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SummaryCortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that embryonic layer 5 pyramidal neurons, identified through single cell transcriptomics, display two phases of circuit assembly in vivo. At E14.5, a multi-layered circuit motif, composed of a single layer 5 cell type, forms. This motif is transient, switching to a second circuit motif, involving all three types, by E17.5. In vivo targeted single cell recordings and two-photon calcium imaging of embryonic layer 5 neurons reveal that, in both phases, neurons have active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses. Embryonic layer 5 neurons strongly express autism-associated genes, and perturbing these genes disrupts the switch between the two motifs. Hence, layer 5 pyramidal neurons form transient active pyramidal-to-pyramidal circuits, at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.

General anesthetics induce loss of consciousness, a global change in behavior. However, a corresponding global change in activity in the context of defined cortical cell types has not been identified. Here, we show that spontaneous activity of mouse layer 5 pyramidal neurons, but of no other cortical cell type, becomes consistently synchronized in vivo by different general anesthetics. This heightened neuronal synchrony is aperiodic, present across large distances, and absent in cortical neurons presynaptic to layer 5 pyramidal neurons. During the transition to and from anesthesia, changes in synchrony in layer 5 coincide with the loss and recovery of consciousness. Activity within both apical and basal dendrites is synchronous, but only basal dendrites' activity is temporally locked to somatic activity. Given that layer 5 is a major cortical output, our results suggest that brain-wide synchrony in layer 5 pyramidal neurons may contribute to the loss of consciousness during general anesthesia.

SummaryTargeting genes to specific neuronal or glial cell types is valuable both for understanding and for repairing brain circuits. Adeno-associated viral vectors (AAVs) are frequently used for gene delivery, but targeting expression to specific cell types is a challenge. We created a library of 230 AAVs, each with a different synthetic promoter designed using four independent strategies. We show that ~11% of these AAVs specifically target expression to neuronal and glial cell types in the mouse retina, mouse brain, non-human primate retinain vivo, and in the human retinain vitro. We demonstrate applications for recording, stimulation, and molecular characterization, as well as the intersectional and combinatorial labeling of cell types. These resources and approaches allow economic, fast, and efficient cell-type targeting in a variety of species, both for fundamental science and for gene therapy.

Animal behaviour arises from computations in neuronal circuits, but our understanding of these computations has been frustrated by the lack of detailed synaptic connection maps, or connectomes. For example, despite intensive investigations over half a century, the neuronal implementation of local motion detection in the insect visual system remains elusive. Here we develop a semi-automated pipeline using electron microscopy to reconstruct a connectome, containing 379 neurons and 8,637 chemical synaptic contacts, within the Drosophila optic medulla. By matching reconstructed neurons to examples from light microscopy, we assigned neurons to cell types and assembled a connectome of the repeating module of the medulla. Within this module, we identified cell types constituting a motion detection circuit, and showed that the connections onto individual motion-sensitive neurons in this circuit were consistent with their direction selectivity. Our results identify cellular targets for future functional investigations, and demonstrate that connectomes can provide key insights into neuronal computations. Reconstruction of a connectome within the fruitfly visual medulla, containing more than 300 neurons and over 8,000 chemical synapses, reveals a candidate motion detection circuit; such a circuit operates by combining displaced visual inputs, an operation consistent with correlation based motion detection. Three papers in this issue of Nature use the retina as a model for mapping neuronal circuits from the level of individual synaptic contacts to the long-range scale of dendritic interactions. Helmstaedter et al. used electron microscopy to map a mammalian retinal circuit of close to a thousand neurons. The work reveals a new type of retinal bipolar neuron and suggests functional mechanisms for known visual computations. The other two groups study the detection of visual motion in the Drosophila visual system — a classic neural computation model. Takemura et al. used semi-automated electron microscopy to reconstruct the basic connectome (8,637 chemical synapses among 379 neurons) of Drosophila's optic medulla. Their results reveal a candidate motion detection circuit with a wiring plan consistent with direction selectivity. Maisak et al. used calcium imaging to show that T4 and T5 neurons are divided into specific subpopulations responding to motion in four cardinal directions, and are specific to 'ON' versus 'OFF' edges, respectively.

How does the brain compute? Answering this question necessitates neuronal connectomes, annotated graphs of all synaptic connections within defined brain areas. Further, understanding the energetics of the brain's computations requires vascular graphs. The assembly of a connectome requires sensitive hardware tools to measure neuronal and neurovascular features in all three dimensions, as well as software and machine learning for data analysis and visualization. We present the state of the art on the reconstruction of circuits and vasculature that link brain anatomy and function. Analysis at the scale of tens of nanometers yields connections between identified neurons, while analysis at the micrometer scale yields probabilistic rules of connection between neurons and exact vascular connectivity.

International audience; Schwann cells elaborate myelin sheaths around axons by spirally wrapping and compacting their plasma membranes. Although actin remodeling plays a crucial role in this process, the effectors that modulate the Schwann cell cytoskeleton are poorly defined. Here, we show that the actin cytoskeletal regulator, neural Wiskott-Aldrich syndrome protein (N-WASp), is upregulated in myelinating Schwann cells coincident with myelin elaboration. When N-WASp is conditionally deleted in Schwann cells at the onset of myelination, the cells continue to ensheath axons but fail to extend processes circumferentially to elaborate myelin. Myelin-related gene expression is also severely reduced in the N-WASp-deficient cells and in vitro process and lamellipodia formation are disrupted. Although affected mice demonstrate obvious motor deficits these do not appear to progress, the mutant animals achieving normal body weights and living to advanced age. Our observations demonstrate that N-WASp plays an essential role in Schwann cell maturation and myelin formation.

Quantum conditions on the control of dynamics of a system coupled to an environment are obtained. Specifically, consider a system initially in a system subspace $H_{0}$ of dimensionality $M_{0}$, which evolves to populate system subspaces $H_{1}$, $H_{2}$ of dimensionality $M_{1}$, $M_{2}$. Then there always exists an initial state in $H_0$ that does not evolve into $H_2$ if $M_{0}>dM_{2},$ where $2 \leq d \leq (M_0 +M_1 +M_2)^2$ is the number of operators in the Kraus representation. Note, significantly, that the maximum $d$ can be far smaller than the dimension of the bath. If this condition is not satisfied then dynamics from $H_{0}$ that avoids $H_{2}$ can only be attained physically under stringent conditions. An example from molecular dynamics and spectroscopy, i.e. donor to acceptor energy transfer, is provided., 4 pages, no figure