Journal of Neurochemistry最新文献

The complex relationship between inflammation, its effects on neuronal excitability and the ensuing plasticity of dorsal root ganglion (DRG) sensory neurons remains to be fully explored. In this study, we have employed a system of experiments assessing the impact of inflammatory conditioned media derived from activated immune cells on the excitability and activity of DRG neurons and how this relates to subsequent growth responses of these cells. We show here that an early phase of increased neuronal activity in response to inflammatory conditioned media is critical for the engagement of plastic processes and that neuronal excitability profiles are linked through time to the structural phenotype of individual neurons. Pharmacological blockade of neuronal activity was able to abolish the growth-promoting effects of inflammatory media. Our results suggest that targeting the activity of DRG neurons may provide a novel therapeutic avenue to manipulate their growth status and potential for plasticity in response to inflammation. Importantly, the same pharmacological blockade in vivo abolished pain responses in a mouse model of multiple sclerosis. While further studies are needed to fully elucidate the underlying mechanisms of the relationship between neural activity and growth status, a more complete understanding of this relationship may ultimately lead to the development of new treatments for neuropathic pain in disorders associated with heightened immune responses such as rheumatoid arthritis and multiple sclerosis.

Different taste cells express unique cell-type markers, enabling researchers to distinguish them and study their functional differentiation. Using single-cell RNA-Seq of taste cells in mouse fungiform papillae, we found that Cellular Communication Network Factor 3 (Ccn3) was highly expressed in Type III taste cells but not in Type II taste cells. Ccn3 is a protein-coding gene involved in various biological processes, such as cell proliferation, angiogenesis, tumorigenesis, and wound healing. Therefore, in this study, we aimed to explore the expression and function of Ccn3 in mouse taste bud cells. Using reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry (IHC), we confirmed that Ccn3 was predominantly expressed in Type III taste cells. Through IHC, quantitative real-time RT-PCR, gustatory nerve recordings, and short-term lick tests, we observed that Ccn3 knockout (Ccn3-KO) mice did not exhibit any significant differences in the expression of taste cell markers and taste responses compared to wild-type controls. To explore the function of Ccn3 in taste cells, bioinformatics analyses were conducted and predicted possible roles of Ccn3 in tissue regeneration, perception of pain, protein secretion, and immune response. Among them, an immune function is the most plausible based on our experimental results. In summary, our study indicates that although Ccn3 is strongly expressed in Type III taste cells, its knockout did not influence the basic taste response, but bioinformatics provided valuable insights into the possible role of Ccn3 in taste buds and shed light on future research directions.

Stress is a significant cause of mental disorders, for which effective treatments remain limited due to an insufficient understanding of its pathogenic mechanisms. Recent research has increasingly focused on non-neuronal cells to elucidate the molecular mechanisms underlying psychopathology. In this review, we summarize the current knowledge on how non-neuronal cells in the central nervous system, including microglia, astrocytes, and oligodendrocytes, respond to peripherally derived stress-related factors and how these responses contribute to the development of mental disorders. A more comprehensive understanding of stress-induced alterations, with careful consideration of the type and timing of stress exposure, will provide fundamental insights into the pathogenesis of diverse stress-related mental disorders.

This study employs single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin with high-throughput sequencing technologies (scATAC-seq) to perform joint sequencing on cells at various time points during the induction of adipose-derived stem cells (ADSCs) into astrocytes. We applied bioinformatics approaches to investigate the differentiation trajectories of ADSCs during their induced differentiation into astrocytes. Pseudotemporal analysis was used to infer differentiation trajectories. Additionally, we assessed chromatin accessibility patterns during the differentiation process. Key transcription factors driving the differentiation of ADSCs into astrocytes were identified using motif and footprint methods. Our analysis revealed significant shifts in gene expression during the induction process, with astrocyte-related genes upregulated and stem cell-related genes downregulated. ADSCs first differentiated into neural stem cell-like cells with high plasticity, which further matured into astrocytes via two distinct pathways. Marked changes in chromatin accessibility were observed during ADSC-induced differentiation, affecting transcription regulation and cell function. Transcription factors analysis identified NFIA/B/C/X and CEBPA/B/D as key regulators in ADSCs differentiation into astrocytes. We observed a correlation between chromatin accessibility and gene expression, with ADSCs exhibiting broad chromatin accessibility prior to lineage commitment, where chromatin opening precedes transcription initiation. In summary, we found that ADSCs first enter a neural stem cell-like state before differentiating into astrocytes. ADSCs also display extensive chromatin accessibility prior to astrocyte differentiation, although transcription has not yet been initiated. These findings offer a theoretical framework for understanding the molecular mechanisms underlying this process.

Altered energy metabolism in Alzheimer's disease (AD) is a major pathological hallmark implicated in the early stages of the disease process. Astrocytes play a central role in brain homeostasis and are implicated in multiple neurodegenerative diseases. Although numerous studies have investigated global changes in brain metabolism, redox status, gene expression and epigenetic markers in AD, the intricate interplay between different metabolic processes, particularly in astrocytes, remains poorly understood. Numerous studies have implicated amyloid-β and the amyloid-β precursor in the development and progression of AD. To determine the effects of amyloid-β peptides or the impact of amyloid-β precursor protein processing on astrocyte metabolism, we differentiated astrocytes from induced pluripotent stem cells derived from people with early onset familial AD and controls. This study demonstrates that familial AD-derived astrocytes exhibit significantly more changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism compared to acute amyloid-β exposure. In addition to changes in major metabolic pathways including glutamate, purine and arginine metabolism and the citric acid cycle, we demonstrate evidence of gliosis in familial AD astrocytes highlighting a potential pathological hallmark. This suggests that chronic alterations in metabolism may occur very early in the disease process and present significant risk factors for disease progression for patients with early onset AD. These findings may also reveal important drivers of disease in late onset dementia and highlights key targets for potential diagnostic features and therapeutic agents in the future.

The capacity of immune cells to alter their function based on their metabolism is the basis of the emerging field of immunometabolism. Microglia are the resident innate immune cells of the central nervous system, and it is a current focus of the field to investigate how alterations in their metabolism impact these cells. Microglia have the ability to utilize lipids, such as fatty acids, as energy sources, but also alterations in lipids can impact microglial form and function. Recent studies highlighting different microglial states and transcriptional signatures have highlighted modifications in lipid processing as defining these states. This review highlights these recent studies and uses these altered pathways to discuss the current understanding of lipid biology in microglia. The studies highlighted here review how lipids may alter microglial phagocytic functioning or alter their pro- and anti-inflammatory balance. These studies provide a foundation by which lipid supplementation or diet alterations could influence microglial states and function. Furthermore, targets modulating microglial lipid metabolism may provide new treatment avenues.

Kenji F. Tanaka is a Professor in Brain Sciences at the Institute for Advanced Medical Research, Keio University School of Medicine in Japan. He has been conducting research on glial cells for more than 20 years and is an expert in cell-type-specific and time-controllable gene expression techniques. Kenji F. Tanaka has been a member of the JNC Editorial Board since 2019 and recently transitioned to the role of Senior Editor for the new JNC manuscript category: “Neurotools, Methods, and Neurochemistry Resources”. We interviewed him to learn about his goals as Senior Editor for this category, as well as key moments in his career and advice for young scientists.

The α4β2 nicotinic acetylcholine receptor (nAChR), an ionophore, has been suggested to signal through metabotropic pathways and interact with other receptor families, such as dopamine receptors. In this study, the interaction between α4β2 nAChR and dopamine receptors was investigated through in vivo and in vitro studies. Nicotine exposure in adolescent rats is known to induce a sustained increase in nicotine's rewarding effects which was assessed by conditioned place preference (CPP) assay. The expression levels of α4β2 nAChR and dopamine D₂/D₃ receptors (D₂R, D₃R) increased after nicotine treatment. To determine which of these two dopamine receptors was increased by nicotine treatment, a newly developed ligand with high selectivity for D₃R was used in the radioligand binding assay. Although the expression of both α4β2 nAChR and D₃R was enhanced by nicotine exposure during adolescence, only the elevated level of D₃R persisted into adulthood. In experiments conducted on mice, D₃R knockout mice showed significantly lower CPP scores in adulthood compared to wild-type mice. Cellular studies showed that an increase in D₃R expression was attributed to enhanced D₃R promoter activity, regulated by a signaling cascade composed of Src, Syk, PKC, and NF-κB. These results demonstrate that the metabotropic signaling pathway is involved in the interaction between α4β2 nAChR and D₃R, and also suggest how nicotine reward initiated in adolescence could relapse after a long abstinence period. Given the significance of adolescent nicotine exposure on nicotine addiction, this study is thought to offer a novel mechanistic perspective for understanding nicotine reward and relapse.

Minimizing central nervous system (CNS) injury from preterm birth depends upon understanding the critical pathways that underlie essential neurodevelopmental and CNS pathophysiology. Signaling by chemokine (C-X-C motif) ligand 1 (CXCL1) through its cognate receptor, CXCR2 [(C-X-C motif) receptor 2] is essential for neurodevelopment. Increased CXCR2 signaling, however, is implicated in a variety of uterine and neuropathologies, and their role in the CNS injury associated with perinatal brain injury is poorly defined. To evaluate the long-term efficacy of CXCR2 blockade in functional repair of brain injury secondary to chorioamnionitis (CHORIO), we used an established preclinical rat model of cerebral palsy. We tested the hypothesis that transient postnatal CXCR2 antagonism with SB225002 would reduce gait deficits, hypermobility, hyperactivity, and disinhibition concomitant with repair of functional and anatomical white and gray matter injury. CHORIO was induced in pregnant Sprague Dawley rats on embryonic day 18 (E18). SB225002 (3 mg/kg) was administered intraperitoneally from postnatal day 1 (P1)-P5. Rats were aged to adulthood and tested for gait, open-field behavior and cognitive and executive function deficits using a touchscreen cognitive assessment platform. Results show that transient CXCR2 blockade attenuated microstructural white matter injury after CHORIO consistent with improved anatomical connectivity, and mitigated deficits in gait coordination, posture, balance, paw placement, and stepping (p < 0.05). Animals with CHORIO were hyperactive and hypermobile with fMRI deficits in neural circuitry central to cognition. However, CXCR2 antagonism in CHORIO animals did not normalize open-field behavior, neural activity, or cognition on a touchscreen task of discrimination learning (all p > 0.05). Studies in CXCR2 knockout mice confirmed significantly impaired cognitive performance independent of CHORIO. Taken together, transient postnatal blockade of CXCR2 ameliorates aspects of the lasting neural injury after CHORIO including normalizing gait deficits and white matter injury. However, improvement in essential functional and cognitive domains are not achieved limiting the utility of this therapeutic approach for treatment of perinatal brain injury. This study emphasizes the complex, multi-faceted role of chemokines in typical neurodevelopment, circuit formation, neural network function, and injury response.

Bone morphogenetic proteins (BMPs), regulators of bone formation, have been implicated in embryogenesis and morphogenesis of various tissues and organs. BMP signaling plays a role in the formation of appropriate synaptic connections and development of normal neural circuits in the brain. However, physiological roles of BMP signaling in postnatal neural functions, including synaptic plasticity, remain largely unknown. Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses in the cerebellum has been suggested one neuronal mechanism underlying cerebellar functions. Here, we explored the contribution of BMP signaling to the induction of mouse cerebellar LTD. We first demonstrated that BMP2 and/or 4 were expressed in GABAergic neurons in mature networks of the cerebellar cortex. mRNA encoding BMP receptor type 1B (Bmpr1b) was expressed in the PC layer. Exogenous application of noggin, a BMP ligand inhibitor, suppressed the induction of cerebellar LTD by conjunctive stimulation, which caused normal LTD under control condition. Furthermore, mice deficient in BMPR1B exhibited attenuation of the extent of LTD induction, whereas they showed normal excitatory synaptic transmission at PF-PC synapses. These results suggest that after postnatal development, BMP signaling activated by BMPR1B, expressed in the PC layer, plays a crucial role in the facilitation of cerebellar LTD, leading to the modulation of cerebellar functions and behaviors.