The role of metabotropic mGluR2 receptors in the chronic cognitive and behavioral effects of blast exposure

代谢型 mGluR2 受体在爆炸暴露的慢性认知和行为影响中的作用

• 批准号: 10693237
• 负责人: Gregory A. Elder
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693237
• 关键词: Acute; Afghanistan; Aftercare; Amygdaloid structure; Animals; Antidepressive Agents; Appearance; Autopsy; Behavior assessment; Behavioral; Blast Injuries; Blood Vessels; Brain; Brain Injuries; Brain region; Cerebellum; Chronic; Cognitive; Collaborations; Data; Department of Defense; Dependence; Development; Dose; Event; Exhibits; Experimental Animal Model; Exposure to; Female; Functional disorder; Health Sciences; Hippocampus; Human; Inflammation; Iraq; Ketamine; Knock-out; Link; Medial; Mental Health; Modeling; Molecular; Neurodegenerative Disorders; Neuroglia; Neurons; Pattern; Pharmacology Study; Phenotype; Post-Concussion Syndrome; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Proteins; Rattus; Receptor Signaling; Recording of previous events; Regimen; Research Personnel; Risk Factors; Role; Signal Pathway; Signal Transduction; Stains; Symptoms; Synapses; Syndrome; Testing; Time; Tissues; Titrations; Traumatic Brain Injury; University Health Services; Veterans; Work; adeno-associated viral vector; age related; antagonist; behavioral phenotyping; blast exposure; brain tissue; cell type; cerebrovascular; cooking; decubitus ulcer; design; glutamatergic signaling; knock-down; male; metabotropic glutamate receptor 2; mild traumatic brain injury; military service; military veteran; neurobehavioral; neurovascular; post-traumatic stress; receptor; service member; side effect; single nucleus RNA-sequencing; sound; symptomatology; therapeutic target; trait

Traumatic brain injury (TBI) has been linked to a variety of chronic mental health problems in veterans. A striking feature in the most recent veterans returning from Iraq and Afghanistan has been the overlap between a history of blast-related mild TBI (mTBI) and post-traumatic stress disorder (PTSD). In many symptoms that follow mTBI persist and evolve into a chronic postconcussion syndrome. In addition, in some new symptoms develop or old symptoms progress and mounting evidence suggests TBI is a risk factor for later development of neurodegenerative diseases. In collaboration with a Department of Defense investigator, Dr. Stephen Ahlers, we have been studying a rat model of blast overpressure injury that was developed to mimic a blast- related human mild TBI or subclinical blast exposure. Prior work established that blast-exposed animals exhibit chronic cognitive and PTSD-related behavioral traits that are present for over one year after blast exposure. Recent work has shown that these traits develop in a delayed and progressive manner. Since prior studies found that a group II metabotropic receptor (mGluR2/3) antagonist reversed many blast-induced behavioral traits, we explored mGluR2/3 expression after blast and found mGluR2 increased after blast exposure at 43 weeks or more in brain and at six weeks in isolated vascular fractions. Our collaborator Dr. David Cook (Puget Sound VA) has found increased immunohistochemical staining for mGluR2/3 in post-mortem brain tissue from blast-exposed veterans with chronic neurobehavioral syndromes. These studies support alterations in mGluR2 receptors as a key pathophysiological event following blast injury. In Specific Aim #1 using blast-exposed rats we will examine the time dependence of mGluR2 expression within the neuronal and neurovascular compartments and how expression correlates with appearance of the delayed behavioral phenotype. Specific Aim #2 will examine the downstream molecular effects of increased mGluR2 expression as well as determine the mGluR2 dependence of the behavioral phenotype by blast exposing mGluR2 KO rats or knocking down mGluR2 on a regional basis using adeno associated viral (AAV) vectors. Specific Aim #3 will determine whether (2R,6R)-hydroxynorketamine can reverse blast-related cognitive and behavioral traits in rats. In Specific Aim #4 in collaboration with Dr. Cook we will determine whether mGluR2 expression is altered in post mortem brain from veterans with chronic neurobehavioral syndromes following blast exposure using tissue from veterans and military service members collected at the Puget Sound VA or provided by Dr. Dan Perl (Uniformed Services University of the Health Sciences). These studies will test the hypothesis that altered mGluR2 expression is a feature of blast-related brain injury in veterans as well as experimental animal models and further test the role of mGluR2 as a therapeutic target in the neurobehavioral syndromes that follow blast injury.

创伤性脑损伤（TBI）与退伍军人的各种慢性心理健康问题有关。一个 从伊拉克和阿富汗返回的最新退伍军人中，引人注目的特征一直是 与爆炸有关的轻度TBI（MTBI）和创伤后应激障碍（PTSD）的病史。在许多症状中 跟随MTBI持续存在，并演变为慢性脑震荡综合征。另外，在一些新症状中 发展或旧症状的进展和越来越多的证据表明TBI是后来发展的危险因素 神经退行性疾病。与国防部调查员Stephen博士合作 啊，我们一直在研究一种大鼠的爆炸超压损伤模型，该模型是为了模仿爆炸的 相关的人类轻度TBI或亚临床爆炸。先前的工作确定了暴露于爆炸的动物 慢性认知和PTSD与PTSD相关的行为特征存在爆炸后一年多。 最近的工作表明，这些特征以延迟和渐进的方式发展。自先前的研究以来 发现II组代谢性受体（MGLUR2/3）拮抗剂逆转了许多爆炸诱导的行为 特征，我们在爆炸后探索了MGLUR2/3表达，发现MGLUR2在43时爆炸后增加 在大脑和六周的孤立血管级分数周或更长时间。我们的合作者David Cook博士（Puget 声音va）发现MGLUR2/3的免疫组织化学染色增加了。 暴露于慢性神经行为综合征的爆炸退伍军人。这些研究支持MGLUR2的改变 受体作为爆炸损伤后的关键病理生理事件。在使用爆炸暴露大鼠的特定目标＃1中 我们将检查神经元和神经血管中MGLUR2表达的时间依赖性 隔室以及表达与延迟行为表型的外观相关。具体的 AIM＃2将检查MGLUR2表达增加的下游分子效应以及 通过爆炸暴露MGLUR2 KO大鼠或 使用Adeno相关病毒（AAV）向量在区域基础上拆卸MGLUR2。特定目标＃3 将确定（2R，6R） - 羟基诺摩甲胺是否可以逆转与爆炸有关的认知和行为特征 老鼠。在与库克博士合作的特定目标＃4中，我们将确定MGLUR2表达是否改变 在爆炸暴露后，在患有慢性神经行为综合征的退伍军人的尸体大脑中 从普吉特声音VA收集或由Dan博士提供的退伍军人和兵役成员的组织 Perl（卫生科学统一服务大学）。这些研究将检验改变的假设 MGLUR2表达是退伍军人和实验动物模型中与爆炸相关的脑损伤的特征 并进一步测试MGLUR2作为伴随爆炸的神经行为综合征中的治疗靶标的作用 受伤。