT OF MC SOMATOTOPY AND ENDOGENOUS OPIOID SIGNALING IN MCS ANALGESIA, I WILL FOCUS ON THE DESCENDING PROJECTION FROM MC TO DESCENDING PAIN CONTROL REGIONS, ROSTRAL VENTROMEDIAL MEDULLA (RVM) AND SPINAL TRIGEMINAL NUCLEUS CAUDALIS (SPVC). I WILL DETERMINE THE POSITIONS OF OPIOID RECEPTOR TYPES AND ENDOGENOUS OPIOID PEPTIDES ALONG THIS CIRCUIT AND THEN ASSESS THE IMPACT OF SSMCS WITH AND WITHOUT OPIOID SIGNALING ON NEURAL ACTIVITY IN MC, RVM, AND SPVC USING CUTTING-EDGE HIGH-DENSITY ELECTROPHYSIOLOGICAL TECHNIQUES. ALTOGETHER, THIS PROJECT WILL DETERMINE HOW MCS MODULATES NOCICEPTION THROUGH ENDOGENOUS OPIOID SIGNALING IN SOMATOTOPICALLY ALIGNED CIRCUITS. THE RESULTS WILL PROVIDE THE FIRST REPORT OF NEURAL ACTIVITY DURING AND AFTER SSMCS AT BOTH THE TARGET AND IN AN MC OUTPUT.

TRANSCRANIAL DIRECT CURRENT STIMULATION AND MOTOR TRAINING IN CHRONIC STROKE

ASSESSING NEURONAL VULNERABILITY IN THE ENTORHINAL CORTEX DUE TO ALZHEIMER'S DISEASE PATHOLOGY - PROJECT SUMMARY UNDERSTANDING HOW SPECIFIC NEURONS IN A SELECTIVELY VULNERABLE REGION SUCH AS THE EC ARE AFFECTED IS CRITICAL TO UNRAVELING THE MECHANISMS UNDERLYING ALZHEIMER'S DISEASE ONSET. WE AND OTHERS HAVE SHOWN THAT NEURONAL HYPEREXCITABILITY IS THE KEY DRIVER THAT MAKES PATHOLOGIES AND SYMPTOMS WORSE AND AMELIORATING HYPEREXCITABILITY SLOWS DOWN AD-RELATED SYMPTOMS. HOWEVER, IT IS UNCLEAR IF THE HYPEREXCITABILITY IS DUE TO AN INCREASED FIRING OF EXCITATORY NEURONS OR DECREASED FIRING OF INHIBITORY NEURONS. WE AIM TO UNDERSTAND THE MECHANISMS UNDERLYING HYPEREXCITABILITY BY STUDYING THE EXCITATORY AND INHIBITORY NEURONS IN THE EC OF APP AND TAU KNOCKIN MICE. TO DETERMINE WHICH TYPE OF NEURONS ARE AFFECTED EARLY IN THE EC, WE WILL INVESTIGATE: AIM 1- EXCITATORY NEURONS IN THE APP KNOCKIN (APPNL-G-F) AND TAU KNOCKIN (HTAU-KI) MICE BY USING INTERSECTIONAL APPROACH WITH OPTOGENETICS AND CHEMOGENETICS IN COMBINATION WITH ELECTROPHYSIOLOGY RECORDINGS AND BEHAVIOR AND AIM 2- INHIBITORY NEURONS (PARVALBUMIN- PV AND SOMATOSTATIN- SST) IN THE APPNL-G-F AND HTAU-KI MICE AS IN AIM 1. USING CRE-SPECIFIC MICE TO TARGET EXCITATORY AND INHIBITORY NEURONS IN COMBINATION WITH OPTO- OR CHEMO- GENETIC APPROACH WE WILL NOT ONLY IDENTIFY SELECTIVELY VULNERABLE NEURON-TYPE, BUT WE WILL ALSO MODULATE THEIR ACTIVITIES TO RESTORE THEIR FUNCTION AND TEST IF BEHAVIORAL DEFICITS ARE REVERSED. WE WILL USE NOVEL COMPUTATIONAL APPROACHES SUCH AS DECODING AND REMAPPING TO DETECT SUBTLE CHANGES IN FIRING ACTIVITY OF EC NEURONS. WE WILL ALSO ASSESS HOW AMYLOID BETA OR TAU AFFECT DIFFERENT NEURON TYPES IN THE EC, AND IF DOWNSTREAM HIPPOCAMPAL NEURONS ARE AFFECTED TOO. THE RESULTS OF THE PROPOSAL WILL DEFINITIVELY ANSWER IF HYPEREXCITABILITY OF NEURONS DUE TO AD PATHOLOGIES IS CAUSED BY DYSFUNCTION OF EXCITATORY OR INHIBITORY NEURONS. THE SENSITIVE COMPUTATIONAL METHODS USED IN THIS PROPOSAL ALLOW FOR MEASUREMENT OF SUBTLE ELECTROPHYSIOLOGICAL CHANGES NOT POSSIBLE PREVIOUSLY AND THEREFORE MIGHT ALLOW FOR DEVELOPMENT OF BETTER DIAGNOSTIC TESTS THAT COULD BE TRANSLATED AND MODIFIED FOR CLINICAL USE IN HUMANS. OVERALL, THE PROPOSAL AIMS TO IDENTIFY WHICH NEURONS IN THE MEC ARE MOST VULNERABLE TO AD PATHOLOGY. THE PROPOSAL IS HIGHLY INNOVATIVE AS IT WILL USE A COMBINATION OF SOPHISTICATED IN VIVO RECORDING IN TWO AD MOUSE MODELS IN COMBINATION WITH OPTOGENETIC AND CHEMOGENETIC TOOLS TO IDENTIFY SPECIFIC CELL TYPE AND MODULATE NEURONAL FIRING TO RESTORE FUNCTION. THE RESULTS FROM THE STUDY WILL BE HIGHLY SIGNIFICANT AS THERAPEUTIC OR CLINICAL APPROACHES TO TARGET VULNERABLE CELL TYPE COULD BE IDENTIFIED. THE PROPOSAL BRINGS TOGETHER DIVERSE FIELDS (ELECTROPHYSIOLOGY, PATHOLOGY AND COMPUTATIONAL NEUROSCIENCE) APPLYING LARGE-SCALE RECORDING TECHNIQUES TO RECORD ENSEMBLE POPULATIONS OF NEURONS TO INTERROGATE WHAT CAUSES HYPEREXCITABILITY IN A VULNERABLE BRAIN REGION THAT IS DYSFUNCTIONAL IN ALZHEIMER’S DISEASE.

ROLE OF SPARC IN WOUND HEALING AFTER SPINAL CORD INJURY - PROJECT SUMMARY: SPINAL CORD INJURY (SCI) TRIGGERS A CELLULAR AND EXTRACELLULAR MATRIX (ECM) REMODELING RESPONSE TO CLOSE THE WOUND. THIS RESPONSE IS DRIVEN LARGELY BY ASTROCYTES FORMING A PROTECTIVE BORDER AROUND INFILTRATING CELLS. THIS PROCESS IS INCOMPLETE IN MOST MAMMALS, FAILING TO RESTORE GROWTH PROMOTING SUBSTRATES, AND LEADING TO EXCESSIVE FIBROSIS. FIBROSIS AFTER SCI IS CHARACTERIZED BY THE SECRETION AND DEPOSITION OF ECM COMPONENTS (EG. COLLAGEN) AND THE ESTABLISHMENT OF A CHRONIC SCAR, IN WHICH CONNECTIVE TISSUE REPLACES NORMAL PARENCHYMA. CONSERVED ROLES FOR NON-NEURAL WOUND HEALING MECHANISMS HAVE BEEN IDENTIFIED IN THE ASTROCYTE RESPONSE TO SCI, BUT THE MOLECULAR CUES THAT DRIVE FIBROSIS AFTER SCI ARE NOT FULLY CHARACTERIZED AND REPRESENT A CRITICAL GAP IMPEDING THE DEVELOPMENT OF STRATEGIES TO IMPROVE SPINAL CORD WOUND HEALING. THE LONG-TERM GOAL IS TO DEVELOP THERAPIES THAT PROMOTE WOUND CLOSURE AND LIMIT FIBROTIC PROCESSES THAT LEAD TO PERSISTENT SCARRING. SPARC (SECRETED PROTEIN ACIDIC AND CYSTEINE RICH) IS A CENTRAL MODULATOR OF BOTH WOUND HEALING AND FIBROSIS. THERE IS A ROBUST AND PERSISTENT INCREASE IN SPARC PROTEIN EXPRESSION IN BORDER-ASSOCIATED ASTROCYTES AFTER SCI AND CONSTITUTIVE KNOCKOUT OF SPARC IMPAIRS WOUND HEALING AND IMPACTS BOTH CELLULAR AND EXTRACELLULAR REMODELING. THE OVERALL OBJECTIVE OF THIS PROPOSAL IS TO DETERMINE THE ROLE OF ASTROCYTIC SPARC SIGNALING IN THE STRUCTURAL AND FUNCTIONAL RESPONSES TO SCI. THE CENTRAL HYPOTHESIS IS THAT ASTROCYTIC SPARC HAS AN ACUTE, EARLY, PRO-WOUND HEALING ROLE AND A SUB-ACUTE, LATE, PRO-FIBROTIC ROLE FOLLOWING SCI. THE FOLLOWING TWO SPECIFIC AIMS ARE PROPOSED: 1) CHARACTERIZE THE TEMPORAL ROLES OF ASTROCYTIC SPARC IN WOUND REMODELING FOLLOWING SCI; 2) DETERMINE THE EFFECT OF ACUTE AND SUB-ACUTE SPARC DELETION IN ASTROCYTES ON FUNCTIONAL RECOVERY AFTER SCI. THE APPROACH IN AIM 1 WILL BE TO TARGET ACUTE AND SUB-ACUTE SPARC EXPRESSION IN ASTROCYTES USING TEMPORAL CONTROL IN A CONDITIONAL KNOCKOUT MOUSE MODEL TO EVALUATE CELLULAR RESPONSES AND ECM COMPOSITION FOLLOWING CONTUSIVE SCI. IN AIM 2, THE APPROACH WILL BE TO ASSESS SENSORY AND MOTOR RECOVERY IN CONTROL AND ASTROCYTE-SPECIFIC CONDITIONAL KNOCKOUT MICE WITH ACUTE OR SUB-ACUTE SPARC DELETION FOLLOWING CONTUSIVE SCI. THE PROPOSED RESEARCH IS INNOVATIVE IN THAT IT CENTERS ON DEFINING THE TEMPORAL AND CELL-TYPE SPECIFICITY FOR A KEY DRIVER OF EPITHELIAL WOUND HEALING AND FIBROSIS IN THE CONTEXT OF SCI, CONNECTING THE FIELDS OF NON-NEURAL AND NEURAL WOUND HEALING. THE PROPOSED STUDIES ARE SIGNIFICANT AS AN UNDERSTANDING OF CONSERVED ROLES FOR NON- NEURAL WOUND HEALING PATHWAYS AFTER SCI, MAY LEAD TO THE DEVELOPMENT OF NEW THERAPEUTIC APPROACHES TO ALTER SCI PROGRESSION, ENHANCE REMODELING, AND LIMIT PATHOLOGICAL SCARRING. THE EXPECTATION IS THAT COMPLETION OF THE PROPOSED STUDIES WILL DETERMINE THE ROLE OF ASTROCYTE-DERIVED SPARC IN WOUND HEALING AND FIBROSIS AFTER SCI. THE IDENTIFICATION OF NEW REGULATORS OF WOUND HEALING AND FIBROSIS WILL ALLOW FOR THE SUBSEQUENT DEVELOPMENT OF THERAPIES TO INCREASE REPAIR BY REDUCING THE GROWTH-RESTRICTIVE ENVIRONMENT AFTER SCI.

AN ADVANCED, HIGH-THROUGHPUT IMAGING SYSTEM FOR THE BNI STRUCTURAL AND FUNCTIONAL IMAGING CORE - THIS APPLICATION IS A REQUEST FOR FUNDS TO ACQUIRE A ZEISS AXIOSCAN 7 SLIDE SCANNER FOR THE STRUCTURAL AND FUNCTIONAL IMAGING CORE AT THE BURKE NEUROLOGICAL INSTITUTE. THE INSTITUTE, DEDICATED TO FINDING CURES FOR CHRONIC NEUROLOGICAL DISABILITIES, REQUIRES AN AUTOMATED IMAGE ACQUISITION SYSTEM TO ADVANCE THEIR NIH-FUNDED RESEARCH. THE MANDATE OF THE IMAGING CORE FACILITY IS TO PROVIDE ACCESS TO A RANGE OF LIGHT MICROSCOPY SYSTEMS AND PROVIDE TECHNICAL ASSISTANCE WITH IMAGE ACQUISITION, PROCESSING, AND ANALYSIS TO ALL RESEARCH GROUPS WITHIN BNI. WHILE THE INSTITUTE HAS INVESTED IN HIGH-RESOLUTION CONFOCAL AND MULTIPHOTON MICROSCOPY SYSTEMS, IT LACKS MODERN EPIFLUORESCENCE AND BRIGHTFIELD IMAGING SYSTEMS. EXISTING MICROSCOPY SOLUTIONS ARE AGING AND LACK CRITICAL FEATURES FOUND IN THE PROPOSED AXIOSCAN 7 SYSTEM. THIS SCARCITY OF RESOURCES POSES A SIGNIFICANT BOTTLENECK FOR THE DIVERSE NIH-FUNDED RESEARCH PROGRAMS AT THE INSTITUTE. THE AXIOSCAN 7 SLIDE SCANNER, WITH ITS AUTOMATED FULL SLIDE WORKFLOW, UNLIMITED Z-STACK ACQUISITION PARAMETERS, AND ADVANCED DECONVOLUTION ALGORITHMS, OFFERS AN OPTIMAL COMBINATION OF FEATURES FOR LARGE AREA TISSUE SCANNING AND STITCHING. THE PROPOSED SYSTEM WILL GREATLY EXPEDITE RESEARCH PROGRESS BY REDUCING ACTIVE USER TIME DURING IMAGE ACQUISITION. FURTHERMORE, THE SURROUNDING AREA LACKS OTHER AUTOMATED, HIGH-THROUGHPUT MICROSCOPY RESOURCES ACCESSIBLE TO BNI INVESTIGATORS, MAKING THE AXIOSCAN 7 AN INDISPENSABLE ASSET. ITS IMPLEMENTATION WILL NOT ONLY BENEFIT CURRENTLY NIH-FUNDED RESEARCH PROGRAMS BUT ALSO CATALYZE THE PROGRESS OF STUDIES THAT ARE YET TO REACH THE MATURITY REQUIRED FOR NIH FUNDING. THE PROPOSED RESEARCH PROJECTS UNDERSCORE THE SHARED NEED FOR AN ADVANCED SLIDE SCANNING SYSTEM. IN CONCLUSION, THE EXTENSIVE CAPABILITIES AND EFFICIENT WORKFLOW OF THE AXIOSCAN 7 WILL EXERT A SUSTAINED, POWERFUL INFLUENCE ON THE CONDUCT OF NIH-FUNDED RESEARCH PROGRAMS AT THE BURKE NEUROLOGICAL INSTITUTE AND SUPPORT BREAKTHROUGHS IN THE UNDERSTANDING AND TREATMENT OF CHRONIC NEUROLOGICAL DISABILITIES.

TRANSCRANIAL DIRECT CURRENT STIMULATION AND ROBOTIC TRAINING IN ADULTS WITH CEREBRAL PALSY

IMPACT OF MOTOR CONNECTIVITY ON EFFICACY OF HAND THERAPY IN CONGENITAL HEMIPLEGIA

THE KNOB SUPINATION TASK: A SENSITIVE TEST OF CORTICOSPINAL FUNCTION IN THE RAT

A SKILLED, AUTOMATED BEHAVIORAL TASK TO ASSESS MOTOR NETWORK FUNCTION DURING IN VIVO IMAGING IN MICE.

ELUCIDATING THE MECHANISMS OF NEUROPROTECTION OF HISTONE DEACETYLASE INHIBITION IN ISCHEMIC STROKE

CORTICOSPINAL NEURON PLASTICITY IN RESPONSE TO DEVELOPMENTAL SPINAL CORD AXOTOMY. - PROJECT ABSTRACT SPINAL CORD INJURY (SCI) IS A DEVASTATING CONDITION WITH LIMITED TREATMENT OPTIONS DUE TO THE RESTRICTED REGENERATIVE CAPACITY OF THE MATURE CENTRAL NERVOUS SYSTEM. DUE TO THE HETEROGENEITY OF SCI ALONG THE NEURAXIS, IT IMPAIRS VARIOUS CORTICOSPINAL CIRCUITRY THAT AFFECTS MOTOR CONTROL. THE CORTICOSPINAL TRACT (CST), ESSENTIAL FOR VOLUNTARY MOVEMENT, CONSISTS OF DIVERSE CORTICOSPINAL NEURON (CSN) SUBTYPES, YET THE ESTABLISHMENT OF THESE DISTINCT SPINAL-PROJECTING NEURONS REMAINS UNCLEAR. RECENT FINDINGS FROM THE SAHNI LAB HAVE IDENTIFIED EARLY MOLECULAR DIFFERENCES IN CSN SUBPOPULATIONS PROJECTING TO THE CERVICAL OR THORACOLUMBAR SPINAL CORD FROM CORTICAL REGIONS OUTSIDE THE CLASSICAL MOTOR CORTEX; HOWEVER, THIS MOLECULAR MAP IS INCOMPLETE. ADDITIONALLY, THE LAB HAS DEVELOPED A NOVEL MICROLESION TECHNIQUE TO AXOTOMIZE THE DEVELOPING CST, ENABLING THE STUDY OF CSN PLASTICITY AND CIRCUIT FORMATION DURING DEVELOPMENT. UNDERSTANDING HOW CSN PROJECTION TYPES AND THEIR POSTSYNAPTIC SPINAL CONNECTIVITY ARE ESTABLISHED IS CRUCIAL FOR DEVELOPING STRATEGIES FOR FUNCTIONAL RECOVERY AFTER SCI. THIS PROPOSAL AIMS TO INVESTIGATE THE MOLECULAR MECHANISMS UNDERLYING CSN DEVELOPMENT AND THEIR LONG-RANGE CORTICOSPINAL CIRCUITS. MY CENTRAL HYPOTHESIS IS THAT INTRINSIC REGULATORS GOVERN SEGMENTALLY DISTINCT CSN IDENTITIES AND SPINAL SYNAPTIC CIRCUITRY. SPECIFIC AIM 1 WILL IDENTIFY MOLECULAR REGULATORS OF CSN DIVERSITY AND DETERMINE WHETHER SEGMENTAL SPINAL TARGETING IS GOVERNED BY INTRINSIC MECHANISMS OR TARGET- DERIVED RETROGRADE SIGNALING. SPECIFIC AIM 2 WILL EXPLORE HOW ROUTE OF AXON EXTENSION INFLUENCES SYNAPTIC SPECIFICITY AND THEIR IMPLICATIONS FOR THE EVOLUTION OF CORTICAL-MOTONEURAL CONNECTIONS AND DEXTERITY. TO ACHIEVE THESE AIMS, WE WILL UTILIZE MOUSE MODELS AND EMPLOY TECHNIQUES SUCH AS VIRAL TRACING AND MICROLESION APPROACHES. THE FINDINGS WILL ENHANCE OUR UNDERSTANDING OF NEURODEVELOPMENTAL PROCESSES AND MAY LEAD TO NEW THERAPEUTIC STRATEGIES FOR SCI RECOVERY. WITH THE SUPPORT OF THIS F32 FELLOWSHIP, I WILL STRENGTHEN MY EXPERTISE IN VIRAL TRACING, MOLECULAR PROFILING, AND BIOINFORMATICS, PREPARING ME TO LEAD AN INDEPENDENT RESEARCH PROGRAM FOCUSED ON LEVERAGING DEVELOPMENTAL MECHANISMS TO REPAIR THE INJURED NERVOUS SYSTEM.