title: Prolonged maternal separation induces undernutrition and systemic inflammation with disrupted hippocampal development in mice.
abstract: OBJECTIVE
  Prolonged maternal separation (PMS) in the first 2 wk of life has been associated with poor growth with lasting effects in brain structure and function. This study aimed to investigate whether PMS-induced undernutrition could cause systemic inflammation and changes in nutrition-related hormonal levels, affecting hippocampal structure and neurotransmission in C57BL/6J suckling mice.
  
  
  METHODS
  This study assessed mouse growth parameters coupled with insulin-like growth factor-1 (IGF-1) serum levels. In addition, leptin, adiponectin, and corticosterone serum levels were measured following PMS. Hippocampal stereology and the amino acid levels were also assessed. Furthermore, we measured myelin basic protein and synapthophysin (SYN) expression in the overall brain tissue and hippocampal SYN immunolabeling. For behavioral tests, we analyzed the ontogeny of selected neonatal reflexes. PMS was induced by separating half the pups in each litter from their lactating dams for defined periods each day (4 h on day 1, 8 h on day 2, and 12 h thereafter). A total of 67 suckling pups were used in this study.
  
  
  RESULTS
  PMS induced significant slowdown in weight gain and growth impairment. Significant reductions in serum leptin and IGF-1 levels were found following PMS. Total CA3 area and volume were reduced, specifically affecting the pyramidal layer in PMS mice. CA1 pyramidal layer area was also reduced. Overall hippocampal SYN immunolabeling was lower, especially in CA3 field and dentate gyrus. Furthermore, PMS reduced hippocampal aspartate, glutamate, and gamma-aminobutyric acid levels, as compared with unseparated controls.
  
  
  CONCLUSIONS
  These findings suggest that PMS causes significant growth deficits and alterations in hippocampal morphology and neurotransmission.
authors.affiliation: Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Ceara, Brazil.
authors.forename: Ítalo Leite
authors.initials: ÍL
authors.lastname: Figueiredo
authors.affiliation: Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Ceara, Brazil.
authors.forename: Priscila B
authors.initials: PB
authors.lastname: Frota
authors.affiliation: Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Ceara, Brazil.
authors.forename: Davi G
authors.initials: DG
authors.lastname: da Cunha
authors.affiliation: Experimental Biology Core, Health Center, University of Fortaleza, Ceara, Brazil.
authors.forename: Ramon
authors.initials: R
authors.lastname: da Silva Raposo
authors.affiliation: Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Ceara, Brazil.
authors.forename: Kildere M
authors.initials: KM
authors.lastname: Canuto
authors.affiliation: Department of Physiology and Pharmacology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Ceara, Brazil.
authors.forename: Geanne M
authors.initials: GM
authors.lastname: de Andrade
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus Gualtar, Braga, Portugal; ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Sousa
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Sean R
authors.initials: SR
authors.lastname: Moore
authors.affiliation: South Texas Veterans Hospital, San Antonio, TX, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Anstead
authors.affiliation: Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Minas Gerais, Brazil.
authors.forename: Jacqueline I
authors.initials: JI
authors.lastname: Alvarez-Leite
authors.affiliation: Center for Global Health, Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Guerrant
authors.affiliation: Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Ceara, Brazil. Electronic address: rbo5u@virginia.edu.
authors.forename: Reinaldo B
authors.initials: RB
authors.lastname: Oriá
mesh_terms: D000596:Amino Acids / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D006624:Hippocampus / Q000254:growth & development* / Q000503:physiopathology; D007249:Inflammation / Q000097:blood / Q000209:etiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D044342:Malnutrition / Q000097:blood / Q000209:etiology*; D008426:Maternal Deprivation; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000596:Amino Acids; D007334:Insulin-Like Growth Factor I
keywords: Hippocampus; IGF-1; Inflammation; Leptin; Malnutrition; Maternal separation; Stereology