Neuromodulators Shape the Retinal Code

Neuromodulators can alter neuronal activity despite fixed anatomical connectivity, thereby contributing to dynamic retinal computation. We found that dopamine, released from retinal interneurons and fluctuating across the day-night cycle, reshapes retinal ganglion cell (RGC) receptive fields in a type-specific way, suggesting that retinal processing varies with circadian rhythm. In addition, we showed that histamine from hypothalamic neurons modulates RGC activity, indicating that retinal processing changes with behavioural state due to elevated histamine levels during arousal.

**Hypothalamic neurons shape the retinal code via histamine release.** Histaminergic retinopetal axons originating from neurons in the hypothalamus enter the retina via the optic disk.

Dopamine has long been reported to strengthen the antagonistic surround of RGCs, sharpening receptive fields and enhancing spatial resolution. However, using multielectrode array (MEA) recordings, we found that dopamine can either enhance or suppress the surround, depending on RGC subtype. This includes transient-Off-α RGCs, where we applied targeted patch-clamp recordings and pharmacology to dissect the underlying mechanisms. We discovered that dopamine enhances the center response of these cells, but differentially modulates the two major pathways contributing to their surround — with effects that can even oppose each other. These findings reveal that dopamine influences RGC subtypes via distinct pathways, suggesting that RGC response properties are differentially tuned across the circadian cycle.

**Dopamine modulates RGCs surround responses.** Left: RGCs recorded on MEA are clustered by light responses, and effect of dopamine is examined. One subtype, the transient-Off-α RGC, is highlighted. Right: Peristimulus time histograms (PSTHs) show responses of transient-Off-α RGCs to a large dark spot stimulating both center and surround. Responses in control solution are on top, after dopamine blockade on bottom. Dopamine blockade reduces antagonistic surround, as the Off response increases. At the same time, an On response appears at stimulus offset (arrow), indicating enhanced surround activation.

Although the retina is often viewed as an autonomous processor of visual input, Ramón y Cajal noted over a century ago that it also receives input from the brain via retinopetal axons. We identified a projection from histaminergic neurons in the hypothalamus to the retina. Using two-photon Ca2+ imaging, MEA and patch-clamp recordings, we found that histamine modulates the activity of various RGCs, including direction selective cells. Specifically, histamine enhances the detection of high-speed motion, potentially improving vision when animals are moving rapidly, consistent with the known increase in histaminergic activity during arousal. These findings reveal a novel form of retinal dynamic computation: visual processing shaped not only by sensory input, but also by behavioral state.

**Histamine enhances responses of direction selective retinal ganglion cells to fast speed motion.** Polar plots of an example direction selective ganglion cell to moving gratings at different speeds (color coded), before (left) and after (right) histamine

Warwick, Heukamp et al., 2023, Dopamine differentially affects retinal circuits to shape the retinal code

Warwick, Riccitelli et al., 2024, Top-down modulation of the retinal code via histaminergic neurons of the hypothalamus