The pore-forming subunit of the cardiac sodium channel, Na v1.5, has been previously found to be mutated in genetically determined arrhythmias. Na v1.5 associates with many proteins that regulate its function and cellular localisation. In order to identify more in situ Na v1.5 interacting proteins, genetically-modified mice with a high-affinity epitope in the sequence of Na v1.5 can be generated.

The retinal output is the sole source of visual information for the brain. Studies in non-primate mammals estimate that this information is carried by several dozens of retinal ganglion cell types, each informing the brain about different aspects of a visual scene. Even though morphological studies of primate retina suggest a similar diversity of ganglion cell types, research has focused on the function of only a few cell types. In human retina, recordings from individual cells are anecdotal or focus on a small subset of identified types. Here, we present the first systematic ex-vivo recording of light responses from 342 ganglion cells in human retinas obtained from donors. We find a great variety in the human retinal output in terms of preferences for positive or negative contrast, spatio-temporal frequency encoding, contrast sensitivity, and speed tuning. Some human ganglion cells showed similar response behavior as known cell types in other primate retinas, while we also recorded light responses that have not been described previously. This first extensive description of the human retinal output should facilitate interpretation of primate data and comparison to other mammalian species, and it lays the basis for the use of ex-vivo human retina for in-vitro analysis of novel treatment approaches.

The physiological aging process of the retina is accompanied by various and sometimes extensive changes: Macular degeneration, retinopathies and glaucoma are the most common findings in the elderly and can potentially lead to irreversible visual disablements up to blindness. To study the aging process and to identify possible therapeutic targets to counteract these diseases, the use of appropriate animal models is mandatory. Besides the most commonly used rodent species, a non-human primate, the common marmoset (Callithrix jacchus) emerged as a promising animal model of human aging over the last years. However, the visual aging process in this species is only partially characterized, especially with regard to retinal aberrations. Therefore, we assessed here for the first time potential changes in retinal morphology of the common marmoset of different age groups. By cell type specific immunolabeling, we analyzed different cell types and distributions, potential photoreceptor and ganglion cell loss, and structural reorganization. We detected no signs of age-related differences in staining patterns or densities of various cell populations. For example, there were no signs of photoreceptor degeneration, and there was only minimal sprouting of rod bipolar cells in aged retinas. Altogether, we describe here the maintenance of a stable neuronal architecture, distribution and number of different cell populations with only mild aberrations during the aging process in the common marmoset retina. These findings are in stark contrast to previously reported findings in rodent species and humans and deserve further investigations to identify the underlying mechanisms and possible therapeutic targets.

Behavioral flexibility requires directing feedforward sensory information to appropriate targets. In the superior colliculus, divergent outputs orchestrate different responses to visual threats, but the circuit organization enabling the flexible routing of sensory information remains unknown. To determine this structure, we focused on inhibitory projection (Gad2) neurons. Trans-synaptic tracing and neuronal recordings revealed that Gad2 neurons projecting to the lateral geniculate nucleus (LGN) and the parabigeminal nucleus (PBG) form two separate populations, each receiving a different set of non-retinal inputs. Inhibiting the LGN- or PBG-projecting Gad2 neurons resulted in opposing effects on behavior; increasing freezing or escape probability to visual looming, respectively. Optogenetic activation of selected inputs to the LGN- and PBG-projecting Gad2 cells predictably regulated responses to visual threat. These data suggest that projection-specific sampling of brain-wide inputs provides a circuit design principle that enables visual inputs to be selectively routed to produce context-specific behavior.

Using sensory information to trigger different behaviors relies on circuits that pass through brain regions. The rules by which parallel inputs are routed to downstream targets are poorly understood. The superior colliculus mediates a set of innate behaviors, receiving input from >30 retinal ganglion cell types and projecting to behaviorally important targets including the pulvinar and parabigeminal nucleus. Combining transsynaptic circuit tracing with in vivo and ex vivo electrophysiological recordings, we observed a projection-specific logic where each collicular output pathway sampled a distinct set of retinal inputs. Neurons projecting to the pulvinar or the parabigeminal nucleus showed strongly biased sampling from four cell types each, while six others innervated both pathways. The visual response properties of retinal ganglion cells correlated well with those of their disynaptic targets. These findings open the possibility that projection-specific sampling of retinal inputs forms a basis for the selective triggering of behaviors by the superior colliculus.

The collective activity pattern of retinal ganglion cells, the retinal code, underlies higher visual processing. How does the ambient illuminance of the visual scene influence this retinal output? We recorded from isolated mouse and pig retina and from mouse dorsal lateral geniculate nucleus in vivo at up to seven ambient light levels covering the scotopic to photopic regimes. Across each luminance transition, most ganglion cells exhibited qualitative response changes, whereas they maintained stable responses within each luminance. We commonly observed the appearance and disappearance of ON responses in OFF cells and vice versa. Such qualitative response changes occurred for a variety of stimuli, including full-field and localized contrast steps and naturalistic movies. Our results suggest that the retinal code is not fixed but varies with every change of ambient luminance. This finding raises questions about signal processing within the retina and has implications for visual processing in higher brain areas.

Rod and cone photoreceptors support vision across large light intensity ranges. Rods, active under dim illumination, are thought to saturate at higher (photopic) irradiances. The extent of rod saturation is not well defined; some studies report rod activity well into the photopic range. Using electrophysiological recordings from retina and dorsal lateral geniculate nucleus of cone-deficient and visually intact mice, we describe stimulus and physiological factors that influence photopic rod-driven responses. We find that rod contrast sensitivity is initially strongly reduced at high irradiances, but progressively recovers to allow responses to moderate contrast stimuli. Surprisingly, rods recover faster at higher light levels. A model of rod phototransduction suggests that phototransduction gain adjustments and bleaching adaptation underlie rod recovery. Consistently, exogenous chromophore reduces rod responses at bright background. Thus, bleaching adaptation renders mouse rods responsive to modest contrast at any irradiance. Paradoxically, raising irradiance across the photopic range increases the robustness of rod responses.

Neuronal cell types are arranged in brain-wide circuits that guide behavior. In mice, the superior colliculus innervates a set of targets that direct orienting and defensive actions. We combined functional ultrasound imaging (fUSI) with optogenetics to reveal the network of brain regions functionally activated by four collicular cell types. Stimulating each neuronal group triggered different behaviors and activated distinct sets of brain nuclei. This included regions not previously thought to mediate defensive behaviors, for example, the posterior paralaminar nuclei of the thalamus (PPnT), which we show to play a role in suppressing habituation. Neuronal recordings with Neuropixels probes show that (1) patterns of spiking activity and fUSI signals correlate well in space and (2) neurons in downstream nuclei preferentially respond to innately threatening visual stimuli. This work provides insight into the functional organization of the networks governing innate behaviors and demonstrates an experimental approach to explore the whole-brain neuronal activity downstream of targeted cell types.

Evading imminent predator threat is critical for survival. Effective defensive strategies can vary, even between closely related species. However, the neural basis of such species-specific behaviours is still poorly understood. Here we find that two sister species of deer mice (genus Peromyscus) show different responses to the same looming stimulus: P. maniculatus, which occupy densely vegetated habitats, predominantly dart to escape, while the open field specialist, P. polionotus, pause their movement. This difference arises from species-specific escape thresholds, is largely context-independent, and can be triggered by both visual and auditory threat stimuli. Using immunohistochemistry and electrophysiological recordings, we find that although visual threat activates the superior colliculus in both species, the role of the dorsal periaqueductal gray (dPAG) in driving behaviour differs. While dPAG activity scales with running speed and involves both excitatory and inhibitory neurons in P. maniculatus, the dPAG is largely silent in P. polionotus, even when darting is triggered. Moreover, optogenetic activation of excitatory dPAG neurons reliably elicits darting behaviour in P. maniculatus but not P. polionotus. Together, we trace the evolution of species-specific escape thresholds to a central circuit node, downstream of peripheral sensory neurons, localizing an ecologically relevant behavioural difference to a specific region of the complex mammalian brain.