Investigating parvalbumin interneuron activity: implications for schizophrenia and potential therapies

研究小清蛋白中间神经元活性：对精神分裂症和潜在疗法的影响

• 批准号: 9013762
• 负责人: Kathleen K.A. Cho
• 金额: $ 8.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-21 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9013762
• 关键词: Accounting; Address; Adult; Affect; Anhedonia; Animals; Antipsychotic Agents; Award; Behavior; Behavioral; Biological Markers; Brain; Brain region; Cells; Cognition; Cognitive; Cognitive deficits; Communication; Communities; Complement; Data; Delusions; Development; Disease; Electroencephalography; Electrophysiology (science); Ensure; Environment; Fiber; Frequencies; Functional disorder; Genetic; Goals; Hallucinations; Hippocampus (Brain); Impaired cognition; In Vitro; Interneuron function; Interneurons; Link; Maps; Measurement; Mentors; Mentorship; Methods; Molecular Biology; Mus; Neurobehavioral Manifestations; Neurons; Parvalbumins; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Photometry; Physiological; Play; Population; Prefrontal Cortex; Process; Research; Research Personnel; Resources; Role; Schizophrenia; Social Interaction; Specificity; Stem cells; Symptoms; System; Techniques; Testing; Therapeutic Intervention; Training; Transgenic Organisms; Transplantation; Viral; Work; base; career; cell type; cognitive task; disability; flexibility; improved; interdisciplinary approach; mouse model; multidisciplinary; mutant; neuropsychiatry; novel therapeutics; optogenetics; public health relevance; relating to nervous system; social cognition; therapeutic target; tool; transcription factor; Accounting; Address; Adult; Affect; Anhedonia; Animals; Antipsychotic Agents; Award; Behavior; Behavioral; Biological Markers; Brain; Brain region; Cells; Cognition; Cognitive; Cognitive deficits; Communication; Communities; Complement; Data; Delusions; Development; Disease; Electroencephalography; Electrophysiology (science); Ensure; Environment; Fiber; Frequencies; Functional disorder; Genetic; Goals; Hallucinations; Hippocampus (Brain); Impaired cognition; In Vitro; Interneuron function; Interneurons; Link; Maps; Measurement; Mentors; Mentorship; Methods; Molecular Biology; Mus; Neurobehavioral Manifestations; Neurons; Parvalbumins; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Photometry; Physiological; Play; Population; Prefrontal Cortex; Process; Research; Research Personnel; Resources; Role; Schizophrenia; Social Interaction; Specificity; Stem cells; Symptoms; System; Techniques; Testing; Therapeutic Intervention; Training; Transgenic Organisms; Transplantation; Viral; Work; base; career; cell type; cognitive task; disability; flexibility; improved; interdisciplinary approach; mouse model; multidisciplinary; mutant; neuropsychiatry; novel therapeutics; optogenetics; public health relevance; relating to nervous system; social cognition; therapeutic target; tool; transcription factor

 DESCRIPTION (provided by applicant): Dysfunction of the prefrontal cortex (PFC) contributes to cognitive deficits that represent the primary cause of disability associated with schizophrenia. However, currently available antipsychotic medications are only minimally effective for cognitive symptoms, demonstrating the need for better therapeutic targets. Treatments for cognitive deficits in schizophrenia remain underdeveloped in large part because the relevant physiological mechanisms remain unclear. A major hypothesis is that in schizophrenia, abnormalities in GABAergic interneurons, particularly fast- spiking interneurons (FSINs) that express parvalbumin (PV) and generate gamma (~30-120 Hz) oscillations, disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. To this end, we studied Dlx5/6+/- mice, which are deficient in transcription factors that regulate FSIN development, and found that abnormal FSIN development coincides with the onset of cognitive inflexibility and deficient task-evoked gamma oscillations. Strikingly, gamma-frequency optogenetic stimulation of PFC interneurons completely normalized cognitive flexibility in adult Dlx5/6+/- mice; inhibition of PFC interneurons in control mice reproduced cognitive inflexibility. These findings provide direct evidence for long hypothesized relationships between interneurons, gamma oscillations, and PFC-dependent cognition implicated in schizophrenia. My immediate goal is to characterize the circuit-specific activity dynamics of only PV interneurons during cognitive tasks in animals with intact and abnormal cognition. My long-term goals are to use these findings toward developing better-targeted treatments for schizophrenia. Under the mentorship of Drs. Vikaas Sohal and John Rubenstein, I will acquire the scientific and professional training necessary to address these goals and to succeed as an independent researcher. The outstanding resources, facilities, and multidisciplinary scientific community at UCSF are an ideal environment to ensure I realize my research and career objectives. My research plan is divided into four main aims: 1) to specifically target PV interneurons and define their role in cognitive flexibility, 2) to define th spatial and temporal activity patterns of PV interneurons in cognitive tasks, 3) to determine the role of long-range projections of PV interneurons in intact and abnormal cognition, and 4) to evaluate the effects of transplantation, a putative treatment. To achieve these aims, I will use a multidisciplinary approach, combining molecular biology, transgenics, fiber photometry, optogenetics, EEG, electrophysiology, and transplantation techniques. Through comparisons between intact and abnormal mouse models and this mechanistic link, we may finally be able to account for the behavioral phenotype in schizophrenia and devise novel therapeutic strategies for treating cognitive aspects of schizophrenia and related conditions.

 描述（由适用提供）：前额叶皮层（PFC）的功能障碍有助于认知缺陷，代表了与精神分裂症相关的残疾的主要原因。 但是，目前可用的抗精神病药物仅对认知症状有效，这表明需要更好的治疗靶点。精神分裂症认知缺陷的治疗方法在很大程度上尚不清楚，因为相关的生理机制仍然不清楚。一个主要的假设是，在精神分裂症中，GABA能中间神经元的异常，尤其是表达parvalbumin（PV）并产生伽玛（〜30-120 Hz）振荡的快速刺激性中间神经元（FSIN），破坏了前额叶皮层（PFC） - 依赖性依赖性依赖性coptitizephia。为此，我们研究了DLX5/6 +/-小鼠，这些小鼠在调节FSIN发育的转录因子上是确定的，发现FSIN发育异常与认知稳健性和缺乏任务诱发的γ振荡的发作相吻合。令人惊讶的是，PFC中间神经元的伽马频率刺激完全使成人DLX5/6 +/-小鼠的认知灵活性完全归一化；抑制PFC中间神经元 在对照小鼠中，重现了认知的僵化。这些发现提供了长期的直接证据 在精神分裂症中实施的中间神经元，γ振荡和PFC依赖性认知之间的假设关系。我的近期目标是表征在具有完整和异常认知动物的认知任务中仅PV中间神经元的特定电路活性动力学。我的长期目标是利用这些发现来开发精神分裂症的靶向更好的治疗方法。在博士的心态下。维卡斯·索哈尔（Vikaas Sohal）和约翰·鲁宾斯坦（John Rubenstein），我将获得必要的科学和专业培训，以解决这些目标并成为独立研究人员。 UCSF的杰出资源，设施和多学科科学界是确保我实现研究和职业目标的理想环境。我的研究计划分为四个主要目的：1）专门针对PV中间神经元并定义了它们在认知灵活性中的作用，2）定义PV Interneurons在认知任务中的空间和临时活动模式，3）确定PV Interneurons在Intact和Absbnormal认知范围内的长距离项目的作用，并进行4）效应，并进行4）的效果，以进行4）效应，以进行4）效果。为了实现这些目标，我将使用一种多学科方法，结合了分子生物学，转基因，纤维光度法，光遗传学，脑电图，电生理学和移植技术。通过完整和异常小鼠模型和这种机械联系之间的比较，我们最终可以考虑精神分裂症的行为表型，并设计出用于治疗精神分裂症和相关疾病认知方面的新型治疗策略。