Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations

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Abstract

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCN ^VIP) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCN ^VIP neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCN ^VIP neurons may regulate LMA rhythms. In vivo photometry revealed that while SCN ^VIP neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNA-sequencing revealed that SCN ^VIP neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCN ^VIP neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCN ^VIP cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCN ^VIP subtypes.

Abstract

Cell groups in the hypothalamic suprachiasmatic clock contribute to the genesis of circadian rhythms. The authors identified two populations of vasoactive intestinal polypeptide-expressing neurons in the suprachiasmatic nucleus which regulate locomotor circadian rhythm in mice.

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Div-Seq: Single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons.

Naomi Habib, Yinqing Li, Matthias Heidenreich … (2016)

Single-cell RNA sequencing (RNA-Seq) provides rich information about cell types and states. However, it is difficult to capture rare dynamic processes, such as adult neurogenesis, because isolation of rare neurons from adult tissue is challenging and markers for each phase are limited. Here, we develop Div-Seq, which combines scalable single-nucleus RNA-Seq (sNuc-Seq) with pulse labeling of proliferating cells by 5-ethynyl-2'-deoxyuridine (EdU) to profile individual dividing cells. sNuc-Seq and Div-Seq can sensitively identify closely related hippocampal cell types and track transcriptional dynamics of newborn neurons within the adult hippocampal neurogenic niche, respectively. We also apply Div-Seq to identify and profile rare newborn neurons in the adult spinal cord, a noncanonical neurogenic region. sNuc-Seq and Div-Seq open the way for unbiased analysis of diverse complex tissues.

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Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons.

Sara Aton, Christopher Colwell, Anthony J. Harmar … (2005)

The mammalian suprachiasmatic nucleus (SCN) is a master circadian pacemaker. It is not known which SCN neurons are autonomous pacemakers or how they synchronize their daily firing rhythms to coordinate circadian behavior. Vasoactive intestinal polypeptide (VIP) and the VIP receptor VPAC(2) (encoded by the gene Vipr2) may mediate rhythms in individual SCN neurons, synchrony between neurons, or both. We found that Vip(-/-) and Vipr2(-/-) mice showed two daily bouts of activity in a skeleton photoperiod and multiple circadian periods in constant darkness. Loss of VIP or VPAC(2) also abolished circadian firing rhythms in approximately half of all SCN neurons and disrupted synchrony between rhythmic neurons. Critically, daily application of a VPAC(2) agonist restored rhythmicity and synchrony to VIP(-/-) SCN neurons, but not to Vipr2(-/-) neurons. We conclude that VIP coordinates daily rhythms in the SCN and behavior by synchronizing a small population of pacemaking neurons and maintaining rhythmicity in a larger subset of neurons.

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Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections.

Eric E. Abrahamson, Robert Moore (2001)

The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker of the mammalian circadian timing system. The SCN is composed of two anatomically and functionally distinct subdivisions, designated core and shell, which can be distinguished on the basis of their chemoarchitecture and connections in the rat. In the present study, we examine the intrinsic organization and the afferent and efferent connections of the mouse SCN using immunocytochemistry and ocular injections of cholera toxin. Neurons of the SCN shell contain GABA, calbindin (CALB), arginine vasopressin (AVP), angiotensin II (AII) and met-enkephalin (mENK), and receive input from galanin (GAL) and vasoactive intestinal polypeptide (VIP) immunoreactive fibers. Neurons of the SCN core synthesize GABA, CALB, VIP, calretinin (CALR), gastrin releasing peptide (GRP), and neurotensin (NT), and receive input from the retina and from fibers that contain neuropeptide Y (NPY) and 5-hydroxytryptamine (5HT). Fibers projecting from SCN neurons that are immunoreactive for AVP and VIP exhibit a characteristic morphology, and project to the lateral septum, a series of medial hypothalamic areas extending from the preoptic to the posterior hypothalamic area and to the paraventricular thalamic nucleus. The organization of the mouse SCN, and its connections, are similar to that in other mammalian species.

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Author and article information

Contributors

Patrick M. Fuller:

ORCID: http://orcid.org/0000-0002-7017-583X

pfuller@bidmc.harvard.edu

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 2 September 2020

Publication date PMC-release: 2 September 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 4410

Affiliations

[1 ]GRID grid.135963.b, ISNI 0000 0001 2109 0381, Department of Zoology and Physiology, Program in Neuroscience, , University of Wyoming, ; Laramie, WY 82071 USA

[2 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Neurology, Beth Israel Deaconess Medical Center, , Division of Sleep Medicine, Harvard Medical School, ; Boston, MA 02215 USA

[3 ]GRID grid.168645.8, ISNI 0000 0001 0742 0364, Department of Neurobiology, , University of Massachusetts Medical School, ; Worcester, MA 01605 USA

[4 ]GRID grid.5288.7, ISNI 0000 0000 9758 5690, Oregon Institute for Occupational Health Sciences and Department of Behavioral Neuroscience, , Oregon Health & Science University, ; Portland, OR 97239 USA

[5 ]GRID grid.27755.32, ISNI 0000 0000 9136 933X, Department of Biology, , University of Virginia, ; Charlottesville, VA USA

[6 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Pediatrics, , University of Michigan, ; Ann Arbor, MI USA

Author information

Anne Venner http://orcid.org/0000-0001-7481-3248

Lauren M. Hablitz http://orcid.org/0000-0001-6159-7742

Charles N. Allen http://orcid.org/0000-0002-3689-2878

David P. Olson http://orcid.org/0000-0001-9249-7760

Patrick M. Fuller http://orcid.org/0000-0002-7017-583X

Article

Publisher ID: 17197

DOI: 10.1038/s41467-020-17197-2

PMC ID: 7468160

PubMed ID: 32879310

SO-VID: 358082b4-01fc-460a-bc21-93d690fbd72f

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 : 4 September 2019

Date accepted : 12 June 2020

Funding

Funded by: FundRef https://doi.org/10.13039/100000957, Alzheimer’s Association;

Award ID: AARF-16-443613

Award Recipient : William D. Todd

Funded by: FundRef https://doi.org/10.13039/100000049, U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging);

Award ID: R03AG062883-01

Award Recipient : William D. Todd

Funded by: FundRef https://doi.org/10.13039/100009365, Sleep Research Society (SRS);

Award ID: 016-JP-17

Award Recipient : Anne Venner

Funded by: FundRef https://doi.org/10.13039/100000025, U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH);

Award ID: K99MH103399

Award Recipient : Christelle Anaclet

Funded by: FundRef https://doi.org/10.13039/100000026, U.S. Department of Health & Human Services | NIH | National Institute on Drug Abuse (NIDA);

Award ID: T32DA007262

Award Recipient : Lauren M. Hablitz

Funded by: FundRef https://doi.org/10.13039/100000065, U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS);

Award ID: NS091126

Award ID: NS036607

Award ID: NS103842

Award ID: NS073613

Award ID: NS092652

Award ID: NS103161

Award Recipient : Elda Arrigoni Charles N. Allen Patrick M. Fuller

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)

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Keywords: circadian mechanisms,circadian regulation

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ScienceOpen disciplines: Uncategorized

Keywords: circadian mechanisms, circadian regulation

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Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations

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Special issue: Socio-Urban Critiques and a New Normal

Most cited references 56

Div-Seq: Single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons.

Vasoactive intestinal polypeptide mediates circadian rhythmicity and synchrony in mammalian clock neurons.

Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections.

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Cited by 48

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