A ventral hippocampus-prefrontal circuit mediates the pro-extinction effects of adult hippocampal neurogenesis on contextual fear.

Abstract

Background: Adult hippocampal neurogenesis (AHN) contributes to hippocampal functions including contextual information processing and stress responses. Inhibiting AHN increases vulnerability to stress and hinders effects of therapeutic interventions for stress-related disorders, especially post-traumatic stress disorder (PTSD) characterized by maladaptive fear response to context, suggesting that promoting AHN may offer promising strategies. We therefore aimed to test whether experimentally enhancing AHN protects against persistent contextual fear memory and examine the underlying neural circuits.

Methods: Using inducible Cre-dependent iBax male mice, we enhanced AHN via tamoxifen pretreatment prior to a high-intensity contextual fear conditioning (footshocks, 1.5mA, 2×2s). We assessed defensive responses to both the conditioning context and a conditioning-associated object, together with spatial memory controls, and combined retrograde labeling with projection-specific optogenetic inhibition.

Results: AHN enhancement reduced the persistence of defensive responses to fear context: accelerating within-session decline of freezing and improving next-day extinction recall, while sparing other hippocampal-dependent memory. Circuit analyses revealed increased recruitment of a ventral hippocampus-prefrontal (infralimbic) cortex pathway in AHN-enhanced mice. Critically, optogenetic inhibition of this projection did not impair extinction per se but selectively abolished the pro-extinction effects induced by AHN enhancement; an effect not reproduced by inhibiting the projection to basolateral amygdala.

Conclusions: Ventral hippocampal input to the prefrontal cortex is not required for baseline extinction but is necessary to mediate the facilitating effects of enhanced AHN on contextual fear extinction in male mice. These findings identify a circuit mechanism through which adult neurogenesis constrains the persistence of contextual fear and promotes adaptive fear regulation.