AgRP neurons trigger long-term potentiation and facilitate food seeking

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Abstract

Sufficient feeding is essential for animals’ survival, which requires a cognitive capability to facilitate food seeking, but the neurobiological processes regulating food seeking are not fully understood. Here we show that stimulation of agouti-related peptide-expressing (AgRP) neurons triggers a long-term depression (LTD) of spontaneous excitatory post-synaptic current (sEPSC) in adjacent pro-opiomelanocortin (POMC) neurons and in most of their distant synaptic targets, including neurons in the paraventricular nucleus of the thalamus (PVT). The AgRP-induced sEPCS LTD can be enhanced by fasting but blunted by satiety signals, e.g. leptin and insulin. Mice subjected to food-seeking tasks develop similar neural plasticity in AgRP-innervated PVT neurons. Further, ablation of the majority of AgRP neurons, or only a subset of AgRP neurons that project to the PVT, impairs animals’ ability to associate spatial and contextual cues with food availability during food seeking. A similar impairment can be also induced by optogenetic inhibition of the AgRP→PVT projections. Together, these results indicate that the AgRP→PVT circuit is necessary for food seeking.

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Most cited references 61

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The Cre/lox system is widely used in mice to achieve cell-type-specific gene expression. However, a strong and universal responding system to express genes under Cre control is still lacking. We have generated a set of Cre reporter mice with strong, ubiquitous expression of fluorescent proteins of different spectra. The robust native fluorescence of these reporters enables direct visualization of fine dendritic structures and axonal projections of the labeled neurons, which is useful in mapping neuronal circuitry, imaging and tracking specific cell populations in vivo. Using these reporters and a high-throughput in situ hybridization platform, we are systematically profiling Cre-directed gene expression throughout the mouse brain in a number of Cre-driver lines, including novel Cre lines targeting different cell types in the cortex. Our expression data are displayed in a public online database to help researchers assess the utility of various Cre-driver lines for cell-type-specific genetic manipulation.

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Genetic dissection of an amygdala microcircuit that gates conditioned fear

Wulf Haubensak, Prabhat Kunwar, Haijiang Cai … (2010)

The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. We used molecular genetic approaches to map the functional connectivity of a subpopulation of GABAergic neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-delta (PKCδ). Channelrhodopsin-2 assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKCδ+ neurons inhibit output neurons in the medial CE (CEm), and also make reciprocal inhibitory synapses with PKCδ− neurons in CEl. Electrical silencing of PKCδ+ neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus (CS), called CEloff units (Ciocchi et al, this issue). This correspondence, together with behavioral data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.

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Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons.

Linh Vong, Chianping Ye, Zongfang Yang … (2011)

Leptin acts in the brain to prevent obesity. The underlying neurocircuitry responsible for this is poorly understood, in part because of incomplete knowledge regarding first-order, leptin-responsive neurons. To address this, we and others have been removing leptin receptors from candidate first-order neurons. While functionally relevant neurons have been identified, the observed effects have been small, suggesting that most first-order neurons remain unidentified. Here we take an alternative approach and test whether first-order neurons are inhibitory (GABAergic, VGAT⁺) or excitatory (glutamatergic, VGLUT2⁺). Remarkably, the vast majority of leptin's antiobesity effects are mediated by GABAergic neurons; glutamatergic neurons play only a minor role. Leptin, working directly on presynaptic GABAergic neurons, many of which appear not to express AgRP, reduces inhibitory tone to postsynaptic POMC neurons. As POMC neurons prevent obesity, their disinhibition by leptin action on presynaptic GABAergic neurons probably mediates, at least in part, leptin's antiobesity effects. Copyright © 2011 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Yanlin He:

ORCID: http://orcid.org/0000-0002-5471-9016

yanlin.he@pbrc.edu

Yong Xu:

ORCID: http://orcid.org/0000-0002-4908-1572

yongx@bcm.edu

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2158-3188

Publication date (Electronic): 5 January 2021

Publication date PMC-release: 5 January 2021

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 11

Affiliations

[1 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Children’s Nutrition Research Center, Department of Pediatrics, , Baylor College of Medicine, ; Houston, TX 77030 USA

[2 ]GRID grid.267308.8, ISNI 0000 0000 9206 2401, Brown Foundation Institute of Molecular Medicine, , University of Texas Health Science Center at Houston, ; Houston, TX 77030 USA

[3 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, , Baylor College of Medicine, ; Houston, TX 77030 USA

[4 ]GRID grid.39382.33, ISNI 0000 0001 2160 926X, Department of Molecular and Cellular Biology, , Baylor College of Medicine, ; Houston, TX 77030 USA

[5 ]GRID grid.410428.b, ISNI 0000 0001 0665 5823, Pennington Biomedical Research Center, , Louisiana State University System, ; Baton Rouge, LA 70808 USA

Author information

Julia Wang http://orcid.org/0000-0003-0343-9820

Makoto Fukuda http://orcid.org/0000-0003-0112-9925

Qingchun Tong http://orcid.org/0000-0002-4561-2540

Zheng Sun http://orcid.org/0000-0002-6858-0633

Yanlin He http://orcid.org/0000-0002-5471-9016

Yong Xu http://orcid.org/0000-0002-4908-1572

Article

Publisher ID: 1161

DOI: 10.1038/s41398-020-01161-1

PMC ID: 7791100

PubMed ID: 33414382

SO-VID: e0805ea1-1a48-4184-bf97-aa97168c95d5

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 2 December 2020

Date revision received : 7 December 2020

Date accepted : 10 December 2020

Funding

Funded by: FundRef https://doi.org/10.13039/100000062, U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases);

Award ID: P01DK113954

Award ID: R01DK115761

Award ID: R01DK117281

Award ID: R01DK120858

Award ID: K99DK107008

Award ID: R01DK092605

Award Recipient : Pingwen Xu Qingchun Tong Yong Xu

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)

Funded by: FundRef https://doi.org/10.13039/100007917, United States Department of Agriculture | Agricultural Research Service (USDA Agricultural Research Service);

Award ID: 51000-064-01S

Award Recipient : Yong Xu

Funded by: FundRef https://doi.org/10.13039/100000968, American Heart Association (American Heart Association, Inc.);

Award ID: 16POST27260254

Award Recipient : Chunmei Wang

Funded by: FundRef https://doi.org/10.13039/100000041, American Diabetes Association (ADA);

Award ID: 1-19-PDF-012

Award ID: 1-15-BS-184

Award ID: 1-17-PDF-138

Award Recipient : Wenjun Zhou Qingchun Tong Yanlin He

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases)

Funded by: FundRef https://doi.org/10.13039/100000066, U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences (NIEHS);

Award ID: R01ES027544

Award Recipient : Zheng Sun