Microglia play critical roles in tissue homeostasis and can also modulate neuronal function and synaptic connectivity. In contrast to astrocytes and oligodendrocytes, which arise from multiple ...progenitor pools, microglia arise from yolk sac progenitors and are widely considered to be equivalent throughout the CNS. However, little is known about basic properties of deep brain microglia, such as those within the basal ganglia (BG). Here, we show that microglial anatomical features, lysosome content, membrane properties, and transcriptomes differ significantly across BG nuclei. Region-specific phenotypes of BG microglia emerged during the second postnatal week and were re-established following genetic or pharmacological microglial ablation and repopulation in the adult, indicating that local cues play an ongoing role in shaping microglial diversity. These findings demonstrate that microglia in the healthy brain exhibit a spectrum of distinct functional states and provide a critical foundation for defining microglial contributions to BG circuit function.
•We provide an extensive definition of basic properties of basal ganglia microglia•Microglia in the healthy brain exist along a spectrum of functional states•Midbrain microglia differ significantly from their cortical counterparts•Region-specific phenotypes reemerge following microglial ablation and repopulation
De Biase et al. show that microglia in different basal ganglia nuclei exhibit region-specific phenotypes, with distinct anatomical features, lysosome content, membrane properties, and transcriptomes. Local regulatory cues guide establishment and maintenance of this regional specialization.
As sudden catastrophic geological disasters, landslides always cause numerous casualties and much property damage. Landslides in reservoir areas are rarely caused by a single influential factor such ...as rainfall or fluctuation of reservoir water level (FRWL); rather, they are frequently caused by the combination of influential factors. Since rainfall and FRWL conditions vary by location in reservoir areas, it is necessary to discuss slope stability under various possible combinations of rainfall and FRWL while considering the specific characteristics of the region. In this paper, model tests on the slope stability of the Three Gorges Reservoir (TGR) area were conducted with S1 sand under three different rainfall and FRWL combinations. Additionally, numerical simulations on the model tests, in which an unsaturated soil constitutive model was selected to describe the mechanical–hydraulic behaviour of saturated/unsaturated soil, were conducted. In the simulation, to reflect the regional characteristics, a relationship between the rainfall infiltration rate and the unsaturated permeability of the sand was proposed. By carefully determining the parameters involved in the constitutive model, soil–water–air coupling finite element analyses were conducted to simulate the model tests on slope stability. By comparing the calculated results with the test results, the numerical method used in this paper offers satisfactory accuracy to describe the various failure mechanisms of the model slopes under different loading combinations. The results of both the model tests and the numerical simulation indicate that in the TGR area during one year of operation, a decrease in the reservoir water level combined with a long weak rainfall is more likely to trigger a landslide than the other combinations studied. Additionally, the combination of a short heavy rainfall with FRWL in the short term during the wet season can be dangerous; thus, this combination needs to be considered in the operation of the TGR.
•Three combinations of rainfall and water level fluctuation are observed in TGR area•Landslides were different under three combination patterns of external loads•Saturated/unsaturated cycles can reduce slope stability and trigger landslide•Combination of water level decrease with weak rainfall is most dangerous to slope
Basalt fibre has attracted great attention in developing fibre-reinforced polymers (FRP) in recent years. The tensile strength of basalt fibre is one of the most important considerations when ...formulating FRP structures. In this study, the strength of seven commercial basalt fibres was studied and compared, and the factors governing the strength of these fibres were investigated. The results showed that the strength of fibre is mainly dominated by the elemental composition of material and sizing on fibre surface, which functioning as “backbone” and “clothing” for the filament, respectively. Correlations between the tensile strength of fibre as a function of Al2O3 content and Fe3+/Σ(Fe3++Fe2+) in the material were also established. Interestingly, as a processing step after fibre spinning, the sizing can increase the strength of material by up to 25%, illustrating the importance of such post-treatment for developing high performance basalt fibres.
Substance use disorder (SUD) is a major public health crisis worldwide, and effective treatment options are limited. During the past 2 decades, researchers have investigated the impact of a variety ...of pharmacological approaches to treat SUD, one of which is the use of medical cannabis or cannabinoids. Significant progress was made with the discovery of rimonabant, a selective CB1 receptor (CB1R) antagonist (also an inverse agonist), as a promising therapeutic for SUDs and obesity. However, serious adverse effects such as depression and suicidality led to the withdrawal of rimonabant (and almost all other CB1R antagonists/inverse agonists) from clinical trials worldwide in 2008. Since then, much research interest has shifted to other cannabinoid-based strategies, such as peripheral CB1R antagonists/inverse agonists, neutral CB1R antagonists, allosteric CB1R modulators, CB2R agonists, fatty acid amide hydrolase (FAAH) inhibitors, monoacylglycerol lipase (MAGL) inhibitors, fatty acid binding protein (FABP) inhibitors, or nonaddictive phytocannabinoids with CB1R or CB2R-binding profiles, as new therapeutics for SUDs. In this article, we first review recent progress in research regarding the endocannabinoid systems, cannabis reward versus aversion, and the underlying receptor mechanisms. We then review recent progress in cannabinoid-based medication development for the treatment of SUDs. As evidence continues to accumulate, neutral CB1R antagonists (such as AM4113), CB2R agonists (JWH133, Xie2-64), and nonselective phytocannabinoids (cannabidiol, β-caryophyllene, ∆
-tetrahydrocannabivarin) have shown great therapeutic potential for SUDs, as shown in experimental animals. Several cannabinoid-based medications (e.g., dronabinol, nabilone, PF-04457845) that entered clinical trials have shown promising results in reducing withdrawal symptoms in cannabis and opioid users.
Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol ...(CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT
receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans.
In this paper, the authors study the global regularity of the 3D magnetohydrodynamics system in terms of one velocity component. In particular, they establish a new Prodi-Serrin type regularity ...criterion in the framework of weak Lebesgue spaces both in time and space variables.
The greatest hindrance for transdermal drug delivery (TDD) is the barrier property of skin, especially the stratum corneum (SC). Various methodologies have been investigated and developed to enhance ...the penetration of drugs through the skin. Among them, the most popular approach is the application of penetration enhancers (PEs), including natural terpenes, a very safe and effective class of PEs. In the present paper, we focused on terpenes as skin PEs for TDD. The mechanism of their action, the factors affecting their penetration enhancement effect, as well as their possible skin toxicity were discussed. Terpenes abundant in nature have great potential in the development of PEs. Compared to synthetic PEs, natural terpenes have been proved to possess higher enhancement activity. Interaction with SC intercellular lipids is the main mechanism of action for terpenes. The key factor affecting the enhancement effect is the lipophilicity of both terpenes and drug molecules. In addition, a lot of terpenes have also been proved to be much less toxic compared to azone, the classic synthetic PE. In summary, terpenes may be preferred over the chemically synthesized compounds as safe and effective PEs to promote the percutaneous absorption of drugs.
Cannabinoid CB ₂ receptors (CB ₂Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we ...report that CB ₂Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB ₂ mRNA and CB ₂R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB ₂Rs by JWH133 or other CB ₂R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB ₁⁻/⁻ mice are blocked by CB ₂R antagonist and absent in CB ₂⁻/⁻ mice. These data suggest that CB ₂R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.
Significance Although early studies suggested that cannabinoid CB ₂ receptors (CB ₂Rs) are absent in the brain, this view has been challenged by recent findings of significant brain CB ₂R involvement in several dopamine (DA)-related CNS disorders. The cellular mechanisms underlying these actions are unclear, however. Using multiple approaches, we found that CB ₂R genes and receptors are expressed in midbrain DA neurons, and that activation of CB ₂Rs inhibits DA neuronal firing and i.v. cocaine self-administration. These findings not only challenge the long-held view that brain CB ₂Rs are not expressed in neurons, but also suggest that neuronal CB ₂Rs modulate DA neuronal activity and DA-regulated behavior. Thus, brain CB ₂Rs may constitute a new therapeutic target in medication development for treatment of a number of CNS disorders.
Cannabinoid CB2 receptors (CB2Rs) are expressed in mouse brain dopamine (DA) neurons and are involved in several DA-related disorders. However, the cell type-specific mechanisms are unclear since the ...CB2R gene knockout mice are constitutive gene knockout. Therefore, we generated Cnr2-floxed mice that were crossed with DAT-Cre mice, in which Cre- recombinase expression is under dopamine transporter gene (DAT) promoter control to ablate Cnr2 gene in midbrain DA neurons of DAT-Cnr2 conditional knockout (cKO) mice. Using a novel sensitive RNAscope in situ hybridization, we detected CB2R mRNA expression in VTA DA neurons in wildtype and DAT-Cnr2 cKO heterozygous but not in the homozygous DAT-Cnr2 cKO mice. Here we report that the deletion of CB2Rs in dopamine neurons enhances motor activities, modulates anxiety and depression-like behaviors and reduces the rewarding properties of alcohol. Our data reveals that CB2Rs are involved in the tetrad assay induced by cannabinoids which had been associated with CB1R agonism. GWAS studies indicates that the CNR2 gene is associated with Parkinson's disease and substance use disorders. These results suggest that CB2Rs in dopaminergic neurons may play important roles in the modulation of psychomotor behaviors, anxiety, depression, and pain sensation and in the rewarding effects of alcohol and cocaine.
•Cannabinoid CB2R was initially assumed to be exclusively in the periphery.•Technological innovations have revealed functional CB2R expression in neurons.•Species differences exist in CB2R genes, ...receptor expression, and function.•Region-specific CB2R transcripts are found in the brain and periphery.•Brain CB2Rs are functional and neuroprotective against various insults.
The type 2 cannabinoid receptor (CB2R) was initially regarded as a peripheral cannabinoid receptor. However, recent technological advances in gene detection, alongside the availability of transgenic mouse lines, indicate that CB2Rs are expressed in both neurons and glial cells in the brain under physiological and pathological conditions, and are involved in multiple functions at cellular and behavioral levels. Brain CB2Rs are inducible and neuroprotective via up-regulation in response to various insults, but display species differences in gene and receptor structures, CB2R expression, and receptor responses to various CB2R ligands. CB2R transcripts also differ between the brain and spleen. In the brain, CB2A is the major transcript isoform, while CB2A and CB2B transcripts are present at higher levels in the spleen. These new findings regarding brain versus spleen CB2R isoforms may in part explain why early studies failed to detect brain CB2R gene expression. Here, we review evidence supporting the expression and function of brain CB2R from gene and receptor levels to cellular functioning, neural circuitry, and animal behavior.
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