Stress causes changes in neurotransmission in the brain, thereby influencing stress-induced behaviors. However, it is unclear how neurotransmission systems orchestrate stress responses at the molecular and cellular levels. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel involved mainly in pain sensation, affects mood and neuroplasticity in the brain, where its role is poorly understood. Here, we show that Trpv1-deficient (Trpv1) mice are more stress resilient than control mice after chronic unpredictable stress. We also found that glucocorticoid receptor (GR)-mediated histone deacetylase 2 (HDAC) 2 expression and activity are reduced in the Trpv1 mice and that HDAC2-regulated, cell-cycle- and neuroplasticity-related molecules are altered. Hippocampal knockdown of TRPV1 had similar effects, and its behavioral effects were blocked by HDAC2 overexpression. Collectively, our findings indicate that HDAC2 is a molecular link between TRPV1 activity and stress responses.

Major depressive disorder (MDD) is a devastating disease that arises in a background of environmental risk factors, such as chronic stress, that produce reactive oxygen species (ROS) in the brain. The chronic stress-induced ROS production involves Ca2+ signals; however, the mechanism is poorly understood. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+-permeable cation channel that is highly expressed in the brain. Here we show that in animal models of chronic unpredictable stress (CUS), deletion of TRPM2 (Trpm2−/−) produces antidepressant-like behaviors in mice. This phenotype correlates with reduced ROS, ROS-induced calpain activation, and enhanced phosphorylation of two Cdk5 targets including synapsin 1 and histone deacetylase 5 that are linked to synaptic function and gene expression, respectively. Moreover, TRPM2 mRNA expression is increased in hippocampal tissue samples from patients with MDD. Our findings suggest that TRPM2 is a key agent in stress-induced depression and a possible target for treating depression.

Silent information regulator 2 (Sirtuin2 / SIRT2) is a NAD+-dependent deacetylase that regulates the cellular oxidative stress response. It modulates transcriptional silencing and protein stability through deacetylation of target proteins including histones. Previous studies have shown that SIRT2 plays a role in mood disorders and hippocampus-dependent cognitive function, but the underlying neurobiological mechanism is poorly understood. Here, we report that chronic stress suppresses SIRT2 expression in the hippocampus. Molecular and biochemical analyses indicate that the stress-induced decrease in the SIRT2 expression downregulates synaptic plasticity-related genes in the hippocampus through the increase of euchromatic histone-lysine N-methyltransferase 2 (Ehmt2) (also known as G9a). shRNA-mediated knockdown of SIRT2 in the dentate gyrus alters the expression of synaptic plasticity-related genes in a way similar to those induced by chronic stress, and produces depression-like behaviors. Our results indicate that SIRT2 plays an important role in the response to stress, thereby modulating depression-like behaviors.

Endoplasmic reticulum (ER) has a unique redox environment, which plays critical roles in the organelle's function and in its pathological responses such as ER stress. In this work, we introduce an ER-targeting fluorogenic reactive oxygen species (ROS) chemosensor (ER-Flu) from copper(I)-catalyzed alkyne-azide cycloaddition of 3-propargyl ester of 2 0 ,7 0-dichlorodihydrofluorescein diacetate and N 3-glibenclamide, which were adopted as a fluorogenic ROS sensing module and an ER-targeting module, respectively. Thereby, a series of confocal microscopic experiments of ER-Flu demonstrated that the sensor localizes in ER of the live cells and that ROS are elevated in the cells by ER stress inducers such as thapsigargin, brefeldin A, and tunicamycin.