title: Blocking glucocorticoid receptors at adolescent age prevents enhanced freezing between repeated cue-exposures after conditioned fear in adult mice raised under chronic early life stress.
abstract: Early life adversity can have long-lasting impact on learning and memory processes and increase the risk to develop stress-related psychopathologies later in life. In this study we investigated (i) how chronic early life stress (ELS) - elicited by limited nesting and bedding material from postnatal day 2 to 9 - affects conditioned fear in adult mice and (ii) whether these effects can be prevented by blocking glucocorticoid receptors (GRs) at adolescent age. In adult male and female mice, ELS did not affect freezing behavior to the first tone 24h after training in an auditory fear-conditioning paradigm. Exposure to repeated tones 24h after training also resulted in comparable freezing behavior in ELS and control mice, both in males and females. However, male (but not female) ELS compared to control mice showed significantly more freezing behavior between the tone-exposures, i.e. during the cue-off periods. Intraperitoneal administration of the GR antagonist RU38486 during adolescence (on postnatal days 28-30) fully prevented enhanced freezing behavior during the cue-off period in adult ELS males. Western blot analysis revealed no effects of ELS on hippocampal expression of glucocorticoid receptors, neither at postnatal day 28 nor at adult age, when mice were behaviorally tested. We conclude that ELS enhances freezing behavior in adult mice in a potentially safe context after cue-exposure, which can be normalized by brief blockade of glucocorticoid receptors during the critical developmental window of adolescence.
authors.affiliation: SILS-Center for Neuroscience, University of Amsterdam, The Netherlands.
authors.forename: J Marit
authors.initials: JM
authors.lastname: Arp
authors.affiliation: SILS-Center for Neuroscience, University of Amsterdam, The Netherlands.
authors.forename: Judith P
authors.initials: JP
authors.lastname: Ter Horst
authors.affiliation: Dept. Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.
authors.forename: Manila
authors.initials: M
authors.lastname: Loi
authors.affiliation: SILS-Center for Neuroscience, University of Amsterdam, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: den Blaauwen
authors.affiliation: SILS-Center for Neuroscience, University of Amsterdam, The Netherlands.
authors.forename: Eline
authors.initials: E
authors.lastname: Bangert
authors.affiliation: Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Guillén
authors.initials: G
authors.lastname: Fernández
authors.affiliation: Dept. Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands.
authors.forename: Marian
authors.initials: M
authors.lastname: Joëls
authors.affiliation: SILS-Center for Neuroscience, University of Amsterdam, The Netherlands.
authors.forename: Melly S
authors.initials: MS
authors.lastname: Oitzl
authors.affiliation: SILS-Center for Neuroscience, University of Amsterdam, The Netherlands. Electronic address: h.krugers@uva.nl.
authors.forename: Harm J
authors.initials: HJ
authors.lastname: Krugers
mesh_terms: D000367:Age Factors; D000818:Animals; D003463:Cues; D005239:Fear / Q000502:physiology*; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000502:physiology*; D006727:Hormone Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000008:administration & dosage / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000502:physiology*; D012737:Sex Factors; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D015735:Mifepristone
keywords: Anxiety; Early life stress; Fear; Fear conditioning; Glucocorticoid receptor; Memory