On September 29, 2023, Hailan Hu's team at Zhejiang University published a research paper titled "Stress relief as a natural resilience mechanism against depression-like behaviors" in Neuron Online, which found that the degree of physical stress relief is closely related to an individual's resilience to depression-like behaviors in chronically stressed mice.
Notably, blocking stress release leads to vulnerability to depressive-like behaviors, whereas natural rewards provided shortly after stress (e.g., natural rewards given sucrose and chocolate) promote resilience. Stress relief is mediated by reward-related mid-limbic dopamine neurons, which show sustained activation for up to one minute after stress termination. Circuit-wise, activation or inhibition of circuits downstream of the ventral tegmental area bi-directionally modulated depressive recovery during transient remission. These results reveal an evolutionary function of stress relief in depressive recovery and identify the neural substrates that mediate this action.
A fascinating feature of emotions is that positive and negative states can be intertwined and closely interact. It is particularly uncanny that the end of a strong emotional state is often followed by the opposite emotional state. While aversive withdrawal from substance-induced pleasurable emotions has been extensively studied, the opposite phenomenon, i.e., the appetitive state at the end of a negative stimulus - so-called "remission" - has rarely been explored.
Notably, blocking stress release leads to vulnerability to depressive-like behaviors, whereas natural rewards provided shortly after stress (e.g., natural rewards given sucrose and chocolate) promote resilience. Stress relief is mediated by reward-related mid-limbic dopamine neurons, which show sustained activation for up to one minute after stress termination. Circuit-wise, activation or inhibition of circuits downstream of the ventral tegmental area bi-directionally modulated depressive recovery during transient remission. These results reveal an evolutionary function of stress relief in depressive recovery and identify the neural substrates that mediate this action.
A fascinating feature of emotions is that positive and negative states can be intertwined and closely interact. It is particularly uncanny that the end of a strong emotional state is often followed by the opposite emotional state. While aversive withdrawal from substance-induced pleasurable emotions has been extensively studied, the opposite phenomenon, i.e., the appetitive state at the end of a negative stimulus - so-called "remission" - has rarely been explored.
The positive efficacy of remission has been demonstrated in Drosophila, rodents, and humans. Using the appetitive state of remission, researchers have established a remission learning paradigm that associates the end/omission of stress, threat, or pain with cues to reinforce behavior. Pharmacology and recent neural circuitry studies suggest that the dopamine (DA) system is activated and necessary for relief-based learning. However, despite advances in relief learning, several fundamental questions about stress relief itself remain unanswered: how do DA neurons and their downstream projections encode stress relief, and on what timescales? What is the evolutionary purpose of the relieved state? Can this positive emotional state be utilized to combat mental illnesses, such as depression?
Mechanism model diagram (Figure from Neuron )
Stress is known to trigger depression in some people, but also resilience in others. The neurobiological basis for such individual differences in stress resilience has been shown to be a series of positive coping processes. Recent studies have revealed mechanisms of recovery at multiple levels, including epigenetic regulation, neuronal activity, and neurogenesis. At the level of neural circuits, the causal role of ventral tegmental area (VTA) DA circuits in regulating resilience has been emphasized. The inherent dichotomy between stress and relief raises the intriguing possibility that relief could counteract the deleterious effects of stress and play a role in stress resilience. However, this possibility has not been tested experimentally.
To address these questions, the authors used calcium photometry as well as electrophysiological and optogenetic techniques to explore the role of stress relief in the ability to recover from depression. The study provided scalable measures of stress relief in mice and determined their appetite valence and transient time windows. Notably, the authors found that the degree of stress relief was positively correlated with the level of resilience to depressive-like behaviors in chronically stressed mice. Fiber photometry and in vivo optogenetic manipulations showed that stress relief enabled separate voxel-wise midbrain DA projections in the lateral shell of the nucleus ambiguus (NAcLat) and the dorsal medial shell (dNAcMed) to prevent different aspects of the depressive-like phenotype. Depression-like behavior can be facilitated or prevented by blocking or enhancing stress release. Overall, this study suggests that stress relief is a natural restorative mechanism against depression, i.e., the positive potency of stress relief is increased by natural rewards to prevent depression.
