Restoring Normal Output After Traumatic Brain Injury

 描述（由申请人提供）：创伤性脑损伤（TBI）是儿童和年轻人死亡和残疾的主要原因。在美国，TBI每年折磨大约200万人，并且不存在有效的治疗方法。与TBI相关的神经损伤包括学习和记忆缺陷以及癫痫发作风险增加。海马体与这两种现象密切相关，并且极易受到创伤性脑损伤的损害。正常的海马依赖性认知需要正常的海马输出。TBI既减少海马输出又损害海马依赖性认知。在海马CA 1区，损伤后输出的减少主要是由于抑制的增加。特别是，抑制性神经的一个子集，胆囊收缩素（CCK）阳性的中间神经元，最近被证明是增加损伤后的抑制。CCK篮细胞中间神经元提供体周抑制作用，并有助于调节CA 1锥体神经元（海马的输出细胞）的动作电位放电。锥体神经元中的刺激诱发的动作电位在损伤后显著降低，并且最近显示用大麻素WIN 55，212-2抑制CCK中间神经元的抑制可恢复CA 1锥体神经元中的正常刺激诱发的动作电位。目前的建议是为了测试以下中央假设：创伤性脑损伤引起增强抑制CCK中间神经元在海马CA 1区。这种增加的抑制减少了海马输出并导致认知障碍。选择性抑制CA 1中的CCK中间神经元将恢复正常的海马输出并减轻损伤诱导的认知障碍。我们将通过在CCK中间神经元中激活化学发生的“神经元沉默物”hM 4Di之前和之后测量体外和体内海马输出来测试这一假设。TBI的有效治疗策略的发展将需要清楚地了解哪些细胞类型受到影响，以及纠正其潜在功能障碍的方法。目前的提案旨在满足这些目标，并将为靶向和修复TBI受损神经元的翻译方法奠定基础。

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the primary cause of death and disability in children and young adults. TBI afflicts approximately two million people annually in the United States and no effective therapy exists. The neurological impairments associated with TBI include learning and memory deficits and increased risk of seizures. The hippocampus is critically involved in both of these phenomena and highly susceptible to damage by traumatic brain injury. Normal hippocampus-dependent cognition requires normal hippocampal output. TBI both diminishes hippocampal output and impairs hippocampus-dependent cognition. In area CA1 of the hippocampus the reduction in output after injury is due primarily to an increase in inhibition. In particular, inhibition from a subset of inhibitory neuros, the cholecystokinin (CCK) positive interneurons, was recently shown to increase after injury. CCK basket cell interneurons provide perisomatic inhibition and are instrumental in regulating action potential firing in CA1 pyramidal neurons, the output cells of the hippocampus. Stimulus-evoked action potentials in pyramidal neurons are significantly reduced after injury, and suppressing inhibition from CCK interneurons with the cannabinoid WIN55,212-2 was recently shown to restore normal stimulus-evoked action potentials in CA1 pyramidal neurons. The current proposal is designed to test the following CENTRAL HYPOTHESIS: Traumatic brain injury causes augmented inhibition from CCK interneurons in hippocampal area CA1. This increased inhibition diminishes hippocampal output and contributes to cognitive impairment. Selectively suppressing CCK interneurons in CA1 will restore normal hippocampal output and mitigate injury- induced cognitive impairment. We will test this hypothesis by measuring hippocampal output both in vitro and in vivo before and after activating the chemogenetic "neuronal silencer" hM4Di in CCK interneurons.. The development of effective therapeutic strategies for TBI will require a clear understanding of which cell types are affected, and a way to correct their underlying dysfunction. The current proposal is designed to meet these objectives, and will lay the groundwork for translational methods to target and repair TBI damaged neurons.