State-dependent modulation of retinothalamic axonal boutons

摘要 知觉不仅取决于环境，还取决于大脑状态。我们实验室和其他人的研究表明 根据动物的唤醒状态，对某些特征的视觉反应是有选择的门控。什么 这些视觉敏感度的状态依赖变化是回路和突触的基础吗？国家-- 感觉反应的依赖调节在视觉皮质中已经得到了很好的描述。研究还表明， 视觉膝状体背外侧核反应神经元的行为调制 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使用了钙 成像和膜片钳记录表明，即使是对视觉传输的调制也具有相当大的容量 在视觉通路的早期，在视网膜轴突输入丘脑的水平。最近，安德曼实验室 发展了对清醒小鼠丘脑中数以千计的视网膜轴突进行成像的方法(梁等， 细胞，2018年)。我们发现，视网膜丘脑的视觉反应在 唤醒，以一种依赖于刺激位置、大小、运动的视觉特征偏好的方式 方向，以及亮度降低/增加(梁等人，当代生物学，在印刷中)。这些结果是 与Chen实验室早期的视网膜神经节细胞(RGC)轴突抑制的体外研究结果惊人地相似 5-羟色胺(5-羟色胺)。值得注意的是，陈的实验室表明，5-羟色胺对RGC轴突的作用很可能 由突触前5-HT1B受体(5-HT1BR)介导，5-HT1BR是5-羟色胺作用的关键受体 轴突终末贯穿整个大脑。初步数据显示，5-HT1BR在 具有较大感受野的基因定义的视网膜节细胞的轴突。此外，我们的初步活体研究表明 中缝背侧5-羟色胺能神经元(I)对行为状态敏感，(II)发出密集的局灶性 投射到dLGN，以及(Iii)抑制RGC轴突的类似子集的视觉反应，即 被唤醒压抑的。基于这些发现，陈和安德曼实验室建议检验这一假说 对dLGN的5-羟色胺能输入在觉醒状态下不同地抑制特定的视觉信息- 依赖的态度。在目标1中，我们将询问dlgn内5-羟色胺能输入的活动是否有助于觉醒。 RGC轴突视觉反应的调制。在目标2中，我们将询问dLGN的5-羟色胺能传入 选择性地控制特定的视觉信息通道。最后，在目标3中，我们将询问5-羟色胺能 对dLGN的输入可以迅速改变dLGN神经元的增益和/或视觉调谐。选择性地抑制 在视网膜轴突水平上的传输提供了一种有效的策略来阻止不明显的视网膜信号 它们被丘脑皮质环放大。陈和安德曼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的早期和易驯服的阶段。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。

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.