title: Genetic strain differences in learned fear inhibition associated with variation in neuroendocrine, autonomic, and amygdala dendritic phenotypes.
abstract: Mood and anxiety disorders develop in some but not all individuals following exposure to stress and psychological trauma. However, the factors underlying individual differences in risk and resilience for these disorders, including genetic variation, remain to be determined. Isogenic inbred mouse strains provide a valuable approach to elucidating these factors. Here, we performed a comprehensive examination of the extinction-impaired 129S1/SvImJ (S1) inbred mouse strain for multiple behavioral, autonomic, neuroendocrine, and corticolimbic neuronal morphology phenotypes. We found that S1 exhibited fear overgeneralization to ambiguous contexts and cues, impaired context extinction and impaired safety learning, relative to the (good-extinguishing) C57BL/6J (B6) strain. Fear overgeneralization and impaired extinction was rescued by treatment with the front-line anxiety medication fluoxetine. Telemetric measurement of electrocardiogram signals demonstrated autonomic disturbances in S1 including poor recovery of fear-induced suppression of heart rate variability. S1 with a history of chronic restraint stress displayed an attenuated corticosterone (CORT) response to a novel, swim stressor. Conversely, previously stress-naive S1 showed exaggerated CORT responses to acute restraint stress or extinction training, insensitivity to dexamethasone challenge, and reduced hippocampal CA3 glucocorticoid receptor mRNA, suggesting downregulation of negative feedback control of the hypothalamic-pituitary-adrenal axis. Analysis of neuronal morphology in key neural nodes within the fear and extinction circuit revealed enlarged dendritic arbors in basolateral amygdala neurons in S1, but normal infralimbic cortex and prelimbic cortex dendritic arborization. Collectively, these data provide convergent support for the utility of the S1 strain as a tractable model for elucidating the neural, molecular and genetic basis of persistent, excessive fear.
authors.affiliation: Laboratory of Behavioral and Genomic Neuroscience, NIAAA, Bethesda, MD, USA.
authors.forename: Marguerite C
authors.initials: MC
authors.lastname: Camp
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Macpherson
authors.forename: Lauren
authors.initials: L
authors.lastname: Lederle
authors.forename: Carolyn
authors.initials: C
authors.lastname: Graybeal
authors.forename: Stefano
authors.initials: S
authors.lastname: Gaburro
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Debrouse
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Ihne
authors.forename: Javier A
authors.initials: JA
authors.lastname: Bravo
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Connor
authors.forename: Stephane
authors.initials: S
authors.lastname: Ciocchi
authors.forename: Cara L
authors.initials: CL
authors.lastname: Wellman
authors.forename: Andreas
authors.initials: A
authors.lastname: Lüthi
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
authors.forename: Andrew
authors.initials: A
authors.lastname: Holmes
mesh_terms: D000679:Amygdala / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001008:Anxiety Disorders / Q000150:complications* / Q000188:drug therapy / Q000473:pathology*; D001342:Autonomic Nervous System Diseases / Q000209:etiology*; D001362:Avoidance Learning / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D003712:Dendrites / Q000473:pathology*; D004192:Discrimination, Psychological; D004195:Disease Models, Animal; D004562:Electrocardiography; D004700:Endocrine System Diseases / Q000209:etiology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005473:Fluoxetine / Q000627:therapeutic use; D006801:Humans; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid; D013686:Telemetry
chemical_list: D018687:Antidepressive Agents, Second-Generation; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D005473:Fluoxetine; D003345:Corticosterone