DBS and Rodent Antidepressant- Screen Models

描述(由申请人提供)：抑郁症是一种普遍存在的神经精神疾病，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，或者有很大的副作用。迫切需要新的治疗方法。这次申请导师临床科学家发展奖是为了响应NIMH情绪障碍研究战略计划的建议，以培养翻译研究方面的专家。像强迫游泳测试(FST)这样的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惊厥治疗都经过了FST的验证。脑深部刺激(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被认为可以抑制功能失调的大脑系统，这些系统涉及对压力的不良适应反应，并与抑郁症的病理生理有关。目前，在抑郁人群中应用DBS的热情受到伦理担忧的限制，因为这些功能失调的抑郁网络并没有在人类身上完全解决，还不清楚在哪里植入DBS电极。也就是说，目前没有足够的基础动物研究来支持目标区域的选择。这项提议旨在填补其中的几个空白。它提供培训候选人成为翻译抑郁研究的专家，培训DBS，啮齿动物抗抑郁反应的预测因子，即刻早期基因表达的免疫细胞化学和先进的研究方法。这一培训奖项中的科学研究旨在向候选人传授新的方法和途径，同时也回答这一领域的重要问题。SD大鼠将按平行双盲设计分为12组，将双侧DBS植入杏仁中央内侧核(CMA)、中缝背侧(DR)或前扣带回(ACC)。每组均接受氟西汀(Floxetine，一种有效的抗抑郁药物)或生理盐水(SAL)的腹腔注射，并用活性DBS(DBS)或假DBS(NoSTM)刺激。对大鼠进行一次实验(FLX/DBS、FLX/NoSTM、SAL/DBS、SAL/NoSTM)。FST不动时间将作为主要结果衡量标准。FST开始30分钟后，用免疫细胞化学方法对脑组织进行c-fos染色。C-fos图谱将作为抗抑郁药物反应和区域回路的探索性指标。这本K08扩展并补充了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和临床研究DBS在难治性抑郁症患者中的抗抑郁效果之间架起桥梁。

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.