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

CTBI：创伤性脑损伤诱发的炎症对认知评估和反应抑制的影响：自杀风险增加的机制

• 批准号: 10292963
• 负责人: Kevin D. Beck
• 金额: --
• 依托单位: VA NEW JERSEY HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292963
• 关键词: Acoustics; Anatomy; Animal Model; Animals; Antiinflammatory Effect; Area; Attenuated; Award; Behavioral; Biological Markers; Blood; Brain; Brain Stem; Brain region; Cell Nucleus; Chronic; Cognitive; Data; Decision Making; Drug abuse; Evaluation; Female; Fluoxetine; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Expression; Gene Expression Profiling; Human; Impulsive Behavior; Impulsivity; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Lateral; Lead; Link; Liquid substance; Measures; Mental Depression; Mild Concussions; Military Personnel; Modeling; Motor; Nerve Degeneration; Neurobiology; Neurons; Pathologic; Percussion; Pontine structure; Procedures; Process; Quality of life; Rattus; Recording of previous events; Research; Rewards; Risk; Risk Factors; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Sex Differences; Site; Social isolation; Startle Reaction; Stress; Suicide; Symptoms; Synapses; Testing; Time; Traumatic Brain Injury; Veterans; Work; behavior test; brain tissue; discounting; fluid percussion injury; frontal lobe; human imaging; imaging biomarker; immunoreactivity; inhibitor; male; mild traumatic brain injury; neural circuit; neuroinflammation; novel; nucleus reticularis; preference; prevent; raphe nuclei; response; suicidal; suicidal behavior; suicidal risk; therapeutic target; trait

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.

该优异提案是 BLR&D TBI (CTBI) 协作优异奖提案的一部分 (RFP #BX-19-006) 涉及三个独立但综​​合的提案，共同研究 TBI 的机制 增强退伍军人的冲动和自杀行为 该合作项目的基本原理是结合起来。 通过人体成像和生物标志物分析对动物进行神经生物学机制研究，以了解 TBI 影响冲动和自杀行为的方式 总体假设是 TBI。 通过炎症和压力增强冲动，这是自杀的危险因素，特别是在应对压力时 血清素系统和额叶电路功能障碍。 去年，美国军队新发的创伤性脑损伤 (TBI) 病例数量增加了一倍多 五年内，TBI 会继续增长，这是自杀的危险因素之一。 创伤性脑损伤后最常见的症状，其本身就是自杀、抑郁和药物滥用的危险因素。 因此，了解导致 TBI 后高冲动的潜在机制是治疗脑损伤的关键。 了解 TBI 和自杀之间的联系对于理性决策和自杀很重要。 之前，我们证明了轻度 TBI (mTBI) 会导致冲动性增加。 动物模型引起听觉惊吓反应（ASR）的长期抑制，病理性 大脑区域尾桥网状核 (PnC) 神经元的炎症和变性 从解剖学上来说，脑桥中缝核中的血清素神经元位于 紧邻 PnC，并且预期 PnC 中存在炎症和神经退行性变并不是没有道理的。 mTBI 后的中缝核，如 PnC 中一样，我们的初步数据也支持这一想法。 初步结果表明，mTBI 会增加侧方液体撞击损伤后的运动和认知冲动 拟议的研究将建立在这些初步结果的基础上，并调查以下假设： 血清素能中缝核的炎症和变性导致 TBI 后冲动性增加。 假设将在三个目标中进行检验，目标 1 将确定轻度 TBI（mTBI）是否单独存在以及是否存在。 与社会隔离压力相结合会增强冲动性。 用于在大鼠中产生 mTBI 将评估冲动的两个方面：运动冲动和认知。 分别使用 Go/No-Go 和延迟折扣程序来抑制冲动。 目标 2 将在 TBI 后 1 个月时增加并在 3 个月时继续恶化。 引起血清素能中缝神经元炎症和变性，预测 mTBI 会引起。 中缝核中的早期炎症反应，随后从 1 开始血清素能神经元的损失 mTBI 后一个月，3 个月时出现更大的退化，目标 3 将确定是否阻止炎症。 mTBI 后立即或 1 周或在行为测试时提高血清素水平将 据预测，用 NF+B 抑制剂阻断炎症可以预防/逆转 TBI 引起的冲动。 将防止 mTBI 后发生炎症，从而防止血清素能神经元变性， 此外，选择性血清素再摄取抑制剂有望增强突触。 血清素，从而逆转 TBI 引起的冲动增强。 拟议的研究将检验新的假设，即脑干血清素神经元的丧失是关键 mTBI 增加冲动的机制，而冲动是自杀的危险因素，而动物模型则不然。 能够直接评估自杀风险，该具体提案将为 TBI 诱发的机制提供解释 冲动，而此协作优点应用程序中的人类研究将提供两者之间的最终联系 冲动和自杀倾向。