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53 Publications

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    Sternson Lab
    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
    Sternson Lab
    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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    Sternson Lab
    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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    Sternson Lab
    08/26/15 | Optogenetics: 10 years after ChR2 in neurons-views from the community.
    Adamantidis A, Arber S, Bains JS, Bamberg E, Bonci A, Buzsáki G, Cardin JA, Costa RM, Dan Y, Goda Y, Graybiel AM, Häusser M, Hegemann P, Huguenard JR, Insel TR, Janak PH, Johnston D, Josselyn SA, Koch C, Kreitzer AC, Lüscher C, Malenka RC, Miesenböck G, Nagel G, Roska B, Schnitzer MJ, Shenoy KV, Soltesz I, Sternson SM, Tsien RW, Tsien RY, Turrigiano GG, Tye KM, Wilson RI
    Nature Neuroscience. 2015 Aug 26;18(9):1202-12. doi: 10.1038/nn.4106
    04/27/15 | Neurons for hunger and thirst transmit a negative-valence teaching signal.
    Betley JN, Xu S, Cao ZF, Gong R, Magnus CJ, Yu Y, Sternson SM
    Nature. 2015 Apr 27;521(7551):180-5. doi: 10.1038/nature14416

    Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

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    Sternson Lab
    12/13/14 | Agouti-related protein neuron circuits that regulate appetite.
    Sternson SM, Atasoy D
    Neuroendocrinology. 2014 Nov 6;507(7491):238-42. doi: 10.1159/000369072

    New tools for mapping and manipulating molecularly defined neural circuits have improved understanding of how the central nervous system regulates appetite. Studies focused on AGRP neurons, a starvation-sensitive hypothalamic population, have identified multiple circuit elements that can elicit or suppress feeding behavior. Distinct axon projections of this neuron population point to different circuits that regulate long-term appetite, short-term feeding, or visceral malaise-mediated anorexia. Here, we review recent studies examining these neural circuits that control food intake. © 2014 S. Karger AG, Basel.

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    Sternson LabScheffer Lab
    12/04/14 | A genetically specified connectomics approach applied to long-range feeding regulatory circuits.
    Atasoy D, Betley JN, Li W, Su HH, Sertel SM, Scheffer LK, Simpson JH, Fetter RD, Sternson SM
    Nature Neuroscience. 2014 Dec;17(12):1830-9. doi: 10.1038/nn.3854

    Synaptic connectivity and molecular composition provide a blueprint for information processing in neural circuits. Detailed structural analysis of neural circuits requires nanometer resolution, which can be obtained with serial-section electron microscopy. However, this technique remains challenging for reconstructing molecularly defined synapses. We used a genetically encoded synaptic marker for electron microscopy (GESEM) based on intra-vesicular generation of electron-dense labeling in axonal boutons. This approach allowed the identification of synapses from Cre recombinase-expressing or GAL4-expressing neurons in the mouse and fly with excellent preservation of ultrastructure. We applied this tool to visualize long-range connectivity of AGRP and POMC neurons in the mouse, two molecularly defined hypothalamic populations that are important for feeding behavior. Combining selective ultrastructural reconstruction of neuropil with functional and viral circuit mapping, we characterized some basic features of circuit organization for axon projections of these cell types. Our findings demonstrate that GESEM labeling enables long-range connectomics with molecularly defined cell types.

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    Sternson Lab
    12/04/14 | Leptin mediates the increase in blood pressure associated with obesity.
    Simonds SE, Pryor JT, Ravussin E, Greenway FL, Dileone R, Allen AM, Bassi J, Elmquist JK, Keogh JM, Henning E, Myers MG, Licinio J, Brown RD, Enriori PJ, O'Rahilly S, Sternson SM, Grove KL, Spanswick DC, Farooqi IS, Cowley MA
    Cell. 2014 Dec 4;159(6):1404-16. doi: 10.1016/j.cell.2014.10.058

    Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.

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    Sternson Lab
    07/08/14 | Chemogenetic tools to interrogate brain functions.
    Sternson SM, Roth BL
    Annual Review of Neuroscience. 2014 Jul 8;37:387-407. doi: 10.1146/annurev-neuro-071013-014048

    Elucidating the roles of neuronal cell types for physiology and behavior is essential for understanding brain functions. Perturbation of neuron electrical activity can be used to probe the causal relationship between neuronal cell types and behavior. New genetically encoded neuron perturbation tools have been developed for remotely controlling neuron function using small molecules that activate engineered receptors that can be targeted to cell types using genetic methods. Here we describe recent progress for approaches using genetically engineered receptors that selectively interact with small molecules. Called "chemogenetics," receptors with diverse cellular functions have been developed that facilitate the selective pharmacological control over a diverse range of cell-signaling processes, including electrical activity, for molecularly defined cell types. These tools have revealed remarkably specific behavioral physiological influences for molecularly defined cell types that are often intermingled with populations having different or even opposite functions.

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    Sternson Lab
    05/21/14 | Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus→midbrain pathway for feeding behavior.
    Stachniak TJ, Ghosh A, Sternson SM
    Neuron. 2014 May 21;82(4):797-808. doi: 10.1016/j.neuron.2014.04.008

    Brain function is mediated by neural circuit connectivity, and elucidating the role of connections is aided by techniques to block their output. We developed cell-type-selective, reversible synaptic inhibition tools for mammalian neural circuits by leveraging G protein signaling pathways to suppress synaptic vesicle release. Here, we find that the pharmacologically selective designer Gi-protein-coupled receptor hM4D is a presynaptic silencer in the presence of its cognate ligand clozapine-N-oxide (CNO). Activation of hM4D signaling sharply reduced synaptic release probability and synaptic current amplitude. To demonstrate the utility of this tool for neural circuit perturbations, we developed an axon-selective hM4D-neurexin variant and used spatially targeted intracranial CNO injections to localize circuit connections from the hypothalamus to the midbrain responsible for feeding behavior. This synaptic silencing approach is broadly applicable for cell-type-specific and axon projection-selective functional analysis of diverse neural circuits.

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