Inhibitory Regulation of Neural Circuit Plasticity in Visual Cortex

视觉皮层神经回路可塑性的抑制调节

基本信息

批准号：
10004651
负责人：
Joshua Trachtenberg
金额：
$ 40.98万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10004651
关键词：
Acetylcholine Address Adolescent Adult Affect Amblyopia Animal Model Apical Arousal Atrophic Blindness Brain Calcium Cataract Cells Characteristics Contralateral D Cells Data Dendrites Disease Electrophysiology (science)Eye Glaucoma Goals Growth Injury Interneurons Ipsilateral Knowledge Learning Maps Measures Mediating Mus Natural regeneration Nerve Degeneration Neuraxis Neurons Ocular Dominance Optic Nerve Parvalbumins Pathway interactions Property Pyramidal Cells Recovery Research Personnel Role Slice Somatostatin Synapses Synaptic plasticity Testing Thalamic structure Therapeutic Vasoactive Intestinal Peptide Vision Disorders Visual Visual Cortex Work area striata basal forebrain base cholinergic common treatment critical period effectiveness evaluation effectiveness testing experimental study hippocampal pyramidal neuron improved in vivo inhibitory neuron monocular deprivation nerve injury neural circuit neuronal cell body neuroregulation novel novel strategies postnatal development receptive field relating to nervous system response therapy outcome two photon microscopy vision development

项目摘要

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.

项目概要拟议的工作解决了 NEI 大胆目标倡议强调的一个问题，即“对于解决”：确定再生受损神经元并促进其与正确目标重新连接的方法在小鼠的中枢神经系统中，被压碎的视神经可以通过同时操作而再生。然而，这些再生的视神经可能无法形成适当的生长控制途径和神经活动。连接，因为它们长成萎缩的丘脑，其对皮质的输入被削弱。功能再生需要加强代表受损眼睛的丘脑皮质输入以重新建立视觉空间到皮质回路的双眼映射在产后早期也面临着类似的挑战。发育时，来自同侧眼睛的微弱传入输入必须与皮层中制定的映射相匹配该提案检查了初级视觉的电路机制。皮层是初级视觉皮层中成功再生和弱输入整合所必需的，使用in- 体内双光子显微镜观察警觉小鼠的钙活性和全细胞切片电生理学，然后进行测试总体假设是，在成年期诱发类似情况的有效性。树突活动促进新输入大规模整合到初级视觉皮层中。表明直接胆碱能输入一类抑制性神经元，即定期尖峰的生长抑素- 表达抑制树突的中间神经元随着关键期的结束而丢失，导致这些神经元发生转变从分隔的树突活性到生长抑素的化学遗传学控制。中间神经元将用于促进成人皮质中的树突区室化，并测试这是否这些实验有望揭示解释如何增强再生的新机制。视觉发展关键时期的结束会降低建立和加强视觉发展的能力从长远来看，这种知识可能会促进弱输入的整合。在成年期受伤或患病后的再生过程中，将其集中到适当的目标上，这将实现 NEI 的主要目标是改善视力丧失的治疗选择。