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 最近从伊拉克和阿富汗返回的退伍军人的显著特点是 有与冲击波相关的轻度脑外伤(MTBI)和创伤后应激障碍(PTSD)的病史。在许多症状中， 遵循mTBI，坚持并演变为慢性脑震荡后综合征。此外，在一些新的症状中， 出现或陈旧症状进展和越来越多的证据表明，脑外伤是后期发展的危险因素 神经退行性疾病。与国防部调查员斯蒂芬博士合作 阿勒斯，我们一直在研究一种爆炸超压损伤的大鼠模型，这种模型是为了模拟爆炸- 与人类相关的轻微脑损伤或亚临床冲击波暴露。先前的研究证实，暴露在爆炸中的动物表现出 慢性认知和创伤后应激障碍相关的行为特征，在爆炸暴露后存在一年以上。 最近的研究表明，这些特征是以延迟和渐进的方式发展的。因为之前的研究 发现II组亲代谢性受体(mGluR2/3)拮抗剂逆转了许多BLAST诱导的行为 我们研究了冲击波后mGluR2/3的表达，发现冲击波暴露后43℃mGluR2表达增加 在脑组织中有6周或更长时间，在孤立的血管部分中有6周。我们的合作者David Cook博士(Puget Sound VA)发现死后脑组织中mGluR2/3的免疫组织化学染色增加 有慢性神经行为综合征的冲击波暴露退伍军人。这些研究支持mGluR2的改变 受体作为冲击伤后的关键病理生理事件。在特定目标#1中使用爆炸暴露的大鼠 我们将研究mGluR2在神经元和神经血管中的表达的时间依赖性 以及表达如何与延迟行为表型的出现相关。特定的 目的#2将研究mGluR2表达增加的下游分子效应以及 通过冲击波暴露mGluR2 KO大鼠或 使用腺相关病毒(AAV)载体在区域基础上击倒mGluR2。具体目标#3 将确定(2R，6R)-羟基去甲氯胺酮是否可以逆转BLAST相关的认知和行为特征 老鼠。在与库克博士合作的具体目标4中，我们将确定mGluR2的表达是否发生改变 在爆炸暴露后患有慢性神经行为综合征的退伍军人的尸检脑中使用 来自退伍军人和军人的组织，在Puget Sound VA收集或由Dan博士提供 Perl(健康科学统一服务大学)。这些研究将检验改变了的假设 MGluR2的表达是退伍军人和实验动物模型爆炸相关脑损伤的特征 并进一步测试mGluR2作为BLAST后神经行为综合征的治疗靶点的作用 受伤。