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Vision plays a crucial role in instructing the brain’s spatial navigation systems. However, little is known about how vision loss affects the neuronal encoding of spatial information. Here, recording from head direction (HD) cells in the anterior dorsal nucleus of the thalamus in mice, we find stable and robust HD tuning in rd1 mice, a model of photoreceptor degeneration, that go blind by approximately one month of age. In contrast, placing sighted animals in darkness significantly impairs HD cell tuning. We find that blind mice use olfactory cues to maintain stable HD tuning and that prior visual experience leads to refined HD cell tuning in blind rd1 adult mice compared to congenitally blind animals. Finally, in the absence of both visual and olfactory cues, the HD attractor network remains intact but the preferred firing direction of HD cells drifts over time. These findings demonstrate flexibility in how the brain uses diverse sensory information to generate a stable directional representation of space. Vision plays an important role in the head direction cell system in animals. Here the authors recorded from head direction cells in rd1 mice that show retinal degeneration at 1 month, and find that they use smell cues to maintain stable HD tuning.

Stereo olfaction, the difference in odor concentration between the two nostrils, has been shown to affect a variety of animal behaviors, including olfactory search. However, it is unknown whether stereo olfaction can enable the formation of allocentric spatial representations. Here, recording from head direction (HD) cells in the anterior dorsal nucleus of the thalamus in blind mice—a model system for studying olfaction-dependent allocentric spatial representations—we find that inhibiting stereo olfaction, by blocking olfactory processing in one nostril or merging the airflow going to both nostrils, drastically impairs head direction coding. To assess the behavioral impact of impaired HD cell tuning caused by loss of stereo olfaction, we developed a closed-loop head direction preference assay, in which a mouse received medial forebrain bundle reward stimulation upon orientating its head in a specific direction. We find that inhibiting stereo olfaction significantly impairs performance in the HD preference assay. These results reveal that stereo olfaction is required for mice to use smell to form a stable allocentric spatial representation of head direction. Stereo olfaction involves comparing odor differences between the two nostrils. Here, using neuronal recordings and a behavioral test, the authors demonstrate that blind mice use stereo olfaction to form a stable spatial representation of head direction.

Individual cortical neurons can selectively respond to specific environmental features, such as visual motion or faces. How this relates to the selectivity of the presynaptic network across cortical layers remains unclear. We used single-cell–initiated, monosynaptically restricted retrograde transsynaptic tracing with rabies viruses expressing GCaMP6s to image, in vivo, the visual motion–evoked activity of individual layer 2/3 pyramidal neurons and their presynaptic networks across layers in mouse primary visual cortex. Neurons within each layer exhibited similar motion direction preferences, forming layer-specific functional modules. In one-third of the networks, the layer modules were locked to the direction preference of the postsynaptic neuron, whereas for other networks the direction preference varied by layer. Thus, there exist feature-locked and feature-variant cortical networks.

Sensory deafferentation resulting from the loss of photoreceptors during retinal degeneration (rd) is often accompanied by a paradoxical increase in spontaneous activity throughout the visual system. Oscillatory discharges are apparent in retinal ganglion cells in several rodent models of rd, indicating that spontaneous activity can originate in the retina. Understanding the biophysical mechanisms underlying spontaneous retinal activity is interesting for two main reasons. First, it could lead to strategies that reduce spontaneous retinal activity, which could improve the performance of vision restoration strategies that aim to stimulate remnant retinal circuits in blind patients. Second, studying emergent network activity could offer general insights into how sensory systems remodel upon deafferentation. Here we provide an overview of the work describing spontaneous activity in the degenerating retina, and outline the current state of knowledge regarding the cellular and biophysical properties underlying spontaneous neural activity.

In this study, the authors show that velocity-dependent lag normalization in the retina is accomplished via a subset of adjacent directionally selective ganglion cells that are electrically coupled, allowing each activated cell to prime its neighbor. Moving objects can cover large distances while they are processed by the eye, usually resulting in a spatially lagged retinal response. We identified a network of electrically coupled motion–coding neurons in mouse retina that act collectively to register the leading edges of moving objects at a nearly constant spatial location, regardless of their velocity. These results reveal a previously unknown neurophysiological substrate for lag normalization in the visual system.

Fine-scale synchrony of neural activity determines the nature of neural coding, but its underlying mechanisms are unclear. Here the authors find that coincident electrical and chemical synaptic inputs are nonlinearly integrated in overlapping retinal ganglion cell dendrites to produce synchronous spiking. Throughout the CNS, gap junction–mediated electrical signals synchronize neural activity on millisecond timescales via cooperative interactions with chemical synapses. However, gap junction–mediated synchrony has rarely been studied in the context of varying spatiotemporal patterns of electrical and chemical synaptic activity. Thus, the mechanism underlying fine-scale synchrony and its relationship to neural coding remain unclear. We examined spike synchrony in pairs of genetically identified, electrically coupled ganglion cells in mouse retina. We found that coincident electrical and chemical synaptic inputs, but not electrical inputs alone, elicited synchronized dendritic spikes in subregions of coupled dendritic trees. The resulting nonlinear integration produced fine-scale synchrony in the cells' spike output, specifically for light stimuli driving input to the regions of dendritic overlap. In addition, the strength of synchrony varied inversely with spike rate. Together, these features may allow synchronized activity to encode information about the spatial distribution of light that is ambiguous on the basis of spike rate alone.

In vertebrate vision, the two types of photoreceptors, rods and cones, operate under low and bright light intensities, respectively. Here the authors show that under bright light conditions, when rods are not sensing light, they act as relay cells for cone-driven surround inhibition. Vertebrate vision relies on two types of photoreceptors, rods and cones, which signal increments in light intensity with graded hyperpolarizations. Rods operate in the lower range of light intensities while cones operate at brighter intensities. The receptive fields of both photoreceptors exhibit antagonistic center-surround organization. Here we show that at bright light levels, mouse rods act as relay cells for cone-driven horizontal cell–mediated surround inhibition. In response to large, bright stimuli that activate their surrounds, rods depolarize. Rod depolarization increases with stimulus size, and its action spectrum matches that of cones. Rod responses at high light levels are abolished in mice with nonfunctional cones and when horizontal cells are reversibly inactivated. Rod depolarization is conveyed to the inner retina via postsynaptic circuit elements, namely the rod bipolar cells. Our results show that the retinal circuitry repurposes rods, when they are not directly sensing light, to relay cone-driven surround inhibition.

The authors monitored neuronal activity in mouse visual cortex during visual-motion stimulation and perturbed retinal direction selectivity. After perturbation, the proportion of posterior-motion-preferring cortical cells decreased, and their response at higher stimulus speeds was reduced. Thus, functionally distinct, retina-dependent and retina-independent computations of visual motion exist in mouse cortex. How neuronal computations in the sensory periphery contribute to computations in the cortex is not well understood. We examined this question in the context of visual-motion processing in the retina and primary visual cortex (V1) of mice. We disrupted retinal direction selectivity, either exclusively along the horizontal axis using FRMD7 mutants or along all directions by ablating starburst amacrine cells, and monitored neuronal activity in layer 2/3 of V1 during stimulation with visual motion. In control mice, we found an over-representation of cortical cells preferring posterior visual motion, the dominant motion direction an animal experiences when it moves forward. In mice with disrupted retinal direction selectivity, the over-representation of posterior-motion-preferring cortical cells disappeared, and their responses at higher stimulus speeds were reduced. This work reveals the existence of two functionally distinct, sensory-periphery-dependent and -independent computations of visual motion in the cortex.

To understand and control complex tissues, the ability to genetically manipulate single cells is required. However, current delivery methods for the genetic engineering of single cells, including viral transduction, suffer from limitations that restrict their application. Here we present a protocol that describes a versatile technique that can be used for the targeted viral infection of single cells or small groups of cells in any tissue that is optically accessible. First, cells of interest are selected using optical microscopy. Second, a micropipette—loaded with magnetic nanoparticles to which viral particles are bound—is brought into proximity of the cell of interest, and a magnetic field is applied to guide the viral nanoparticles into cellular contact, leading to transduction. The protocol, exemplified here by stamping cultured neurons with adeno-associated viruses (AAVs), is completed in a few minutes and allows stable transgene expression within a few days, at success rates that approach 80%. We outline how this strategy is applied to single-cell infection in complex tissues, and is feasible both in organoids and in vivo. This protocol describes the targeted viral infection of single cells or small groups of cells by magnetically guided virus stamping, allowing for controlled genetic engineering, exemplified here by stamping cultured neurons with adeno-associated viruses.

Viruses are transduced to single cells in tissues, organoids and in the mouse brain using mechanical carriers. Genetic engineering by viral infection of single cells is useful to study complex systems such as the brain. However, available methods for infecting single cells have drawbacks that limit their applications. Here we describe 'virus stamping', in which viruses are reversibly bound to a delivery vehicle—a functionalized glass pipette tip or magnetic nanoparticles in a pipette—that is brought into physical contact with the target cell on a surface or in tissue, using mechanical or magnetic forces. Different single cells in the same tissue can be infected with different viruses and an individual cell can be simultaneously infected with different viruses. We use rabies, lenti, herpes simplex, and adeno-associated viruses to drive expression of fluorescent markers or a calcium indicator in target cells in cell culture, mouse retina, human brain organoid, and the brains of live mice. Virus stamping provides a versatile solution for targeted single-cell infection of diverse cell types, both in vitro and in vivo .