Adult brain serotonin deficiency causes hyperactivity, circadian disruption, and elimination of siestas
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UNLABELLED: Serotonin (5-HT) is a crucial neuromodulator linked to many psychiatric disorders. However, after more than 60 years of study, its role in behavior remains poorly understood, in part because of a lack of methods to target 5-HT synthesis specifically in the adult brain. Here, we have developed a genetic approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system by stereotaxic injection of an adeno-associated virus expressing Cre recombinase (AAV-Cre) into the midbrain/pons of mice carrying a loxP-conditional tryptophan hydroxylase 2 (Tph2) allele. We investigated the behavioral effects of deficient brain 5-HT synthesis and discovered a unique composite phenotype. Surprisingly, adult 5-HT deficiency did not affect anxiety-like behavior, but resulted in a robust hyperactivity phenotype in novel and home cage environments. Moreover, loss of 5-HT led to an altered pattern of circadian behavior characterized by an advance in the onset and a delay in the offset of daily activity, thus revealing a requirement for adult 5-HT in the control of daily activity patterns. Notably, after normalizing for hyperactivity, we found that the normal prolonged break in nocturnal activity (siesta), a period of rapid eye movement (REM) and non-REM sleep, was absent in all animals in which 5-HT deficiency was verified. Our findings identify adult 5-HT as a requirement for siestas, implicate adult 5-HT in sleep-wake homeostasis, and highlight the importance of our adult-specific 5-HT-synthesis-targeting approach in understanding 5-HT's role in controlling behavior. SIGNIFICANCE STATEMENT: Serotonin (5-HT) is a crucial neuromodulator, yet its role in behavior remains poorly understood, in part because of a lack of methods to target specifically adult brain 5-HT synthesis. We developed an approach that reproducibly achieves near-complete elimination of 5-HT synthesis from the adult ascending 5-HT system. Using this technique, we discovered that adult 5-HT deficiency led to a novel compound phenotype consisting of hyperactivity, disrupted circadian behavior patterns, and elimination of siestas, a period of increased sleep during the active phase. These findings highlight the importance of our approach in understanding 5-HT's role in behavior, especially in controlling activity levels, circadian behavior, and sleep-wake homeostasis, behaviors that are disrupted in many psychiatric disorders such as attention deficit hyperactivity disorder.
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The DR serotonin system negatively regulates locomotion.
“The DR serotonin system has been consistently shown to negatively regulate locomotion (Correia et al., 2017; Teissier et al., 2015; Whitney et al., 2016).”
From Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems (2018) · cites this paper as Whitney et al., 2016
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- Authors
- Whitney, M. S., Shemery, A. M., Yaw, A. M., Donovan, L. J., Glass, J. D., & Deneris, E. S.
- Affiliations
- Case Western Reserve University (US)
- Kent State University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2016-09-21
- Volume
- 36
- Issue
- 38
- Pages
- 9828-9842
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5030349
- OpenAlex
- W2522990604
- Cited by
- 77
- References
- 72
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 11 · 2021: 9 · 2020: 3 · 2019: 12 · 2018: 9 · 2017: 6 · 2016: 3
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- National Institutes of Health (MH096972)
- National Institute of Mental Health (P50MH096972, F30MH099704, R01MH062723)
- National Institute of General Medical Sciences (T32GM007250)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Keywords
- serotonin deficiency, hyperactivity, circadian activity, siesta, sleep homeostasis, tryptophan hydroxylase 2, REM sleep, attention deficit hyperactivity disorder, anxiety-like behavior, mice, mental illness, daily activity patterns
- MeSH terms
- Analysis of Variance, Animals, Brain, Chromatography, High Pressure Liquid, Exploratory Behavior, Female, Hyperkinesis, Male, Mice, Inbred C57BL, Mice, Transgenic, RNA, Messenger, Serotonin, Transduction, Genetic, Tryptophan Hydroxylase, Maze Learning, Parasomnias, Chronobiology Disorders, Green Fluorescent Proteins, Mice
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