Synaptic integration of newborn neurons after traumatic brain injury

描述（由申请人提供）：创伤性脑损伤（TBI）通常会导致学习和记忆的长期缺陷（8）。海马体是记忆的关键脑结构（9，10），在TBI后产生数量增加的新生神经元（11- 14）。这些新的神经元可能有助于认知恢复（15-18）。然而，在病理条件下出生的神经元往往形成适应不良的连接，这将影响他们在记忆形成方面的效用，并可能导致癫痫发作等疾病（19，20）。创伤后神经发生的潜在机制尚不清楚，尽管已知多种神经递质系统调节神经发生，最显著的是GABA α和NMDA受体信号传导（21-24）。重要的是，这两种受体都是在严重头部受伤患者受伤后立即护理中使用的镇静剂的直接靶向。例如，新生神经元的增殖、分化和成熟由GABA能信号传导调节（21，22），并且新生细胞的存活由NMDA受体调节（21，23，24）。因此，可以想象，镇静剂，如地西泮和氯胺酮，调节这些受体，可能会不同地影响创伤后神经原性反应，改变新生细胞的增殖，存活和整合，这可能会影响功能恢复。这项研究的长期目标是确定TBI后产生的新生神经元是否改变了功能特性，并确定损伤后暴露于特定镇静剂是否改变了这一过程。我们的假设是，TBI后出生的细胞具有加速的发育和突触整合，这涉及GABA能信号传导的变化，并且新生神经元的增殖和整合将受到镇静剂的不同影响。具体目标1将开始通过确定TBI后出生的海马神经元的增殖、迁移、树突形态和电生理特性的变化来解决这一问题，包括分析GABA能受体活性。具体目标2将确定暴露于机制上不同的镇静剂是否会改变神经发生的这些特性[并确定镇静剂介导的创伤后神经发生的变化是否与认知功能和/或癫痫易感性的变化相关]。我们的目标是更好地了解损伤后产生的神经元的功能，以及了解损伤后的神经发生如何受到镇静药物的影响。这项工作的发现将导致转化研究，目标是优化TBI后的医院护理和改善脑损伤后的功能恢复。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) often causes long-term deficits in learning and memory (8). The hippocampus, a critical brain structure for memory (9, 10), generates an increased number of newborn neurons after TBI (11- 14). These new neurons may contribute to cognitive recovery (15-18). However, neurons born in pathologic conditions often form maladaptive connections that would impact their utility in terms of memory formation and could lead to disorders such as seizures (19, 20). The mechanisms underlying post-traumatic neurogenesis are not clear, although a variety of neurotransmitter systems are known to modulate neurogenesis, most notably GABAa and NMDA receptor signaling (21-24). Importantly, both of these receptors are directly targeted by sedatives used in severely head injured patients during immediate post-injury care. For instance, the proliferation, differentiatio and maturation of newborn neurons are regulated by GABAergic signaling (21, 22), and the survival of newborn cells is regulated by NMDA receptors (21, 23, 24). As such, it is conceivable that sedatives, such as diazepam and ketamine, which modulate these receptors, might differentially affect the post-traumatic neurogenic response, altering the proliferation, survival and integration of newborn cells, which could affect functional recovery. The long-term objectives of this research are to determine whether newborn neurons generated after TBI have altered functional properties, and to determine whether exposure to specific sedatives after injury alters this process. Our hypothesis is that cells born after TBI have an accelerated development and synaptic integration, that this involves changes in GABAergic signaling, and that both the proliferation and integration of newborn neurons will be differentially affected by sedatives. Specific Aim 1 will begin addressing this by determining changes in the proliferation, migration, dendritic morphology and electrophysiological properties of hippocampal neurons born after TBI, including an analysis of GABAergic receptor activity. Specific Aim 2 will determine whether exposure to mechanistically distinct sedatives alters these properties of neurogenesis [and also determine whether sedative-mediated changes in post-traumatic neurogenesis are associated with changes in cognitive function and/or seizure susceptibility.] Our goal is to gain a better understanding of the function of the neurons generated after injury, as well as gain an understanding of how neurogenesis after injury is affected by sedative medications. The findings from this work will lead to translational studies with the goal of optimizing post-TBI hospital care and improving functional recovery after brain injury.