Your browser doesn't support javascript.
loading
Enhancing HIF-1α-P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience.
Zhang, Yuan; Pan, Yi-da; Zheng, Wen-Ying; Li, Huan-Yu; Zhu, Min-Zhen; Ou Yang, Wen-Jie; Qian, Yu; Turecki, Gustavo; Mechawar, Naguib; Zhu, Xin-Hong.
Afiliação
  • Zhang Y; School of Psychology, Shenzhen University, Shenzhen, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, China.
  • Pan YD; Research Center for Brain Health, Pazhou Lab, Guangzhou, China.
  • Zheng WY; School of Psychology, Shenzhen University, Shenzhen, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, China.
  • Li HY; Research Center for Brain Health, Pazhou Lab, Guangzhou, China.
  • Zhu MZ; Research Center for Brain Health, Pazhou Lab, Guangzhou, China.
  • Ou Yang WJ; School of Psychology, Shenzhen University, Shenzhen, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, China.
  • Qian Y; Research Center for Brain Health, Pazhou Lab, Guangzhou, China; School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.
  • Turecki G; Department of Psychiatry, McGill University, McGill Group for Suicide Studies, Douglas Mental Health University Institute, 6875 LaSalle Blvd, Verdun, (Québec), Canada.
  • Mechawar N; Department of Psychiatry, McGill University, McGill Group for Suicide Studies, Douglas Mental Health University Institute, 6875 LaSalle Blvd, Verdun, (Québec), Canada.
  • Zhu XH; School of Psychology, Shenzhen University, Shenzhen, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, China; School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China. Electronic address: zhuxh527@126.com.
Redox Biol ; 69: 103005, 2024 Feb.
Article em En | MEDLINE | ID: mdl-38150991
ABSTRACT
Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transtorno Depressivo Maior / Resiliência Psicológica Limite: Animals / Humans Idioma: En Revista: Redox Biol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transtorno Depressivo Maior / Resiliência Psicológica Limite: Animals / Humans Idioma: En Revista: Redox Biol Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China