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质量有深远的影响 生活，与康复过程中功能有限的改善相关并增加 死亡率。这些人的抑郁症发生的事件是 一般人群，虽然对经典抗抑郁药的反应率要低得多。 尚不清楚导致SCI诱导抑郁症的基本物理机制； 但是，促炎细胞因子（例如白介素（IL）-6和TNFα）的水平通常是 大抑郁症患者的血清中升高。就SCI而言，有证据表明 与情绪有关 调节，例如背raphe核。作为血清素能输入的主要来源 大脑，背raphe的扰动可能导致5-羟色胺的失衡 - 神经递质与抑郁症经典相关。 5-羟色胺神经元的活性通常是 通过5-羟色胺自身受体在soma和dendrites上的局部结合，作为调节 以及从前额叶皮层到局部gabaergic Interneron的谷氨酸能项目 背raphe。背raphe的神经回路可以提供潜在的来源 通过谷氨酸稳态的破坏来炎症。初步数据 从我们的实验室指示背侧raphe中TNFα水平增加的显着相关性 中度胸脊髓挫伤后具有抑郁行为。这种细胞因子已经 显示出降低谷氨酸转运蛋白GLT1的表达，显着损害 谷氨酸再摄取。细胞外谷氨酸的增加可能导致 GABA能中间神经元，降低血清素活性。我们假设Sci引起了 抑郁症是由5-羟色胺神经元在背侧raphe中介导的，由 TNFα介导的谷氨酸不平衡。我们将使用中线中线胸骨挫伤模型 在成年雌性大鼠中以检验我们的假设。抑郁表型将使用 一系列行为测试，模仿患者抑郁症的经典症状。我们相信 这种抑郁表型可以通过受伤后的TNFα抑制来改善，并将 测试用XPRO 1595的急性或延迟治疗后的效率测试。这项研究将为我们提供 更深入地了解Sci诱导的抑郁症机制，以及新型的潜力 治疗。