Elevation of hilar mossy cell activity suppresses hippocampal excitability and avoidance behavior.

Kai-Yi Wang,Kazu Nakazawa,Jei-Wei Wu,Jen-Kun Cheng,Gábor Tamás,Chun-Chung Chen,Wai-Yi Wong,Cheng-Chang Lien,Robert G Averkin

doi:10.1016/j.celrep.2021.109702

Abstract

Modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate the feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unclear. Moreover, the correlation between MC activity and anxiety states is unclear. In this study, we first demonstrate, by means of calcium fiber photometry, that MC activity in the ventral hippocampus (vHPC) of mice increases while they explore anxiogenic environments. Next, juxtacellular recordings reveal that optogenetic activation of MCs preferentially recruits GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons. Finally, chemogenetic excitation of MCs in the vHPC reduces avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs but also suggest that MCs may be a potential therapeutic target for anxiety disorders.

Highlights

Anxiety disorders are associated with the dysfunction of g-aminobutyric acid (GABA)-ergic transmission and altered neuronal activity in the hippocampal subfields (Dong et al, 2020; Engin et al, 2016; Schoenfeld et al, 2013)
mossy cells (MCs) activity increased during open-arm exploration To correlate MC activity with avoidance behavior in freely behaving mice, we used fiber photometry to assess the changes of Ca2+ levels in MCs while mice were subjected to anxiogenic environments
As previously described (Jinde et al, 2012), GCaMP6s-expressing cells in the dentate gyrus (DG) were restricted to the hilus (Figure 1B)

Summary

Introduction

Anxiety disorders are associated with the dysfunction of g-aminobutyric acid (GABA)-ergic transmission and altered neuronal activity in the hippocampal subfields (Dong et al, 2020; Engin et al, 2016; Schoenfeld et al, 2013). Increased DG excitability is associated with a higher susceptibility to stress-induced anxiety disorders. Attenuated DG excitability of the vHPC confers stress resilience (Anacker et al, 2018). Information mainly flows from the DG to the CA1 output neurons via the trisynaptic pathway. CA1 neurons in the vHPC are shown to encode anxiety-related information (Ciocchi et al, 2015; Jimenez et al, 2018; Padilla-Coreano et al, 2016)

Methods

Results

Discussion

Conclusion