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，具有毁灭性的医学和社会经济后果。尽管许多患者对当前治疗做出反应，但多达25％的患者没有反应或具有重大副作用。迫切需要新的治疗方法。这一申请指导的临床科学家发展奖对NIMH战略情绪障碍研究的建议做出了回应，以培养转化研究专家。抑郁症的动物模型，例如强制游泳试验（FST）预测人类抗抑郁活性。通过FST验证了几乎所有用于日常临床实践中使用的抗抑郁药和电击疗法。深脑刺激（DBS）是一种侵入性技术，它可能在抗药性患者的靶向抗抑郁治疗中发挥作用。假定DBS抑制功能障碍的脑系统，该系统与对压力的不良反应有关，并与抑郁症的病理生理相关。目前，在抑郁症人群中应用DBS的热情受到道德上的关注，即由于这些功能失调的抑郁网络在人类中没有充分处理，因此尚不清楚将DBS电极植入人的位置。也就是说，目前的基本动物研究不足以支持目标区域的选择。该建议旨在填补这些空白的几个。它提出培训候选人成为翻译抑郁研究的专家，并在DBS上进行了培训，啮齿动物中抗抑郁反应的预测因素，即时基因表达的免疫细胞化学和先进的研究方法论。该培训奖中的科学研究旨在教授候选新方法和方法，同时还回答了该领域的重要问题。 Sprague-Dawley大鼠将在平行的双盲设计中分为12组，并用双侧DBS植入至中心中层杏仁核（CMA），背侧Raphe（DR）或前扣带回皮层（ACC）。每组将接受腹膜内注射氟西汀（FLX）（有效的抗抑郁药）或盐水（SAL），并用活性DBS（DBS）或假DBS（NOSTM）​​刺激。将对大鼠进行一次测试（FLX/DBS，FLX/NOSTM，SAL/DBS，SAL/NOSTM）​​。 FST固定时间将作为主要结果指标。从FST开始30分钟，将使用免疫细胞学方法对C-FOS进行染色。 C-FOS轮廓将用作抗抑郁反应和区域电路的探索性措施。该K08扩大并补充了候选人在应用于情绪障碍的电气神经调节临床研究方面的特殊专业知识。这个5年职业发展奖的知识将使他更好地指导DBS的未来治疗应用。未来的工作将在更全面的抑郁模型中验证这些发现与对抗治疗抑郁症患者的DBS抗抑郁作用的临床研究之间的核对。