Neuron activity–induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit

Abstract

Brain-derived neurotrophic factor (BDNF) is a master regulator of synaptic plasticity in various neural circuits of the mammalian central nervous system. Neuron activity-induced BDNF gene expression is regulated through the Ca/CREB pathway, but other regulatory factors may also be involved in controlling BDNF levels. We report here that Wnt/β-catenin signaling plays a key role in controlling neuron activity-regulated BDNF expression. Using primary cortical cultures, we show that blockade of Wnt/β-catenin signaling inhibits the BDNF up-regulation that is induced by activation of the -methyl-d-aspartic acid (NMDA) receptor and that activation of the Wnt/β-catenin signaling pathway stimulates BDNF expression., Wnt/β-catenin signaling activated BDNF expression and was required for peripheral pain-induced up-regulation of BDNF in the mouse spine. We also found that conditional deletion of one copy of either Wntless (Wls) or β-catenin by Nestin-Cre-mediated recombination is sufficient to inhibit the pain-induced up-regulation of BDNF. We further show that the Wnt/β-catenin/BDNF axis in the spinal neural circuit plays an important role in regulating capsaicin-induced pain. These results indicate that neuron activity-induced Wnt signaling stimulates BDNF expression in the pain neural circuits. We propose that pain-induced Wnt secretion may provide an additional mechanism for intercellular coordination of BDNF expression in the neural circuit.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Specifically, β‐catenin controls Dicer gene expression, thus highlighting WβC‐Dicer crosstalk as an important step in determining neuronal fate. Also, emerging evidence implicates several miRNAs in controlling WβC; for example, overexpression of miR‐21 in primary rat NSCs in vitro was shown to promote NSC proliferation and neural differentiation via the WβC signalling pathway (Zhang, Zhang, Deng, et al, ; Zhang, Shi, et al, ; Zhang, Zhang, Yang, et al, ). Thus, both miRNAs and Wnt‐signalling pathways form a network (Ashmawy et al, ) that is likely to play a significant role in adult neurogenesis.…”

“…Micro/nanoparticulate delivery vehicles may be engineered to release multiple biomolecules with spatio‐temporal control are being developed, aimed at mobilizing NSCs efficiently from their niches to promote their engraftment at lesioned areas, or creating a long term anti‐inflammatory microenvironment (Li et al, ; Riabov et al, ; Tiwari et al, ; Zhang, Zhang, Deng, et al, ; Zhang, Shi, et al, ; Zhang, Zhang, Yang, et al, ; Zhang, Huang, et al, ). Curcumin‐loaded nanoparticles powerfully induce adult neurogenesis and reverse cognitive deficits in an Alzheimer's disease model via the activation of WβC‐signalling pathway (Tiwari et al, , ).…”

“…WβC-signalling also plays a key role in controlling neuron activity-regulated neurotrophic factor (i.e. Bdnf) expression (Zhang, Zhang, Deng, et al, 2018a;Zhang, Shi, et al, 2018b;Zhang, Zhang, Yang, et al, 2018c). Also, in human NSCs, Yang et al (2016) showed the ability of BDNF to promote their growth via GSK-3β-mediated crosstalk with the WβC-signalling pathway, and Li et al (2017) involved the contribution of the PI3K/Akt/GSK-3β/β-catenin pathway in BDNF-induced neuron and NSC growth.…”

“…Herein, after a description of the key Wnt‐signalling components and a synopsis of adult neurogenesis in PD, we will focus on the role of WβC‐signalling as a common final pathway in mediating NSC regulation, from development to aging and PD degeneration. We aim to survey recent literature in the field supporting the upregulation of WβC as a means to re‐activate neurogenesis and incite regeneration in the injured brain, particularly in the context of modalities through which the inherent self‐repair capacities of the aged PD brain, can be engaged (Chen et al, ; Kase et al, ; Kaur, Saunders, & Tolwinski, ; Mishra et al, ; Zeng et al, ; Zhao, et al, ; Zhang et al, a,b,c; and following sections).…”

Morphine exposure exacerbates HIV-1 Tat driven changes to neuroinflammatory factors in cultured astrocytes

“…Approximately 150 β-catenin-regulated genes are estimated in primary astrocytes are comprising at least five broad categories including inflammation, transport, exocytosis, apoptosis, and trafficking [61]. Of these, β-catenin responsive genes that are neuroinflammatory in nature include BDNF (Brain-Derived Neurotrophic Factor), a member of the BDNF/TrkB (Tropomyosin receptor kinase B) signaling axis [66][67][68].…”