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

项目总结 创伤性脑损伤是导致儿童和青少年死亡和残疾的主要原因1。TBI 在美国，每年有200多万人受到影响，估计有530万TBI幸存者 患有持久的神经损伤2、3.轻度脑损伤(MTBI)或脑震荡，占脑损伤的近90%， 症状包括学习和记忆障碍，深刻影响日常生活和整体健康 脑外伤幸存者的数量。尽管脑外伤幸存者遭受一系列认知障碍，但学习和训练方面的缺陷 记忆是最常见的4-6。海马体与这两种现象密切相关，而且 容易受到TBI的损害。对海马区损伤的确切机制知之甚少 会造成记忆缺陷。我们的初步数据表明，空间记忆(一种情节记忆 对于空间移动的物体的辨别所需)，需要协调的海马theta和 局部场电位和神经元放电的伽马节律与这些节律时间锁定(图7-9和 创新部分)。这两个必需的组件都严重依赖于 抑制神经元，以及海马区CA1区和齿状回(DG)的特异性抑制神经元 根据这些结果，我们推测改变了突触传递 在特定的海马区，抑制性神经元群体改变了兴奋和兴奋之间的平衡 抑制(E/I平衡)，导致局部回路功能障碍和显著减弱 正常空间记忆所需的协调的海马体振荡和神经元放电。为了测试 这一假说、体内和体外记录以及特定的化学遗传操作 CA1和DG区抑制性神经元亚群将用于确定是否恢复正常 抑制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 记忆。

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.