title: Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas.
abstract: 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.
  
  
  
  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.
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106; and.
authors.forename: Meredith Sorenson
authors.identifier: 0000-0002-1013-6599
authors.initials: MS
authors.lastname: Whitney
authors.affiliation: School of Biomedical Sciences, Kent State University, Kent, Ohio 44240.
authors.forename: Ashley M
authors.identifier: 0000-0002-6858-3471
authors.initials: AM
authors.lastname: Shemery
authors.affiliation: School of Biomedical Sciences, Kent State University, Kent, Ohio 44240.
authors.forename: Alexandra M
authors.identifier: 0000-0003-4415-4450
authors.initials: AM
authors.lastname: Yaw
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106; and.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Donovan
authors.affiliation: School of Biomedical Sciences, Kent State University, Kent, Ohio 44240.
authors.forename: J David
authors.initials: JD
authors.lastname: Glass
authors.affiliation: Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106; and esd@case.edu.
authors.forename: Evan S
authors.identifier: 0000-0003-4211-9934
authors.initials: ES
authors.lastname: Deneris
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D021081:Chronobiology Disorders / Q000235:genetics* / Q000473:pathology; D005106:Exploratory Behavior; D005260:Female; D049452:Green Fluorescent Proteins / Q000172:deficiency* / Q000235:genetics; D006948:Hyperkinesis / Q000235:genetics* / Q000473:pathology; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020447:Parasomnias / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012701:Serotonin / Q000172:deficiency*; D014161:Transduction, Genetic; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase
keywords: circadian behavior; hyperactivity; serotonin; siesta; tryptophan hydroxylase