State-dependent modulation of retinothalamic axonal boutons

视网膜丘脑轴突布顿的状态依赖性调节

• 批准号: 10231288
• 负责人: Mark L Andermann
• 金额: $ 45.83万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10231288
• 关键词: Affect; Animals; Arousal; Attention; Axon; Behavior; Behavioral; Biology; Brain; Calcium; Cells; Code; Collaborations; Data; Dorsal; Environment; Eye; FOXP2 gene; Genetic; Geniculate body structure; Glutamates; Image; In Vitro; Location; Mediating; Motion; Mus; Nature; Neocortex; Neurons; Optic Nerve; Optic Nerve Injuries; Optic tract structure; Pattern; Perception; Pharmacology; Photometry; Play; Population; Presynaptic Terminals; Primates; Process; Resolution; Retina; Retinal Ganglion Cells; Role; Sensory; Serotonin; Serotonin Receptor 5-HT1B; Signal Transduction; Site; Stimulus; Stroke; Synapses; Testing; Thalamic structure; Visual; Visual Cortex; Visual Pathways; Work; awake; base; cell type; dorsal raphe nucleus; imaging modality; in vivo; luminance; nerve damage; nervous system disorder; neuroregulation; optic nerve regeneration; optogenetics; patch clamp; preference; presynaptic; receptive field; receptor; response; retinal axon; retinal prosthesis; sight restoration; transmission process; two-photon; visual information; visual processing; visual stimulus

Summary Perception does not depend on environment alone, but also on brain state. Work from our lab and others show that visual responses to certain features are selectively gated depending on an animal's arousal state. What are the circuit and synaptic bases for these state-dependent shifts in visual sensitivity? State- dependent modulation of sensory responses has been well-described in visual cortex. Studies have also identified behavioral modulation of responses neurons in the dorsolateral geniculate nucleus of the visual thalamus (dLGN) of mice and primates. Remarkably, in vitro studies from the Chen lab, employing calcium imaging and patch-clamp recordings, suggest substantial capacity for modulation of visual transmission even earlier in the visual pathway, at the level of retinal axonal inputs to thalamus. Recently, the Andermann lab developed methods for imaging thousands of retinal axonal boutons in thalamus of awake mice (Liang et al., Cell, 2018). We found that visual responses in retinothalamic boutons can be profoundly suppressed during arousal, in a manner dependent on the boutons' visual feature preferences for stimulus location, size, motion direction, and for luminance decreases/increases (Liang et al., Current Biology, in press). These results are strikingly similar to the Chen lab's earlier in vitro findings of suppression of retinal ganglion cell (RGC) axonal boutons by serotonin (5-HT). Notably, the Chen lab showed that the actions of 5-HT on RGC axons are likely mediated by the presynaptic 5-HT1B receptor (5-HT1BR), a key receptor mediating serotonin's actions on axon terminals throughout the brain. Preliminary data suggest that the 5-HT1BR is more strongly expressed in axons of genetically defined RGCs with larger receptive fields. Further, our preliminary in vivo studies show that dorsal raphe serotonergic neurons (i) are sensitive to behavioral state, (ii) send a dense and focal projection to the dLGN, and (iii) suppress visual responses in a similar subset of RGC axons that is suppressed by arousal. Based on these findings, the Chen and Andermann labs propose to test the hypothesis that serotonergic inputs to the dLGN differentially suppress specific visual information in an arousal state- dependent manner. In Aim 1, we will ask whether activity of serotonergic inputs in dLGN contribute to arousal modulation of visual responses in RGC axons. In Aim 2, we will ask whether serotonergic inputs to dLGN selectively gate specific channels of visual information. Finally, in Aim 3, we will ask whether serotonergic inputs to dLGN can rapidly modify the gain and/or visual tuning of dLGN neurons. Selective suppression of transmission at the level of retinal axons offers an efficient strategy to block non-salient retinal signals before they are amplified by thalamocortical loops. The bridging of expertise between the Chen and Andermann labs will establish a unified framework for understanding selective sensory processing across behavioral states at a surprisingly early and tractable stage of visual processing. Our studies suggest that neuromodulation of retinal axons should be considered when developing strategies for restoring vision following optic nerve damage.

概括 感知不仅仅取决于环境，还取决于大脑状态。我们实验室和其他实验室的工作表明 根据动物的唤醒状态选择性地控制对某些特征的视觉反应。什么 这些视觉敏感性状态依赖性变化的电路和突触基础是什么？状态- 感觉反应的依赖性调节已在视觉皮层中得到很好的描述。研究还 确定了视觉背外侧膝状核中反应神经元的行为调节 小鼠和灵长类动物的丘脑（dLGN）。值得注意的是，陈实验室的体外研究采用钙 成像和膜片钳记录表明，即使在视觉传输调制方面也具有巨大的能力 在视觉通路的早期，在丘脑的视网膜轴突输入水平。最近，安德曼实验室 开发了对清醒小鼠丘脑中数千个视网膜轴突纽扣进行成像的方法（Liang 等人， 细胞，2018）。我们发现，视网膜丘脑的视觉反应在 唤醒，在某种程度上取决于按钮对刺激位置、大小、运动的视觉特征偏好 方向，以及亮度减少/增加（Liang 等人，Current Biology，出版中）。这些结果是 与 Chen 实验室早期抑制视网膜神经节细胞 (RGC) 轴突的体外研究结果惊人地相似 5-羟色胺 (5-HT) 的 boutons。值得注意的是，Chen 实验室表明 5-HT 对 RGC 轴突的作用可能是 由突触前 5-HT1B 受体 (5-HT1BR) 介导，5-HT1B 是介导血清素作用的关键受体 整个大脑的轴突末端。初步数据表明 5-HT1BR 在 具有较大感受野的基因定义的 RGC 轴突。此外，我们的初步体内研究表明 中缝背侧血清素能神经元 (i) 对行为状态敏感，(ii) 发送密集且集中的信号 投射到 dLGN，并且 (iii) 抑制 RGC 轴突的类似子集中的视觉反应，即 被唤醒所抑制。基于这些发现，陈和安德曼实验室提议检验这一假设 dLGN 的血清素输入会差异性地抑制唤醒状态下的特定视觉信息 依赖方式。在目标 1 中，我们将询问 dLGN 中的血清素输入活性是否有助于唤醒 RGC 轴突视觉反应的调节。在目标 2 中，我们将询问 dLGN 是否有血清素输入 有选择地控制视觉信息的特定通道。最后，在目标 3 中，我们会问是否血清素能 dLGN 的输入可以快速修改 dLGN 神经元的增益和/或视觉调节。选择性抑制 视网膜轴突水平的传输提供了一种有效的策略，可以在之前阻断不显着的视网膜信号 它们被丘脑皮质环放大。 Chen 和 Andermann 实验室之间的专业知识桥梁 将建立一个统一的框架来理解跨行为状态的选择性感觉处理 令人惊讶的是，视觉处理处于早期且易于处理的阶段。我们的研究表明视网膜的神经调节 在制定视神经损伤后恢复视力的策略时应考虑轴突。