Inhibitory Regulation of Neural Circuit Plasticity in Visual Cortex

项目摘要 拟议的工作解决了NEI大胆目标倡议强调的一个问题， 解决”：确定再生受损神经元并促进其重新连接到正确目标的方法 在中枢神经系统中。在小鼠中，可以通过同时操作 生长控制途径和神经活动。然而，这些再生的视神经可能无法形成适当的 因为它们生长成萎缩的丘脑，丘脑对皮层的输入减弱。因此，在本发明中， 功能性再生需要加强代表受损眼睛的丘脑皮质输入， 建立视觉空间到皮层回路的双眼映射。产后早期也面临类似的挑战。 当来自同侧眼睛的微弱输入必须与皮层中的映射相匹配时， 已经被对侧眼控制了本研究旨在探讨初级视觉系统的电路机制， 皮质必要的成功再生和整合弱输入在初级视觉皮层，使用在- 活体双光子显微镜检查alert小鼠的钙活性和全细胞切片电生理，然后进行测试 在成年期诱导类似条件的有效性。总的假设是， 树突活动促进新输入到初级视觉皮层的大规模整合。初步数据 表明胆碱能直接输入到一类抑制性神经元，即有规律尖峰，生长抑素- 表达抑制树突的中间神经元，随着关键期的结束而丢失，导致这些神经元转移 从区室化的树突活动到更同步的活动。生长抑素的化学发生调控 interneurons将用于促进成年皮层中的树突区室化，并测试这是否 增强再生能力。预计这些实验将揭示新的机制，解释如何 视觉发展的关键时期的结束降低了建立和加强 皮层的突触连接从长远来看，这种知识可能会促进弱投入的整合 在成年期受伤或疾病后的再生过程中，将其适当的目标，这将实现 NEI的关键目标，并改善视力丧失的治疗方案。

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.