Neuroscience Letters最新文献

The behavioral sensitization, characterized by escalated behavioral responses triggered by recurrent exposure to psychostimulants, involves neurobiological mechanisms that are brain-region and cell-type specific. Enduring neuroadaptive changes have been observed in response to methamphetamine (METH) within the orbitofrontal cortex (OFC), the cell-type specific transcriptional alterations in response to METH sensitization remain understudied. In this study, we utilized Single-nucleus RNA-sequencing (snRNA-seq) to profile the gene expression changes in the OFC of a rat METH sensitization model. The analyses of differentially expressed genes (DEGs) unveiled cell-type specific transcriptional reactions associated with METH sensitization, with the most significant alterations documented in microglial cells. Bioinformatic investigations revealed that distinct functional and signaling pathways enriched in microglia-specific DEGs majorly involved in macroautophagy processes and the activation of N-methyl-D-aspartate ionotropic glutamate receptors (NMDAR). To validate the translational relevance of our findings, we analyzed our snRNA-seq data in conjunction with a transcriptomic study of individuals with opioid use disorder (OUD) and a large-scale Genome-Wide Association Studies (GWAS) from multiple externalizing phenotypes related to drug addiction. The validation analysis confirmed the consistent expression changes of key microglial DEGs in human METH addiction. Moreover, the integration with GWAS data revealed associations between addiction risk genes and the DEGs observed in specific cell types, particularly microglia and excitatory neurons. Our study highlights the importance of cell-type specific transcriptional alterations in the OFC in the context of METH sensitization and their potential translational relevance to human drug addiction.

Previous work from our laboratory showed that cotinine, a nicotine metabolite, reverses three nicotine-induced behavioral effects in freshwater planarians: motility decrease, seizure-like movements, and withdrawal-like behaviors. The present work explored whether cotinine, a nicotine metabolite, antagonized the nicotine-induced effects on planarian motility in a concentration-dependent manner. We found that nicotine decreased planarian motility at nicotine concentrations above 60 μM but increased planarian velocity at concentrations equal to or below 50 μM, in agreement with previous data. Cotinine did not affect planarian motility at a concentration range between 250 and 2750 μM. Furthermore, we found that cotinine alleviated the 100 μM nicotine-induced motility decrease in a concentration-dependent manner and reversed the low nicotine concentration motility increase, albeit in a concentration-independent manner. The apparent concentration-dependent alleviation of >60 μM nicotine-induced motility decrease by cotinine suggests an orthosteric relationship between nicotine and cotinine. On the other hand, the evident concentration-independent cotinine alleviation of the increase in motility induced by 50 μM nicotine suggests an allosteric relationship. Our data is consistent with the existing literature about the relationship between nicotine and cotinine in various models, reinforcing the case for the usefulness of the planarian model in pharmacological studies.

Mesenchymal stem cells (MSCs) are involved in tissue repair and anti-inflammatory activities and have shown promising therapeutic efficiency in different animal models of neurodegenerative disorders. Microvesicles (MVs), implicated in cellular communication, are secreted from MSCs and play a key role in determining the fate of cell differentiation. Our study examines the effect of human umbilical cord MSC-derived MVs (hUC-MSC MVs) on the proliferation and differentiation potential of adult neural stem cells (NSCs). Results showed that 0.2 μg MSC derived MVs significantly increased the viability of NSCs and their proliferation, as demonstrated by an increase in the number of neurospheres and their derived cells, compared to controls. In addition, all hUC-MSC MVs concentrations (0.1, 0.2 and 0.4 µg) induced the differentiation of NSCs toward precursors (Olig2 + ) and mature oligodendrocytes (MBP+). This increase in mature oligodendrocytes was inversely proportional to the dose of MVs. Moreover, hUC-MSC MVs induced the differentiation of NSCs into neurons (β-tubulin + ), in a dose-dependent manner, but had no effect on astrocytes (GFAP+). Furthermore, treatment of NSCs with hUC-MSC MVs (0.1 and 0.2 μg) significantly increased the expression levels of the proliferation marker Ki67 gene, compared to controls. Finally, hUC-MSC MVs (0.1 μg) significantly increased the expression level of Sox10 transcripts; but not Pax6 gene, demonstrating an increased NSC ability to differentiate into oligodendrocytes. In conclusion, our study showed that hUC-MSC MVs increased NSC proliferation in vitro and induced NSC differentiation into oligodendrocytes and neurons, but not astrocytes.

This study investigated the antioxidant and neuroprotective effects of nicotinamide combined with ischemic preconditioning against cerebral ischemia reperfusion (CIR) injury. Thirty-five Wistar albino male rats were randomly divided into five groups: sham, preconditioned ischemia/reperfusion (IP+IR), ischemia/reperfusion (IR), preconditioned ischemia/reperfusion + nicotinamide (IP+IR+N), and ischemia/reperfusion + nicotinamide (IR+N). CIR was achieved with bilateral common carotid artery occlusion. IP+IR and IP+IR+N groups 30 min before ischemia; Three cycles of 10 sec ischemia/30 sec reperfusion followed by 20 min IR were applied. The IP+IR+N and IR+N groups received 500 mg/kg nicotinamide intraperitoneally. After 24 h of reperfusion, a neurological evaluation was performed and vertıcal pole test. Biochemically, malondialdehyde (MDA), glutathione (GSH) levels and catalase (CAT) activity were measured in blood and brain tissue samples. Rates of red neurons, sateliosis and spongiosis were determined histopathologically in the prefrontal cortex areas.

After CIR, MDA levels increased significantly in serum and brain tissue in the IR group compared to the sham group, while GSH and CAT activity decreased in the brain tissue (p < 0.05). MDA levels in the tissues were found significantly decreased in the IR+N group compared to the IR group (p < 0.05). Administration of nicotinamide together with IP significantly decreased MDA levels in brain tissue and increased GSH and CAT activity (p < 0.05). Compared to the IR group, the morphological and neurological damage in the prefrontal cortex areas decreased in the IP+IR, IP+IR+N, and IR+N groups (p < 0.05). In addition, red neuron, sateliosis and spongiosis rates increased significantly in the IR group compared to the Sham, IP+IR+N, IR+N groups (p < 0.001 for all). In neurological evaluation, while the neurological score increased and the time on the vertical pole decreased significantly in the IR group, preconditioning, and nicotinamide groups reversed (p < 0.05). The study’s results show that nicotinamide administration with ischemic preconditioning alleviates cerebral ischemia/reperfusion injury.

Osteoarthritis (OA) pain originates in the joint by sensitization of articular nociceptors. While behavioural assessments provide valuable information regarding pain symptoms, the techniques are subjective and open to interpretation by the experimenter. This study used in vivo electrophysiological approaches to measure objectively joint nociceptor properties in three rodent models of OA. Single unit extracellular recordings of joint mechanosensitive afferents were carried out in male and female rats following either (1) transection of the medial meniscus (MMT: post-traumatic OA), (2) intra-articular injection of sodium monoiodoacetate (MIA: chemically-induced OA), or (3) intra-articular injection of lysophosphatidic acid (LPA: neuropathic OA). In naïve male control rats, the mechanical threshold of joint mechanonociceptors (23.5 ± 1.8 mNm) was significantly reduced with MMT (9.4 ± 1.1 mNm) and MIA (15.1 ± 1.6 mNm). In females, the mechanical threshold of naïve rats (23.2 ± 3.1 mNm) was reduced following induction of MMT (8.3 ± 1.0 mNm) and LPA (10.6 ± 2.2 mNm). Afferent firing frequency increased in male MMT (∼275 %), LPA (∼175 %), MIA (225 %), and female MMT (∼146 %), LPA (∼200 %), and MIA (∼192 %). Mechanical threshold and evoked firing were negatively correlated in all models for both sexes except LPA rats (male + female) and female MMT. These data indicate that MMT, MIA, and LPA induce peripheral sensitization of joint afferents thereby validating their use in OA pain studies.

The paraventricular hypothalamic nucleus (PVH) is an important neuroendocrine center involved in pain regulation, but the nociceptive afferent routes for the nucleus are still unclear. We examined the profile of PVH receiving injurious information by a combination of retrograde tracing with Fluoro-Gold (FG) and FOS expression induced by formalin stimuli. The result showed that formalin injection induced significantly increased expression of FOS in the PVH, among which oxytocin containing neurons are one neuronal phenotype. Immunofluorescent staining of FG and FOS revealed that double labeled neurons were strikingly distributed in the area 2 of the cingulate cortex (Cg2), the lateral septal nucleus (LS), the periaqueductal gray (PAG), the posterior hypothalamic area (PH), and the lateral parabrachial nucleus (LPB). In the five regions, LPB had the biggest number and the highest ratio of FOS expression in FG labeled neurons, with main subnuclei distribution in the external, superior, dorsal, and central parts. Further immunofluorescent triple staining disclosed that about one third of FG and FOS double labeled neurons in the LPB were immunoreactive for calcitonin gene related peptide (CGRP). In conclusion, the present study demonstrates the nociceptive input profile of the PVH area under inflammatory pain and suggests that neurons in the LPB may play essential roles in transmitting noxious information to the PVH.

Depression and anxiety are prominent symptoms of withdrawal syndrome, often caused by the abuse of addictive drugs like morphine. N-palmitoylethanolamide (PEA), a biologically active lipid, is utilized as an anti-inflammatory and analgesic medication. Recent studies have highlighted PEA’s role in mitigating cognitive decline and easing depression resulting from chronic pain. However, it remains unknown whether PEA can influence negative emotions triggered by morphine withdrawal. This study seeks to explore the impact of PEA on such emotions and investigate the underlying mechanisms. Mice subjected to morphine treatment underwent a 10-day withdrawal period, followed by assessments of the effect of PEA on anxiety- and depression-like behaviors using various tests. Enzyme-linked immunosorbent assay was conducted to measure levels of monoamine neurotransmitters in specific brain regions. The findings indicate that PEA mitigated anxiety and depression symptoms and reduced 5-hydroxytryptamine, noradrenaline, and dopamine levels in the hippocampus and prefrontal cortex. In summary, PEA demonstrates a significant positive effect on negative emotions associated with morphine withdrawal, accompanied with the reduction in levels of monoamine neurotransmitters in key brain regions. These insights could be valuable for managing negative emotions arising from morphine withdrawal.

One of the pathologic hallmarks of Alzheimer’s disease (AD) is neurofibrillary tau tangles. Despite our knowledge that tau typically initiates in the medial temporal lobe (MTL), the mechanisms driving tau to spread beyond MTL remain unclear. Emerging evidence reveals distinct patterns of functional connectivity change during aging and preclinical AD: while connectivity within-network decreases, connectivity between-network increases. Building upon increased between-network connectivity, our study hypothesizes that this increase may play a critical role in facilitating tau spread in early stages. We conducted a longitudinal study over two to three years intervals on a cohort of 46 healthy elderly participants (mean age 64.23 ± 3.15 years, 26 females). Subjects were examined clinically and utilizing advanced imaging techniques that included resting-state functional MRI (rs-fMRI), structural magnetic resonance imaging (MRI), and a second-generation positron emission tomography (PET) tau tracer, 18F-MK6240. Through unsupervised agglomerative clustering and increase in between-network connectivity, we successfully identified individuals at increased risk of future tau elevation and AD progression. Our analysis revealed that individuals with increased between-network connectivity are more likely to experience more future tau deposition, entorhinal cortex thinning, and lower selective reminding test (SRT) delayed scores. Additionally, in the limbic network, we found a strong association between tau progression and increased between-network connectivity, which was mainly driven by beta-amyloid (Aβ) positive participants. These findings provide evidence for the hypothesis that an increase in between-network connectivity predicts future tau deposition and AD progression, also enhancing our understanding of AD pathogenesis in the preclinical stages.

Objective

Bipolar disorder (BD) is a debilitating neuropsychiatric disorder, which is associated with genetic variation through “vast but mixed” Genome-Wide Association Studies (GWAS). Transcriptome-Wide Association Study (TWAS) is more effective in explaining genetic factors that influence complex diseases and can help identifying risk genes more reliably. So, this study aims to identify potential BD risk genes in pedigrees with TWAS.

Methods

We conducted a TWAS analysis with expression quantitative trait loci (eQTL) analysis on extended BD pedigrees, and the BD genome-wide association study (GWAS) summary data acquired from the Psychiatric Genomics Consortium (PGC). Furthermore, the BD-associated genes identified by TWAS were validated by mRNA expression profiles from the Gene Expression Omnibus (GEO) Datasets (GSE23848 and GSE46416). Functional enrichment and annotation analysis were implemented by RStudio (version 4.2.0).

Results

TWAS identified 362 genes with P value < 0.05, and 18 genes remain significant after Bonferroni correction, such as SEMA3G (P_TWAS=1.07 × 10^-11), ALOX5AP (P_TWAS=3.12 × 10^-8), and PLEC (P_TWAS=1.27 × 10^-7). Further 6 overlapped genes were detected in integrative analysis, such as UQCRB (P_TWAS=0.0020, P_mRNA=0.0000), TMPRSS9 (P_TWAS=0.0405, P_mRNA=0.0032), and SNX10 (P_TWAS=0.0104, P_mRNA=0.0015). Using genes identified by TWAS, Gene Ontology (GO) enrichment analysis identified 40 significant GO terms, such as mitochondrial ATP synthesis coupled electron transport, mitochondrial respiratory, aerobic electron transport chain, oxidative phosphorylation, mitochondrial membrane proteins, and ubiquinone activity. The Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway enrichment analysis identified significant 15 pathways for BD, such as Oxidative phosphorylation, endocannabinoids signaling, neurodegeneration, and reactive oxide species.

Conclusions

We found a set of BD-associated genes and pathways, validating the important role of neurodevelopmental abnormalities, inflammatory responses, and mitochondrial dysfunction in the pathology of BD, offering novel information for comprehending the genetic basis of BD.

Synucleins, including α-synuclein (α-syn), β-syn, and γ-syn, have been implicated in various synucleinopathies, notably Parkinson’s disease (PD), which has generated increased interest in understanding their roles. Although α-syn and β-syn have contrasting neuropathological consequences, the precise role of γ-syn remains unclear. This study validated non-motor symptoms, specifically anxiety-like behavior, along with the degradation of dopaminergic (DAergic) neurons in the nigrostriatal system and DAergic neurites in the prefrontal cortex and hippocampus of rats infused with striatal 6-hydroxydopamine (6-OHDA). Our study further investigated the alterations in γ-syn expression levels in the prefrontal cortices and hippocampi of these 6-OHDA–treated rats, aiming to establish foundational insights into the neuropathophysiology of DA depletion, a central feature of PD. Our findings revealed a significant increase in the expression of γ-syn mRNA and protein in these brain regions, in contrast to unaltered α- and β-syn expression levels. This suggests a distinct role of γ-syn within the neurobiological milieu under conditions of DA deficiency. Overall, our data shed light on the neurobiological changes observed in the hemiparkinsonian rat model induced with 6-OHDA, underscoring the potential significance of γ-syn in PD pathology.