CTBI: Traumatic brain injury-induced inflammation effects on cognitive evaluations and response inhibition: Mechanisms of increased risk for suicidality

本建议书是BLR&D TBI(CTBI)建议书(RFP#BX-19-006)合作建议书的一部分。 涉及三个独立但综合的提案，共同调查TBI 增强退伍军人的冲动和自杀行为。协作项目的基本原理是将 通过对动物神经生物学机制的研究，结合人体成像和生物标志物分析来了解 脑外伤影响冲动和自杀行为的方式。最重要的假设是，TBI 增强冲动，这是自杀的一个危险因素，特别是在应对压力时，通过炎症和 5-羟色胺系统和额叶回路功能障碍。 美军新的创伤性脑损伤(TBI)病例数量在过去的几年里增加了一倍多 五年，并将继续增长。脑外伤是自杀的危险因素。此外，冲动的增加是一种 这是脑损伤后最常见的症状之一，本身也是自杀、抑郁和药物滥用的危险因素。 因此，了解导致脑外伤后高冲动的潜在机制是关键。 了解脑外伤和自杀之间的联系。5-羟色胺对理性决策和损失很重要 5-羟色胺神经元的数量增加会增加冲动。此前，我们证明了轻度脑损伤(MTBI)在 动物模型引起的声学惊厥反应(ASR)的长期抑制，病理 脑桥尾侧网状核(PNC)神经元的炎症和变性 对ASR至关重要。从解剖学上讲，桥中缝核内的5-羟色胺能神经元位于 PNC附近，并不是没有道理的预期炎症和神经变性 MTBI后的中缝核，如PNC。我们的初步数据支持这一观点。我们还介绍了 MTBI增加侧向液压冲击伤后运动和认知冲动的初步结果 在老鼠身上。拟议的研究将建立在这些初步结果的基础上，并调查假设 5-羟色胺能中缝核团的炎症和变性导致脑外伤后冲动性增加。这 假设将在三个目标中得到检验。目标1将确定轻度脑损伤(MTBI)是否单独和在 与社交隔离压力相结合，会增强冲动。侧向液压冲击伤模型将为 用于在大鼠身上产生mTBI。我们将评估冲动性的两个方面：运动冲动性和认知 分别使用进行/不进行和延迟折扣程序的冲动性。据预测，冲动 伤后1个月将增加，伤后3个月继续恶化。目标2将确定mTBI是否 引起5-羟色胺能中缝神经元的炎症和变性。据预测，mTBI将导致 中缝核团的早期炎症反应，随后5-羟色胺能神经元从1 伤后1个月，伤后3个月退变较大。目标3将确定是否阻止炎症 在mTBI后立即或1周或在行为测试时升高5-羟色胺水平将 预防/逆转脑损伤引起的冲动。据预测，使用一种核因子B的抑制剂来抑制炎症 将防止mTBI后发生炎症，从而防止5-羟色胺能神经元的退化， 和冲动。此外，选择性5-羟色胺再摄取抑制剂有望增强突触 5-羟色胺，从而逆转因脑外伤而增强的冲动性。 拟议中的研究将检验脑干5-羟色胺神经元丢失是关键的新假设。 MTBI增加冲动的机制，冲动是自杀的危险因素。而动物模型则不是 能够直接评估自杀风险，这项具体的建议将提供一个机制上的解释，由脑损伤引起 冲动，而这一Collaborative Merit应用程序中的人类研究将提供 冲动和自杀倾向。

This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19-006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine neurobiological mechanistic studies in animals with human imaging and biomarker analysis to understand the manner in which TBI influences impulsivity and suicidal behavior. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. The number of new traumatic brain injury (TBI) cases for U.S. Military forces has more than doubled in the last five years and will continue to grow. TBI is a risk factor for suicidality. Moreover, increased impulsivity is one of the most prevalent symptoms following TBI, and is itself a risk factor for suicide, depression and drug abuse. Thus, understanding the underlying mechanisms responsible for high impulsivity following TBI is key to understanding the link between TBI and suicide. Serotonin is important for rational decision-making and loss of serotonin neurons leads to increased impulsivity. Previously, we demonstrated that mild TBI (mTBI) in an animal model caused long-lasting suppression of the acoustic startle response (ASR), pathological inflammation and degeneration of neurons in the nucleus reticularis pontis caudalis (PnC), a brain region essential for ASR. Anatomically, serotonergic neurons in the pontine raphe nucleus are located in the immediate vicinity of the PnC, and it is not unreasonable to expect inflammation and neurodegeneration in the raphe nucleus following mTBI, as in the PnC. Our preliminary data support this idea. We also present preliminary results that mTBI increases motor and cognitive impulsivity following lateral fluid percussion injury in rats. The proposed studies will build on these preliminary results and investigate the hypothesis that inflammation and degeneration of the serotonergic raphe nuclei lead to increased impulsivity after TBI. This hypothesis will be tested in three aims. Aim 1 will determine whether mild TBI (mTBI) alone and in combination with social isolation stress enhances impulsivity. The lateral fluid percussion injury model will be used to generate mTBI in rats. Two aspects of impulsivity will be assessed: motor impulsivity and cognitive impulsivity using a Go/No-Go and a delay discounting procedure, respectively. It is predicted that impulsivity will be increased at 1 month and continue to worsen at 3 months after TBI. Aim 2 will determine whether mTBI causes inflammation and degeneration of serotonergic raphe neurons. The prediction is that mTBI will cause an early inflammatory response in the raphe nuclei, followed by loss of serotonergic neurons starting at 1 month after mTBI with greater degeneration at 3 months. Aim 3 will determine if blocking inflammation immediately or 1 week after mTBI or enhancing serotonin levels at the time of behavioral testing will prevent/reverse the TBI-induced impulsivity. It is predicted that blocking inflammation with an inhibitor of NFB will prevent inflammation from occurring after mTBI and thereby prevent degeneration of serotonergic neurons, and impulsivity. Additionally, selective serotonin reuptake inhibitors are expected to enhance synaptic serotonin and thereby reverse the enhanced impulsivity due to TBI. The proposed studies will test the novel hypothesis that loss of brainstem serotonin neurons is a key mechanism by which mTBI increases impulsiveness, a risk factor for suicide. While animal models are not able to directly assess suicide risk, this specific proposal will provide a mechanistic explanation of TBI-induced impulsivity, while human studies in this Collaborative Merit application will provide the final link between impulsivity and suicidality.