Restoring Normal Output After Traumatic Brain Injury

 描述(申请人提供)：创伤性脑损伤(TBI)是导致儿童和年轻人死亡和残疾的主要原因。在美国，每年大约有200万人受到脑损伤的困扰，目前还没有有效的治疗方法。与脑外伤相关的神经损伤包括学习和记忆障碍以及癫痫发作风险增加。海马体与这两种现象密切相关，极易受到创伤性脑损伤的损害。正常的海马体依赖认知需要正常的海马体输出。脑外伤既减少了海马区的输出，又损害了海马区依赖的认知。在海马区CA1区，损伤后输出的减少主要是由于抑制的增加。特别是，最近发现损伤后，来自抑制性神经的一个亚群，即CCK阳性中间神经元的抑制作用增加。CCK篮细胞中间神经元提供周身抑制，并有助于调节CA1锥体神经元的动作电位放电，CA1锥体神经元是海马区的输出细胞。锥体神经元的刺激诱发动作电位在损伤后显著降低，最近发现用大麻素WIN55,212-2抑制CCK中间神经元可以使CA1锥体神经元的刺激诱发动作电位恢复正常。目前的提议旨在检验以下中心假设：创伤性脑损伤导致海马区CA1区CCK中间神经元的增强抑制。这种增加的抑制会减少海马区的输出，并导致认知障碍。选择性抑制CA1区CCK中间神经元将恢复正常的海马输出，减轻损伤所致的认知功能障碍。我们将通过在体外和体内测量激活CCK中间神经元中化学生成的“神经元沉默”hM4Di前后的海马输出来验证这一假说。制定有效的治疗策略将需要清楚地了解哪些细胞类型受到影响，并找到纠正其潜在功能障碍的方法。目前的提议旨在实现这些目标，并将为靶向和修复脑损伤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.