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54 Publications

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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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    Sternson Lab
    12/05/13 | Parallel, redundant circuit organization for homeostatic control of feeding behavior.
    Betley JN, Cao ZF, Ritola KD, Sternson SM
    Cell. 2013 Dec 5;155(6):1337-50. doi: 10.1016/j.cell.2013.11.002

    Neural circuits for essential natural behaviors are shaped by selective pressure to coordinate reliable execution of flexible goal-directed actions. However, the structural and functional organization of survival-oriented circuits is poorly understood due to exceptionally complex neuroanatomy. This is exemplified by AGRP neurons, which are a molecularly defined population that is sufficient to rapidly coordinate voracious food seeking and consumption behaviors. Here, we use cell-type-specific techniques for neural circuit manipulation and projection-specific anatomical analysis to examine the organization of this critical homeostatic circuit that regulates feeding. We show that AGRP neuronal circuits use a segregated, parallel, and redundant output configuration. AGRP neuron axon projections that target different brain regions originate from distinct subpopulations, several of which are sufficient to independently evoke feeding. The concerted anatomical and functional analysis of AGRP neuron projection populations reveals a constellation of core forebrain nodes, which are part of an extended circuit that mediates feeding behavior.

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    Sternson Lab
    06/01/13 | Neural circuits and motivational processes for hunger.
    Sternson SM, Betley JN, Cao ZF
    Current Opinion in Neurobiology. 2013 Jun;23(3):353-60. doi: 10.1016/j.conb.2013.04.006

    How does an organism’s internal state direct its actions? At one moment an animal forages for food with acrobatic feats such as tree climbing and jumping between branches. At another time, it travels along the ground to find water or a mate, exposing itself to predators along the way. These behaviors are costly in terms of energy or physical risk, and the likelihood of performing one set of actions relative to another is strongly modulated by internal state. For example, an animal in energy deficit searches for food and a dehydrated animal looks for water. The crosstalk between physiological state and motivational processes influences behavioral intensity and intent, but the underlying neural circuits are poorly understood. Molecular genetics along with optogenetic and pharmacogenetic tools for perturbing neuron function have enabled cell type-selective dissection of circuits that mediate behavioral responses to physiological state changes. Here, we review recent progress into neural circuit analysis of hunger in the mouse by focusing on a starvation-sensitive neuron population in the hypothalamus that is sufficient to promote voracious eating. We also consider research into the motivational processes that are thought to underlie hunger in order to outline considerations for bridging the gap between homeostatic and motivational neural circuits.

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    Sternson Lab
    03/06/13 | Hypothalamic survival circuits: blueprints for purposive behaviors.
    Sternson SM
    Neuron. 2013 Mar 6;77(5):810-24. doi: 10.1016/j.neuron.2013.02.018

    Neural processes that direct an animal’s actions toward environmental goals are critical elements for understanding behavior. The hypothalamus is closely associated with motivated behaviors required for survival and reproduction. Intense feeding, drinking, aggressive, and sexual behaviors can be produced by a simple neuronal stimulus applied to discrete hypothalamic regions. What can these "evoked behaviors" teach us about the neural processes that determine behavioral intent and intensity? Small populations of neurons sufficient to evoke a complex motivated behavior may be used as entry points to identify circuits that energize and direct behavior to specific goals. Here, I review recent applications of molecular genetic, optogenetic, and pharmacogenetic approaches that overcome previous limitations for analyzing anatomically complex hypothalamic circuits and their interactions with the rest of the brain. These new tools have the potential to bridge the gaps between neurobiological and psychological thinking about the mechanisms of complex motivated behavior.

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    Sternson Lab
    08/09/12 | Deconstruction of a neural circuit for hunger.
    Atasoy D, Betley JN, Su HH, Sternson SM
    Nature. 2012 Aug 9;488(7410):172-7. doi: 10.1038/nature11270

    Hunger is a complex behavioural state that elicits intense food seeking and consumption. These behaviours are rapidly recapitulated by activation of starvation-sensitive AGRP neurons, which present an entry point for reverse-engineering neural circuits for hunger. Here we mapped synaptic interactions of AGRP neurons with multiple cell populations in mice and probed the contribution of these distinct circuits to feeding behaviour using optogenetic and pharmacogenetic techniques. An inhibitory circuit with paraventricular hypothalamus (PVH) neurons substantially accounted for acute AGRP neuron-evoked eating, whereas two other prominent circuits were insufficient. Within the PVH, we found that AGRP neurons target and inhibit oxytocin neurons, a small population that is selectively lost in Prader-Willi syndrome, a condition involving insatiable hunger. By developing strategies for evaluating molecularly defined circuits, we show that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding. These experiments reveal a new neural circuit that regulates hunger state and pathways associated with overeating disorders.

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    Sternson LabLooger LabLavis Lab
    03/27/12 | Selective esterase-ester pair for targeting small molecules with cellular specificity.
    Tian L, Yang Y, Wysocki LM, Arnold AC, Hu A, Ravichandran B, Sternson SM, Looger LL, Lavis LD
    Proceedings of the National Academy of Sciences of the United States of America. 2012 Mar 27;109:4756-61. doi: 10.1073/pnas.1111943109

    Small molecules are important tools to measure and modulate intracellular signaling pathways. A longstanding limitation for using chemical compounds in complex tissues has been the inability to target bioactive small molecules to a specific cell class. Here, we describe a generalizable esterase-ester pair capable of targeted delivery of small molecules to living cells and tissue with cellular specificity. We used fluorogenic molecules to rapidly identify a small ester masking motif that is stable to endogenous esterases, but is efficiently removed by an exogenous esterase. This strategy allows facile targeting of dyes and drugs in complex biological environments to label specific cell types, illuminate gap junction connectivity, and pharmacologically perturb distinct subsets of cells. We expect this approach to have general utility for the specific delivery of many small molecules to defined cellular populations.

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    Sternson Lab
    02/08/12 | Neuron transplantation partially reverses an obesity disorder in mice.
    Sternson SM
    Cell Metabolism. 2012 Feb 8;15(2):133-4. doi: 10.1016/j.cmet.2012.01.011

    Mice lacking leptin receptors are grossly obese and diabetic, in part due to dysfunction in brain circuits important for energy homeostasis. Transplantation of leptin receptor-expressing hypothalamic progenitor neurons into the brains of leptin receptor deficient mice led to integration into neural circuits, reduced obesity, and normalized circulating glucose levels.

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    Sternson Lab
    01/15/12 | Regulation of neuronal input transformations by tunable dendritic inhibition.
    Lovett-Barron M, Turi GF, Kaifosh P, Lee PH, Bolze F, Sun X, Nicoud Jc, Zemelman BV, Sternson SM, Losonczy A
    Nature Neuroscience. 2012 Jan 15;15(3):423-30. doi: 10.1038/nn.3024

    Transforming synaptic input into action potential output is a fundamental function of neurons. The pattern of action potential output from principal cells of the mammalian hippocampus encodes spatial and nonspatial information, but the cellular and circuit mechanisms by which neurons transform their synaptic input into a given output are unknown. Using a combination of optical activation and cell type-specific pharmacogenetic silencing in vitro, we found that dendritic inhibition is the primary regulator of input-output transformations in mouse hippocampal CA1 pyramidal cells, and acts by gating the dendritic electrogenesis driving burst spiking. Dendrite-targeting interneurons are themselves modulated by interneurons targeting pyramidal cell somata, providing a synaptic substrate for tuning pyramidal cell output through interactions in the local inhibitory network. These results provide evidence for a division of labor in cortical circuits, where distinct computational functions are implemented by subtypes of local inhibitory neurons.

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    Sternson Lab
    09/16/11 | Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop.
    Yang Y, Atasoy D, Su HH, Sternson SM
    Cell. 2011 Sep 16;146:992-1003. doi: 10.1016/j.cell.2011.07.039

    Synaptic plasticity in response to changes in physiologic state is coordinated by hormonal signals across multiple neuronal cell types. Here, we combine cell-type-specific electrophysiological, pharmacological, and optogenetic techniques to dissect neural circuits and molecular pathways controlling synaptic plasticity onto AGRP neurons, a population that regulates feeding. We find that food deprivation elevates excitatory synaptic input, which is mediated by a presynaptic positive feedback loop involving AMP-activated protein kinase. Potentiation of glutamate release was triggered by the orexigenic hormone ghrelin and exhibited hysteresis, persisting for hours after ghrelin removal. Persistent activity was reversed by the anorexigenic hormone leptin, and optogenetic photostimulation demonstrated involvement of opioid release from POMC neurons. Based on these experiments, we propose a memory storage device for physiological state constructed from bistable synapses that are flipped between two sustained activity states by transient exposure to hormones signaling energy levels.

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    Sternson Lab
    09/08/11 | Metabolism: let them eat fat.
    Sternson SM
    Nature. 2011 Sep 8;477(7363):166-7. doi: 10.1038/477166a

    A specialist neuron uses an intriguing process to help control the body's response to hunger. A lipid pathway involving the breakdown of cellular components regulates the expression of a neuropeptide that affects feeding and body weight.

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