Summary The distributions of neurons in sensory circuits display ordered spatial patterns arranged to enhance or encode specific regions or features of the external environment. Indeed, visual space is not sampled uniformly across the vertebrate retina. Retinal ganglion cell (RGC) density increases and dendritic arbor size decreases towards retinal locations with higher sampling frequency, such as the fovea in primates and area centralis in carnivores [1]. In these locations, higher acuity at the level of individual cells is obtained because the receptive field center of a RGC corresponds approximately to the spatial extent of its dendritic arbor [2, 3]. For most species, structurally and functionally distinct RGC types appear to have similar topographies; collectively scaling their cell densities and arbor sizes towards the same retina location [4]. Thus, visual space is represented across the retina in parallel by multiple distinct circuits [5]. In contrast, we find a population of mouse RGCs, known as alpha or alpha-like [6], that displays a nasal-to-temporal gradient in cell density, size and receptive fields, which facilitates enhanced visual sampling in frontal visual fields. The distribution of alpha-like RGCs contrasts with other known mouse RGC types, and suggests that unlike most mammals, RGC topographies in mice are arranged to sample space differentially.

Proper functioning of sensory systems requires the generation of appropriate numbers and proportions of neuronal subtypes that encode distinct information. Perception of color relies on signals from multiple cone photoreceptor types. In cone-dominated retinas, each cone expresses a single opsin type with peak sensitivity to UV, long (L) (red), medium (M) (green), or short (S) (blue) wavelengths. The modes of cell division generating distinct cone types are unknown. We report here a mechanism whereby zebrafish cone photoreceptors of the same type are produced by symmetric division of dedicated precursors. Transgenic fish in which the thyroid hormone receptor β2 (trβ2) promoter drives fluorescent protein expression before L-cone precursors themselves are produced permitted tracking of their division in vivo. Every L cone in a local region resulted from the terminal division of an L-cone precursor, suggesting that such divisions contribute significantly to L-cone production. Analysis of the fate of isolated pairs of cones and time-lapse observations suggest that other cone types can also arise by symmetric terminal divisions. Such divisions of dedicated precursors may help to rapidly attain the final numbers and proportions of cone types (L > M, UV > S) in zebrafish larvae. Loss-and gain-of-function experiments show that L-opsin expression requires trβ2 activity before cone differentiation. Ectopic expression of trβ2 after cone differentiation produces cones with mixed opsins. Temporal differences in the onset of trβ2 expression could explain why some species have mixed, and others have pure, cone types.vertebrate cone photoreceptors | cone genesis | zebrafish retina | in vivo time-lapse imaging T he proper functioning of neuronal circuits requires the generation and wiring of a diversity of neuronal cell types. A single neuronal cell class often comprises many subtypes that share similar properties, such as neurotransmitter phenotype, but differ in their precise molecular expression profile, morphology, and physiology (1, 2). How neuronal subtypes that share connectivity with the same populations of postsynaptic cells are produced is not well understood, particularly for vertebrate circuits in vivo. Specifically, are distinct presynaptic partner types of a given postsynaptic cell generated together or produced from separate divisions? When during cell genesis do the presynaptic cell types adopt their respective identities?Cell lineage analyses have demonstrated that many neurogenic divisions are asymmetric, sometimes producing distinct neuronal classes or a neuron together with a nonneuronal cell type (3, 4). Examples of progenitors that give rise to a single neuronal class have also been reported (5-13). A single progenitor, however, can also produce two distinct neuronal subtypes (14-17). In some instances, neurons of the same functional subtype may also share a common progenitor (18), but their generation may involve both symmetric and asymmetric divisions (13,19,20). Recent retroviral studies in chick retina r...

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer’s disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram, in vivo imaging, biochemical characterization, and behavioral assessments. The data from this study is publicly available through the AD Knowledge Portal.

Summary The starburst amacrine cell in the mouse retina presents an opportunity to examine the precise role of sensory input location on neuronal computations. Using visual receptive field mapping, glutamate uncaging, two-photon Ca2+ imaging, and genetic labeling of putative synapses, we identify a unique arrangement of excitatory inputs and neurotransmitter release sites on starburst amacrine cell dendrites: the excitatory input distribution is skewed away from the release sites. By comparing computational simulations with Ca2+ transients recorded near release sites, we show that this anatomical arrangement of inputs and outputs supports a dendritic mechanism for computing motion direction. Direction selective Ca2+ transients persist in the presence of a GABA-A receptor antagonist, though the directional tuning is reduced. These results indicate a synergistic interaction between dendritic and circuit mechanisms for generating direction selectivity in the starburst amacrine cell.

Electron microscopy (EM) is widely used for studying cellular structure and network connectivity in the brain. We have built a parallel imaging pipeline using transmission electron microscopes that scales this technology, implements 24/7 continuous autonomous imaging, and enables the acquisition of petascale datasets. The suitability of this architecture for large-scale imaging was demonstrated by acquiring a volume of more than 1 mm3 of mouse neocortex, spanning four different visual areas at synaptic resolution, in less than 6 months. Over 26,500 ultrathin tissue sections from the same block were imaged, yielding a dataset of more than 2 petabytes. The combined burst acquisition rate of the pipeline is 3 Gpixel per sec and the net rate is 600 Mpixel per sec with six microscopes running in parallel. This work demonstrates the feasibility of acquiring EM datasets at the scale of cortical microcircuits in multiple brain regions and species.