title: Ongoing neurogenesis in the adult dentate gyrus mediates behavioral responses to ambiguous threat cues.
abstract: Fear learning is highly adaptive if utilized in appropriate situations but can lead to generalized anxiety if applied too widely. A role of predictive cues in inhibiting fear generalization has been suggested by stress and fear learning studies, but the effects of partially predictive cues (ambiguous cues) and the neuronal populations responsible for linking the predictive ability of cues and generalization of fear responses are unknown. Here, we show that inhibition of adult neurogenesis in the mouse dentate gyrus decreases hippocampal network activation and reduces defensive behavior to ambiguous threat cues but has neither of these effects if the same negative experience is reliably predicted. Additionally, we find that this ambiguity related to negative events determines their effect on fear generalization, that is, how the events affect future behavior under novel conditions. Both new neurons and glucocorticoid hormones are required for the enhancement of fear generalization following an unpredictably cued threat. Thus, adult neurogenesis plays a central role in the adaptive changes resulting from experience involving unpredictable or ambiguous threat cues, optimizing behavior in novel and uncertain situations.
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America.|Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: Lucas R
authors.initials: LR
authors.lastname: Glover
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Schoenfeld
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Karlsson
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, United Kingdom.
authors.forename: David M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Cameron
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D003213:Conditioning, Psychological; D003433:Crosses, Genetic; D003463:Cues; D018891:Dentate Gyrus / Q000166:cytology* / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D003863:Depression / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D005106:Exploratory Behavior; D046352:Freezing Reaction, Cataleptic; D005794:Generalization, Response; D005938:Glucocorticoids / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000473:pathology / Q000502:physiology; D017966:Pyramidal Cells / Q000166:cytology* / Q000473:pathology / Q000502:physiology; D011897:Random Allocation
chemical_list: D005938:Glucocorticoids