State-dependent modulation of retinothalamic axonal boutons

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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.