Inhibitory control of visual cortical circuits

项目摘要 大脑皮层中的神经元活动是基本大脑功能的基础，包括感知和认知， 并灵活地改变以适应不断变化的行为状态和环境输入。几行 有证据表明，使用GABA作为神经递质的抑制性中间神经元可能是关键的调节器。 具有灵活的皮质功能。然而，皮质GABA能中间神经元由几个高度不同的 具有复杂交互作用的亚群，并在安静等行为状态下被不同地激活 清醒、运动和唤醒。这给确定他们的确切角色带来了挑战。有趣的是， 我们的初步数据表明，在小鼠的视皮层中，两个特定的中间神经元之间的相互作用 表达生长抑素(SST-INS)的群体和表达血管活性的群体 肠肽(VIP-INS)显著影响行为状态依赖的视觉加工。 这项研究将直接使用尖端的、多层次的方法，结合计算建模和 定量数据分析、双光子激光扫描显微镜(2PLSM)和基因靶向 对清醒、行为正常的小鼠大脑回路的光遗传操作。我们将因果性地测试 确定的细胞群体在不同的行为状态和感觉处理过程中的活动。我们将解决 目的如下：(1)我们将确定细胞类型特定的GABA能中间神经元对感觉的贡献 处理，(2)确定行为状态如何调节GABA能抑制的影响，(3)确定如何 不同的GABA能中间神经元群体调节视觉诱发活动的相关结构，并且 (4)确定IN-IN交互作用如何动态调节视觉调节。我们的结果将产生 对已识别的中间神经元群体功能的前所未有的洞察，发现基础 计算主题的视觉功能和功能障碍，并提供了一个紧密结合 弗格森博士长期研究计划的计算/实验基础。这项研究具有 对GABA能中间神经元在视觉加工障碍中的作用提供新的见解 在神经和精神疾病方面。 上述工作将由耶鲁大学神经科学系的弗格森博士进行 在她的导师杰西卡·卡丁博士和她的合作者Dr。 迈克尔·希格利和布伦特·多伦。这项提议是精心设计的，目的是扩大弗格森博士的 技术技能，磨练科学推理，并提供职业发展培训，为她做好准备 在K99阶段结束时成为助理教授，并在K99阶段结束时申请独立R01资助 R00阶段结束。这些目标将通过弗格森博士的计划实现，如本文所述 应用程序，进行研究；经常与她的导师、合作者和 拥有与这些研究相关的研究兴趣/技术技能的耶鲁大学教职员工；并参加科学会议。

Project Summary Neuronal activity in the cerebral cortex underlies essential brain functions, including perception and cognition, and changes flexibly to adapt to changing behavioral states and environmental inputs. Several lines of evidence suggest that inhibitory interneurons, which use GABA as a neurotransmitter, may be key regulators of flexible cortical function. However, cortical GABAergic interneurons comprise several highly diverse subpopulations with complex interactions, and are differentially activated during behavioral states such as quiet wakefulness, locomotion, and arousal. This presents a challenge to identifying their precise roles. Interestingly, our preliminary data suggest that in the mouse visual cortex, interactions between two specific interneuron populations, those expressing the peptide somatostatin (SST-INs) and those expressing the vasoactive intestinal peptide (VIP-INs) dramatically affect behavioral state-dependent visual processing. This research will directly, using a cutting-edge, multi-level approach combining computational modeling and quantitative data analysis, two-photon laser scanning microscopy (2PLSM), and genetically targeted optogenetic manipulation of brain circuits in awake, behaving mice. We will causally test the links between the activity of defined cell populations during distinct behavioral states and sensory processing. We will address the following aims: (1) we will identify cell-type specific GABAergic interneuron contributions to sensory processing, (2) determine how behavioral state modulates the impact of GABAergic inhibition, (3) identify how distinct GABAergic interneuron populations regulate the correlational structure of visually evoked activity, and (4) determine how IN-IN interactions dynamically regulate visual tuning. Our results will generate unprecedented insight into the function of identified interneuron populations, discover fundamental computational motifs of visual function and dysfunction, and provide a tightly integrated computational/experimental foundation for Dr. Ferguson's long-term research program. This research has the potential to provide novel insight into the role of GABAergic interneurons in the impairment of visual processing in neurological and psychiatric disease. The work described above will be carried out by Dr. Ferguson in the Department of Neuroscience at the Yale University School of Medicine, under the supervision of her mentor, Dr. Jessica Cardin, and collaborators Drs. Michael Higley and Brent Doiron. The proposal is carefully designed to broaden Dr. Ferguson's arsenal of technical skills, hone her scientific reasoning, and provide career development training to prepare her to become an Assistant Professor at the end of the K99 phase, and to apply for independent R01 funding at the end of the R00 phase. These goals will be achieved through Dr. Ferguson's plans, described in this application, to perform research; to meet frequently with her mentor, collaborators, and other members of the Yale faculty with research interests/technical skills relevant to these studies; and to attend scientific meetings.