title: Early experience of a novel-environment in isolation primes a fearful phenotype characterized by persistent amygdala activation.
abstract: Prolonged maternal separation (MS) activates the neonate's hypothalamus-pituitary-adrenal axis causing elevated basal and stress-induced corticosterone levels that may initiate amygdala-dependent fear learning. Here we test the hypothesis that the adult fearful phenotype is programmed by the pup's stressful experience during prolonged MS rather than by prolonged maternal absence per se. For this purpose, Wistar rat pups were exposed, on postnatal-day (pnd) 3, to: (i) repeated-MS in home-environment (HOME-SEP), 8h-MS daily for three days with the pups remaining together in the home-cage; (ii) repeated-MS in a novel-environment (NOVEL-SEP), with the same separation procedure, but now the pups were individually housed in a novel-environment during the 8h dam's absence; (iii) repeated handling, which consisted of daily brief (15 min instead of 8h) MS in the home-altogether or in a novel-environment individually (HOME-HAN and NOVEL-HAN, respectively); (iv) no-separation/no-handling (NON-SEP/NON-HAN) control condition, in which pups were left undisturbed in their home-cage. Compared to HOME-SEP rats, the NOVEL-SEP rats showed one day after the last MS enhanced stress-induced amygdala c-Fos expression and ACTH-release, despite of reduced adrenal corticosterone secretion. The higher amygdala c-Fos expression, ACTH-release and reduced corticosterone output observed postnatally, persisted into adulthood of the NOVEL-SEP animals. Behaviorally, NOVEL-SEP juvenile rats displayed deficits in social play, had intact spatial memory in the peri-pubertal period and showed more contextual fear memory compared to HOME-SEP in adulthood. Finally, NOVEL-HAN, compared to HOME-HAN, displayed increased stress-induced corticosterone output, no deficits in social play and reduced contextual fear. In conclusion, programming of an adult fearful phenotype linked to amygdala priming develops if pups are repeatedly isolated from peers in a novel-environment, while away from the dam for a prolonged period of time.
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands; Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden University, Leiden, The Netherlands; Traumatic Stress Studies Division & Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, USA; Mental Health Care Center, PTSD Clinical Research Program and Laboratory of Clinical Neuroendocrinology and Neurochemistry, James J. Peters Veterans Affairs Medical Center, Bronx, USA. Electronic address: nikolaos.daskalakis@mssm.edu.
authors.forename: Nikolaos P
authors.initials: NP
authors.lastname: Daskalakis
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands; Laboratory of Biology-Biochemistry, Faculty of Nursing, School of Health Sciences, University of Athens, Greece; Department of Psychiatry, Columbia University, New York, NY, USA.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Diamantopoulou
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
authors.forename: Sanne E F
authors.initials: SEF
authors.lastname: Claessens
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
authors.forename: Elisa
authors.initials: E
authors.lastname: Remmers
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
authors.forename: Marika
authors.initials: M
authors.lastname: Tjälve
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
authors.forename: Melly S
authors.initials: MS
authors.lastname: Oitzl
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Champagne
authors.affiliation: Division of Medical Pharmacology, Leiden Academic Center for Drug Research, Leiden University Medical Center, Leiden University, Leiden, The Netherlands; Department of Endocrinology and Metabolism, Leiden University Medical Center, Leiden University, Leiden, The Netherlands.
authors.forename: E Ronald
authors.initials: ER
authors.lastname: de Kloet
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D004777:Environment; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear / Q000502:physiology*; D006799:Housing, Animal; D008426:Maternal Deprivation; D010988:Play and Playthings; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012919:Social Behavior; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology
chemical_list: D016760:Proto-Oncogene Proteins c-fos
keywords: ACTH; Amygdala; Corticosterone; Fear-conditioning; Maternal separation; Novelty stress; Short-term memory; Social play; c-Fos