Chronic Inflammation and Depression after Spinal Cord Injury

脊髓损伤后的慢性炎症和抑郁

• 批准号: 9327359
• 负责人: Kaitlin Farrell
• 金额: $ 4.4万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-12 至 2021-07-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327359
• 关键词: Accelerometer; Acute; Adrenergic alpha-Antagonists; Adult; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Area; Astrocytes; Autoreceptors; Binding; Brain; Brain region; Cells; Central Nervous System Diseases; Chest; Chronic; Comorbidity; Complex; Contusions; Data; Dendrites; Development; Dorsal; Electrophysiology (science); Emotional; Enzyme-Linked Immunosorbent Assay; Etiology; Female; General Population; Glutamate Transporter; Glutamates; Guidelines; Homeostasis; Hyperactive behavior; Immune system; Immunohistochemistry; Impairment; Incidence; Individual; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Interleukin-6; Interneurons; Link; Major Depressive Disorder; Measures; Mediating; Mental Depression; Modeling; Multiple Sclerosis; Neuraxis; Neurons; Neurotransmitters; Output; Pathology; Patients; Phenotype; Physiological; Prefrontal Cortex; Quality of life; Rattus; Recovery; Regulation; Rehabilitation therapy; Reporting; Selective Serotonin Reuptake Inhibitor; Serotonin; Serum; Source; Spinal cord injury; Sucrose; Swimming; System; TNF gene; Testing; Therapeutic; Thoracic spinal cord structure; Time; behavior test; clinical care; cytokine; depressive behavior; depressive symptoms; disability; dorsal raphe nucleus; efficacy testing; emotion regulation; extracellular; functional improvement; immune function; insight; mortality; neural circuit; neuronal cell body; novel; novel therapeutics; object recognition; patch clamp; preference; prevent; response; reuptake; social; subcutaneous; success; treatment duration

Abstract Major depressive disorder in individuals with spinal cord injury has a profound impact on quality of life, correlating with limited functional improvement during rehabilitation and increased mortality rates. The incidence of depression in these individuals is three times higher than the general population, while response rates to classical antidepressants are much lower. The underlying physiological mechanisms responsible for SCI-induced depression are not known; however, levels of pro-inflammatory cytokines, such as Interleukin (IL)-6 and TNFα, are often elevated in the serum of patients with major depression. In the case of SCI, there is evidence of remote, chronic inflammation in supraspinal brain regions that are associated with emotional regulation, such as the dorsal raphe nucleus. As the primary source of serotonergic input to the brain, perturbations of the dorsal raphe could result in an imbalance in serotonin- the neurotransmitter classically associated with depression. Activity of serotonin neurons is normally modulated through both local binding of serotonin autoreceptors on the soma and dendrites, as well as glutamatergic projections from the prefrontal cortex to local GABAergic interneurons in the dorsal raphe. The neural circuitry of the dorsal raphe could provide a potential source of vulnerability to inflammation through a disruption in glutamate homeostasis. Preliminary data from our lab indicate a significant correlation of increased levels of TNFα in the dorsal raphe with depressive behaviors after moderate thoracic spinal cord contusion. This cytokine has been shown to decrease expression of the glutamate transporter GLT1, significantly impairing glutamate reuptake. Increased extracellular glutamate could result in hyperactivity of the GABAergic interneurons, decreasing serotonin activity. We hypothesize that SCI-induced depression is mediated by hypoactivity of serotonin neurons in the dorsal raphe, resulting from TNFα-mediated glutamate imbalance. We will use a moderate, midline thoracic contusion model in adult female rats to test our hypothesis. Depressive phenotype will be assessed using a battery of behavioral tests that mimic classic symptoms of depression in patients. We believe this depressive phenotype can be ameliorated through the inhibition of TNFα after injury and will test for efficacy after acute or delayed treatment with XPro 1595.This study will provide us with greater insight into the mechanism of SCI-induced depression, as well as a potential for novel therapeutic treatment.

抽象的 脊髓损伤患者的重度抑郁症对生活质量产生深远影响 生活的影响，与康复过程中有限的功能改善和增加的功能相关 这些人的抑郁症发病率是普通人的三倍。 一般人群，而对经典抗抑郁药的反应率要低得多。 导致 SCI 诱发抑郁症的潜在生理机制尚不清楚； 然而，促炎细胞因子的水平，如白细胞介素 (IL)-6 和 TNFα，通常会低于正常水平。 有证据表明，重度抑郁症患者血清中的 SCI 浓度升高。 与情绪相关的脊髓上脑区域的远程慢性炎症 调节，例如中缝背核作为血清素输入的主要来源。 在大脑中，中缝背侧的扰动可能会导致血清素失衡 血清素神经元的活性通常与抑郁症相关。 通过体细胞和树突上血清素自身受体的局部结合进行调节，如 以及从前额皮质到局部 GABA 能中间神经元的谷氨酸能投射 中缝背侧的神经回路可以提供潜在的来源。 初步数据表明，谷氨酸稳态受到破坏，容易发生炎症。 我们实验室的研究表明中缝背侧 TNFα 水平的增加存在显着相关性 中度胸脊髓挫伤后出现抑郁行为。 显示可降低谷氨酸转运蛋白 GLT1 的表达，显着损害 谷氨酸再摄取增加可能导致细胞过度活跃。 GABA 能中间神经元，降低了 SCI 诱导的血清素活性。 抑郁症是由中缝背侧血清素神经元活性低下介导的，其原因是 TNFα 介导的谷氨酸失衡我们将使用中度胸部挫伤模型。 将使用成年雌性大鼠来评估抑郁表型。 我们相信，一系列模仿患者抑郁症典型症状的行为测试。 这种抑郁表型可以通过损伤后抑制 TNFα 得到改善，并且会 使用 XPro 1595 进行急性或延迟治疗后的疗效测试。这项研究将为我们提供 更深入地了解 SCI 诱发抑郁症的机制，以及开发新药物的潜力 治疗性治疗。