Inhibitory circuitry mechanisms underlying visual cortical development and plasti

视觉皮层发育和塑性的抑制电路机制

• 批准号: 8285561
• 负责人: Huizhong Whit Tao
• 金额: $ 24.58万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8285561
• 关键词: Address; Adult; Affect; Age; Amblyopia; Cells; Development; Disease; Equilibrium; Eye; Fluorescence; Image; Label; Laboratories; Lead; Measurement; Measures; Modification; Mus; Nature; Neurons; Ocular Dominance; Output; Process; Property; Proteins; Relative (related person); Reporting; Research; Sensory; Staging; Stimulus; Synapses; Techniques; Testing; Transgenic Mice; Ursidae Family; Visual; Visual Cortex; Visual evoked cortical potential; Work; area striata; critical period; excitatory neuron; experience; in vivo; inhibitory neuron; monocular deprivation; neural circuit; orientation selectivity; research study; response; sensory cortex; synaptic inhibition; two-photon; visual deprivation; voltage clamp

DESCRIPTION (provided by applicant): Various functional properties of visual cortical neurons, as usually measured by their output responses, undergo progressive developmental maturations, the process of which can be susceptible to experience-dependent modifications during a critical period (CP). The functional changes of neuronal responses during development or induced by specific sensory experience can be attributed to changes in cortical synaptic circuitry, the nature of which has remained largely unknown. This is mainly due to a lack of measurements of stimulus-evoked excitatory and inhibitory synaptic inputs to neurons in the developing visual cortex, techniques for which remain very challenging. In this project, we will explore the possibility of probing into the functional synaptic circuits of the developing cortex b applying the-state-of-the-art in vivo whole-cell voltage-clamp recording and two-photon imaging guided patch-recording in young mice at various developmental stages. We will focus on orientation selectivity (OS) and ocular dominance (OD) properties in layer 4 of the primary visual cortex (V1). In Aim1, we will determine the progression of OS development by recording spike responses at different developmental stages. We will then carry out voltage-clamp recordings to determine excitatory and inhibitory inputs underlying OS during stages when significant sharpening of OS occurs. We will test the hypothesis that the developmental sharpening of OS can be mainly attributed to a broadening of inhibitory tuning, rather than a sharpening of excitatory tuning or a decrease in excitation/inhibition (E/I) ratio. We will also record from genetically labeled inhibitory neuron subtypes to test the hypothesis that the broadening of inhibitory tuning can be attributed to a weakening of OS of specific inhibitory neurons. In Aim2, we will compare eye-specific excitatory and inhibitory inputs to excitatory neurons between mice experiencing monocular deprivation (MD) during the CP and age-matched control mice. We will determine whether the MD-induced OD shift away from the deprived eye is mainly attributed to a weakening of synaptic excitation or a strengthening of synaptic inhibition driven by that eye. Finally, we will examine how specific inhibitory neurons shift their OD in response to MD. This line of research will greatly enhance our understanding of synaptic circuitry mechanisms underlying the normal cortical functional development as well as the plasticity induced by visual deprivation. PUBLIC HEALTH RELEVANCE: This project investigates the excitatory and inhibitory circuit mechanisms underlying normal development of visual cortical functions as well as cortical plasticity after abnormal visual experience such as monocular deprivation. Understanding how the organization of synaptic circuits changes during development is necessary to identify mechanisms that go awry in developmental diseases. The work proposed here bears directly on a key theme in research on amblyopia, the examination of how abnormal visual experience leads to changes in cortical circuits.

描述（由申请人提供）：视觉皮层神经元的各种功能特性（通常通过其输出反应测量）经历渐进性发育成熟，其过程可能在关键期（CP）期间容易受到经验依赖性修改的影响。在发育过程中或由特定感觉经验诱导的神经元反应的功能变化可以归因于皮质突触回路的变化，其性质在很大程度上仍然未知。这主要是由于缺乏对发育中的视觉皮层神经元的刺激诱发的兴奋性和抑制性突触输入的测量，这方面的技术仍然非常具有挑战性。在本研究中，我们将探索应用最先进的在体全细胞电压钳记录和双光子成像引导的膜片钳记录技术在不同发育阶段的幼龄小鼠中探索发育皮层B功能突触回路的可能性。我们将重点关注初级视觉皮质（V1）第4层中的方向选择性（OS）和眼优势（OD）特性。在Aim 1中，我们将通过记录不同发育阶段的峰电位反应来确定OS发育的进展。然后，我们将进行电压钳记录，以确定兴奋性和抑制性输入的基础OS在阶段时，OS显着锐化发生。我们将测试的假设，发展锐化OS可以主要归因于抑制调谐的扩大，而不是锐化兴奋调谐或兴奋/抑制（E/I）比的下降。我们还将从基因标记的抑制性神经元亚型中记录以检验抑制性调谐的扩大可以归因于特定抑制性神经元的OS的减弱的假设。在Aim 2中，我们将比较在CP期间经历单眼剥夺（MD）的小鼠和年龄匹配的对照小鼠之间的眼睛特异性兴奋性和抑制性输入到兴奋性神经元。我们将确定MD诱导的OD偏移远离剥夺眼是否主要归因于该眼驱动的突触兴奋的减弱或突触抑制的加强。最后，我们将研究特定的抑制神经元如何改变其OD响应MD。这一系列的研究将大大提高我们对正常皮层功能发育的突触回路机制以及视觉剥夺诱导的可塑性的理解。 公共卫生相关性：本研究旨在探讨视觉皮层功能正常发育的兴奋性和抑制性回路机制，以及异常视觉体验（如单眼剥夺）后的皮层可塑性。了解突触回路的组织在发育过程中如何变化，对于确定发育性疾病中出错的机制是必要的。这里提出的工作直接关系到弱视研究的一个关键主题，即检查异常的视觉体验如何导致皮层回路的变化。