Spatially mapped single-cell chromatin accessibility.

High-throughput single-cell epigenomic assays can resolve cell type heterogeneity in complex tissues, however, spatial orientation is lost. Here, we present single-cell combinatorial indexing on Microbiopsies Assigned to Positions for the Assay for Transposase Accessible Chromatin, or sciMAP-ATAC, as a method for highly scalable, spatially resolved, single-cell profiling of chromatin states. sciMAP-ATAC produces data of equivalent quality to non-spatial sci-ATAC and retains the positional information of each cell within a 214 micron cubic region, with up to hundreds of tracked positions in a single experiment. We apply sciMAP-ATAC to assess cortical lamination in the adult mouse primary somatosensory cortex and in the human primary visual cortex, where we produce spatial trajectories and integrate our data with non-spatial single-nucleus RNA and other chromatin accessibility single-cell datasets. Finally, we characterize the spatially progressive nature of cerebral ischemic infarction in the mouse brain using a model of transient middle cerebral artery occlusion.

A Fly's Eye View of Natural and Drug Reward.

Animals encounter multiple stimuli each day. Some of these stimuli are innately appetitive or aversive, while others are assigned valence based on experience. Drugs like ethanol can elicit aversion in the short term and attraction in the long term. The reward system encodes the predictive value for different stimuli, mediating anticipation for attractive or punishing stimuli and driving animal behavior to approach or avoid conditioned stimuli. The neurochemistry and neurocircuitry of the reward system is partly evolutionarily conserved. In both vertebrates and invertebrates, including Drosophila melanogaster, dopamine is at the center of a network of neurotransmitters and neuromodulators acting in concert to encode rewards. Behavioral assays in D. melanogaster have become increasingly sophisticated, allowing more direct comparison with mammalian research. Moreover, recent evidence has established the functional modularity of the reward neural circuits in Drosophila. This functional modularity resembles the organization of reward circuits in mammals. The powerful genetic and molecular tools for D. melanogaster allow characterization and manipulation at the single-cell level. These tools are being used to construct a detailed map of the neural circuits mediating specific rewarding stimuli and have allowed for the identification of multiple genes and molecular pathways that mediate the effects of reinforcing stimuli, including their rewarding effects. This report provides an overview of the research on natural and drug reward in D. melanogaster, including natural rewards such as sugar and other food nutrients, and drug rewards including ethanol, cocaine, amphetamine, methamphetamine, and nicotine. We focused mainly on the known genetic and neural mechanisms underlying appetitive reward for sugar and reward for ethanol. We also include genes, molecular pathways, and neural circuits that have been identified using assays that test the palatability of the rewarding stimulus, the preference for the rewarding stimulus, or other effects of the stimulus that indicate how it can modify behavior. Commonalities between mechanisms of natural and drug reward are highlighted and future directions are presented, putting forward questions best suited for research using D. melanogaster as a model organism.