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39 Janelia Publications

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    10/16/20 | Behavioral state coding by molecularly defined paraventricular hypothalamic cell type ensembles.
    Xu S, Yang H, Menon V, Lemire AL, Wang L, Henry FE, Turaga SC, Sternson SM
    Science. 2020 Oct 16;370(6514):. doi: 10.1126/science.abb2494

    Brains encode behaviors using neurons amenable to systematic classification by gene expression. The contribution of molecular identity to neural coding is not understood because of the challenges involved with measuring neural dynamics and molecular information from the same cells. We developed CaRMA (calcium and RNA multiplexed activity) imaging based on recording in vivo single-neuron calcium dynamics followed by gene expression analysis. We simultaneously monitored activity in hundreds of neurons in mouse paraventricular hypothalamus (PVH). Combinations of cell-type marker genes had predictive power for neuronal responses across 11 behavioral states. The PVH uses combinatorial assemblies of molecularly defined neuron populations for grouped-ensemble coding of survival behaviors. The neuropeptide receptor neuropeptide Y receptor type 1 (Npy1r) amalgamated multiple cell types with similar responses. Our results show that molecularly defined neurons are important processing units for brain function.

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    09/17/20 | Exploring internal state-coding across the rodent brain.
    Sternson SM
    Current Opinion in Neurobiology. 2020 Sep 17;65:20-26. doi: 10.1016/j.conb.2020.08.009

    The influence of peripheral physiology on goal-directed behavior involves specialized interoceptive sensory neurons that signal internal state to the brain. Here, we review recent progress to examine the impact of these specialized cell types on neurons and circuits throughout the central nervous system. These new approaches are important for understanding how the needs of the body interact and guide goal-directed behaviors.

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    09/17/20 | Hindbrain double-negative feedback mediates palatability-guided food and water consumption.
    Gong R, Xu S, Hermundstad A, Yu Y, Sternson SM
    Cell. 2020 Sep 17;182(6):1589-1605. doi: 10.1016/j.cell.2020.07.031

    Hunger and thirst have distinct goals but control similar ingestive behaviors, and little is known about neural processes that are shared between these behavioral states. We identify glutamatergic neurons in the peri-locus coeruleus (periLC neurons) as a polysynaptic convergence node from separate energy-sensitive and hydration-sensitive cell populations. We develop methods for stable hindbrain calcium imaging in free-moving mice, which show that periLC neurons are tuned to ingestive behaviors and respond similarly to food or water consumption. PeriLC neurons are scalably inhibited by palatability and homeostatic need during consumption. Inhibition of periLC neurons is rewarding and increases consumption by enhancing palatability and prolonging ingestion duration. These properties comprise a double-negative feedback relationship that sustains food or water consumption without affecting food- or water-seeking. PeriLC neurons are a hub between hunger and thirst that specifically controls motivation for food and water ingestion, which is a factor that contributes to hedonic overeating and obesity.

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    07/27/20 | Seeing the forest for the trees in obesity.
    Sternson SM
    Nature Metabolism. 2020 Jul 27:. doi: 10.1038/s42255-020-0259-9
    09/19/19 | Reconstruction of 1,000 projection neurons reveals new cell types and organization of long-range connectivity in the mouse brain.
    Winnubst J, Bas E, Ferreira TA, Wu Z, Economo MN, Edson P, Arthur BJ, Bruns C, Rokicki K, Schauder D, Olbris DJ, Murphy SD, Ackerman DG, Arshadi C, Baldwin P, Blake R, Elsayed A, Hasan M, Ramirez D, Dos Santos B, Weldon M, Zafar A, Dudman JT, Gerfen CR, Hantman AW, Korff W, Sternson SM, Spruston N, Svoboda K, Chandrashekar J
    Cell. 2019 Sep 19;179(1):268-81. doi: 10.1016/j.cell.2019.07.042

    Neuronal cell types are the nodes of neural circuits that determine the flow of information within the brain. Neuronal morphology, especially the shape of the axonal arbor, provides an essential descriptor of cell type and reveals how individual neurons route their output across the brain. Despite the importance of morphology, few projection neurons in the mouse brain have been reconstructed in their entirety. Here we present a robust and efficient platform for imaging and reconstructing complete neuronal morphologies, including axonal arbors that span substantial portions of the brain. We used this platform to reconstruct more than 1,000 projection neurons in the motor cortex, thalamus, subiculum, and hypothalamus. Together, the reconstructed neurons constitute more than 85 meters of axonal length and are available in a searchable online database. Axonal shapes revealed previously unknown subtypes of projection neurons and suggest organizational principles of long-range connectivity.

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    03/14/19 | Ultrapotent chemogenetics for research and potential clinical applications.
    Magnus CJ, Lee PH, Bonaventura J, Zemla R, Gomez JL, Ramirez MH, Hu X, Galvan A, Basu J, Michaelides M, Sternson SM
    Science. 2019 Mar 14;364(6436):eaav5282. doi: 10.1126/science.aav5282

    Chemogenetics enables non-invasive chemical control over cell populations in behaving animals. However, existing small molecule agonists show insufficient potency or selectivity. There is also need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the anti-smoking drug varenicline. We then synthesized novel sub-nanomolar potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.

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    12/12/17 | Chemogenetic tools for causal cellular and neuronal biology.
    Atasoy D, Sternson SM
    Physiological Reviews. 2017 Dec 12:. doi: 10.1152/physrev.00009.2017

    Chemogenetic technologies enable selective pharmacological control of specific cell populations. An increasing number of approaches have been developed that modulate different signaling pathways. Selective pharmacological control over G protein-coupled receptor signaling, ion channel conductances, protein association, protein stability, and small molecule targeting allows modulation of cellular processes in distinct cell types. Here, we review these chemogenetic technologies and instances of their applications in complex tissues in vivo and ex vivo.

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    07/27/17 | Raphe circuits on the menu.
    Yang H, Sternson SM
    Cell. 2017 Jul 27;170(3):409-10. doi: 10.1016/j.cell.2017.07.017

    The dorsal raphe nucleus (DRN) is an important brain area for body-weight regulation. In this issue of Cell, Nectow et al. uncover cell-type-specific neural circuitry and pharmacology for appetite control within the DRN.

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    11/28/16 | Three pillars for the neural control of appetite.
    Sternson SM, Eiselt A
    Annual Review of Physiology. 2016 Nov 28;79:401-23. doi: 10.1146/annurev-physiol-021115-104948

    The neural control of appetite is important for understanding motivated behavior along with the present rising prevalence of obesity. Over the past several years, new tools for cell type-specific neuron activity monitoring and perturbation have enabled increasingly detailed analyses of the mechanisms underlying appetite-control systems. Three major neural circuits strongly and acutely influence appetite but with notably different characteristics. Although these circuits interact, they have distinct properties and thus appear to contribute to separate but interlinked processes influencing appetite, thereby forming three pillars of appetite control. Here, we summarize some of the key characteristics of appetite circuits that are emerging from recent work and synthesize the findings into a provisional framework that can guide future studies. Expected final online publication date for the Annual Review of Physiology Volume 79 is February 10, 2017. Please see for revised estimates.

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    08/22/16 | Functional and anatomical dissection of feeding circuits.
    Atasoy D, Sternson SM
    Neuroendocrinology of Appetite:112-133. doi: 10.1002/9781118839317.ch6

    This chapter reviews the application of new genetically encoded tools in feeding circuits that regulate appetite. Rapid activation and inhibition of agouti related peptide (AgRP) neurons conclusively established a causal role for rapid control of food intake. Chemogenetic activation of AgRP neurons using hM3Dq avoids the invasive protocols required for ChR2 activation. ChR2 distributes into axons, and selective optogenetic activation of AgRP neuron axon projection fields in distinct brain areas was used to examine their individual contribution to feeding behavior. Some of the brain areas targeted by AgRP neuron axon projections have been examined further for cell type specific control of appetite. Rodents with bed nucleus of stria terminalis (BNST) lesions show hyperphagia and obesity, indicating that reduced BNST output promotes feeding. pro-opiomelanocortin (POMC) neurons regulate feeding over longer timescales. parabrachial nucleus (PBN) neurons have a powerful inhibitory role on food intake, but their inhibition does not strongly elevate food intake.

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