Supramammillary glutamate neurons are a key node of the arousal system
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Abstract Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuM vglut2 ) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuM vglut2 neurons. Inhibition of SuM vglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuM vglut2 neurons include a subpopulation containing both glutamate and GABA (SuM vgat/vglut2 ) and another also expressing nitric oxide synthase (SuM Nos1/Vglut2 ). Activation of SuM vgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuM vgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuM Nos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuM vglut2 neurons as a key node of the wake−sleep regulatory system.
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Chemogenetic manipulation of SuM-to-dentate gyrus projections indicates this circuit regulates arousal.
“Studies using chemogenetic manipulation of projections from the SuM to DG reveal that this circuit is involved in the regulation of arousal. 30”
From Synaptic and circuit functions of multitransmitter neurons in the mammalian brain (2023) · cites this paper as [30]
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References 69 · Cited by 203
Research works printed but not linked: 2
- [65]Paxinos, G. & Franklin, K. B. The Mouse Brain in Stereotaxic Coordinates 1–350 (San Diego: Acacdemic Press, 2001).
- [72]Grove EA Neural associations of the substantia innominata in the rat: Afferent connections J. Comp. Neurol. 1988 277 315 346 10.1002/cne.902770302 2461972 · DOI
- Authors
- Pedersen, N. P., Ferrari, L., Venner, A., Wang, J. L., Abbott, S. B. G., Vujovic, N., Arrigoni, E., Saper, C. B., & Fuller, P. M.
- Affiliations
- Emory University (US)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Pedersen, Nigel P.
- Fuller, Patrick M.
- ORCID
- Venue
- Nature Communications
- Published
- 2017-11-10
- Volume
- 8
- Issue
- 1
- Pages
- 1405-1405
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5680228
- OpenAlex
- W2767588029
- Cited by
- 203
- References
- 69
- Citations by year
- 2026: 21 · 2025: 20 · 2024: 28 · 2023: 28 · 2022: 20 · 2021: 20 · 2020: 20 · 2019: 25 · 2018: 18 · 2017: 2 · 2016: 1
- FWCI
- 10.20
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- American Brain Foundation
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council (1052674)
- National Heart, Lung, and Blood Institute (P01HL095491)
- National Institute of Neurological Disorders and Stroke (R25NS070682, R21NS082854, R01NS092652, R01NS085477, R01NS103161, R01NS073613)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- supramammillary nucleus, glutamatergic neurons, VGLUT2, nitric oxide synthase, arousal system, wakefulness, REM sleep, theta oscillations, gamma oscillations, EEG, dentate gyrus granule cells, glutamate release, GABA release, caudal hypothalamus, chemogenetic activation, optogenetics, sleep regulation
- MeSH terms
- Animals, Arousal, Hypothalamus, Posterior, Male, Mice, Transgenic, Neurons, Sleep, REM, Theta Rhythm, Wakefulness, Mice, Knockout, Glutamic Acid, Vesicular Inhibitory Amino Acid Transport Proteins, Vesicular Glutamate Transport Protein 2, Mice, Nitric Oxide Synthase Type I
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