title: Sex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats.
abstract: Early noxious stimuli may alter the neurogenesis rate in the dentate gyrus and the behavioral repertoire of adult rats. This study evaluated the long-term effects of noxious stimulation, imposed in different phases of development, on nociceptive and anxiety-like behaviors, hippocampal activation, cell proliferation, hippocampal BDNF and plasma corticosterone levels in 40 day-old male and female adolescents. Noxious stimulation was induced by intra-plantar injection of Complete Freund's adjuvant (CFA), on postnatal days (P) 1 (group P1), 8 (P8) or 21 (P21). Control animals were not stimulated in any way. On P21 a subset of animals from each group received BrdU and was perfused on P40 for identification of proliferating cells in the granule cell layer of the dentate gyrus. Another subset of rats was subjected to behavioral testing on P40 and one week later, to magnetic resonance imaging (MRI) acquisition. Noxious stimulation evoked hypoalgesia in adolescents, mainly in females (P < 0.02), reflected by greater latency to withdraw the paw and less paw lickings in the hot plate test than controls (P < 0.001). It also resulted in more time spent in the open arms, e.g., less anxiety-like behavior than controls (P < 0.01), especially in females (P < 0.01, compared with males). Proliferative cell rate in the dentate gyrus was the highest in P8 males and females (P < 0.001), with males exhibiting more proliferation than females on P1 and P8, which was directly related to the hippocampal levels of BDNF and inversely related to plasma corticosterone. Sex differences were also detected in manganese-enhanced MRI signal, which was more prominent in P1 females than males (P < 0.01). This study represents the first step of investigation on the cellular basis of the sex-dependent long-term consequences of nociceptive stimuli in newborns.
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil.
authors.forename: Márcia
authors.initials: M
authors.lastname: Lima
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil; Centro de Imagens e Espectroscopia in vivo por Ressonância Magnética (CIERMag), Instituto de Física de São Carlos, Universidade de São Paulo (IFSC-USP), São Carlos 13566-590, Brazil.
authors.forename: Jackeline
authors.initials: J
authors.lastname: Malheiros
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Negrigo
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil.
authors.forename: Fabio
authors.initials: F
authors.lastname: Tescarollo
authors.affiliation: Departamento de Ciências Fisiológicas, Universidade Federal Rural do Rio de Janeiro, Seropédica 23890-000, Brazil.
authors.forename: Magda
authors.initials: M
authors.lastname: Medeiros
authors.affiliation: Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil.
authors.forename: Deborah
authors.initials: D
authors.lastname: Suchecki
authors.affiliation: Centro de Imagens e Espectroscopia in vivo por Ressonância Magnética (CIERMag), Instituto de Física de São Carlos, Universidade de São Paulo (IFSC-USP), São Carlos 13566-590, Brazil.
authors.forename: Alberto
authors.initials: A
authors.lastname: Tannús
authors.affiliation: Disciplina de Pediatria Neonatal, Departamento de Pediatria, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil.
authors.forename: Ruth
authors.initials: R
authors.lastname: Guinsburg
authors.affiliation: Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil. Electronic address: lcovolan@unifesp.br.
authors.forename: Luciene
authors.initials: L
authors.lastname: Covolan
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049109:Cell Proliferation; D003345:Corticosterone / Q000097:blood; D005260:Female; D006624:Hippocampus / Q000254:growth & development / Q000378:metabolism*; D008297:Male; D055495:Neurogenesis / Q000502:physiology; D059225:Nociception / Q000502:physiology*; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003345:Corticosterone
keywords: CFA; Hippocampus; MEMRI; MRI; Magnetic resonance image; Manganese-enhance MRI; Newborn; Nociception; P1; P21; P8; Proliferation; Sex difference; complete Freund's adjuvant; postnatal Day 1; postnatal Day 21; postnatal Day 8