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: 10621870
• 负责人: Mark L Andermann
• 金额: $ 43.95万
• 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/10621870
• 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; Laboratory Finding; Location; Mediating; Motion; Mus; Nature; Neocortex; Neurons; Optic Nerve; Optic Nerve Injuries; Optic tract structure; Pattern; Perception; 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; genetic manipulation; imaging modality; in vivo; luminance; neocortical; nerve damage; nervous system disorder; neuroregulation; optic nerve regeneration; optogenetics; patch clamp; pharmacologic; 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 感知不仅取决于环境，而且还取决于大脑状态。从我们的实验室和其他节目中的工作 根据动物的唤醒状态，对某些特征的视觉响应有选择性地封闭。什么 视觉灵敏度中这些状态依赖性变化的电路和突触底座是吗？状态- 感觉反应的依赖调制已在视觉皮层中很好地描述。研究也有 鉴定出反应神经元在视觉的背外侧核核中的行为调节 小鼠和灵长类动物的丘脑（DLGN）。值得注意的是，使用钙的陈实验室的体外研究 成像和贴片钳记录，提出了重大调制视觉传输的能力 在视觉途径的早期，在视网膜轴突输入的水平上。最近，安德曼实验室 开发了在清醒小鼠的丘脑中成像数千个视网膜轴突式胸子的方法（Liang等， Cell，2018）。我们发现，视网膜丘脑胸子中的视觉反应可以被深深地抑制 唤醒，以boutons的刺激位置，大小，运动的视觉特征偏好的方式取决于 方向和亮度降低/增加（Liang等人，当前的生物学，印刷中）。这些结果是 与陈实验室早期抑制视网膜神经节细胞（RGC）轴突的体外发现非常相似 5-羟色胺（5-HT）的胸部。值得注意的是，陈实验室表明5-HT对RGC轴突的作用可能是 由突触前5-HT1B受体（5-HT1BR）介导的介导的关键受体介导5-羟色胺对作用对5-羟色胺的作用 整个大脑的轴突终端。初步数据表明，5-HT1BR在 具有较大接收场的遗传定义的RGC的轴突。此外，我们的初步体内研究表明 背侧raphe血清素能神经元（i）对行为状态敏感，（ii）发送一个致密和焦点 对DLGN的投影，（iii）在类似的RGC轴突中抑制视觉响应 被唤醒抑制。基于这些发现，陈和安德曼实验室提议检验假设 DLGN的血清素能输入在唤醒状态下差异抑制了特定的视觉信息 依赖方式。在AIM 1中，我们将询问DLGN中血清素能输入的活动是否有助于唤醒 RGC轴突中视觉响应的调节。在AIM 2中，我们将询问血清素能输入到DLGN 有选择性的视觉信息特定渠道。最后，在AIM 3中，我们将询问血清素能是否能 DLGN的输入可以快速修改DLGN神经元的增益和/或视觉调整。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，以阻止非偏好视网膜信号 它们被丘脑皮层环扩增。陈和安德曼实验室之间的专业知识的桥接 将建立一个统一的框架，以理解跨行为状态的选择性感官处理 令人惊讶的是，视觉处理的早期且可进行的阶段。我们的研究表明，视网膜神经调节 在开发恢复视力神经损伤后恢复视力的策略时，应考虑轴突。