Optogenetic Stimulation of mPFC Alleviates White Matter Injury‐Related Cognitive Decline after Chronic Ischemia through Adaptive Myelination

• Published in: Advanced science 2023-02, Vol.10 (5), p.e2202976-n/a
• Main Authors: Deng, Shiji, Shu, Shu, Zhai, Lili, Xia, Shengnan, Cao, Xiang, Li, Huiya, Bao, Xinyu, Liu, Pinyi, Xu, Yun
• Format: Article
• Language: English
• Subjects: adaptive myelination; Alzheimer's disease; Animals; Carotid arteries; chemogenetics; chronic ischemia; Cognitive ability; Cognitive Dysfunction - etiology; Cognitive Dysfunction - therapy; Dementia; Ischemia - complications; Mice; Myelin Sheath - metabolism; optogenetics; Optogenetics - methods; Signal transduction; Surgery; Veins & arteries; White Matter - injuries; Wnt2
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202202976

White matter injury (WMI), which reflects myelin loss, contributes to cognitive decline or dementia caused by cerebral vascular diseases. However, because pharmacological agents specifically for WMI are lacking, novel therapeutic strategies need to be explored. It is recently found that adaptive myelination is required for homeostatic control of brain functions. In this study, adaptive myelination‐related strategies are applied to explore the treatment for ischemic WMI‐related cognitive dysfunction. Here, bilateral carotid artery stenosis (BCAS) is used to model ischemic WMI‐related cognitive impairment and uncover that optogenetic and chemogenetic activation of glutamatergic neurons in the medial prefrontal cortex (mPFC) promote the differentiation of oligodendrocyte precursor cells (OPCs) in the corpus callosum, leading to improvements in myelin repair and working memory. Mechanistically, these neuromodulatory techniques exert a therapeutic effect by inducing the secretion of Wnt2 from activated neuronal axons, which acts on oligodendrocyte precursor cells and drives oligodendrogenesis and myelination. Thus, this study suggests that neuromodulation is a promising strategy for directing myelin repair and cognitive recovery through adaptive myelination in the context of ischemic WMI. Optogenetic and chemogenetic activation of mPFC glutamatergic neurons after chronic ischemia upregulate the expression of neuron‐derived Wnt2, which acts on OPCs and promotes their differentiation toward oligodendrocytes, leading to myelin repair and improved cognitive function. The current finding highlights that neuromodulation is a promising strategy for directing adaptive myelination in the context of chronic ischemia.