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Objectives: Emerging evidence indicates that the composition of movement behaviours within a 24-h period is associated with multiple health benefits across the lifespan. A concept that emphasises an individual's active lifestyle is physical literacy (PL), yet empirical research exploring the potential associations between PL and 24-h movement guidelines remains scarce. This study aimed to evaluate the associations between levels of PL and adherence to the guidelines among Chinese university students. Study design: A cross-sectional study. Methods: Seven hundred and ninety-eight university students (390 male, 19.2 ± 1.2 years) completed all the measurements. Levels of PL and participants' adherence to guidelines including physical activity, sedentary behaviour and sleep were self-reported through Perceived Physical Literacy Instrument, International Physical Activity Questionnaire and Pittsburgh Sleep Quality Index, respectively. Two-way ANOVA was conducted to determine the associations between the number of guidelines met (0, 1, 2, or 3) and levels of PL. Results: The results demonstrate that 36.5% (n = 291) of the participants met all the three guidelines, while 4.1% (n = 33) met none. Further analysis indicated that meeting physical activity or sedentary behaviour guidelines was associated with significantly higher total PL scores, and scores in the sub-domains of Confidence and Physical Competence and Motivation. Conclusions: The findings provide evidence that young adults who obtained higher PL scores may meet more guidelines during a 24-h period. Future studies should incorporate accelerometer-based physical activity measurements and investigate the causal relationship between PL and adherence to the movement guidelines.
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Mutations in GBA, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), represent the greatest genetic risk factor for developing synucleinopathies including Parkinson's disease (PD). Additionally, PD patients harboring a mutant GBA allele present with an earlier disease onset and an accelerated disease progression of both motor and non-motor symptoms. Preclinical studies in mouse models of synucleinopathy suggest that modulation of the sphingolipid metabolism pathway via inhibition of glucosylceramide synthase (GCS) using a CNS-penetrant small molecule may be a potential treatment for synucleinopathies. Here, we aim to alleviate the lipid storage burden by inhibiting the de novo synthesis of the primary glycosphingolipid substrate of GCase, glucosylceramide (GlcCer). We have previously shown that systemic GCS inhibition reduced GlcCer and glucosylsphingosine (GlcSph) accumulation, slowed α-synuclein buildup in the hippocampus, and improved cognitive deficits. Here, we studied the efficacy of a brain-penetrant clinical candidate GCS inhibitor, venglustat, in mouse models of GBA-related synucleinopathy, including a heterozygous Gba mouse model which more closely replicates the typical GBA-PD patient genotype. Collectively, these data support the rationale for modulation of GCase-related sphingolipid metabolism as a therapeutic strategy for treating GBA-related synucleinopathies.
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Carbamatos/farmacología , Glucosilceramidasa/metabolismo , Glucosilceramidas/metabolismo , Glucosiltransferasas/antagonistas & inhibidores , Quinuclidinas/farmacología , Sinucleinopatías/tratamiento farmacológico , Sinucleinopatías/metabolismo , Animales , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutación/genética , Enfermedad de Parkinson/metabolismoRESUMEN
Fragile X syndrome (FXS) is one of the most common inherited intellectual disability (ID) disorders, in which the loss of FMRP protein induces a range of cellular signaling changes primarily through excess protein synthesis. Although neuron-centered molecular and cellular events underlying FXS have been characterized, how different CNS cell types are involved in typical FXS synaptic signaling changes and behavioral phenotypes is largely unknown. Recent evidence suggests that selective loss of astroglial FMRP is able to dysregulate glutamate uptake, increase spine density, and impair motor-skill learning. Here we investigated the effect of astroglial FMRP on synaptic signaling and FXS-related behavioral and learning phenotypes in astroglial Fmr1 cKO and cON mice in which FMRP expression is selectively diminished or restored in astroglia. We found that selective loss of astroglial FMRP contributes to cortical hyperexcitability by enhancing NMDAR-mediated evoked but not spontaneous miniEPSCs and elongating cortical UP state duration. Selective loss of astroglial FMRP is also sufficient to increase locomotor hyperactivity, significantly diminish social novelty preference, and induce memory acquisition and extinction deficits in astroglial Fmr1 cKO mice. Importantly, re-expression of astroglial FMRP is able to significantly rescue the hyperactivity (evoked NMDAR response, UP state duration, and open field test) and social novelty preference in astroglial Fmr1 cON mice. These results demonstrate a profound role of astroglial FMRP in the evoked synaptic signaling, spontaneously occurring cortical UP states, and FXS-related behavioral and learning phenotypes and provide important new insights in the cell type consideration for the FMRP reactivation strategy.
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Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil , Síndrome del Cromosoma X Frágil , Animales , Astrocitos , Modelos Animales de Enfermedad , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Ratones , Fenotipo , Receptores de N-Metil-D-AspartatoRESUMEN
Astrocytes exhibit a region-dependent molecular and functional heterogeneity in the CNS. Although cortical astrocytes proliferate robustly during the first postnatal week and become proliferation quiescent, the temporal proliferation dynamics of astrocytes in subcortical regions during postnatal development remain essentially unknown. Whether subcortical astrocytes mature similarly to cortical astrocytes is also unexplored. In this current study, we examined proliferation of subcortical, especially hypothalamic, astrocytes during postnatal development using genetic labeling of astrocytes and pulse-chase EdU labeling of proliferating cells. While a lower number of proliferating astrocytes was found in the hypothalamus compared to cortex during the first postnatal week, astrocyte proliferation is much more active in hypothalamus than in cortex from P15 to P30 in both proliferating astrocyte density and percentage, indicating a persistent and distinct proliferation pattern of astrocytes in hypothalamus. This observation is further confirmed by Ki67 immunostaining with genetically or immunolabeled astrocytes in hypothalamus and cortex during P15-30. In addition, astrocytes in representative subcortical regions have a modest growth of their domain size and exhibit a significantly smaller domain size compared to cortical astrocytes at P30 when astrocytes have generally completed postnatal maturation. However, the expression of astrocyte-derived Sparc, an important synaptogenic inhibitor, is consistently higher in hypothalamic astrocytes than in cortical astrocytes throughout postnatal development. In summary, our study unveiled a distinct proliferation and maturation pattern of subcortical, especially hypothalamic, astrocytes during postnatal development.
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Astroglia play active and diverse roles in modulating neuronal/synaptic functions in the CNS. How these astroglial functions are regulated, especially by neuronal signals, remains largely unknown. Exosomes, a major type of extracellular vesicles (EVs) that originate from endosomal intraluminal vesicles (ILVs), have emerged as a new intercellular communication process. By generating cell-type-specific ILVs/exosome reporter (CD63-GFPf/f) mice and immuno-EM/confocal image analysis, we found that neuronal CD63-GFP+ ILVs are primarily localized in soma and dendrites, but not in axonal terminals in vitro and in vivo. Secreted neuronal exosomes contain a subset of microRNAs (miRs) that is distinct from the miR profile of neurons. These miRs, especially the neuron-specific miR-124-3p, are potentially internalized into astrocytes. MiR-124-3p further up-regulates the predominant glutamate transporter GLT1 by suppressing GLT1-inhibiting miRs. Our findings suggest a previously undescribed neuronal exosomal miR-mediated genetic regulation of astrocyte functions, potentially opening a new frontier in understanding CNS intercellular communication.
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Astrocitos/metabolismo , Comunicación Celular , Sistema Nervioso Central/metabolismo , Exosomas/metabolismo , Genes Reporteros , Neuronas/metabolismo , Animales , Astrocitos/ultraestructura , Transportador 2 de Aminoácidos Excitadores/metabolismo , Exosomas/ultraestructura , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Modelos Biológicos , Neuronas/ultraestructuraRESUMEN
The molecular signature and functional properties of astroglial subtypes in the adult CNS remain largely undefined. By using translational ribosome affinity purification followed by RNA-Seq, we profiled astroglial ribosome-associated (presumably translating) mRNAs in major cortical and subcortical brain regions (cortex, hippocampus, caudate-putamen, nucleus accumbens, thalamus, and hypothalamus) of BAC aldh1l1-translational ribosome affinity purification (TRAP) mice (both sexes). We found that the expression of astroglial translating mRNAs closely follows the dorsoventral axis, especially from cortex/hippocampus to thalamus/hypothalamus posteriorly. This region-specific expression pattern of genes, such as synaptogenic modulator sparc and transcriptional factors (emx2, lhx2, and hopx), was validated by qRT-PCR and immunostaining in brain sections. Interestingly, cortical or subcortical astrocytes selectively promote neurite growth and synaptic activity of neurons only from the same region in mismatched cocultures, exhibiting region-matched astrocyte to neuron communication. Overall, these results generated new molecular signature of astrocyte types in the adult CNS, providing insights into their origin and functional diversity.SIGNIFICANCE STATEMENT We investigated the in vivo molecular and functional heterogeneity of astrocytes inter-regionally from adult brain. Our results showed that the expression pattern of ribosome-associated mRNA profiles in astrocytes closely follows the dorsoventral axis, especially posteriorly from cortex/hippocampus to thalamus/hypothalamus. In line with this, our functional results further demonstrated region-selective roles of cortical and subcortical astrocytes in regulating cortical or subcortical neuronal synaptogenesis and maturation. These in vivo studies provide a previously uncharacterized and important molecular atlas for exploring region-specific astroglial functions.
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Astrocitos/metabolismo , Encéfalo/metabolismo , Regulación de la Expresión Génica , Ratones/metabolismo , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/metabolismo , Animales , Astrocitos/clasificación , Astrocitos/citología , Encéfalo/citología , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
UNLABELLED: How the loss of fragile X mental retardation protein (FMRP) in different brain cell types, especially in non-neuron glial cells, induces fragile X syndrome (FXS) phenotypes has just begun to be understood. In the current study, we generated inducible astrocyte-specific Fmr1 conditional knock-out mice (i-astro-Fmr1-cKO) and restoration mice (i-astro-Fmr1-cON) to study the in vivo modulation of FXS synaptic phenotypes by astroglial FMRP. We found that functional expression of glutamate transporter GLT1 is 40% decreased in i-astro-Fmr1-cKO somatosensory cortical astrocytes in vivo, which can be fully rescued by the selective re-expression of FMRP in astrocytes in i-astro-Fmr1-cON mice. Although the selective loss of astroglial FMRP only modestly increases spine density and length in cortical pyramidal neurons, selective re-expression of FMRP in astrocytes significantly attenuates abnormal spine morphology in these neurons of i-astro-Fmr1-cON mice. Moreover, we found that basal protein synthesis levels and immunoreactivity of phosphorylated S6 ribosomal protein (p-s6P) is significantly increased in i-astro-Fmr1-cKO mice, while the enhanced cortical protein synthesis observed in Fmr1 KO mice is mitigated in i-astro-Fmr1-cON mice. Furthermore, ceftriaxone-mediated upregulation of surface GLT1 expression restores functional glutamate uptake and attenuates enhanced neuronal excitability in Fmr1 KO mice. In particular, ceftriaxone significantly decreases the growth rate of abnormally accelerated body weight and completely corrects spine abnormality in Fmr1 KO mice. Together, these results show that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, presumably through dysregulated astroglial glutamate transporter GLT1 and impaired glutamate uptake. These results suggest the involvement of astrocyte-mediated mechanisms in the pathogenesis of FXS. SIGNIFICANCE STATEMENT: Previous studies to understand how the loss of function of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) have largely focused on neurons; whether the selective loss of astroglial FMRP in vivo alters astrocyte functions and contributes to the pathogenesis of FXS remain essentially unknown. This has become a long-standing unanswered question in the fragile X field, which is also relevant to autism pathogenesis. Our current study generated astrocyte-specific Fmr1 conditional knock-out and restoration mice, and provided compelling evidence that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, likely through the dysregulated astroglial glutamate transporter GLT1 expression and impaired glutamate uptake. These results demonstrate previously undescribed astrocyte-mediated mechanisms in the pathogenesis of FXS.
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Astrocitos/metabolismo , Corteza Cerebral/patología , Transportador 2 de Aminoácidos Excitadores/metabolismo , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil , Potenciales de Acción/genética , Factores de Edad , Animales , Animales Recién Nacidos , Astrocitos/ultraestructura , Modelos Animales de Enfermedad , Antagonistas de Estrógenos/farmacología , Transportador 2 de Aminoácidos Excitadores/genética , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/metabolismo , Síndrome del Cromosoma X Frágil/patología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Técnicas In Vitro , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células Piramidales/efectos de los fármacos , Células Piramidales/fisiología , Tamoxifeno/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Astroglia, the most abundant glial cells in the mammalian central nervous system (CNS), are considered an emerging key player in seizure induction and progression. Although astrocytes undergo reactive gliosis in temporal lobe epilepsy (TLE) with dramatic morphological and molecular changes, specific astrocyte targets/molecular pathways that contribute to the induction and progression of seizure remain largely unknown. By combining translating ribosomal affinity purification (TRAP) with the pilocarpine model of TLE in BAC aldh1l1 TRAP mice, we profiled translating mRNAs from hippocampal or cortical astrocytes at different phases (3days, 30days, and 60days post-pilocarpine injections) of pilocarpine-induced epilepsy models. Our results found that hippocampal (but not cortical) astrocytes undergo early and unique molecular changes at 3days post-pilocarpine injections. These changes indicate a potentially primary pathogenic role of hippocampal astrocytes in seizure induction and progression and provide new insights about the involvement of specific astrocytic pathways/targets in epilepsy. In particular, we validated expression changes of ocrl and aeg1 in pilocarpine models. Follow-up studies on these genes may reveal new roles of hippocampal astrocytes in TLE.