title: Early-life inflammation with LPS delays fear extinction in adult rodents.
abstract: A large body of evidence has been brought forward connecting developmental immune activation to abnormal fear and anxiety levels. Anxiety disorders have extremely high lifetime prevalence, yet susceptibility factors that contribute to their emergence are poorly understood. In this research we investigated whether an inflammatory insult early in life can alter the response to fear conditioning in adulthood. Fear learning and extinction are important and adaptive behaviors, mediated largely by the amygdala and its interconnectivity with cortico-limbic circuits. Male and female rat pups were given LPS (100μg/kg i.p.) or saline at postnatal day 14; LPS activated cFos expression in the central amygdala 2.5h after exposure, but not the basal or lateral nuclei. When tested in adulthood, acquisition of an auditory cued or contextual learned fear memory was largely unaffected as was the extinction of fear to a conditioned context. However, we detected a deficit in auditory fear extinction in male and female rats that experienced early-life inflammation, such that there is a significant delay in fear extinction processes resulting in more sustained fear behaviors in response to a conditioned cue. This response was specific to extinction training and did not persist into extinction recall. The effect could not be explained by differences in pain threshold (unaltered) or in baseline anxiety, which was elevated in adolescent females only and unaltered in adolescent males and adult males and females. This research provides further evidence for the involvement of the immune system during development in the shaping of fear and anxiety related behaviors.
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; Department of Neuroscience, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada. Electronic address: vdoenni@ucalgary.ca.
authors.forename: V M
authors.initials: VM
authors.lastname: Doenni
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
authors.forename: C M
authors.initials: CM
authors.lastname: Song
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
authors.forename: M N
authors.initials: MN
authors.lastname: Hill
authors.affiliation: Hotchkiss Brain Institute, Cumming School of Medicine, Mathison Center for Mental Health, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
authors.forename: Q J
authors.initials: QJ
authors.lastname: Pittman
mesh_terms: D000223:Adaptation, Psychological; D000679:Amygdala / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000378:metabolism; D001008:Anxiety Disorders; D003214:Conditioning, Classical / Q000502:physiology; D003213:Conditioning, Psychological / Q000502:physiology; D003463:Cues; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000502:physiology*; D005260:Female; D007249:Inflammation; D007858:Learning; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D011939:Mental Recall / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012377:Rodentia; D013315:Stress, Psychological / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides
keywords: Amygdala; Anxiety; Cytokines; Extinction; Inflammation; PTSD; Pavlovian conditioning; Stress