title: Alteration of synaptic activity-regulating genes underlying functional improvement by long-term exposure to an enriched environment in the adult brain.
abstract: BACKGROUND
  Housing animals in an enriched environment (EE) enhances behavioral function. However, the mechanism underlying this EE-mediated functional improvement and the resultant changes in gene expression have yet to be elucidated.
  
  
  OBJECTIVE
  We attempted to investigate the underlying mechanisms associated with long-term exposure to an EE by evaluating gene expression patterns.
  
  
  METHODS
  We housed 6-week-old CD-1 (ICR) mice in standard cages or an EE comprising a running wheel, novel objects, and social interaction for 2 months. Motor and cognitive performances were evaluated using the rotarod test and passive avoidance test, and gene expression profile was investigated in the cerebral hemispheres using microarray and gene set enrichment analysis (GSEA).
  
  
  RESULTS
  In behavioral assessment, an EE significantly enhanced rotarod performance and short-term working memory. Microarray analysis revealed that genes associated with neuronal activity were significantly altered by an EE. GSEA showed that genes involved in synaptic transmission and postsynaptic signal transduction were globally upregulated, whereas those associated with reuptake by presynaptic neurotransmitter transporters were downregulated. In particular, both microarray and GSEA demonstrated that EE exposure increased opioid signaling, acetylcholine release cycle, and postsynaptic neurotransmitter receptors but decreased Na+ / Cl- -dependent neurotransmitter transporters, including dopamine transporter Slc6a3 in the brain. Western blotting confirmed that SLC6A3, DARPP32 (PPP1R1B), and P2RY12 were largely altered in a region-specific manner.
  
  
  CONCLUSIONS
  An EE enhanced motor and cognitive function through the alteration of synaptic activity-regulating genes, improving the efficient use of neurotransmitters and synaptic plasticity by the upregulation of genes associated with postsynaptic receptor activity and downregulation of presynaptic reuptake by neurotransmitter transporters.
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Lee
authors.forename: Ji Hea
authors.initials: JH
authors.lastname: Yu
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Seo
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Park
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.forename: Hyongbum
authors.initials: H
authors.lastname: Kim
authors.forename: Sung-Rae
authors.initials: SR
authors.lastname: Cho
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D004777:Environment; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D007398:Interpersonal Relations; D008570:Memory, Short-Term / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004745:Enkephalins; C548577:P2ry12 protein, mouse; C497929:Ppp1r1b protein, mouse; D011498:Protein Precursors; D017447:Receptors, Dopamine D1; D058925:Receptors, Purinergic P2Y12; C493215:Slc6a3 protein, mouse; C033660:preproenkephalin
keywords: enriched environment; gene expression; gene set enrichment analysis; synaptic activity