Adult Hippocampal Neurogenesis Modulates Fear Learning through Associative and Nonassociative Mechanisms.
Adult hippocampal neurogenesis is believed to support hippocampus-dependent learning and emotional regulation. These putative functions of adult neurogenesis have typically been studied in isolation, and little is known about how they interact to produce adaptive behavior. We used trace fear conditioning as a model system to elucidate mechanisms through which adult hippocampal neurogenesis modulates processing of aversive experience. To achieve a specific ablation of neurogenesis, we generated transgenic mice that express herpes simplex virus thymidine kinase specifically in neural progenitors and immature neurons. Intracerebroventricular injection of the prodrug ganciclovir caused a robust suppression of neurogenesis without suppressing gliogenesis. Neurogenesis ablation via this method or targeted x-irradiation caused an increase in context conditioning in trace but not delay fear conditioning. Data suggest that this phenotype represents opposing effects of neurogenesis ablation on associative and nonassociative components of fear learning. Arrest of neurogenesis sensitizes mice to nonassociative effects of fear conditioning, as evidenced by increased anxiety-like behavior in the open field after (but not in the absence of) fear conditioning. In addition, arrest of neurogenesis impairs associative trace conditioning, but this impairment can be masked by nonassociative fear. The results suggest that adult neurogenesis modulates emotional learning via two distinct but opposing mechanisms: it supports associative trace conditioning while also buffering against the generalized fear and anxiety caused by fear conditioning.


CONCLUSIONS
The role of adult hippocampal neurogenesis in fear learning is controversial, with some studies suggesting neurogenesis is needed for aspects of fear learning and others suggesting it is dispensable. We generated transgenic mice in which neural progenitors can be selectively and inducibly ablated. Our data suggest that adult neurogenesis supports fear learning through two distinct mechanisms: it supports the ability to learn associations between traumatic events (unconditioned stimuli) and predictors (conditioned stimuli) while also buffering against nonassociative, anxiogenic effects of a traumatic experience. As a result, arrest of neurogenesis can enhance or impair learned fear depending on intensity of the traumatic experience and the extent to which it recruits associative versus nonassociative learning.
Center for Learning and Memory, Department of Neuroscience, and Department of Psychology, The University of Texas at Austin, Austin, Texas 78712.
Dong-Oh
http://orcid.org/0000-0003-0315-4489
DO
Seo
Barnard College, Columbia University, New York, New York 10032.
Mary Ann
MA
Carillo
Division of Integrative Neuroscience, New York State Psychiatric Institute/Research Foundation for Mental Hygiene, New York, New York 10027, and.
Sean
S
Chih-Hsiung Lim
Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Kenji F
KF
Tanaka
Center for Learning and Memory, Department of Neuroscience, and mdrew@utexas.edu.
Michael R
MR
Drew
D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D001245:Association Learning / Q000187:drug effects / Q000502:physiology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000502:physiology*; D015774:Ganciclovir / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D015774:Ganciclovir
adult neurogenesis; anxiety; dentate gyrus; doublecortin; fear conditioning; trace conditioning