State-dependent modulation of retinothalamic axonal boutons

总结 感知不仅取决于环境，还取决于大脑状态。我们实验室和其他人的工作表明， 对某些特征的视觉反应是根据动物的唤醒状态选择性地进行门控的。什么 是这些视敏度状态依赖性变化的回路和突触基础吗？说明─ 感觉反应的依赖性调节在视觉皮层中已有很好的描述。研究也 确定了视觉背外侧膝状体核中反应神经元的行为调制 丘脑（dLGN）的小鼠和灵长类。值得注意的是，来自陈实验室的体外研究，使用钙 成像和膜片钳记录，表明调节视觉传输的实质性能力， 在视觉通路的早期，在视网膜轴突输入丘脑的水平。最近，Andermann实验室 开发了对清醒小鼠丘脑中的数千个视网膜轴突终扣进行成像的方法（Liang等人， Cell，2018）。我们发现，在视网膜丘脑终扣的视觉反应，可以深刻的抑制， 唤醒，以依赖于钮扣对刺激位置、大小、运动的视觉特征偏好的方式 方向，以及亮度降低/增加（Liang等人，《当代生物学》，出版中）。这些结果 这与Chen实验室早期在体外发现的视网膜神经节细胞（RGC）轴突抑制惊人相似， 5-羟色胺（5-HT）。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-HT 1B受体（5-HT 1BR）介导，5-HT 1BR是介导5-羟色胺作用的关键受体， 轴突末梢遍布大脑。初步数据表明，5-HT 1BR的表达更强烈， 具有较大感受野的遗传定义的RGC的轴突。此外，我们初步的体内研究表明， 中缝背核神经元（i）对行为状态敏感，（ii）发送密集和局灶性的 投射到dLGN，和（iii）抑制RGC轴突的类似子集中的视觉反应， 被性唤起所抑制基于这些发现，Chen和Andermann实验室提议检验这一假设 在唤醒状态下，dLGN的多巴胺能输入会不同程度地抑制特定的视觉信息- 依赖的方式。在目的1中，我们将询问dLGN中的多巴胺能输入活动是否有助于唤醒 调节RGC轴突的视觉反应。在目标2中，我们将询问dLGN的多巴胺能输入是否 选择性地控制视觉信息的特定通道。最后，在目标3中，我们将询问是否具有促肾上腺素能。 dLGN的输入可以快速修改dLGN神经元的增益和/或视觉调谐。选择性抑制 在视网膜轴突水平的传输提供了一种有效的策略，以阻止非显着的视网膜信号之前， 它们被丘脑皮层回路放大。Chen和Andermann实验室之间的专业桥梁 将建立一个统一的框架，以理解跨行为状态的选择性感觉处理， 令人惊讶的早期和易处理的视觉处理阶段。我们的研究表明，视网膜神经调节 在制定视神经损伤后恢复视力的策略时，应考虑轴突。

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.