title: Brain-derived neurotrophic factor in the amygdala mediates susceptibility to fear conditioning.
abstract: Fear conditioning in animals has been used extensively to model clinical anxiety disorders. While individual animals exhibit marked differences in their propensity to undergo fear conditioning, the physiologically relevant mediators have not yet been fully characterized. Here, we demonstrate that C57BL/6 inbred mouse strain subjected to a regimen of chronic social defeat stress (CSDS) can be separated into susceptible and resistant subpopulations that display different levels of fear responses in an auditory fear conditioning paradigm. Susceptible mice had significantly more c-Fos protein expression in neurons of the basolateral amygdala (BLA) following CSDS and showed exaggerated conditioned fear responses, while there were no significant differences between groups in innate anxiety- and depressive-like behaviors. Through the use of conditional brain-derived neurotrophic factor (BDNF) knockout strategies, we find that elevated BLA BDNF level following fear conditioning training is a key mediator contributing to determine the levels of conditioned fear responses. Our results also show that relative to susceptible mice, resistant mice had a much faster recovery from conditioned stimuli-induced cardiovascular and corticosterone responses. Systemic administration of norepinephrine reuptake inhibitor atomoxetine increased c-Fos protein expression in BLA neurons following fear conditioning training and promoted the expression of conditioned fear in resistant mice. Conversely, administration of β-adrenergic receptor antagonist propranolol reduced fear conditioning training-induced c-Fos protein expression in BLA neurons and reduced conditioned fear responses in susceptible mice. These findings reveal a novel role for the BDNF signaling within the BLA in mediating individual differences in autonomic, neuroendocrine and behavioral reactivity to fear conditioning.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Dylan
authors.initials: D
authors.lastname: Chou
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan. Electronic address: richard@mail.ncku.edu.tw.
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
mesh_terms: D000161:Acoustic Stimulation; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology*; D000069445:Atomoxetine Hydrochloride; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011437:Propylamines / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D019208:Brain-Derived Neurotrophic Factor; D011437:Propylamines; D016760:Proto-Oncogene Proteins c-fos; D000069445:Atomoxetine Hydrochloride
keywords: Amygdala; Anxiety; BDNF; Fear conditioning; Social defeat stress