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Activation of CREB-BDNF Pathway in Pyramidal Neurons in the Hippocampus Improves the Neurological Outcome of Mice with Ischemic Stroke

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Abstract

Cerebral ischemia is characterized by several pathological reaction evolving over time. Hyperactivation of glutamatergic neurons is the main factor leading to excitotoxicity which potentiates oxidative stress and triggers the mechanisms of neural apoptosis after cerebral ischemia. However, it is unclear whether glutamate in the ventral hippocampal Cornus Ammonis 1 (vCA1) acts a part in neurological deficits, pain perception, anxiety, and depression induced by ischemic stroke. We investigated the effects of chemogenetic inhibition or activation of vCA1 pyramidal neurons which are mainly glutamatergic neurons on sequelae induced by cerebral ischemia. Our results revealed that inhibition of vCA1 pyramidal neurons by chemogenetics alleviated neurological deficits, pain perception, anxiety, and depression caused by cerebral ischemia in mice, but activation of vCA1 pyramidal neurons had limited effects. Moreover, we found that stroke was accompanied by decreased levels of cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in vCA1, which are modulated by glutamate. In this study, overexpression of CREB protein in pyramidal neurons in vCA1 by AAV virus significantly upregulated the content of BDNF and ameliorated the dysfunction induced by ischemic stroke. Our results demonstrated activation of the CREB-BDNF pathway in vCA1 pyramidal neurons significantly improved neurological deficits, pain perception, anxiety, and depression induced by ischemic stroke.

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Data Availability

The datasets generated and/or analyzed during the current study are available upon reasonable request.

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Funding

This work is supported by the National Natural Science Foundation of China (No. 81901196 and No. 82001182).

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Authors and Affiliations

  1. Department of Neuropharmacology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China

    Yingying Jiang, Yumei Zhao, Chunyang Wang & Ming Sun

  2. Department of Pain Management, the First Affiliated Hospital, Zhengzhou University, Henan, China

    Qingying Liu

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Contributions

YJ, QL, and MS developed the study concept and experimental design. YJ and YZ were involved in conducting the experiment and data collection. YJ, CW, and MS analyzed the data. YJ wrote the paper, and MS edited the paper. All coauthors have approved the paper submitted for publication.

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Correspondence to Ming Sun.

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The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of Beijing Neurosurgical Institute (Permit Number: 201904004).

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Jiang, Y., Liu, Q., Zhao, Y. et al. Activation of CREB-BDNF Pathway in Pyramidal Neurons in the Hippocampus Improves the Neurological Outcome of Mice with Ischemic Stroke. Mol Neurobiol 60, 1766–1781 (2023). https://doi.org/10.1007/s12035-022-03174-x

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