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32 Janelia Publications

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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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    06/16/16 | Near-perfect synaptic integration by Nav1.7 in hypothalamic neurons regulates body weight.
    Branco T, Tozer A, Magnus CJ, Sugino K, Tanaka S, Lee AK, Wood JN, Sternson SM
    Cell. 2016 Jun 16;165(7):1749-61. doi: 10.1016/j.cell.2016.05.019

    Neurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration. Scn9a deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions.

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    12/24/15 | An emerging technology framework for the neurobiology of appetite.
    Sternson SM, Atasoy D, Betley JN, Henry FE, Xu S
    Cell Metabolism. 2015 Dec 24;23(2):234-53. doi: 10.1016/j.cmet.2015.12.002

    Advances in neuro-technology for mapping, manipulating, and monitoring molecularly defined cell types are rapidly advancing insight into neural circuits that regulate appetite. Here, we review these important tools and their applications in circuits that control food seeking and consumption. Technical capabilities provided by these tools establish a rigorous experimental framework for research into the neurobiology of hunger.

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    11/04/15 | Applying the brakes: when to stop eating.
    Betley JN, Sternson SM
    Neuron. 2015 Nov 4;88(3):440-1. doi: 10.1016/j.neuron.2015.10.034

    The nucleus accumbens regulates consummatory behaviors, such as eating. In this issue of Neuron, O'Connor et al. (2015) identify dopamine receptor 1-expressing neurons that project to the lateral hypothalamus as mediating rapid control over feeding behavior.

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    10/26/15 | Hunger: The carrot and the stick.
    Sternson SM
    Molecular Metabolism. 2016 Jan;5(1):1-2. doi: 10.1016/j.molmet.2015.10.002
    09/11/15 | Cell type-specific pharmacology of NMDA receptors using masked MK801.
    Yang Y, Lee P, Sternson SM
    eLife. 2015 Sep 11;4:. doi: 10.7554/eLife.10206

    N-Methyl-D-aspartate receptors (NMDA-Rs) are ion channels that are important for synaptic plasticity, which is involved in learning and drug addiction. We show enzymatic targeting of an NMDA-R antagonist, MK801, to a molecularly defined neuronal population with the cell-type-selectivity of genetic methods and the temporal control of pharmacology. We find that NMDA-Rs on dopamine neurons are necessary for cocaine-induced synaptic potentiation, demonstrating that cell type-specific pharmacology can be used to dissect signaling pathways within complex brain circuits.

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    09/02/15 | Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss.
    Henry FE, Sugino K, Tozer A, Branco T, Sternson SM
    eLife. 2015 Sep 2;4:. doi: 10.7554/eLife.09800

    Molecular and cellular processes in neurons are critical for sensing and responding to energy deficit states, such as during weight-loss. AGRP neurons are a key hypothalamic population that is activated during energy deficit and increases appetite and weight-gain. Cell type-specific transcriptomics can be used to identify pathways that counteract weight-loss, and here we report high-quality gene expression profiles of AGRP neurons from well-fed and food-deprived young adult mice. For comparison, we also analyzed POMC neurons, an intermingled population that suppresses appetite and body weight. We find that AGRP neurons are considerably more sensitive to energy deficit than POMC neurons. Furthermore, we identify cell type-specific pathways involving endoplasmic reticulum-stress, circadian signaling, ion channels, neuropeptides, and receptors. Combined with methods to validate and manipulate these pathways, this resource greatly expands molecular insight into neuronal regulation of body weight, and may be useful for devising therapeutic strategies for obesity and eating disorders.

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