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Reduced Neuronal cAMP in the Nucleus Accumbens Damages Blood-Brain Barrier Integrity and Promotes Stress Vulnerability

  • Yue Zhang
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Wuhuan Lu
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Zibin Wang
    Affiliations
    Analytical and Testing Center, Nanjing Medical University, Nanjing, China
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  • Ran Zhang
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Yuan Xie
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Suhan Guo
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Li Jiao
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Yu Hong
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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  • Zizhen Di
    Affiliations
    Liaoning Provincial Academy of Traditional Chinese Medicine, Shenyang, China
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  • Guangji Wang
    Correspondence
    Address correspondence to Guangji Wang, Ph.D., or Jiye Aa, Ph.D., Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, 210009, China.
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
    Search for articles by this author
  • Jiye Aa
    Correspondence
    Address correspondence to Guangji Wang, Ph.D., or Jiye Aa, Ph.D., Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, 210009, China.
    Affiliations
    Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
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      Abstract

      Background

      Studies have suggested that chronic social stress specifically downregulates endothelial tight junction protein expression in the nucleus accumbens (NAc), thus increasing blood-brain barrier (BBB) permeability and promoting depression-like behaviors. However, the molecular mechanism underlying the reduction in tight junction protein, particularly in the NAc, is largely uncharacterized.

      Methods

      We performed comparative metabolomic profiling of the nucleus accumbens, prefrontal cortex, and hippocampus of social defeat–stressed mice to identify the molecular events that mediate BBB breakdown.

      Results

      We identified the levels of cyclic adenosine monophosphate (cAMP) that were specifically reduced in the NAc and positively correlated with the degree of social avoidance. Replenishing cAMP in the NAc was sufficient to improve BBB integrity and depression-like behaviors. We further found that cAMP levels were markedly decreased in neurons of the NAc, rather than in endothelial cells, astrocytes, or microglia. RNA-sequencing data showed that adenylate cyclase 5 (Adcy5), an enzyme responsible for the synthesis of cAMP from adenosine triphosphate (ATP), was predominantly expressed in the NAc; it also resided exclusively in neurons. Endogenous modulation of cAMP synthesis in neurons through the knockdown of Adcy5 in the NAc regulated the sensitivity to social stress. Moreover, deficient neuronal cAMP production in the NAc decreased the expression of reelin, while supplementary injection of exogenous reelin into the NAc promoted BBB integrity and ameliorated depression-like behaviors.

      Conclusions

      Chronic social stress diminished cAMP synthesis in neurons, thus damaging BBB integrity in the NAc and promoting stress vulnerability. These results characterize neuron-produced cAMP in the NAc as a biological mechanism of neurovascular pathology in social stress.

      Keywords

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