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A hypothalamic circuit for the circadian control of aggression
Open accessAbstract
'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZ GABA) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZ GABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZ GABA transmission phase-dependently increases aggression. Finally, SPZ GABA-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.
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“A recent study in mice revealed that rhythms in the propensity of aggressive behaviours are modulated via a polysynaptic circuit from VIP neurons in the SCN to GABAergic neurons of the subparaventricular zone, which in turn innervate the ventromedial hypothalamus, an area known to regulate aggression283.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [283]
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“This chemogenetic study in mice reveals a neural circuit involving projections from the SCN to the ventromedial hypothalamus that drives time-of-day-dependent aggressive behaviours.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [283]
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Metadata
- Authors
- Todd, W. D., Fenselau, H., Wang, J. L., Zhang, R., Machado, N. L., Venner, A., Broadhurst, R. Y., Kaur, S., Lynagh, T., Olson, D. P., Lowell, B. B., Fuller, P. M., & Saper, C. B.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Boston Children's Hospital (US)
- Universidade Federal de Minas Gerais (BR)
- University of Copenhagen (DK)
- University of Michigan (US)
- Corresponding author
- Saper, Clifford B.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2018-04-09
- Volume
- 21
- Issue
- 5
- Pages
- 717-724
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5920747
- OpenAlex
- W2797554353
- Cited by
- 154
- References
- 58
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 16 · 2023: 19 · 2022: 18 · 2021: 21 · 2020: 22 · 2019: 14 · 2018: 18
- FWCI
- 10.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Alzheimer's Association (AARF-16-443613)
- California Institute of Technology
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (2014‐0)
- National Institutes of Health (HL00701-15, DK057521, DK089044, DK111401, HL095491, DK046200, NS073613, NS072337)
- National Institute on Aging (R03AG062883, P01AG009975)
- National Heart, Lung, and Blood Institute (P01HL095491, T32HL007901)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, R01DK075632, R01DK089044, P30DK046200, K08DK071561, R01DK111401, R01DK096010)
- National Institute of Neurological Disorders and Stroke (R01NS072337, R01NS092652, R01NS085477, R01NS103161, F32NS084582, R01NS073613)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- circadian clock, aggression, suprachiasmatic nucleus, GABAergic neurons, ventromedial hypothalamus, vasoactive intestinal peptide, attack behavior, sundowning, Alzheimer's disease, dementia, chemogenetic inhibition
- MeSH terms
- Aggression, Animals, Brain Mapping, Circadian Rhythm, Corticosterone, gamma-Aminobutyric Acid, Hypothalamus, Male, Mice, Inbred C57BL, Neural Pathways, Paraventricular Hypothalamic Nucleus, Suprachiasmatic Nucleus, Vasoactive Intestinal Peptide, Ventromedial Hypothalamic Nucleus, Excitatory Postsynaptic Potentials, Mice, Optogenetics
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