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Abstract: Recent findings suggest that the neurotransmitter dopamine (DA) system plays a role in motor control and the acquisition of habits and skills. However, isolating DA-mediated motor learning from motor performance remains challenging as most studies include often severely DA-depleted mice. Using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we investigated the effect of various degrees of DA-depletion in mice on three tests of motor behaviors: the accelerating rotarod, wire suspension and pole tests. Three protocols were performed to decrease DA synthesis to various extents: 4 injections (i.p.) of 9mg/kg in 1 day; 4 injections (i.p.) of 15mg/kg in 1 day; or 5 injections (s.c.) of 30mg/kg in 5 days. Severity of DA-depletion was assessed by the evaluation of tyrosine hydroxylase (TH) and dopamine transporter levels in the striatum using the Western blot technique. Mice were gathered into four different groups according their TH levels: mild, moderate, marked and severe. In these mice, the general motor abilities such as coordination, motion speed and muscular strength were relatively intact whereas impaired acquisition of skilled behavior occurred in mice with marked and severe reduction in TH levels. Marked and severely DA-depleted mice exhibited lower scores within the first trials of the first training day as well as a much slower progression in the following days on the accelerating rotarod. Based on these results, we conclude that the learning of a skilled behavior is more vulnerable to DA depletion than the DA-mediated control of motor activity. [Copyright &y& Elsevier]

Abstract: Glutamatergic neurotransmission plays an important role in the behavioral and molecular plasticity observed in cocaine mediated locomotor sensitization. Recent studies show that glutamatergic signaling is regulated by receptor trafficking, synaptic localization, and association with scaffolding proteins. The trafficking of the glutamate receptors was investigated in the dorsal and ventral prefrontal cortex at 1 and 21 days after repeated cocaine administration which produced robust locomotor sensitization. A subcellular fractionation technique was used to isolate the cellular synaptosomal fraction containing the postsynaptic density. At early withdrawal, the prefrontal cortex displayed a reduction in the synaptosomal content of the AMPA and NMDA receptor subunits. In contrast, after extended withdrawal, there was a significant increase in the trafficking of the receptors into the synaptosomal compartment. These changes were accompanied by corresponding trafficking of the postsynaptic glutamatergic scaffolding proteins. Thus, enhanced trafficking of glutamate receptors from cytosolic to synaptosomal compartment is associated with prolonged withdrawal from repeated exposure to cocaine and may have functional consequences for the synaptic and behavioral plasticity. [Copyright &y& Elsevier]

CD169+ macrophages reside in lymph node (LN) and spleen and play an important role in the immune defense against pathogens. As resident macrophages, they are responsive to environmental cues to shape their tissue-specific identity. We have previously shown that LN CD169+ macrophages require RANKL for formation of their niche and their differentiation. Here, we demonstrate that they are also dependent on direct lymphotoxin beta (LTβ) receptor (R) signaling. In the absence or the reduced expression of either RANK or LTβR, their differentiation is perturbed, generating myeloid cells expressing SIGN-R1 in LNs. Conditions of combined haploinsufficiencies of RANK and LTβR revealed that both receptors contribute equally to LN CD169+ macrophage differentiation. In the spleen, the Cd169-directed ablation of either receptor results in a selective loss of marginal metallophilic macrophages (MMMs). Using a RANKL reporter mouse, we identify splenic marginal zone stromal cells as a source of RANKL and demonstrate that it participates in MMM differentiation. The loss of MMMs had no effect on the splenic B cell compartments but compromised viral capture and the expansion of virus-specific CD8+ T cells. Taken together, the data provide evidence that CD169+ macrophage differentiation in LN and spleen requires dual signals from LTβR and RANK with implications for the immune response. [ABSTRACT FROM AUTHOR]

Introduction: Prior data suggest associations between hearing loss, cardiovascular (CV) risk factors, and CV disease. Whether specific hearing loss patterns, including a strial pattern associated with inner ear vascular disease, are associated with systemic endothelial dysfunction and carotid intima–media thickness (IMT) remains unclear. Methods: We evaluated participants without prevalent CVD in the Framingham Offspring Study who underwent formal audiogram testing and brachial and carotid artery ultrasounds. Audiograms were categorized as normal or as belonging to one of four abnormal patterns: cochlear-conductive, low-sloping, sensorineural, or strial. Endothelial function as measured by brachial artery flow-mediated dilation (FMDmm and FMD%). Internal and common intima–media thicknesses (icIMT and ccIMT, respectively) were compared between audiogram patterns. Results: We studied 1672 participants (mean age 59 years, 57.6% women). The prevalence of each hearing pattern was as follows: 43.7% normal; 20.3% cochlear-conductive; 20.3% sensorineural; 7.7% low-sloping; and 8.0% strial. Strial pattern hearing loss was nearly twice as prevalent (p = 0.001) in those in the highest quartile of ccIMT and nearly 50% higher in those in the highest icIMT quartile (p = 0.04). There were no statistically significant differences between the prevalence of the strial pattern comparing the lowest quartiles of FMDmm and FMD% with the upper three quartiles. Age- and sex-adjusted linear regression models did not show significant associations between the vascular measures and hearing patterns. Conclusion: Abnormal hearing patterns were not significantly associated with impaired brachial FMD and increased carotid IMT after adjusting for age and sex effects, which may reflect age and sex-related distributional differences based on hearing loss pattern. [ABSTRACT FROM AUTHOR]

Background: Immune modulation by vitamin D3 through dendritic cells (DCs) remains controversial. Human DCs exposed in vitro counteract type‐1 T‐helper (Th1) differentiation and induce regulatory T cells. However, cutaneous application on mice promotes Th2‐driven inflammation resembling atopic dermatitis and relying on thymic stromal lymphopoietin (TSLP) from keratinocytes and T‐cell orientation by TSLP‐stimulated skin DCs. We studied the effects of vitamin D3 in human skin, focusing on TSLP production and the role of skin DCs in T‐cell differentiation. Methods: Human healthy skin explants were exposed in vitro to vitamin D3 analogs. Migrating DCs were analyzed and TSLP quantified in the supernatant. Allogeneic naïve CD4+ T cells were cocultured with DCs to assess their proliferation and cytokine production. Results: Vitamin D3 induced skin DCs to differentiate Th2 cells producing IL‐4 and IL‐13. Vitamin D3 triggered TSLP release in ~30% of skin explants, correlating with IL‐13 detection in Th2 cells. In these donors, blocking TSLP receptor during skin explant cultures abrogated IL‐13 production, yet IL‐4+ Th2 cells were unaffected. Among skin DCs emerged CD14+ cells that had responded directly to vitamin D3 and differed from classical CD14+ dermal emigrants. Vitamin D3‐elicited CD14+ DCs sufficed to promote IL‐4+ Th2 cells in a TSLP‐independent manner. Conclusion: Vitamin D3, despite inducing TSLP in some donors, had a direct influence on skin DCs, affecting their phenotype and ability to drive Th2 responses independently of TSLP. Our findings pave the way toward in vitro systems that accurately model human cutaneous Th2 responses, notably involved in atopic dermatitis. [ABSTRACT FROM AUTHOR]

Zoledronic acid (ZOL), a nitrogen bisphosphonate (N-BP), is currently used to treat and control pediatric osteolytic diseases. Variations in the intensity of the effects and side effects of N-BPs have been reported with no clear explanations regarding their origins. We wonder if such variations could be associated with different levels of RANKL signaling activity in growing bone during and after the treatment with N-BPs. To answer this question, ZOL was injected into neonate C57BL/6J mice with different genetically-determined RANKL signaling activity levels (Opg+/+\RankTg−, Opg+/+\RankTg+, Opg+/−\RankTg−, Opg+/−\RankTg+, Opg−/−\RankTg− and Opg−/−\RankTg+ mice) following a protocol (4 injections from post-natal day 1 to 7 at the dose of 50 μg/kg) that mimics those used in onco-pediatric patients. At the end of pediatric growth (1 and half months) and at an adult age (10 months), the bone morphometric and mineral parameters were measured using μCT in the tibia and skull for the different mice. A histologic analysis of the dental and periodontal tissues was also performed. At the end of pediatric growth, a delay in long bone and skull bone growth, a blockage of tooth eruption, some molar root alterations and a neoplasia-like structure associated with incisor development were found. Interestingly, the magnitude of these side effects was reduced by Opg deficiency (Opg−/−) but increased by Rank overexpression (RankTg). Analysis of the skeletal phenotype at ten months confirmed respectively the beneficial and harmful effects of Opg deficiency and Rank overexpression. These results validated the hypothesis that the RANKL signaling activity level in the bone microenvironment is implicated in the modulation of the response to ZOL. Further studies will be necessary to understand the underlying molecular mechanisms, which will help decipher the variability in the effects of N-BPs reported in the human population. The present study establishes that in mice the RANKL signaling activity level is a major modulator of the effects and side-effects of bisphosphonates on the individual skeleton during growth. However, the modulatory actions are dependent on the ways in which this level of activity is increased. A decrease in OPG expression is beneficial to the skeletal phenotype observed at the end of growth, while RANK overexpression deteriorates it. Far removed from pediatric treatment, in adults, the skeletal phenotypes initially observed at the end of growth for the different levels of RANKL signaling activity were maintained, although significant improvement was associated only with reductions in OPG expression. [ABSTRACT FROM AUTHOR]

Abstract Glycolipid mimetics consisting of a bicyclic polyhydroxypiperidine-cyclic carbamate core and a pseudoanomeric hydrophobic tail, termed sp2-iminosugar glycolipids (sp2-IGLs), target microglia during neuroinflammatory processes. Here we have synthesized and investigated new variants of sp2-IGLs for their ability to suppress the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) signaling through Toll-like receptor 4. We report that the best lead was (1 R)-1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ), able to inhibit LPS-induced TNFα production and maturation of DCs. Immunovisualization experiments, using a mannoside glycolipid conjugate (MGC) that also suppress LPS-mediated DC activation as control, evidenced a distinct mode of action for the sp2-IGLs: unlike MGCs, DSO 2 -ONJ did not elicit internalization of the LPS co-receptor CD14 or induce its co-localization with the Toll-like receptor 4. In a mouse model of LPS-induced acute inflammation, DSO 2 -ONJ demonstrated anti-inflammatory activity by inhibiting the production of the pro-inflammatory interleukin-6. The ensemble of the data highlights sp2-IGLs as a promising new class of molecules against inflammation by interfering in Toll-like receptor intracellular signaling. Graphical abstract Image 1 Highlights • sp2-Iminosugar glycolipids (sp2-IGLs) with S-linked aglycones have been synthesized. • The configuration modulates the antiinflammatory response in LPS-activated human DCs. • sp2-IGLs interfere with TLR-4 intracellular signaling, likely by binding to p38α MAPK. • The best candidate proved efficacy in an in vivo model of LPS-mediated inflammation. [ABSTRACT FROM AUTHOR]