Ventral hippocampal inhibitory microcircuits for anxiety and fear

In emotion research, anxiety and fear have always been interconnected, sharing overlapping brain structures and neural circuitry. Recent investigations, however, have unveiled parallel long-range projection pathways originating from the ventral hippocampus, shedding light on their distinct roles in anxiety and fear. Specifically, vCA1 projections to the lateral hypothalamus and medial prefrontal cortex are associated with anxiety-related experiences, whereas vCA1 projections to the amygdala mediate context-dependent fear. However, the precise mechanisms coordinating these parallel vCA1 projection pathways during anxiety and fear remain unclear. In this study, we used longitudinal in vivo Ca2+ imaging and optogenetic manipulations in vCA1 pyramidal neurons and subclasses of GABAergic interneurons, as well as monosynaptic tracing, we discovered a division of labor in inhibitory microcircuits during anxiety and fear-related behaviors. VIP and Sst interneurons form a microcircuit that dis-inhibit a subpopulation of pyramidal neurons during fear learning (‘the vCA1 fear microcircuit’), while PV interneurons targeting a distinct subpopulation of pyramidal neurons regulate anxiety (‘the vCA1 anxiety microcircuit’). Our results reveal the intricate neuronal microcircuitry within the vCA1. The vCA1 region functions as the central hub, orchestrating responses to both anxiety and fear-related behavior, by integrating signals from distant brain regions associated with emotions and leveraging the activity of distinct GABAergic interneurons and projection neurons. Such complex and dynamic circuit organization allows animals to promptly evaluate and react to diverse threats, promoting learning processes, such as in the case of fear conditioning, or the execution of innate behaviors, as observed in anxiety.