Ventral hippocampus interacts with prelimbic cortex during inhibition of threat response via learned safety in both mice and humans

Abstract

Significance Although fear can contribute to survival, difficulty regulating threat responses can interfere with goal-directed activities and is the hallmark of anxiety disorders. These disorders are the most common psychiatric illnesses, affecting up to one-third of the population. In parallel studies across species, we identify a pathway that engages the ventral hippocampus for the attenuation of threat responses through conditioned inhibition. Conditioned inhibition relies on the specific involvement of ventral hippocampal neurons projecting to the prelimbic cortex in mice and homologous ventral hippocampal–dorsal anterior cingulate cortex functional connectivity in humans. These findings highlight a pathway for the inhibition of fear with the potential to enhance interventions for anxiety disorders by targeting an alternative neural circuitry through safety signal learning. Heightened fear and inefficient safety learning are key features of fear and anxiety disorders. Evidence-based interventions for anxiety disorders, such as cognitive behavioral therapy, primarily rely on mechanisms of fear extinction. However, up to 50% of clinically anxious individuals do not respond to current evidence-based treatment, suggesting a critical need for new interventions based on alternative neurobiological pathways. Using parallel human and rodent conditioned inhibition paradigms alongside brain imaging methodologies, we investigated neural activity patterns in the ventral hippocampus in response to stimuli predictive of threat or safety and compound cues to test inhibition via safety in the presence of threat. Distinct hippocampal responses to threat, safety, and compound cues suggest that the ventral hippocampus is involved in conditioned inhibition in both mice and humans. Moreover, unique response patterns within target-differentiated subpopulations of ventral hippocampal neurons identify a circuit by which fear may be inhibited via safety. Specifically, ventral hippocampal neurons projecting to the prelimbic cortex, but not to the infralimbic cortex or basolateral amygdala, were more active to safety and compound cues than threat cues, and activity correlated with freezing behavior in rodents. A corresponding distinction was observed in humans: hippocampal–dorsal anterior cingulate cortex functional connectivity—but not hippocampal–anterior ventromedial prefrontal cortex or hippocampal–basolateral amygdala connectivity—differentiated between threat, safety, and compound conditions. These findings highlight the potential to enhance treatment for anxiety disorders by targeting an alternative neural mechanism through safety signal learning.