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

• 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
• 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

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.

项目摘要 创伤性脑损伤（TBI）是儿童和年轻人死亡和残疾的主要原因1。TBI 在美国，每年有200多万人受到创伤，估计有530万TBI幸存者 生活在持续的神经损伤中2，3.轻度TBI（mTBI）或脑震荡，占TBI的近90%， 症状包括学习和记忆缺陷，深刻影响日常生活和整体健康 TBI幸存者虽然TBI幸存者遭受一系列认知障碍，但学习和 内存是最常见4 -6.海马体在这两种现象中都有重要的作用， 易受TBI损伤。海马损伤的确切机制知之甚少， 产生记忆缺陷我们的初步数据表明，空间记忆（一种情景记忆） 空间移动物体的辨别所需），需要协调的海马体θ， 局部场电位中的γ节律和与这些节律时间锁定的神经元放电（图7-9和 创新部分）。这两个必要的组成部分都严重依赖于 海马CA 1区和齿状回（DG）的抑制性神经元和特异性抑制性神经元。 在TBI后显著改变7，8。基于这些结果，我们假设突触传递的改变 在特定的海马抑制性神经元群体中， 抑制（E/I平衡），导致局部电路功能障碍和显著削弱的 协调海马振荡和正常空间记忆所需的神经元放电。测试 这一假设，在体内和体外记录与化学遗传操作的具体 CA 1和DG区抑制性神经元的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的节律、时间锁定的动作电位放电和正常的空间电位。 记忆