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.

该优点提案是TBI（CTBI）提案（RFP＃BX-19-006）的BLR＆D协作功绩奖的一部分 涉及三个独立但集成的建议，共同研究了TBI的机制 增强了退伍军人的冲动性和自杀行为。协作项目的理由是结合 具有人类成像和生物标志物分析的动物的神经生物学机械研究，以了解 TBI影响冲动和自杀行为的方式。总体假设是TBI 增强冲动性，自杀的危险因素，特别是通过注射和通过注射和 5-羟色胺系统和额叶电路的功能障碍。 美国军事力量的新脑损伤（TBI）案件的数量增加了一倍以上 五年，将继续增长。 TBI是自杀的危险因素。而且，增加的冲动是一个 TBI之后最普遍的症状是自杀，抑郁和吸毒的危险因素。 那就是，了解tbi之后负责高冲动性的基本机制是 了解TBI与自杀之间的联系。 5-羟色胺对于理性决策和损失很重要 5-羟色胺神经元导致冲动性增加。以前，我们证明了一个轻度的TBI（MTBI） 动物模型引起了对声学惊吓反应（ASR）的长期抑制，病理学 神经元的炎症和变性，脑区域核核核核（PNC） 对于ASR至关重要。从解剖学上，蓬丁raphe Nucus中的血清素能神经元位于 PNC的直接附近，期望注射和神经退行性在 MTBI之后的Raphe核，如PNC中。我们的初步数据支持这一想法。我们也出席 初步结果，MTBI在侧向流体损伤后增加运动和认知冲动性 在老鼠中。拟议的研究将以这些初步结果为基础，并研究以下假设。 血清素能raphe核导致TBI后冲动性增加的炎症和变性。这 假设将以三个目标进行检验。 AIM 1将确定轻度TBI（MTBI）是否单独并在 结合社会隔离压力增强了冲动。横向流体打击乐损伤模型将是 用于在大鼠中生成mtbi。将评估冲动的两个方面：运动冲动和认知能力 冲动分别使用GO/No-Go和延迟折现程序。预计冲动性 TBI后3个月将在1个月时增加，并将继续更糟。 AIM 2将确定MTBI是否 引起炎症和血清素能神经元的变性。预测是mtbi会导致 raphe核的早期炎症反应，随后丧失了血清能神经元，从1开始 MTBI后一个月，在3个月时变性更大。 AIM 3将确定是否阻塞炎症 MTBI立即或在行为测试时提高血清素水平后1周将 防止/逆转TBI诱导的冲动性。可以预测，用NFB的抑制剂阻止注射 将防止MTBI后发生炎症，从而防止血清素能神经元退化， 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，从而扭转了由于TBI引起的增强冲动。 拟议的研究将检验新的假设，即脑干5-羟色胺神经元的丧失是关键 MTBI增加冲动性的机制，这是自杀的危险因素。虽然动物模型不是 可以直接评估自杀风险，该具体建议将提供TBI诱导的机械解释 冲动性，而在此协作功绩应用中的人类研究将提供最终联系 冲动和自杀。