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The Forced Swim Test as a Model of Depressive-like Behavior
Published on: March 2, 2015
CRHR1 antagonist alleviated depression-like behavior by downregulating p62 in a rat model of post-stroke depression
Huanhuan Liu1, Yunfei Zhang2, Xiaoli Hou3
1Henan Key Laboratory of Biological Psychiatry, the Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China; Henan Engineering Research Center of Physical Diagnostics and Treatment Technology for the Mental and Neurological Diseases, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China; Henan Collaborative Innovation Center of Prevention and treatment of mental disorder, the Second Affiliated Hospital of Xinxiang Medical University.
Insights
Post-stroke depression (PSD) is linked to elevated Corticotropin-Releasing Hormone (CRH) and p62 accumulation, which impairs synaptic plasticity. Blocking CRH receptors alleviates depression-like behaviors and synaptic loss in rats, suggesting a new therapeutic target for PSD.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Post-stroke depression (PSD) is a common complication following cerebrovascular events, increasing mortality.
- Corticotropin-Releasing Hormone (CRH) plays a role in stress response and synaptic plasticity, with potential links to depression.
- The Keap1-Nrf2-p62 pathway is crucial for antioxidant response and autophagy, and its dysregulation may contribute to neurological disorders.
Purpose of the Study:
- To investigate the role of CRH and the Keap1-Nrf2-p62 pathway in the pathogenesis of PSD.
- To explore the potential of targeting CRH signaling for PSD treatment.
Main Methods:
- Serum CRH levels were measured in PSD patients and healthy controls.
- An animal model of PSD was established using MCAO combined with chronic unpredictable mild stress (CUMS) and sleep deprivation (SD) in rats.
- The effects of a CRHR1 antagonist on synaptic plasticity, depression-like behavior, and the Keap1-Nrf2-p62 pathway were assessed in PSD rats.
Main Results:
- Patients with PSD exhibited higher serum CRH levels compared to healthy subjects.
- CRHR1 antagonist treatment prevented hippocampal synaptic loss and reduced depression-like behaviors in PSD rats.
- CRH induced p62 accumulation in the prefrontal cortex via CRHR1, which was attenuated by the antagonist, alongside reduced oxidative stress.
- Abnormal p62 accumulation was identified as a driver of PSD, with its inhibition and clearance alleviating depression-like behaviors.
Conclusions:
- CRH signaling and the Keap1-Nrf2-p62 pathway are implicated in the pathophysiology of PSD.
- Targeting CRH receptor 1 (CRHR1) may offer a novel therapeutic strategy for PSD by mitigating synaptic deficits and oxidative stress.
- Modulating p62 levels presents a potential avenue for treating PSD.
Abstract:
Post-stroke depression (PSD) is a complication of cerebrovascular disease, which can increase mortality after stroke. CRH is one of the main signaling peptides released after activation of the hypothalamic-pituitary-adrenal (HPA) axis in response to stress. It affects synaptic plasticity by regulating inflammation, oxidative stress and autophagy in the central nervous system. And the loss of spines exacerbates depression-like behavior. Therefore, synaptic deficits induced by CRH may be related to post-stroke depression. However, the underlying mechanism remains unclear. The Keap1-Nrf2 complex is one of the core components of the antioxidant response. As an autophagy associated protein, p62 participates in the Keap1-NrF2 pathway through its Keap1 interaction domain. Oxidative stress is involved in the feedback regulation between Keap1-Nrf2 pathway and p62.However, whether the relationship between CRH and the Keap1-Nrf2-p62 pathway is involved in PSD remains unknown. This study found that serum levels of CRH in 22 patients with PSD were higher than those in healthy subjects. We used MCAO combined with CUMS single-cage SD rats to establish an animal model of PSD. Animal experiments showed that CRHR1 antagonist prevented synaptic loss in the hippocampus of PSD rats and alleviated depression-like behavior. CRH induced p62 accumulation in the prefrontal cortex of PSD rats through CRHR1. CRHR1 antagonist inhibited Keap1-Nrf2-p62 pathway by attenuating oxidative stress. In addition, we found that abnormal accumulation of p62 induces PSD. It alleviates depression-like behavior by inhibiting the expression of p62 and promoting the clearance of p62 in PSD rats. These findings can help explore the pathogenesis of PSD and design targeted treatments for PSD.
