DBS and Rodent Antidepressant- Screen Models

DBS 和啮齿动物抗抑郁药 - 筛选模型

• 批准号: 7091507
• 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/7091507
• 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）：抑郁症是一种普遍的神经精神疾病，具有破坏性的医疗和社会经济后果。尽管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。本申请的指导临床科学家发展奖回应了NIMH情绪障碍研究战略计划的建议，以培养转化研究专家。强迫游泳测试（FST）等抑郁症动物模型可以预测人类的抗抑郁活性。几乎所有日常临床实践中使用的抗抑郁药物和电痉挛疗法都已通过FST验证。深部脑刺激（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被认为可以抑制与压力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，在抑郁症人群中应用DBS的热情受到伦理问题的限制，因为这些功能失调的抑郁症网络尚未在人类中完全研究出来，因此尚不清楚在人类的哪里植入DBS电极。也就是说，目前没有足够的基础动物研究来支持选择一个目标区域。该提案旨在填补其中的一些空白。它提供培训候选人成为翻译抑郁症研究专家，培训内容包括DBS，啮齿动物抗抑郁反应的预测因素，即时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方法，同时也回答该领域的重要问题。采用平行双盲设计将Sprague-Dawley大鼠分为12组，分别在中内侧杏仁核（CMA）、中缝背（DR）或前扣带皮层（ACC）植入双侧DBS。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）的腹腔注射，并接受活性DBS （DBS）或假DBS （nosm）的刺激。大鼠实验1次（FLX/DBS、FLX/NoSTM、SAL/DBS、SAL/NoSTM）。FST静止时间将作为主要的结果衡量标准。FST开始30分钟后，用免疫细胞化学方法对大脑进行c-fos染色。C-fos谱将作为抗抑郁反应和区域回路的探索性措施。该K08扩展并补充了候选人在电神经调节应用于情绪障碍的临床研究方面的特殊专业知识。从这5年的职业发展奖项中获得的知识将使他能够更好地指导未来DBS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，并在难治性抑郁症患者中进行DBS抗抑郁效果的临床研究。