title: Development of anxiety-like behavior via hippocampal IGF-2 signaling in the offspring of parental morphine exposure: effect of enriched environment.
abstract: Opioid addiction is a major social, economic, and medical problem worldwide. Long-term adverse consequences of chronic opiate exposure not only involve the individuals themselves but also their offspring. Adolescent maternal morphine exposure results in behavior and morphologic changes in the brain of their adult offspring. However, few studies investigate the effect of adult opiate exposure on their offspring. Furthermore, the underlying molecular signals regulating the intergenerational effects of morphine exposure are still elusive. We report here that morphine exposure of adult male and female rats resulted in anxiety-like behavior and dendritic retraction in the dentate gyrus (DG) region of the hippocampus in their adult offspring. The behavior and morphologic changes were concomitant with the downregulation of insulin-like growth factor (IGF)-2 signaling in the granular zone of DG. Overexpression of hippocampal IGF-2 by bilateral intra-DG injection of lentivirus encoding the IGF-2 gene prevented anxiety-like behaviors in the offspring. Furthermore, exposure to an enriched environment during adolescence corrected the reduction of hippocampal IGF-2 expression, normalized anxiety-like behavior and reversed dendritic retraction in the adult offspring. Thus, parental morphine exposure can lead to the downregulation of hippocampal IGF-2, which contributed to the anxiety and hippocampal dendritic retraction in their offspring. An adolescent-enriched environment experience prevented the behavior and morphologic changes in their offspring through hippocampal IGF-2 signaling. IGF-2 and an enriched environment may be a potential intervention to prevention of anxiety and brain atrophy in the offspring of parental opioid exposure.
authors.affiliation: Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
authors.forename: Chang-Qi
authors.initials: CQ
authors.lastname: Li
authors.affiliation: Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
authors.forename: Yan-Wei
authors.initials: YW
authors.lastname: Luo
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Bi
authors.affiliation: Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
authors.forename: Tao-Tao
authors.initials: TT
authors.lastname: Cui
authors.affiliation: Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.affiliation: Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
authors.forename: Wen-Yu
authors.initials: WY
authors.lastname: Cao
authors.affiliation: Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
authors.forename: Jian-Yi
authors.initials: JY
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Neurobiology, Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
authors.forename: Jun-Mei
authors.initials: JM
authors.lastname: Xu
authors.affiliation: Institute of Mental Health, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hao
authors.affiliation: Center for Medical Experiments, Third Xiang-Ya Hospital of Central South University, Changsha, Hunan Province, China.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Xing
authors.affiliation: School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Zhou
authors.affiliation: School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, China.
authors.forename: Ru-Ping
authors.initials: RP
authors.lastname: Dai
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D015153:Blotting, Western; D003712:Dendrites / Q000473:pathology / Q000502:physiology; D018891:Dentate Gyrus / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology*; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006799:Housing, Animal; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D018782:Maze Learning / Q000502:physiology; D009020:Morphine / Q000633:toxicity*; D009294:Narcotics / Q000633:toxicity*; D018812:Paternal Exposure / Q000009:adverse effects; D017207:Rats, Sprague-Dawley
chemical_list: C000599313:Igf2 protein, rat; D009294:Narcotics; D007335:Insulin-Like Growth Factor II; D009020:Morphine