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Motor learning (ML), which plays a fundamental role in growth and physical rehabilitation, involves different stages of learning and memory processes through different brain regions. However, the neural mechanisms that underlie ML are not sufficiently understood. Here, a previously unreported neuronal projection from the dorsal hippocampus (dHPC) to the zona incerta (ZI) involved in the regulation of ML behaviors is identified. Using recombinant adeno‐associated virus, the projections to the ZI are surprisingly identified as originating from the dorsal dentate gyrus (DG) and CA1 subregions of the dHPC. Furthermore, projection‐specific chemogenetic and optogenetic manipulation reveals that the projections from the dorsal CA1 to the ZI play key roles in the acquisition and consolidation of ML behaviors, whereas the projections from the dorsal DG to the ZI mediate the retrieval/retention of ML behaviors. The results reveal new projections from the dorsal DG and dorsal CA1 to the ZI involved in the regulation of ML and provide insight into the stages over which this regulation occurs. [ABSTRACT FROM AUTHOR]

Aims: Adenosine 2A receptor (A2AR) is widely expressed in the brain and plays important roles in neuroinflammation, and the nucleotide‐binding oligomerization domain, leucine‐rich repeat, and pyrin domain‐containing protein 3 (NLRP3) inflammasome is a crucial component of the innate immune system while the regulation of A2AR on it in the central nervous system (CNS) has not been clarified. Methods: The effects of microglial A2AR on NLRP3 inflammasome assembly and activation were investigated in wild‐type, A2AR‐ or NLRP3‐knockout primary microglia with pharmacological treatment. Microglial A2AR or NLRP3 conditional knockout mice were used to interrogate the effects of this regulation on neuroinflammation posttraumatic brain injury (TBI). Results: We found that A2AR directly interacted with NLRP3 and facilitated NLRP3 inflammasome assembly and activation in primary microglia while having no effects on mRNA levels of inflammasome components. Inhibition of the interaction via A2AR agonist or knockout attenuated inflammasome assembly and activation in vitro. In the TBI model, microglial A2AR and NLRP3 were co‐expressed at high levels in microglia next to the peri‐injured cortex, and abrogating of this interaction by microglial NLRP3 or A2AR conditional knockout attenuated the neurological deficits and neuropathology post‐TBI via reducing the NLRP3 inflammasome activation. Conclusion: Our results demonstrated that inhibition of the interaction between A2AR and NLRP3 in microglia could mitigate the NLRP3 inflammasome assembly and activation and ameliorate the neuroinflammation post‐TBI. It provides new insights into the effects of A2AR on neuroinflammation regulation post‐TBI and offers a potential target for the treatment of NLRP3 inflammasome‐related CNS diseases. [ABSTRACT FROM AUTHOR]

【Abstract】Objective: Radiation is an important cause of delayed wound healing, and there still exist many questions regarding the patterns and mechanisms of wound healing. This study investigated the characteristics of wound healing after varying doses of local radiation and explored possible causes of the delay in healing caused by radiation. Methods: A full-thickness dorsal longitudinal skin tissue, 2 cm in diameter, was excised after local irradiation on one side of the back of swine, and the other side was wounded as a control. The size of the wound area was re-corded every two days after injury. Pathological changes, proliferating cell nuclear antigen (PCNA, immunohisto-chemistry) and apoptosis levels (TUNEL assay) were mea-sured at different time points after wounding. Results: The course of wound healing can be divided into four phases, namely: the arresting phase, the healing priming phase, the fast healing phase, and the healed phase. Although the total wound healing time was closely corre-lated to the dose of irradiation (R 2 = 0.9758), it was more dependent on the length of the arresting phase (R 2 =0.9903) because once the arresting phase ended, the wound healed at a similar speed regardless of radiation doses. Pathologi-cal analysis showed that compared with the control side there were more necrotic tissues, slower epithelial crawling, as well as fewer blood vessels and cellular components in the irradiated side at the arresting phase, while other phases revealed no significant difference concerning these measurements. Immunohistochemistry showed that the ir-radiated wounds had significantly less PCNA-positive and more TUNEL-positive labeling of cells in the arresting phase than in other phases. Moreover, the changes were posi-tively related to the radiation doses, but there was no obvi-ous difference in cell proliferation or apoptosis among the healing priming phase, fast healing phase or healed phase, whether on the control side or on the irradiated side. Conclusions: After local irradiation, the length of the arresting phase determines the wound healing time. In-creased apoptosis and decreased cell proliferation might be an important reason for the formation of the arresting phase. Key words: Apoptosis; Cell proliferation; Radiation; Wound healing

Objectives: The present study clarified the role and signalling pathway of Ski in regulating proliferation and apoptosis in fibroblasts under high‐glucose (HG) conditions. Materials and Methods: The proliferation and apoptosis of rat primary fibroblasts were assessed using EdU incorporation and TUNEL assays. The protein and phosphorylation levels of the corresponding factors were measured using immunofluorescence staining and Western blotting. Immunoprecipitation was used to determine the interactions between Ski and FoxO1 or Ski and HDAC1. The Ski protein was overexpressed via recombinant adenovirus transfection, and FoxO1 and HDAC1 were knocked down using targeted small‐interfering RNA. Results: The present study found that HG inhibited fibroblast proliferation, increased apoptosis and reduced Ski levels in rat primary fibroblasts. Conversely, increasing Ski protein levels alleviated HG‐induced proliferation inhibition and apoptosis promotion. Increasing Ski protein levels also increased Ski binding to FoxO1 to decrease FoxO1 acetylation, and interfering with FoxO1 caused loss of the regulatory effect of Ski in fibroblasts under HG. Increasing Ski protein levels decreased FoxO1 acetylation via HDAC1‐mediated deacetylation. Conclusions: Therefore, these findings confirmed for the first time that Ski regulated fibroblast proliferation and apoptosis under HG conditions via the FoxO1 pathway. [ABSTRACT FROM AUTHOR]

Spatial recognition memory impairment is an important complication after traumatic brain injury (TBI). We previously found that spatial recognition memory impairment can be alleviated in adenosine A2A receptor knockout (A2AR KO) mice after TBI, but the mechanism remains unclear. In the current study, we used manganese‐enhanced magnetic resonance imaging and the Y‐maze test to determine whether the electrical activity of neurons in the retrosplenial cortex (RSC) was reduced and spatial recognition memory was impaired in wild‐type (WT) mice after moderate TBI. Furthermore, spatial recognition memory was damaged by optogenetically inhibiting the electrical activity of RSC neurons in WT mice. Additionally, the electrical activity of RSC neurons was significantly increased and spatial recognition memory impairment was reduced in A2AR KO mice after moderate TBI. Specific inhibition of A2AR in the ipsilateral RSC alleviated the impairment in spatial recognition memory in WT mice. In addition, A2AR KO improved autophagic flux in the ipsilateral RSC after injury. In primary cultured neurons, activation of A2AR reduced lysosomal‐associated membrane protein 1 and cathepsin D (CTSD) levels, increased phosphorylated protein kinase A and phosphorylated extracellular signal‐regulated kinase 2 levels, reduced transcription factor EB (TFEB) nuclear localization and impaired autophagic flux. These results suggest that the impairment of spatial recognition memory after TBI may be associated with impaired autophagic flux in the RSC and that A2AR activation may reduce lysosomal biogenesis through the PKA/ERK2/TFEB pathway to impair autophagic flux. [ABSTRACT FROM AUTHOR]

Pathogens such as bacterial lipopolysaccharide (LPS) play an important role in promoting the production of the inflammatory cytokines interleukin-1 beta (IL-1β) and tumour necrosis factor-α (TNF-α) in response to infection or damage in microglia. However, whether different signalling pathways regulate these two inflammatory factors remains unclear. The protein kinase C (PKC) family is involved in the regulation of inflammation, and our previous research showed that the activation of the PKC pathway played a key role in the LPS-induced transformation of the adenosine A2A receptor (A2AR) from anti-inflammatory activity to pro-inflammatory activity under high glutamate concentrations. Therefore, in the current study, we investigated the role of PKC in the LPS-induced production of these inflammatory cytokines in mouse primary microglia. GF109203X, a specific PKC inhibitor, inhibited the LPS-induced expression of IL-1β messenger ribonucleic acid and intracellular protein in a dose-dependent manner. Moreover, 5 µM GF109203X prevented LPS-induced IL-1β expression but did not significantly affect LPS-induced TNF-α expression. PKC promoted IL-1β expression by regulating the activity of NF-κB but did not significantly impact the activity of ERK1/2. A2AR activation by CGS21680, an A2AR agonist, facilitated LPS-induced IL-1β expression through the PKC pathway at high glutamate concentrations but did not significantly affect LPS-induced TNF-α expression. Taken together, these results suggest a new direction for specific intervention with LPS-induced inflammatory factors in response to specific signalling pathways and provide a mechanism for A2AR targeting, especially after brain injury, to influence inflammation by interfering with A2AR. [ABSTRACT FROM AUTHOR]