DBS and Rodent Antidepressant- Screen Models

DBS 和啮齿动物抗抑郁药 - 筛选模型

• 批准号: 6866788
• 负责人: Ziad Nahas
• 金额: $ 17.65万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866788
• 关键词: amygdala; antidepressants; brain electrical activity; brain electronic stimulator; cingulate gyrus; clinical depression; disease /disorder model; dorsal raphe nucleus; fluoxetine; fos protein; immunocytochemistry; laboratory rat; mood disorders

DESCRIPTION (provided by applicant): Depression is a prevalent neuropsychiatric illness with devastating medical and socio-economic consequences. Although many patients respond to current treatments, up to 25% do not respond, or have substantial side effects. New treatments are desperately needed. This application for Mentored Clinical Scientist Development Award responds to the NIMH Strategic Plan for Mood Disorder Research recommendation to develop experts in translational research. Animal models of depression like the Forced Swim Test (FST) predict human antidepressant activity. Almost all antidepressant drugs and electro-convulsive therapy used in daily clinical practice have been validated with the FST. Deep brain stimulation (DBS) is an invasive technique that could potentially play a role in targeted antidepressant treatment delivery in medication resistant patients. DBS is postulated to inhibit dysfunctional brain systems implicated in maladaptive responses to stress and linked to the pathophysiology of depression. At the moment, enthusiasm for applying DBS in depressed populations is limited by the ethical concern that since these dysfunctional depression networks are not fully worked out in humans, it is unclear where to implant a DBS electrode in man. That is, there is inadequate basic animal research at the moment to support the choice of a targeted area. This proposal is designed to fill several of these gaps. It offers to train the candidate to become an expert in translation depression research, with training in DBS, predictors of antidepressant response in rodents, immunocytochemistry of immediate early gene expression and advanced research methodology. The scientific study within this training award is designed to teach the candidate new methods and approaches, while also answering important questions in this area. Sprague-Dawley rats will be divided into 12 groups in a parallel double-blind design and implanted with bilateral DBS to either the centro-medial amygdala (CMA), dorsal raphe (DR), or anterior cingulate cortex (ACC). Each group will receive an intraperitoneal injection of fluoxetine (FLX) (an effective antidepressant drug) or saline (SAL) and be stimulated with either active DBS (DBS) or sham DBS (NoSTM). Rats will be tested once (FLX/DBS, FLX/NoSTM, SAL/DBS, SAL/NoSTM). FST immobility time will serve as a primary outcome measure. 30 minutes from FST start, the brains will be stained for c-fos using immunocychemistry method. C-fos profiles will serve as exploratory measures of antidepressant response and regional circuitry. This K08 expands on and complements the candidate's special expertise in clinical research of electrical neuromodulation applied to mood disorders. The knowledge from this 5-year career development award will position him to better guide future therapeutic applications of DBS. Future work will bridge between validating these findings in more comprehensive models of depression and clinical investigations of the DBS antidepressant effect in patients with treatment resistant depression.

描述（由申请人提供）：抑郁症是一种流行的神经精神疾病，具有毁灭性的医疗和社会经济后果。虽然许多患者对目前的治疗有反应，但高达25%的患者没有反应，或有严重的副作用。迫切需要新的治疗方法。指导临床科学家发展奖的申请响应了NIMH情绪障碍研究战略计划的建议，以培养转化研究专家。抑郁症的动物模型，如强迫游泳试验（FST）预测人类抗抑郁活性。在日常临床实践中使用的几乎所有抗抑郁药物和电休克治疗都已通过FST验证。脑深部电刺激（DBS）是一种侵入性技术，可能在耐药患者的靶向抗抑郁治疗中发挥作用。DBS被认为可以抑制与对压力的适应不良反应有关的功能失调的大脑系统，并与抑郁症的病理生理学有关。目前，由于这些功能失调的抑郁网络在人类身上还没有完全建立起来，因此还不清楚在人体的何处植入DBS电极，也就是说，目前还没有足够的基础动物研究来支持目标区域的选择，因此，在抑郁人群中应用DBS的热情受到伦理问题的限制。本提案旨在填补其中几个空白。它提供培训候选人成为翻译抑郁症研究的专家，培训DBS，啮齿动物抗抑郁反应的预测因子，立即早期基因表达的免疫细胞化学和先进的研究方法。该培训奖项中的科学研究旨在教授候选人新的方法和途径，同时回答该领域的重要问题。将Sprague-Dawley大鼠以平行双盲设计分为12组，并将双侧DBS植入中央内侧杏仁核（CMA）、中缝背核（DR）或前扣带皮层（ACC）。每组将接受氟西汀（FLX）（一种有效的抗抑郁药物）或生理盐水（SAL）的腹膜内注射，并使用活性DBS（DBS）或假DBS（NoSTM）进行刺激。大鼠将接受一次测试（FLX/DBS、FLX/NoSTM、SAL/DBS、SAL/NoSTM）。FST不动时间将作为主要结局指标。FST开始后30分钟，使用免疫细胞化学方法对脑进行c-fos染色。C-fos曲线将作为抗抑郁反应和区域回路的探索性测量。这个K 08扩展和补充候选人在应用于情绪障碍的电神经调节临床研究方面的特殊专业知识。从这个为期5年的职业发展奖中获得的知识将使他能够更好地指导DBS未来的治疗应用。未来的工作将在更全面的抑郁症模型中验证这些发现与DBS抗抑郁作用在难治性抑郁症患者中的临床研究之间架起桥梁。