Synaptic integration of newborn neurons after traumatic brain injury

描述(由申请人提供)：创伤性脑损伤(TBI)通常会导致长期的学习和记忆障碍(8)。海马体是记忆的关键大脑结构(9，10)，在脑外伤(11-14)后产生更多的新生神经元。这些新神经元可能有助于认知恢复(15-18)。然而，在病理性条件下出生的神经元经常形成适应不良的连接，这将影响它们在记忆形成方面的效用，并可能导致癫痫等疾病。创伤后神经发生的机制尚不清楚，尽管已知有多种神经递质系统调节神经发生，最著名的是GABAA和NMDA受体信号(21-24)。重要的是，这两种受体都是在严重颅脑损伤患者受伤后立即护理期间使用的镇静剂直接靶向的。例如，新生神经元的增殖、分化和成熟受GABA能信号(21，22)的调节，新生细胞的存活受NMDA受体(21，23，24)的调节。因此，可以想象，调节这些受体的镇静剂，如安定和氯胺酮，可能会不同地影响创伤后的神经源性反应，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脑外伤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，脑外伤后出生的细胞具有加速发育和突触整合的能力，这涉及GABA能信号的变化，新生神经元的增殖和整合都将受到镇静剂的不同影响。具体目标1将通过确定脑损伤后新生海马神经元的增殖、迁移、树突形态和电生理特性的变化来开始解决这一问题，包括对GABA能受体活性的分析。具体目标2将确定接触机械上不同的镇静剂是否改变了神经发生的这些特性[也确定了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有关。]我们的目标是更好地了解损伤后产生的神经元的功能，以及了解镇静药物对损伤后神经发生的影响。这项工作的发现将导致转化性研究，目标是优化脑损伤后的医院护理，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.