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SUMMARY A recent article in Cell reported a new form of modified rabies virus that was apparently capable of labeling neurons “without adverse effects on neuronal physiology and circuit function”. These “self-inactivating” rabies (“SiR”) viruses differed from the widely-used first-generation deletion-mutant (ΔG) rabies viruses only by the addition of a destabilization domain to the viral nucleoprotein. However, we observed that the transsynaptic tracing results from that article were inconsistent with the logic described in it, and we hypothesized that the viruses used were actually mutants that had lost the intended modification to the nucleoprotein. We obtained samples of two SiR viruses from the authors and show here that, in both “SiR-CRE” and “SiR-FLPo”, the great majority of viral particles were indeed mutants that had lost the intended modification and were therefore just first-generation, ΔG rabies viruses. We also found that SiR-CRE killed 70% of infected neurons in vivo within two weeks. We have shown elsewhere that a ΔG rabies virus encoding Cre can leave a large percentage of labeled neurons alive; we presume that Ciabatti et al. found such remaining neurons at long survival times and mistakenly concluded that they had developed a nontoxic version of rabies virus. Here we have analyzed only the two samples that were sent to MIT by Ciabatti et al., and these may not be from the same batches that were used for their paper. However, 1) both of the two viruses that we analyzed had independently lost the intended modification, 2) the mutations in the two samples were genetically quite distinct from each other yet in both cases caused the same result: total or near-total loss of the C-terminal modification, and 3) the mutations that we found in these two virus samples perfectly explain the otherwise-paradoxical transsynaptic tracing results from Ciabatti et al.’s paper. We suggest that the SiR strategy, or any other such attempt to attenuate a virus by addition rather than deletion, is an inherently unstable approach that can easily be evaded by mutation, as it was in this case.

Descending command neurons instruct spinal networks to execute basic locomotor functions, such as which gait and what speed. The command functions for gait and speed are symmetric, implying that a separate unknown system directs asymmetric movements—the ability to move left or right. Here we report the discovery that Chx10-lineage reticulospinal neurons act to control the direction of locomotor movements in mammals. Chx10 neurons exhibit ipsilateral projection, and can decrease spinal limb-based locomotor activity ipsilaterally. This circuit mechanism acts as the basis for left or right locomotor movements in freely moving animals: selective unilateral activation of Chx10 neurons causes ipsilateral movements whereas inhibition causes contralateral movements. Spontaneous forward locomotion is thus transformed into an ipsilateral movement by braking locomotion on the ipsilateral side. We identify sensorimotor brain regions that project onto Chx10 reticulospinal neurons, and demonstrate that their unilateral activation can impart left/right directional commands. Together these data identify the descending motor system which commands left/right locomotor asymmetries in mammals

There are two electrophysiological dichotomous populations of parvalbumin (PV) interneurons located in the dorsal striatum. Striatal PV interneurons in medial and lateral regions differ significantly in their intrinsic excitability. Parvalbumin interneurons in the dorsomedial striatum, but not in the dorsolateral striatum, receive afferent glutamatergic input from cingulate cortex., Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard and a doctoral fellowship from the Portuguese Foundation for Science and Technology to P.M. (SFRH/BD/33894/2009). Research in the Laboratory of Guoping Feng has been supported by the Poitras Center for Affective Disorders Research at MIT, Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, National Institute of Health (NINDS and NIMH), Alfred P. Sloan Foundation, American Heart Association, The Arnold and Mabel Beckman Foundation, The EJLB Foundation, The Esther A. & Joseph Klingenstein Fund, The Hartwell Foundation, March of Dimes Birth Defects Foundation, McKnight Endowment Fund for Neuroscience, Nancy Lurie Marks Family Foundation, Ruth K. Broad Foundation for Biomedical Research, Simons Foundation Autism Research Initiative (SFARI), and The Whitehall Foundation. B.B. was supported by postdoctoral fellowships from the Simons Center for the Social Brain at MIT and the Autism Science Foundation and is currently a faculty at The School of Psychological Sciences and Sagol School of Neuroscience, Tel Aviv University, Israel. P.M. is currently supported by Society in Science, The Branco Weiss Fellowship, administered by Eidgenössische Technische Hochschule (ETH) Zürich, and European Molecular Biology Organization (EMBO) Long-Term Fellowship (ALTF 89 – 2016), info:eu-repo/semantics/publishedVersion

Summary The immense behavioral repertoire of animals necessitates mechanisms that select and suppress specific actions depending on current goals. The prefrontal cortex (PFC) has been suggested to orchestrate these processes by biasing activity in its target structures, but how its vastly converging inputs and diverging outputs are coordinated to control goal-oriented actions remains unclear. Here we use a bilateral task in which mice select between symmetric but opposing actions to show that distinct outputs from a subdivision of the PFC, the anterior cingulate cortex (ACC), promote correct and suppress incorrect actions. Surprisingly, ACC outputs to the superior colliculus principally inhibit incorrect actions. Optogenetic analyses and a projection-based activity model make the unexpected prediction that feedback from the ACC to the visual cortex promotes correct actions, which we confirm. Our results show that anatomically non-overlapping but functionally complementary PFC outputs bidirectionally control actions, and suggest a candidate organizing principle for PFC circuits.

Key points: There are two electrophysiological dichotomous populations of parvalbumin (PV) interneurons located in the dorsal striatum. Striatal PV interneurons in medial and lateral regions differ significantly in their intrinsic excitability. Parvalbumin interneurons in the dorsomedial striatum, but not in the dorsolateral striatum, receive afferent glutamatergic input from cingulate cortex. Abstract: Dorsomedial striatum circuitry is involved in goal-directed actions or movements that become habits upon repetition, as encoded by the dorsolateral striatum. An inability to shift from habits can compromise action-control and prevent behavioural adaptation. Although these regions appear to be clearly behaviourally distinct, little is known about their distinct physiology. Parvalbumin (PV) interneurons are a major source of striatal inhibition and are usually considered as a homogeneous population in the entire dorsal striatum. In the present study, we recorded PV interneurons in dorsal striatum slices from wild-type male mice and suggest the existence of two electrophysiological dichotomous populations. We found that PV interneurons located at the dorsomedial striatum region have increased intrinsic excitability compared to PV interneurons in dorsolateral region. We also found that PV interneurons in the dorsomedial region, but not in the dorsolateral striatum region, receive short-latency excitatory inputs from cingulate cortex. Therefore, the results of the present study demonstrate the importance of considering region specific parvalbumin interneuron populations when studying dorsal striatal function.

We have developed two new tools for tracing neural connections. The first is a means of identifying cells that project to a region of interest within the brain, illuminating these cells with intense fluorescence and allowing their finest morphological details to be seen. This permits either highly detailed reconstruction of the cells' anatomy or their targeting, in live tissue, on the basis of their morphology for physiological study. The second tool is a means of identifying, on a large scale, neurons which are directly presynaptic to either a targeted cell type or indeed a single neuron. Because this technique also results in intensely fluorescent cellular details, this too could be used either for detailed anatomical studies or for physiological ones. This should allow a significantly more precise understanding of the organization of nervous systems than has previously been possible

Whole-cell patch clamping in vivo is an important neuroscience technique that uniquely provides access to both suprathreshold spiking and subthreshold synaptic events of single neurons in the brain. This article describes how to set up and use the autopatcher, which is a robot for automatically obtaining high-yield and high-quality whole-cell patch clamp recordings in vivo. By following this protocol, a functional experimental rig for automated whole-cell patch clamping can be set up in 1 week. High-quality surgical preparation of mice takes ~1 h, and each autopatching experiment can be carried out over periods lasting several hours. Autopatching should enable in vivo intracellular investigations to be accessible by a substantial number of neuroscience laboratories, and it enables labs that are already doing in vivo patch clamping to scale up their efforts by reducing training time for new lab members and increasing experimental durations by handling mentally intensive tasks automatically., National Eye Institute, National Institute of Mental Health (U.S.) (1-U01-MH106027-01), United States. National Institutes of Health (EY023173), National Science Foundation (U.S.) (HER 0965945), National Science Foundation (U.S.) (CISE 1110947), National Science Foundation (U.S.) (5T90DA032466), Georgia Institute of Technology, United States. National Institutes of Health (1R01EY023173), New York Stem Cell Foundation (Robertson Neuroscience Investigator Award), United States. National Institutes of Health (1DP1NS087724), United States. National Institutes of Health (1R24MH106075), United States. National Institutes of Health (1R01MH103910)

A comprehensive characterization of neuronal cell types, their distributions, and patterns of connectivity is critical for understanding the properties of neural circuits and how they generate behaviors. Here we review the experiences of the BRAIN Initiative Cell Census Consortium, ten pilot projects funded by the U.S. BRAIN Initiative, in developing, validating, and scaling up emerging genomic and anatomical mapping technologies for creating a complete inventory of neuronal cell types and their connections in multiple species and during development. These projects lay the foundation for a larger and longer-term effort to generate whole-brain cell atlases in species including mice and humans. In this Perspective, Ecker et al. discuss the efforts of the BRAIN Initiative Cell Census Consortium, ten pilot projects whose collective goal was to develop and validate methods for generating comprehensive atlases of neuronal cell types in the mammalian brain., BRAIN Initiative

Perturbations in neural circuits can provide mechanistic understanding of the neural correlates of behavior. In M71 transgenic mice with a “monoclonal nose”, glomerular input patterns in the olfactory bulb are massively perturbed and olfactory behaviors are altered. To gain insights into how olfactory circuits can process such degraded inputs we characterized odor-evoked responses of olfactory bulb mitral cells and interneurons. Surprisingly, calcium imaging experiments reveal that mitral cell responses in M71 transgenic mice are largely normal, highlighting a remarkable capacity of olfactory circuits to normalize sensory input. In vivo whole cell recordings suggest that feedforward inhibition from olfactory bulb periglomerular cells can mediate this signal normalization. Together, our results identify inhibitory circuits in the olfactory bulb as a mechanistic basis for many of the behavioral phenotypes of mice with a “monoclonal nose” and highlight how substantially degraded odor input can be transformed to yield meaningful olfactory bulb output.