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 expressing herpes simplex virus thymidine kinase (HSV-TK) under the dcx gene promoter, which directs expression to neural progenitors and immature neurons. Intracerebralventricular injection of the prodrug ganciclovir (GCV) caused a robust suppression of neurogenesis without suppressing gliogenesis. Neurogenesis ablation via this method (DCX-TK/GCV system) or targeted x-irradiation caused an increase in context conditioning in trace but not delay fear conditioning. The 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.