Fear learning-related reconfiguration of local and large-scale cortical networks

项目总结 新大脑皮层的神经活动在一系列时间尺度上是可塑性的。学习之间的联系 感觉刺激和与行为相关的结果驱动皮质可塑性，是生物体 生死存亡。慢性应激也可以影响神经回路，尽管它对感觉皮质连接有贡献 而感觉编码尚不清楚。新大脑皮层信息处理的变化可以在不同的时间发生 空间尺度：在由不同类型的兴奋和抑制细胞组成的局部微电路中，以及在更大的范围内 相互连接的皮质网络。过去十年的啮齿动物研究揭示了一个复杂的网络 可能涉及视觉引导行为的次要视觉区域，例如关联初始中性 带有厌恶事件的视觉刺激。然而，这些辅助区域的动态网络连接和 它们对习得的、视觉引导的恐惧行为的独特贡献尚不清楚。恐惧--学习会增强 预测足部电击的皮质刺激表示，但目前尚不清楚是否存在不同的抑制作用 元素支持视觉刺激表现形式中的这些变化。 使用创新的成像方法，本提案将解决3个目标：(1)确定以下方面的变化 伴随恐惧学习而来的网络动态和功能连接。拟议中的实验将 使用同时双视技术研究初级和次级视觉皮质对习得恐惧行为的贡献 双光子/宽视场成像和皮质失活方法。(2)确定贡献的微电路 与恐惧学习相关的皮质反应变化有关。使用细胞型特定的双光子成像和 光遗传学莫伯利博士将测试VIP介导的去抑制增强皮质输出神经元的假说 回应。(3)研究应激对功能性感觉皮层网络结构的影响。 它与正在进行的行为状态的关系。 莫伯利博士将在他的导师杰西卡·卡丁博士和迈克尔·希格利博士的实验室进行这项研究 在耶鲁大学医学院，由咨询委员会成员Marina Picciotto博士提供意见 还有迈克尔·克雷尔。在K99期间，莫伯利博士将学习蜂窝双光子和 结合光遗传学和数量行为学的双双光子/宽视场同时成像 接近了。拟议的实验和多方面的培训计划将为莫伯利博士提供一个独特的 技能的结合，将使他作为一个系统过渡到成功的独立职业生涯 神经学家。

PROJECT SUMMARY Neural activity in the neocortex is plastic over a range of temporal scales. Learning associations between sensory stimuli and behaviorally relevant outcomes drives cortical plasticity and is fundamental to an organism’s survival. Chronic stress can also impact neural circuits although its contributions to sensory cortex connectivity and sensory encoding is unclear. Changes in information processing in the neocortex can take place at different spatial scales: in local microcircuits made up of heterogeneous excitatory and inhibitory cell types and in larger interconnected cortical networks. Rodent studies from the last decade have revealed an elaborate network of secondary visual areas that may be involved in visually-guided behaviors such as associating initially neutral visual stimuli with aversive events. However, the dynamic network connectivity of these secondary areas and their distinct contributions to learned, visually guided fear behavior is unknown. Fear-learning enhances the cortical representation of stimuli that predict a foot shock, but it is currently unknown if different inhibitory elements support these changes in visual stimulus representations. Using innovative imaging approaches this proposal will address 3 Aims: (1) Determine the changes in network dynamics and functional connectivity that accompany fear learning. The proposed experiments will investigate primary and secondary visual cortical contributions to learned fear behavior using simultaneous dual 2-photon/widefield imaging and cortical inactivation approaches. (2) Determine the microcircuits that contribute to fear-learning related changes in cortical responses. Using cell-type specific 2-photon imaging and optogenetics Dr. Moberly will test the hypothesis that VIP-mediated disinhibition enhances cortical output neuron responses. (3) Investigate the consequences of stress for functional sensory cortical network architecture and its relationship to ongoing behavioral state. Dr. Moberly will conduct this research in the labs of his mentors Drs. Jessica Cardin and Michael Higley at the Yale University School of Medicine with input from advisory committee members, Drs. Marina Picciotto and Michael Crair. In the K99 period, Dr. Moberly will learn new technical skills in cellular 2-photon and simultaneous dual 2-photon/widefield imaging in combination with optogenetics and quantitative behavioral approaches. The proposed experiments and multifaceted training plan will impart Dr. Moberly with a unique combination of skills that will position him to transition into a successful independent career as a systems neuroscientist.