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Role of hippocampal interneurons in aberrant neurogenesis and epilepsy after traumatic brain injury

海马中间神经元在脑外伤后异常神经发生和癫痫中的作用

基本信息

批准号：
10590467
负责人：
CORWIN BUTLER
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10590467
关键词：
Acute Adult Affect Anatomy Animal Model Animals Area Automobile Driving Brain Brain Injuries Brain region Calcium Channel Cell Maturation Cell physiology Cells Clinical Data Communities Data Development Disease Electrophysiology (science)Epilepsy Epileptogenesis Failure Frequencies Functional disorder Funding Future Genetic Goals Hilar Hippocampus Histologic Homeostasis Injury Interneurons Intervention Knowledge Label Learning Life Link Measures Medial Mediating Mediator Medical Membrane Potentials Memory Middle East Military Personnel Modeling Monitor Mus Myoepithelial cell Neurons Neurosciences Output Parvalbumins Pathogenesis Pathway interactions Patients Pharmacogenetics Phase Play Population Post-Traumatic Epilepsy Predisposition Prevention strategy Process Proliferating Recurrence Regulation Research Research Personnel Rest Retroviral Vector Retroviridae Role Seizures Signal Transduction Slice Structure Synapses Techniques Temporal Lobe Epilepsy Testing Training Transgenic Mice Trauma Traumatic Brain Injury Veterans Viral Work adult neurogenesis calcium indicator cohort combat controlled cortical impact dentate gyrus entorhinal cortex epileptiform experience experimental study gamma-Aminobutyric Acid granule cell improved improved outcome in vivo injured mouse model nerve supply nervous system disorder neuroblast neurogenesis neuronal circuitry neurotransmitter release novel therapeutic intervention optogenetics patient population pharmacologic preservation presynaptic prevent programs receptor recruit response selective expression sham surgery therapeutic development translational approach translational study treatment strategy

项目摘要

Abstract Post-traumatic epilepsy (PTE) can result from combat-related traumatic brain injury (TBI), a well-documented phenomenon that has caused substantial neurologic disease in Veterans, most recently in relation to conflicts in the Middle East (>350,000 cases of combat-related TBI since 2000). Unfortunately, current treatments for PTE are of limited efficacy, and thus many Veterans with PTE do not have effective seizure control. PTE often manifests as a form of temporal lobe epilepsy, which involves cellular and functional circuit alterations in the hippocampal region of the brain. In the healthy hippocampus, dentate granule cells (DGCs) form a principal cell layer that prevent hyperexcitability through their low firing frequency and relatively hyperpolarized resting membrane potentials. Additionally, the dentate gyrus is a region of ongoing neurogenesis, in which new DGCs are generated throughout adult life and integrate into the existing circuitry, in a process critical to learning and memory. TBI and epilepsy involve the aberrant maturation and integration of adult-born DGCs in the hippocampus, which is thought to disrupt hippocampal function and increase brain excitability leading to seizures. In this region, parvalbumin-positive (PV+) inhibitory basket interneurons not only mediate feed-forward inhibition, but release the neurotransmitter GABA onto immature granule cells and neuroblasts, which modulates circuit integration of these cells as they mature in the hippocampus. Although these interneurons are preserved in many animal models of epilepsy, PV+ basket cells undergo numerous functional and network changes, including reduced excitatory input, increased output failure, and presynaptic calcium channel dysfunction. Prior hypotheses have examined the potential direct contribution of PV+ cell dysfunction to hippocampal hyperexcitability after TBI. In this proposal, I hypothesize that dysfunction of PV+ basket cells after TBI contributes indirectly to hyperexcitability, by driving aberrant maturation and integration of adult-born DGCs. I will investigate how TBI impacts PV+ basket cell function at the cellular and network level, how this dysfunction influences development and integration of adult-born DGCs, and whether changes in PV-cell specific microcircuit structure and function drive whole animal seizure susceptibility following TBI. This proposal will use transgenic mice to selectively target the PV+ basket cell population for expression of calcium indicators, excitatory channelrhodopsins, or specific synthetic receptors to measure PV-cell specific network activity after TBI, as well as the functional outputs of these cells. I will also combine these techniques with retrovirus-mediated labeling of adult-born DGCs, to determine whether changes in post-TBI PV+ basket cell function alter the maturation, integration, or circuit dynamics of adult-born DGCs after TBI. Finally, I will manipulate activity of the PV+ basket cells in vivo to assess their role in neuronal circuit rewiring after TBI, and modulate their activity after TBI in hopes of reducing seizure susceptibility. The knowledge gathered from this study will help guide future work that will refine our understanding of interneuron dysfunction for post-TBI injured Veterans using clinical data, which might one day be able to prevent the development of PTE.