Biology subjects

He, X.-B.

Publications and source records attributed to He, X.-B..

6 recordsLinked to original sources

bioRxiv2022

JMJD3 is a Key Regulator of Dopamine Synthesis in Ventral Tegmental Area Dopamine Neurons.

Chronic pain is associated with midbrain dopamine levels. The molecules and mechanisms modulating this association remain to be elucidated. By using conditional knockout mice, we report that JMJD3 deficiency in midbrain dopamine neurons causes prolonged mechanical hyperalgesia regardless of sex and age. Both genetic defect and pharmaceutical inhibition of JMJD3 decrease dopamine level in midbrain and striatum, resulting from reduced tyrosine hydroxylase expression in midbrain dopamine neurons. Furthermore, epigenetic experiments reveal that JMJD3 is indispensable for the transcription of tyrosine hydroxylase through direct and indirect manners. These findings suggest JMJD3 and midbrain dopamine neurons as novel players and pharmaceutical targets for chronic pain regulation.

neuroscience↗

bioRxiv2022

Acrylamide Induces Protein Aggregation in CNS through Suppression of FoxO1-mediated Autophagy.

Proteotoxic stress is a major stimulus and risk factor for the neuropathogenesis in central nervous system (CNS), which is tightly associated with neurodegenerative diseases. Here, we identify acrylamide (ACR), a type-2 alkene that is commonly detected in deep-fried starch food and used in water industry and biomedical laboratories, as a potent and universal inducer of proteotoxic stress in mouse brain, as well as in cultured mouse neural stem cells, neurons and astrocytes, three major cell types in CNS. Aggregations of ubiquitin-labeled misfolded proteins and neurodegeneration-related proteins including amyloid precursor protein and presenilin 1 were drastically induced by ACR, leading to cell-defensive aggresome formation that was able to temporarily counteract with ACR toxicity. However, a defected clearance of aggresomes eventually led to apoptotic cell death, which was largely attributed to the breakdown of cytoskeleton and impairment of macroautophagy/autophagy, as evidenced by an aggregation of filament actin and an almost complete loss of LC3-positive autophagosomes. A series of core autophagy-related genes responsible for autophagosome formation were down-regulated, indicating an ACR-induced transcriptional suppression of autophagy. In addition, FoxO1, the master transactivator of these genes, were both transcriptionally repressed and nuclear excluded by ACR. Overexpression of FoxO1 rescued ACR-induced autophagy defects and attenuated the proteotoxicity. In summary, we spotlight proteotoxic stress as a novel feature of ACR neurotoxicity in CNS, and implicate FoxO1 as a critical therapeutic target.

pathology↗

bioRxiv2022

Starvation Induces Diverse Autophagic Response in Cardiomyocytes and Noncardiomyocytes.

Cardiac autophagy serves as a potential mechanism to be genetically, epigenetically and pharmaceutically manipulated to prevent or alleviate pathological conditions in heart diseases. One of the complexities of this manipulation comes from the cellular heterogeneity of the heart. In this study, we assessed the dynamics of nutrient deprivation-induced autophagy activation in four major cardiac cell types in vitro and in vivo and found a major difference between cardiomyocyte and other three types of noncardiomyocyte. In comparison to the constant increase and maintenance of autophagic activity in noncardiomyocytes, cardiomyocyte undergoes rapid gain and loss of autophagic activity. This difference contributes to at least two aspects of cardiomyocyte pathophysiology: high vulnerability to nutrient deprivation-induced cell death and unresponsiveness to pharmaceutical regulation of autophagy. Our present findings support a cell type-specific targeting of autophagy for therapeutic intervention of cardiac diseases.

cell biology↗

bioRxiv2021

Diverse roles of MeCP2 in the specification and maintenance of midbrain dopamine phenotype.

Midbrain dopamine (DA) neurons are associated with locomotor and psychiatric disorders. DA subtype is specified in ancestral neural precursor cells (NPCs) and maintained throughout neuronal differentiation. Here we show that endogenous expression of MeCP2 coincides with DA subtype specification in mouse mesencephalon, and premature expression of MeCP2 prevents in vitro cultured NPCs from acquiring DA subtype through interfering NURR1 transactivation of DA phenotype genes. By contrast, MeCP2 overexpression does not disturb DA subtype in DA neurons. By analyzing the dynamic change of DNA methylation along DA neuronal differentiation at the promoter of DA phenotype gene tyrosine hydroxylase (Th), we show that Th expression is determined by TET1-mediated de-methylation of NURR1 binding sites within Th promoter. Chromatin immunoprecipitation assays demonstrate that MeCP2 dominates the DNA binding of the corresponding sites thereby blocking TET1 function in DA NPCs, whereas TET1-mediated de-methylation prevents excessive MeCP2 binding in DA neurons. The significance of temporal DNA methylation status is further confirmed by targeted methylation/demethylation experiments showing that targeted de-methylation in DA NPCs protects DA subtype specification from MeCP2 overexpression, whereas targeted methylation disturbs subtype maintenance in MeCP2-overexpressed DA neurons. These findings suggest the appropriate timing of MeCP2 expression as a novel determining factor for guiding NPCs into DA lineage.

neuroscience↗

bioRxiv2021

A novel histone deacetylase inhibitor-based approach to eliminate microglia and retain astrocyte properties in glial cell culture.

The close association between astrocytes and microglia causes great difficulties to distinguish their individual roles in innate immune responses in central nervous system. Current chemical-based methods to eliminate microglia in glial cell culture introduce various molecular and functional alterations to astrocytes. Here, we describe a novel two-step approach to achieve a complete elimination of microglia without affecting the biological properties of co-cultured astrocytes by temporal treatment of histone deacetylase inhibitor trichostatin A (TSA). We verify TSA as a potent inducer for microglial-specific cell death, which also causes comprehensive gene expression changes in astrocytes. However, withdrawal of TSA not only ensures no microglia repopulation, but also restores all the gene expression changes in terms of astrocyte functions, including neurotrophic factors, glutamate and potassium transporters, and reactive astrocyte subtypes. By contrast, withdrawal of PLX5622, the commonly used colony-stimulating factor 1 receptor inhibitor neither prevents microglia repopulation nor restores the gene expression changes mentioned above. Using this method, we are able to discriminate differential roles of microglia and astrocytes in the induced expression of antiviral and pro-inflammatory cytokines upon various pathological stimuli including the spike protein of SARS-CoV-2. This simple and efficient method can be customized for the understanding of microglia-astrocyte interaction and the development of epigenetic therapies that target over-activated microglia in neuroinflammation-related diseases.

neuroscience↗

bioRxiv2017

Cholecystokinin release triggered by presynaptic NMDA receptors produces LTP and sound-sound associative memory formation

Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA-dependent long-term potentiation (LTP). There is evidence that entorhinal cortex enables neocortical neuroplasticity through cholecystokinin (CCK)-containing neocortical projections. Here we show that a CCKB antagonist blocks high-frequency stimulation (HFS)-induced LTP in the auditory cortex, whereas local infusion of CCK induces LTP. CCK-/- mice lacked neocortical LTP and showed deficits in a cue-cue associative learning paradigm; administration of CCK rescued associative learning. HFS of CCK-containing entorhino-neocortical projection neurons in anesthetized mice enabled cue-cue associative learning. Furthermore, when one cue was pre-conditioned to footshock, the mouse showed a freezing response to the other cue, indicating that the mice had formed an association. HFS-induced neocortical LTP was completely blocked by either NMDA antagonist or CCK-BR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation (LFS). Moreover, in the presence of CCK LTP was still induced, even after blockade of NMDA receptors. Local application of NMDA induced CCK release in the neocortex. To identify how NMDA receptor switches LTP, a stimulation protocol of 25 pulse-pairs was adopted to replace HFS; NMDA-dependent LTP was induced with the inter-pulse intervals between 10 and 100 ms, but not with those of 5 and 200 ms. LTP-mediated plasticity was linked to localization of the NMDA receptor subunit NR2a on cortical CCK terminals originating in the entorhinal cortex. These novel findings suggest that presynaptic NMDA receptors on CCK terminals control the release of CCK, which enables neocortical LTP and formation of cue-cue associative memory.\n\nOne Sentence SummaryPresynaptic NMDA receptors switches the release of CCK from entorhinal neurons, which enables neocortical LTP and formation of sound-sound associative memory.

neuroscience↗