Inhibitory Regulation of Neural Circuit Plasticity in Visual Cortex

项目摘要 这项拟议的工作解决了NEI大胆目标倡议强调的一个问题，该倡议认为 解决“：确定再生受损神经元的方法，并促进它们与正确的目标重新连接 在中枢神经系统中。在小鼠身上，挤压的视神经可以通过同时操作 生长控制通路和神经活动。然而，这些再生的视神经可能不会形成适当的 因为它们生长成萎缩的丘脑，其皮质的输入被削弱。因此， 功能性再生需要加强代表受损眼睛的丘脑皮质输入，以修复 建立视觉空间到大脑皮层回路的双目标测。在出生后早期也面临着类似的挑战 发育，当来自同侧眼的弱传入输入必须与皮层中的映射匹配时 已经被对侧的眼睛控制了。这项建议主要研究电路机制。 在初级视觉皮质中，成功再生和整合弱输入所必需的皮质，使用In-。 体内双光子显微镜观察警觉小鼠的钙活动和全细胞切片电生理，然后测试 在成年期诱发类似情况的有效性。总体假设是，划分为 树突状细胞活动促进新的输入大规模整合到初级视皮层。初步数据 提示胆碱能直接传入一类抑制性神经元，即规则峰电位、生长抑素- 随着关键期的结束，表达抑制树突的中间神经元丢失，导致这些神经元移位 从分区化的树枝状活动转向更同步的活动。生长抑素的化学发生调控 中间神经元将被用来促进成人皮质中树突状细胞的区域化，并测试这是否 增强再生能力。这些实验有望揭示新的机制，解释 结束视觉发展的关键时期降低了建立和加强 大脑皮层的突触连接。从长远来看，这一知识可能会促进纳入弱投入 在成年后受伤或疾病后的再生过程中找到合适的目标，这将实现 NEI的关键目标，并改进视力丧失的治疗选择。

Project Summary The proposed work addresses a problem highlighted by the NEI Audacious Goals Initiative as “essential to resolve”: identifying ways to regenerate damaged neurons and promote their reconnection to the correct targets in the central nervous system. In mice, a crushed optic nerve can be regenerated by concurrent manipulation of growth-control pathways and neural activity. Yet these regenerating optic nerves may not form appropriate connections because they grow into an atrophied thalamus whose inputs to cortex are weakened. Thus, functional regeneration requires strengthening of thalamocortical inputs representing the damaged eye to re- establish binocular mapping of visual space onto cortical circuits. Similar challenges are faced in early postnatal development, when a weak incoming input from the ipsilateral eye must match the mapping laid down in a cortex already dominated by the contralateral eye. This proposal examines the circuit mechanisms in primary visual cortex necessary for successful regeneration and integration of weak inputs in primary visual cortex, using in- vivo two-photon microscopy of calcium activity in alert mice and whole-cell slice electrophysiology, and then tests the effectiveness of inducing similar conditions in adulthood. The overall hypothesis is that compartmentalized dendritic activity promotes large-scale integration of new inputs into primary visual cortex. Preliminary data suggest that direct cholinergic input to one class of inhibitory neurons, the regular-spiking, somatostatin- expressing interneurons that inhibit dendrites, is lost as the critical period closes, leading these neurons to shift from compartmentalized dendritic activity to more synchronous activity. Chemogenetic control of somatostatin interneurons will be used to promote dendritic compartmentalization in adult cortex and to test whether this enhances regeneration. These experiments are expected to reveal new mechanisms that explain how the closure of a critical period in visual development reduces the capacity for establishment and strengthening of synaptic connections in cortex. In the long term, this knowledge is likely to promote incorporation of weak inputs onto their appropriate targets during regeneration after injury or disease in adulthood, which would achieve a key goal of the NEI and improve treatment options for vision loss.