Inhibitory circuitry mechanisms underlying visual cortical development and plasti

描述（由申请人提供）：视觉皮质神经元的各种功能特性，通常通过它们的输出反应来衡量，经历渐进式发育成熟，这一过程在关键时期（CP）可能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引起的神经元反应的功能变化可归因于皮质突触回路的变化，其性质在很大程度上仍是未知的。这主要是由于缺乏刺激诱发的兴奋性和抑制性突触输入到发育中的视觉皮层神经元的测量，技术仍然非常具有挑战性。在这个项目中，我们将探索利用最先进的全细胞电压钳记录和双光子成像引导的补丁记录在不同发育阶段的年轻小鼠中探测发育皮层功能突触回路的可能性。我们将重点研究初级视觉皮层（V1）第4层的定向选择性（OS）和眼优势（OD）特性。在Aim1中，我们将通过记录不同发育阶段的峰值反应来确定OS的发展进程。然后，我们将进行电压钳记录，以确定在OS发生显著锐化的阶段中OS的兴奋性和抑制性输入。我们将检验OS的发育锐化主要归因于抑制性调谐的扩大，而不是兴奋性调谐的锐化或兴奋/抑制（E/I）比的降低的假设。我们还将从基因标记的抑制神经元亚型中进行记录，以验证抑制调谐的扩大可归因于特定抑制神经元的OS减弱的假设。在ai2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眼睛特异性兴奋性和抑制性兴奋性神经元的输入。我们将确定md诱导的视线从被剥夺的眼睛转移主要是由于突触兴奋的减弱还是由该眼睛驱动的突触抑制的加强。最后，我们将研究特定的抑制性神经元如何改变其OD以响应MD。这条研究路线将极大地增强我们对正常皮层功能发育以及视觉剥夺诱导的可塑性背后的突触回路机制的理解。

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.