Functional Circuitry of Visual Adaptation

描述（由申请人提供）：我的长期目标是将视觉感知与潜在的神经回路和计算联系起来。我从这个问题开始：电路如何根据视觉场景的对比调整它们的属性？对比度适应对视觉很重要：在低对比度下，它增加了对小信号编码的灵敏度；而在高对比度下，它会降低灵敏度以防止响应饱和。我们知道这发生在很多层面，从视网膜到大脑皮层。但为了解决电路和细胞机制，我建议在哺乳动物视网膜上工作，在那里我们知道许多基本的细胞类型和电路，在那里视觉反应可以在细胞内被记录下来，在体外。在视网膜中，对比度适应在多个空间尺度上起作用。神经节细胞适应其外周感受野（距离树突野毫米）的时间对比，但也适应树突野的时间对比。在这两个区域，对比降低了兴奋性输入的增益并导致膜电位的移位，但外周对比导致超极化，而局部对比导致去极化。对比适应也在多个时间尺度上起作用。例如，突触增益的变化在高对比度时持续存在，而膜电位的变化则缓慢衰减。我们预计，对比适应涉及多种细胞机制，调整到不同的空间和时间属性的视觉输入。我们假设外周感受野对对比的适应是由轴突无突细胞（抑制性中间神经元）网络驱动的，该网络向神经节细胞发送信号超过mm，在那里它们打开Cl-和K+通道，使神经节细胞超极化并抑制突触前双极终端（Aim 1）。下一个主要问题是神经节细胞树突状场的局部对比是否通过双极细胞固有的突触前机制或神经节细胞的突触后机制引起适应。我们将使用几种方法来区分这些相互竞争的假设（目的2）。我们预测对尖峰反应的适应部分是通过神经节细胞的固有特性产生的，包括缓慢调制的K+电导和增加的尖峰阈值。我们预测神经节细胞去极化也通过刺激抑制神经节细胞的无突细胞（通过间隙连接）驱动反馈回路（Aim 3）。提出的研究解决了神经节细胞生理学的基本机制，这将进一步加深我们对人类健康和疾病视觉的理解。

DESCRIPTION (provided by applicant): My long-term goal is to relate visual perception to the underlying neuronal circuits and computations. I am starting with the question: how do circuits adjust their properties to the contrast of a visual scene? Contrast adaptation is important for vision: at low contrast, it increases sensitivity to encode small signals; whereas at high contrast, it decreases sensitivity to protect against response saturation. We know this occurs at many levels, from retina through cortex. But to address circuits and cellular mechanisms, I propose to work in mammalian retina, where we know many of the basic cell types and circuits and where visual responses can be recorded intracellularly, in vitro. In retina, contrast adaptation acts over multiple spatial scales. A ganglion cell adapts to temporal contrast over its peripheral receptive field (mm from its dendritic field) but also to contrast over its dendritic field. In either region, contrast reduces the gain of excitatory inputs and causes a shift in the membrane potential, but peripheral contrast causes hyperpolarization, whereas local contrast causes depolarization. Contrast adaptation also acts over multiple temporal scales. For example, changes in synaptic gain persist during high contrast, whereas shifts in the membrane potential slowly decay. We expect that contrast adaptation involves multiple cellular mechanisms, tuned to different spatial and temporal properties of the visual input. We hypothesize that adaptation to contrast in the peripheral receptive field is driven by a network of axon-bearing amacrine cells (inhibitory interneurons) that send signals over mm to ganglion cells, where they open Cl- and K+ channels to hyperpolarize the ganglion cell and inhibit the presynaptic bipolar terminal (Aim 1). The next major question is whether contrast local to the ganglion cell's dendritic field causes adaptation via either a presynaptic mechanism, intrinsic to bipolar cells, or a postsynaptic mechanism in ganglion cells. We will use several approaches to distinguish between these competing hypotheses (Aim 2). We predict that adaptation of spiking responses arises partly through ganglion cell intrinsic properties, including a slowly modulated K+ conductance and an increased spike threshold. We predict that ganglion cell depolarization also drives a feedback circuit by exciting amacrine cells (via gap junctions) that inhibit the ganglion cell (Aim 3). The proposed studies address fundamental mechanisms of ganglion cell physiology that would further our understanding of human vision in health and disease.