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Principal Investigator: Vijayalakshmi Santhakumar
Organization: UNIVERSITY OF CALIFORNIA RIVERSIDE
Fiscal Year: 2024
Award: $443,495
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary: Neurological disorders such as epilepsy and memory loss develop several years after
traumatic brain injury (TBI) and are a major source of physical disability and economic burden. The delay
between the initial trauma and eventual disability results from progressive neuropathology that could be limited
by early interventions. However, mechanisms by which TBI impacts memory and seizure susceptibility are not
fully understood. The hippocampal dentate gyrus, a circuit critical for memory processing, a key regulator of
information transfer from entorhinal cortex to hippocampus, and a niche region for adult neurogenesis, is a
focus of neuronal damage and increased excitability after TBI. Although adult born granule cells (abGCs) are
implicated in memory processing, the contribution of abGCs to dentate spikes which represent entorhinal
cortex to dentate information flow and support memory consolidation is not known and how injury-induced
changes in neurogenesis affect memory processing is not fully understood. Unexpectedly, we find that
suppressing injury-induced increase in neurogenesis reduces dentate excitability one week after TBI, during
the same period when posttraumatic increase the innate immune receptor, toll-like receptor 4 (TLR4)
augments dentate excitability. TLR4 is known to suppress neurogenesis in naïve animals and paradoxically
increase neurogenesis in stroke. While the molecular mechanisms by which TLR4 regulates excitability and
neurogenesis are unknown, recent findings that TLR4 enhances the endopeptidase, matrix metalloproteinase-
9 (MMP-9), a critical player in synaptic plasticity and neurogenesis provides a promising molecular link
between trauma, TLR4 and aberrant network plasticity. In an integrative approach spanning molecular to
cellular to network function, we propose that early increase in neurogenesis and excitability after TBI disrupt
dentate regulation of cortico-hippocampal throughput and contribute deficits in memory processing by TLR4-
dependent persistent elevation of MMP-9 activity. Using the fluid percussion injury model in mice and current in
vivo and ex vivo electro- and optophysiological techniques, Aim 1 will determine the role of TLR4 signaling in
altered development, maturation and circuit integration of abGCs born after injury. Aim 2 will test if altered DG
excitability and neurogenesis after TBI compromise oscillatory coupling between dentate and hippocampus
which can be prevented by blocking TLR4 early after injury. Finally, Aim 3 will use a combination of
histological, biochemical, physiological, and behavioral assays to test if aberrant TLR4 signaling after TBI
results in persistent increase in MMP-9 which can be targeted to limit aberrant neurogenesis, deficits in
oscillatory coupling and memory deficits after TBI. Such preventive strategies will greatly improve the quality of
life of patients after TBI and address the NINDS mission of decreasing the long-term health care burden posed
by post-traumatic neurological diseases.
Terms: <21+ years old><92-kDa Gelatinase><92-kDa Type IV Collagenase><Acceleration><Acquired brain injury><Address><Adult><Adult Human><Affect><American><Ammon Horn><Animals><Apoplexy><Assay><Award><Behavioral Assay><Bioassay><Biochemical><Biological Assay><Birth><Brain Injuries><Brain Trauma><Brain Vascular Accident><CNS plasticity><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cells><Cellular Immune Function><Cellular Migration><Cellular Motility><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Communication><Control Animal><Cornu Ammonis><Coupling><Data><Dentate Fascia><Development><Dysfunction><EEG><Early Intervention><Economic Burden><Electroencephalogram><Electroencephalography><Endopeptidases><Entorhinal Area><Epilepsy><Epileptic Seizures><Epileptics><Epileptogenesis><Equilibrium><Event><Fascia Dentata><Feedback><Frequencies><Functional disorder><Gelatinase B><Genetic><Gyrus Dentatus><Gyrus Hippocampi><Gyrus Parahippocampalis><Hippocampal Gyrus><Hippocampus><Histologic><Histologically><Histology><Homolog of Drosophila TOLL><Immunologic Receptors><Immunological Receptors><In Situ><Injury><Intracellular Communication and Signaling><Link><MMP-9><MMP-9 Protein><Macrophage Gelatinase><Matrix Metalloproteinase-9><Mediating><Memory><Memory Deficit><Memory Loss><Memory impairment><Mice><Mice Mammals><Mission><Modeling><Molecular><Murine><Mus><NINDS><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Disorders><Neurologic Dysfunctions><Neurological Disorders><Neuronal Plasticity><Neurons><Parahippocampal Gyrus><Parturition><Pathologic><Pathway interactions><Patients><Peptide Peptidohydrolases><Pharmacology><Physiologic><Physiological><Physiology><Physiopathology><Pilot Projects><Predisposition><Preventative strategy><Prevention strategy><Preventive strategy><Publishing><QOL><Quality of life><Regulation><Reporter><Role><Seizure Disorder><Seizures><Signal Transduction><Signal Transduction Systems><Signaling><Source><Stroke><Structure><Susceptibility><Synapses><Synaptic><Synaptic plasticity><TLR4><TLR4 gene><Techniques><Testing><Therapeutic><Toll Homologue><Transgenic Mice><Trauma><Traumatic Brain Injury><Type V Collagenase><abnormal brain function><adult neurogenesis><adulthood><adverse consequence><adverse outcome><after stroke><antagonism><antagonist><balance><balance function><biological signal transduction><brain attack><brain damage><brain dysfunction><brain impairment><brain-injured><cell culture><cell cultures><cell motility><central nervous system plasticity><cerebral vascular accident><cerebrovascular accident><cognitive disability><cognitively disabled><dentate gyrus><developmental><disability><disability burden><dysfunctional brain><entorhinal cortex><epilepsia><epileptogenic><experiment><experimental research><experimental study><experiments><fluid percussion injury><genetic approach><genetic strategy><granule cell><healthcare burden><hippocampal><immune function><immune receptor><improved><in vivo><injuries><memory consolidation><memory decline><memory dysfunction><memory process><memory processing><migration><neocortical><neural plasticity><neurochemical><neurochemistry><neurogenesis><neurological disease><neurological dysfunction><neuronal><neuropathologic><neuropathological><neuropathology><neurophysiological><neurophysiology><neuroplastic><neuroplasticity><novel><pathophysiology><pathway><physical disability><physically disabled><physically handicapped><pilot study><post stroke><poststroke><prevent><preventing><social role><stroked><strokes><synapse><timeline><toll-like receptor 4><traumatic brain damage>