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54 Publications

Showing 11-20 of 54 results
Hermundstad LabSternson Lab
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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Sternson Lab
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
Dudman LabSternson LabSpruston LabSvoboda LabMouseLight
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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Sternson Lab
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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Sternson Lab
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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Sternson Lab
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 http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Sternson Lab
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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Lee (Albert) LabSternson Lab
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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Sternson Lab
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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