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Updated: Nov 2, 2025

The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice
Published on: October 24, 2018
Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway
Yusuke Sakai1, Haiyan Li1, Hiromichi Inaba1,2
1SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Abstract:
Although stressful events predispose individuals to psychiatric disorders, such as depression, not all people who undergo a stressful life experience become depressed, suggesting that gene-environment interactions (GxE) determine depression risk. The ventral hippocampus (vHPC) plays key roles in motivation, sociability, anhedonia, despair-like behaviors, anxiety, sleep, and feeding, pointing to the involvement of this brain region in depression. However, the molecular mechanisms underlying the cross talk between the vHPC and GxE in shaping behavioral susceptibility and resilience to chronic stress remain elusive. Here, we show that Ca2+/calmodulin-dependent protein kinase IIβ (CaMKIIβ) activity in the vHPC is differentially modulated in GxE mouse models of depression susceptibility and resilience, and that CaMKIIβ-mediated TARPγ-8 phosphorylation enhances the expression of AMPA receptor subunit GluA1 in the postsynaptic sites to enable stress resilience. We present previously missing molecular mechanisms underlying chronic stress-elicited behavioral changes, providing strategies for preventing and treating stress-related psychiatric disorders.
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