Chemogenetic inhibition of ventral hippocampal inputs to the basal amygdala reduces anxiety-like behavior

Anxiety disorders pose a major global health burden, with an urgent need for improved, circuit-informed treatments. Recent studies have suggested a key role for the ventral hippocampus (vHpc), with diverse outputs from the vHpc implicated in the modulation of anxiety-like behavior. In this study, we focus on vHpc projections to the basal amygdala (BA), a prominent limbic circuit that regulates affect-related behavioral responses. Using a chemogenetic approach with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we selectively inhibited CaMKII-expressing neurons in the vHpc CA1 subfield and show that it reduces anxiety-like behavior on the elevated plus maze (EPM). Further, we used dual viral transduction strategy with the Cre-DIO (Double-floxed Inverted Open reading frame) system to specifically target vHpc inputs to the BA, with anterograde Cre expressed in vHpc CamKII neurons and retrograde DIO-hM4Di/hM3Dq expressed in the BA. We find that hM4Di-mediated chemogenetic inhibition of vHpc-BA inputs evokes a decline in anxiety-like behavior on the EPM. However, hM3Dq-mediated chemogenetic activation of the vHpc-BA pathway did not appear to alter anxiety-like measures on the EPM. These findings suggest that circuit-specific inhibition of vHpc to BA afferents is sufficient to evoke a decline in anxiety-like behavior on the EPM, whereas activation of the same pathway does not appear to regulate anxiety-like behavior in adult male Sprague-Dawley rats. Our results underscore the importance of analyzing projection-specific activation and inhibition of specific limbic brain circuits to determine their importance in modulating anxiety-like behavior.