A neural circuit for circadian regulation of arousal
Abstract
An unknown aspect of behavioral state regulation is how the circadian oscillator of the suprachiasmatic nucleus (SCN) regulates sleep and waking. In this report, we describe the necessary elements for a circuit that provides circadian regulation of arousal. Trans-synaptic retrograde tracing revealed a prominent indirect projection from the SCN to the noradrenergic nucleus locus coeruleus (LC), a brain arousal system. Double-labeling experiments revealed several possible links between the SCN and the LC, including the dorsomedial (DMH) and paraventricular hypothalamic nuclei (PVN), as well as medial and ventrolateral pre-optic areas. Lesion studies confirmed that the DMH is a substantial relay in this circuit. Next, neurophysiology experiments revealed circadian variations in LC impulse activity. Lesions of the DMH eliminated these circadian changes in LC activity, confirming the functionality of the SCN-DMH-LC circuit. These results reveal mechanisms for regulation of circadian and sleep-waking functions.
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Sympathovagal balance is lowest during REM sleep, when the locus coeruleus, the main brain source of catecholamine biosynthesis, is silent.
“Sympathovagal balance is lowest during REM sleep, when the locus coeruleus, the main brain source of catecholamine biosynthesis, is silent.71”
From Interacting epidemics? Sleep curtailment, insulin resistance, and obesity (2012) · cites this paper as [71]
Projections from the suprachiasmatic nucleus to the locus coeruleus are important for transitions from focused attention to behavioral flexibility.
“and are important for transitions from focused attention to behavioral flexibility (Aston-Jones et al., 2001)”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Aston-Jones et al., 2001
Projections from the suprachiasmatic nucleus to the locus coeruleus facilitate circadian regulation of noradrenergic activity.
“For example, projections from the SCN to the locus coeruleus (LC) facilitate circadian regulation of noradrenergic activity”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Aston-Jones et al., 2001
The neuroanatomical circuit mediating circadian regulation of arousal is a multisynaptic pathway between the suprachiasmatic nucleus and the noradrenergic neurons of the locus coeruleus.
“The neuroanatomical circuit mediating circadian regulation of arousal is a multisynaptic pathway between the SCN and the noradrenergic neurons of the LC (Aston-Jones et al., 2001; Deurveilher and Semba, 2005).”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Aston-Jones et al., 2001
Lesions of the dorsomedial hypothalamus eliminate the circadian rhythm in locus coeruleus neuronal activity, whereas lesions of the locus coeruleus decrease the amplitude of circadian rhythms of slow-wave activity in the cortex.
“The functional importance of this circuit was demonstrated by the findings that lesions of the DMH eliminate the circadian rhythm in LC neuronal activity, whereas lesions of the LC decrease the amplitude of circadian rhythms of slow-wave activity in the cortex (Aston-Jones et al., 2001).”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Aston-Jones et al., 2001
Neurons in the suprachiasmatic nucleus project to the dorsomedial hypothalamus, which in turn projects to the locus coeruleus.
“As shown by neuroanatomical tract-tracing as well as lesion studies, the neurons in the SCN, which receives retinal input, project to the dorsomedial hypothalamus (DMH), which in turn projects to the LC (Aston-Jones et al., 2001; Deurveilher and Semba, 2005).”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Aston-Jones et al., 2001
An indirect projection from the SCN to the locus coeruleus appears to regulate the circadian rhythm in noradrenergic neuronal activity.
“For example, an indirect projection from the SCN to the locus coeruleus appears to regulate the circadian rhythm in noradrenergic neuronal activity (Aston-Jones et al., 2001).”
From Circadian genes, rhythms and the biology of mood disorders (2007) · cites this paper as Aston-Jones et al., 2001
Major neurotransmitters implicated in mood regulation, including serotonin, norepinephrine, and dopamine, have a circadian rhythm in their levels, release, and synthesis-related enzymes.
“Indeed some of the major neurotransmitters that have been implicated in mood regulation, including serotonin, norepinephrine and dopamine, have a circadian rhythm in their levels, release, and synthesis-related enzymes (Weiner et al., 1992; Shieh et al., 1997; Aston-Jones et al., 2001; Barassin et al., 2002; Khaldy et al., 2002; Castaneda et al., 2004; Weber et al., 2004; Malek et al., 2005).”
From Circadian genes, rhythms and the biology of mood disorders (2007) · cites this paper as Aston-Jones et al., 2001
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- Authors
- Aston-Jones, G., Chen, S., Zhu, Y., & Oshinsky, M. L.
- Affiliations
- Long Island Jewish Medical Center (US)
- University of Pennsylvania (US)
- Thomas Jefferson University (US)
- Venue
- Nature Neuroscience
- Published
- 2001-07
- Volume
- 4
- Issue
- 7
- Pages
- 732-738
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W1488974332
- Cited by
- 632
- References
- 51
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 19 · 2023: 23 · 2022: 14 · 2021: 20 · 2020: 23 · 2019: 16 · 2018: 38 · 2017: 21 · 2016: 31 · 2015: 23 · 2014: 23 · 2013: 22 · 2012: 35
- FWCI
- 9.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (R01NS024698, NS 24698)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- circadian rhythm, arousal, suprachiasmatic nucleus, locus coeruleus, noradrenergic system, dorsomedial hypothalamus, paraventricular nucleus, preoptic area, sleep-wake regulation, circadian oscillations, neural circuits, retrograde tracing
- MeSH terms
- Animals, Arousal, Circadian Rhythm, Electrophysiology, Hypothalamus, Immunohistochemistry, Locus Coeruleus, Male, Microinjections, Microscopy, Fluorescence, Herpesvirus 1, Suid, Suprachiasmatic Nucleus, Rats, Sprague-Dawley, Rats
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