title: SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive.
abstract: SIRT1 is a NAD(+)-dependent deacetylase that governs a number of genetic programs to cope with changes in the nutritional status of cells and organisms. Behavioral responses to food abundance are important for the survival of higher animals. Here we used mice with increased or decreased brain SIRT1 to show that this sirtuin regulates anxiety and exploratory drive by activating transcription of the gene encoding the monoamine oxidase A (MAO-A) to reduce serotonin levels in the brain. Indeed, treating animals with MAO-A inhibitors or selective serotonin reuptake inhibitors (SSRIs) normalized anxiety differences between wild-type and mutant animals. SIRT1 deacetylates the brain-specific helix-loop-helix transcription factor NHLH2 on lysine 49 to increase its activation of the MAO-A promoter. Both common and rare variations in the SIRT1 gene were shown to be associated with risk of anxiety in human population samples. Together these data indicate that SIRT1 mediates levels of anxiety, and this regulation may be adaptive in a changing environment of food availability.
authors.affiliation: Paul F. Glenn Laboratory, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sergiy
authors.initials: S
authors.lastname: Libert
authors.forename: Kelli
authors.initials: K
authors.lastname: Pointer
authors.forename: Eric L
authors.initials: EL
authors.lastname: Bell
authors.forename: Abhirup
authors.initials: A
authors.lastname: Das
authors.forename: Dena E
authors.initials: DE
authors.lastname: Cohen
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Karen
authors.initials: K
authors.lastname: Kapur
authors.forename: Sven
authors.initials: S
authors.lastname: Bergmann
authors.forename: Martin
authors.initials: M
authors.lastname: Preisig
authors.forename: Takeshi
authors.initials: T
authors.lastname: Otowa
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kendler
authors.forename: Xiangning
authors.initials: X
authors.lastname: Chen
authors.forename: John M
authors.initials: JM
authors.lastname: Hettema
authors.forename: Edwin J
authors.initials: EJ
authors.lastname: van den Oord
authors.forename: Justin P
authors.initials: JP
authors.lastname: Rubio
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D004328:Drive; D005106:Exploratory Behavior; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D008995:Monoamine Oxidase / Q000737:chemistry / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics
chemical_list: D014157:Transcription Factors; D008995:Monoamine Oxidase; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1