INJURY-INDUCED SPATIAL MEMORY IMPAIRMENTS ARE LINKED TO UNCOORDINATED HIPPOCAMPAL NEURONAL FIRING

受伤引起的空间记忆损伤与海马神经元放电不协调有关

基本信息

批准号：
10375816
负责人：
Akiva S Cohen
金额：
$ 42.71万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10375816
关键词：
Action Potentials Affect Animal Model Area Brain Concussion Cause of Death Child Cholecystokinin Data Direct Expenditure Discrimination Episodic memory Equilibrium Frequencies Functional disorder Goals Health Healthcare Systems Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Injury Interneurons Lateral Learning Life Link Measures Mediating Medical Memory Memory impairment Neurologic Neurons Parvalbumins Pathology Patients Performance Persons Population Public Health Research Rodent Site Stimulus Study models Survivors Symptoms Synaptic Transmission Testing Therapeutic Time Translating Traumatic Brain Injury United States Work base behavioral study bench to bedside care systems cell type cost dentate gyrus disability economic evaluation fluid percussion injury improved in vivo inhibitory neuron innovation mild traumatic brain injury neuronal circuitry spatial memory synaptic inhibition

项目摘要

PROJECT SUMMARY Traumatic brain injury (TBI) is the primary cause of death and disability in children and young adults1. TBI afflicts more than two million people annually in the United States, with an estimated 5.3 million TBI survivors living with lasting neurological impairments2,3. Mild TBI (mTBI) or concussion, accounts for nearly 90% of TBIs, with symptoms including deficits in learning and memory that profoundly affect the daily life and overall health of TBI survivors. Although TBI survivors suffer a range of cognitive impairments, deficits in learning and memory are most common4–6. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by TBI. Little is known about the precise mechanisms by which hippocampal damage produces memory deficits. Our preliminary data indicate that spatial memory (a type of episodic memory required for the discrimination of a spatially moved object), requires coordinated hippocampal theta and gamma rhythms in the local field potential and neuronal firing time-locked to those rhythms (Figures 7-9 and Innovation section below). Both of these required components are critically dependent on the activity of inhibitory neurons, and specific inhibitory neurons in hippocampal area CA1 and the dentate gyrus (DG) are significantly altered after TBI7,8. Based on these results we hypothesize that altered synaptic transmission in specific hippocampal inhibitory neuron populations alters the balance between excitation and inhibition (E/I balance), leading to local circuit dysfunction and significant weakening of the coordinated hippocampal oscillations and neuronal firing required for normal spatial memory. To test this hypothesis, in vivo and in vitro recordings together with chemogenetic manipulation of specific subpopulations of inhibitory neurons in area CA1 and DG will be used to determine whether restoring normal inhibitory neuron function will reinstate normal rhythms, time-locked action potential firing, and normal spatial memory.

项目概要创伤性脑损伤 (TBI) 是儿童和青少年 TBI 死亡和残疾的主要原因1。在美国，每年有超过 200 万人遭受这种病的折磨，估计有 530 万 TBI 幸存者患有持久神经功能障碍2,3 的患者中，有近 90% 是轻度 TBI (mTBI) 或脑震荡。具有学习和记忆缺陷等症状，严重影响日常生活和整体健康尽管 TBI 幸存者患有一系列认知障碍、学习和能力缺陷。记忆最常见4-6 海马体与这两种现象密切相关，并且高度相关。对于 TBI 造成的损伤的易感性，人们对海马损伤的确切机制知之甚少。我们的初步数据表明空间记忆（情景记忆的一种）。需要区分空间移动的物体），需要协调的海马θ和局部场电位中的伽马节律和与这些节律时间锁定的神经放电（图 7-9 和下面的创新部分）。抑制性神经元，以及海马区 CA1 和齿状回 (DG) 的特异性抑制性神经元 TBI7,8 后显着改变根据这些结果，我们发现突触传递发生了改变。在特定的海马抑制神经元群体中，改变兴奋和抑制之间的平衡抑制（E/I 平衡），导致局部电路功能障碍和显着削弱测试正常空间记忆所需的协调海马振荡和神经放电。这一假设，体内和体外记录以及特定的化学遗传学操作 CA1区和DG区的抑制性神经元亚群将用于确定是否恢复正常抑制性神经元功能将恢复正常节律、时间锁定的动作电位放电和正常空间记忆。