Ventral Hippocampal Temporoammonic and Schaffer Collateral Pathways Differentially Control Fear- and Anxiety-Related Behaviors

The ventral hippocampus plays a crucial role in regulating anxiety- and fear-related behaviors. Previously, we demonstrated that diazepam reduces anxiety-like behavior by inhibiting the dentate gyrus and CA3 principal neurons via α2-GABA _A Rs, while inhibition of CA1 pyramidal neurons is necessary to suppress fear-related responses. This study investigated the role of inputs from ventral CA3 (vCA3) and entorhinal cortex to ventral CA1 (vCA1) in anxiety- and fear-like behavior using bidirectional optogenetic modulations. Adult C57BL/6J male and female mice were subjected to bilateral stereotaxic injection of a viral vector expressing channelrhodopsin or halorhodopsin into vCA3 or into layers II-III of lateral entorhinal cortex, followed by bilateral implantation of fiberoptic ferrules into vCA1. After four weeks of recovery, mice were assessed for anxiety-like behavior in the novel open field, elevated plus maze, and Vogel conflict tests, and by contextual and trace fear conditioning for fear. The behavior of the mice was recorded under laser ‘ON’ and ‘OFF’ conditions in all experiments. The activation of vCA3 to vCA1 projections (i.e., Schaffer collateral pathway) increased anxiety- and fear-related behaviors, whereas inhibition reduced such behaviors. In contrast, optogenetic activation or inhibition of EC to vCA1 projections (i.e., temporoammonic pathway) had no effect on anxiety-related behavior but positively or negatively modulated fear-related behavior, respectively. These results suggest that while fear-related behavior is modulated by both inputs to vCA1, modulation of anxiety-related behavior is input-specific for the vCA3 to vCA1 projection. In summary, this study offers mechanistic insights into the complex organization of hippocampal circuitry underlying fear and anxiety.