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      A spatially dynamic network underlies the generation of inspiratory behaviors

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Significance

          Breathing is a vital rhythmic behavior that originates from neural networks within the brainstem. It is hypothesized that the breathing rhythm is generated by spatially distinct networks localized to discrete kernels or compartments. Here, we provide evidence that the functional boundaries of these compartments expand and contract dynamically based on behavioral or physiological demands. The ability of these rhythmic networks to change in size may allow the breathing rhythm to be very reliable, yet flexible enough to accommodate the large repertoire of mammalian behaviors that must be integrated with breathing.

          Abstract

          The ability of neuronal networks to reconfigure is a key property underlying behavioral flexibility. Networks with recurrent topology are particularly prone to reconfiguration through changes in synaptic and intrinsic properties. Here, we explore spatial reconfiguration in the reticular networks of the medulla that generate breathing. Combined results from in vitro and in vivo approaches demonstrate that the network architecture underlying generation of the inspiratory phase of breathing is not static but can be spatially redistributed by shifts in the balance of excitatory and inhibitory network influences. These shifts in excitation/inhibition allow the size of the active network to expand and contract along a rostrocaudal medullary column during behavioral or metabolic challenges to breathing, such as changes in sensory feedback, sighing, and gasping. We postulate that the ability of this rhythm-generating network to spatially reconfigure contributes to the remarkable robustness and flexibility of breathing.

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          Most cited references 90

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          The Human Cell Atlas

          The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, and also provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas, including a commitment to open data, code, and community.
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            Functional organization of the hippocampal longitudinal axis.

            The precise functional role of the hippocampus remains a topic of much debate. The dominant view is that the dorsal (or posterior) hippocampus is implicated in memory and spatial navigation and the ventral (or anterior) hippocampus mediates anxiety-related behaviours. However, this 'dichotomy view' may need revision. Gene expression studies demonstrate multiple functional domains along the hippocampal long axis, which often exhibit sharply demarcated borders. By contrast, anatomical studies and electrophysiological recordings in rodents suggest that the long axis is organized along a gradient. Together, these observations suggest a model in which functional long-axis gradients are superimposed on discrete functional domains. This model provides a potential framework to explain and test the multiple functions ascribed to the hippocampus.
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              Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons.

              Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT⁺) or excitatory (glutamatergic, VGLUT2⁺). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                9 April 2019
                27 March 2019
                27 March 2019
                : 116
                : 15
                : 7493-7502
                Affiliations
                aCenter for Integrative Brain Research, Seattle Children’s Research Institute , Seattle, WA 98101;
                bDepartment of Neurological Surgery, University of Washington , Seattle, WA 98104;
                cDepartment of Pediatrics, University of Washington , Seattle, WA 98195
                Author notes

                Edited by Peter L. Strick, University of Pittsburgh, Pittsburgh, PA, and approved March 7, 2019 (received for review January 16, 2019)

                Author contributions: N.A.B. and J.-M.R. designed research; N.A.B., L.J.S., and T.M.A. performed research; N.A.B. analyzed data; and N.A.B. and J.-M.R. wrote the paper.

                Article
                201900523
                10.1073/pnas.1900523116
                6462111
                30918122
                Copyright © 2019 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                Page count
                Pages: 10
                Product
                Funding
                Funded by: HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) 100000050
                Award ID: K99HL145004
                Award Recipient : Nathan Andrew Baertsch Award Recipient : Jan-Marino Ramirez
                Funded by: HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) 100000050
                Award ID: F32HL134207
                Award Recipient : Nathan Andrew Baertsch Award Recipient : Jan-Marino Ramirez
                Funded by: HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) 100000050
                Award ID: R01HL126523
                Award Recipient : Nathan Andrew Baertsch Award Recipient : Jan-Marino Ramirez
                Funded by: HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) 100000050
                Award ID: P01HL090554
                Award Recipient : Nathan Andrew Baertsch Award Recipient : Jan-Marino Ramirez
                Categories
                PNAS Plus
                Biological Sciences
                Neuroscience
                PNAS Plus

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