The therapeutic potential of the cerebellum in schizophrenia

 描述(申请人提供)：候选人：克里斯特尔·帕克博士是爱荷华大学神经病学系的博士后研究学者。她拥有出色的系统神经科学背景，拥有小脑电路博士学位，并接受过小脑参与神经精神疾病的临床培训。她的主要研究兴趣包括研究利用小脑治疗神经精神疾病认知功能障碍的机制。职业发展：该奖项将确保Parker博士完成高级系统神经科学技术的培训，如多部位神经元记录与光遗传学相结合，以及2)准备平稳过渡到一名独立科学家，专注于为因神经和精神疾病而患有认知异常的患者开发新的治疗方法。这项提议将使帕克博士在独立的职业生涯中处于最佳地位，将对基本小脑回路功能作用的见解转化为可以帮助认知功能障碍患者的治疗方法。研究策略：目前还没有有效的治疗神经精神疾病认知功能障碍的方法，因为潜在的机制尚不清楚。帕克博士和纳拉亚南实验室使用间隔计时任务来研究认知缺陷。这项任务非常适合于研究精神分裂症的基本认知回路，因为患者有可靠的缺陷，任务表现取决于已知的前额叶回路，而且可以在表现出分裂样表型的动物身上进行研究。小脑对认知是必不可少的，帕克博士的初步数据显示，它也是间隔计时所必需的。此外，小脑和 在患有认知功能障碍的精神分裂症患者中，前额叶皮质一直存在功能障碍。帕克博士的初步数据概括了动物模型中两个大脑区域的时间缺陷。她的总体目标是开发一个独立的实验室，专注于利用小脑与额叶皮质的联系来开发精神分裂症的新疗法。拟议的实验结合了尖端技术来测试小脑调节精神分裂症受损的功能失调的前额叶电路的假设。我们预计，这项研究的见解将指导未来对认知受损患者的治疗。导师和顾问：对于这项提议，帕克博士已经确定了一支强大的指导团队。她的主要导师将是纳拉亚南博士，一位创新的系统神经学家和神经学家，他将教她光遗传学、神经元集成记录和数据分析技术。同时，她将与资深导师威廉·塔尔曼博士合作，后者将在她博士后研究期间的许多职业发展方面以及使用共聚焦显微镜进行免疫组化方面对她进行深入指导。约翰·弗里曼博士将就小脑依赖行为、小脑神经元记录和小脑组织学方面与帕克博士进行非正式咨询。帕克博士意识到她需要精神分裂症方面的导师，并与比塔·莫哈达姆博士和米哈伊尔·普列特尼科夫博士合作，他们是动物实验方案方面的专家，可能与精神分裂症相关。她将参观他们的实验室，学习他们的方法， 沉浸在他们的研究计划中，并与他们和他们的实验室成员讨论她的结果和实验设计。环境：爱荷华大学拥有卓越的研究环境，拥有神经精神病学研究领域的领军人物。此外，神经科大力支持这位候选人，并将为帕克博士提供所有必要的资源，以完成她提出的实验，并促进她向独立的过渡。

 DESCRIPTION (provided by applicant): Candidate: Dr. Krystal Parker is a postdoctoral research scholar in the Department of Neurology at the University of Iowa. She has an outstanding systems neuroscience background with a PhD in cerebellar circuitry and clinical training in cerebellar involvement in neuropsychiatric illness. Her primary research interests involve investigating mechanisms to harness the cerebellum to treat cognitive dysfunction in neuropsychiatric illness. Career Development: This award will 1) ensure Dr. Parker finalizes training in advanced systems neuroscience techniques such as multisite neuronal recordings paired with optogenetics and 2) is poised to make a smooth transition to an independent scientist focused on developing new treatments for patients suffering cognitive abnormalities stemming from neurological and psychiatric disease. This proposal will optimally position Dr. Parker for an independent career translating insights on the functional role of basic cerebellar circuitry into therapies that could help patients with cognitive dysfunction. Research Strategy: There are currently no effective treatments for cognitive dysfunction in neuropsychiatric illness as the underlying mechanisms are unknown. Dr. Parker and the Narayanan laboratory study cognitive deficits using an interval timing task. This task is ideally suited to study the basic circuitry of cognition in schizophrenia as patients have reliable deficits, task performance depends on known prefrontal circuitry, and it can be investigated in animals displaying schizophrenia-like phenotypes. The cerebellum is essential for cognition and Dr. Parker's preliminary data show that it is also required for interval timing. In addition, the cerebellum and prefrontal cortex are both consistently dysfunctional in schizophrenia patients suffering from cognitive dysfunction. Dr. Parker's preliminary data recapitulates timing deficits with disruption f both brain areas in animal models. Her overall goal is to develop an independent laboratory that focuses on leveraging the cerebellar connections to the frontal cortex to develop novel therapies in schizophrenia. The proposed experiments combine cutting-edge techniques to test the hypothesis that the cerebellum modulates dysfunctional prefrontal circuits impaired in schizophrenia. We expect that insights from this research will guide future therapies for patients suffering from impaired cognition. Mentors and Consultants: For this proposal, Dr. Parker has identified a strong mentoring team. Her primary mentors will be Dr. Narayanan, an innovative systems neuroscientist and neurologist who will teach her techniques for optogenetics, neuronal ensemble recordings, and data analysis. In parallel, she will work with senior established mentor, Dr. William Talman, who will intensively mentor her in many of the career development aspects during her postdoctoral fellowship period but also in immunohistochemistry using confocal microscopy. Dr. John Freeman will informally consult with Dr. Parker in aspects of cerebellar dependent behavior, cerebellar neuronal recordings, and cerebellar histology. Dr. Parker recognizes her need for mentors in schizophrenia and has joined forces with Drs. Bita Moghaddam and Mikhail Pletnikov, experts in experimental protocols in animals that are potentially relevant to schizophrenia. She will visit their laboratories to learn their methods, be immersed in their research programs, and discuss her results and experimental designs with them and their lab members. Environment: The University of Iowa boasts an exceptional research environment with leaders in neuropsychiatric research. In addition, the Department of Neurology strongly supports the candidate and will provide all the resources necessary for Dr. Parker to complete her proposed experiments and facilitate her transition to independence.