Diminished Medial Prefrontal Activity behind Autistic Social Judgments of Incongruent Information

Individuals with autism spectrum disorders (ASD) tend to make inadequate social judgments, particularly when the nonverbal and verbal emotional expressions of other people are incongruent. Although previous behavioral studies have suggested that ASD individuals have difficulty in using nonverbal cues when presented with incongruent verbal-nonverbal information, the neural mechanisms underlying this symptom of ASD remain unclear. In the present functional magnetic resonance imaging study, we compared brain activity in 15 non-medicated adult males with high-functioning ASD to that of 17 age-, parental-background-, socioeconomic-, and intelligence-quotient-matched typically-developed (TD) male participants. Brain activity was measured while each participant made friend or foe judgments of realistic movies in which professional actors spoke with conflicting nonverbal facial expressions and voice prosody. We found that the ASD group made significantly less judgments primarily based on the nonverbal information than the TD group, and they exhibited significantly less brain activity in the right inferior frontal gyrus, bilateral anterior insula, anterior cingulate cortex/ventral medial prefrontal cortex (ACC/vmPFC), and dorsal medial prefrontal cortex (dmPFC) than the TD group. Among these five regions, the ACC/vmPFC and dmPFC were most involved in nonverbal-information-biased judgments in the TD group. Furthermore, the degree of decrease of the brain activity in these two brain regions predicted the severity of autistic communication deficits. The findings indicate that diminished activity in the ACC/vmPFC and dmPFC underlies the impaired abilities of individuals with ASD to use nonverbal content when making judgments regarding other people based on incongruent social information

NG2-positive pericytes regulate homeostatic maintenance of slow-type skeletal muscle with rapid myonuclear turnover

Abstract Background Skeletal muscle comprises almost 40% of the human body and is essential for movement, structural support and metabolic homeostasis. Size of multinuclear skeletal muscle is stably maintained under steady conditions with the sporadic fusion of newly produced myocytes to compensate for the muscular turnover caused by daily wear and tear. It is becoming clear that microvascular pericytes (PCs) exhibit myogenic activity. However, whether PCs act as myogenic stem cells for the homeostatic maintenance of skeletal muscles during adulthood remains uncertain. Methods We utilized PC-fused myofibers using PC-specific lineage tracing mouse (NG2-CreERT/Rosa-tdTomato) to observe whether muscle resident PCs have myogenic potential during daily life. Genetic PC deletion mouse model (NG2-CreERT/DTA) was used to test whether PC differentiates to myofibers for maintenance of muscle structure and function under homeostatic condition. Results Under steady breeding conditions, tdTomato-expressing PCs were infused into myofibers, and subsequently, PC-derived nuclei were incorporated into myofibers. Especially in type-I slow-type myofibers such as the soleus, tdTomato+ myofibers were already observed 3 days after PC labeling; their ratio reached a peak (approximately 80%) within 1 month and was maintained for more than 1 year. Consistently, the NG2+ PC-specific deletion induced muscular atrophy in a slow-type myofiber-specific manner under steady breeding conditions. The number of myonucleus per volume of each myofiber was constant during observation period. Conclusions These findings demonstrate that the turnover of myonuclei in slow-type myofibers is relatively fast, with PCs acting as myogenic stem cells—the suppliers of new myonuclei under steady conditions—and play a vital role in the homeostatic maintenance of slow-type muscles

Additional file 1 of NG2-positive pericytes regulate homeostatic maintenance of slow-type skeletal muscle with rapid myonuclear turnover

Additional file 1: Fig. S1. Localization of NG2+ cells in adult skeletal muscle tissues. Circulating vessels in NG2-DsRed mice were visualized by intravenous injection of FITC-conjugated lectin. The lower limb skeletal muscles (gastrocnemius and soleus) were fixed and transparentized with RapiClear reagent. Microvessels, lectin-labeled endothelium tubes (lectin; green), and NG2+ cells (DsRed; red) within transparent muscles were visualized in a 3D view using confocal fluorescent microscopy. The nuclei were counterstained with DAPI. Scale bar = 50 µm. Fig. S2. NG2+ cell lineage tracing within the skeletal muscle. The tdTomato expression driven by the universal Rosa26 promoter was specifically induced in NG2+ cells using NG2-CreERT/Rosa-tdTomato mice. After five days of constitutive treatment with Tam, NG2+ cells were expressed. B. On day 1 of the observation period, tdTomato+ cells were observed only at perivascular sites, such as PCs. On day 21, tdTomato-expressing myofibers were observed in most muscle tissues. The ratio of tdTomato+ myofibers to total myofibers varied by muscle site, i.e., over 80% of tdTomato+ myofibers in the soleus and diaphragm and 20–30% in the gastrocnemius and rectus abdominal muscles. Scale bar = 200 µm. Fig. S3. Schematic diagram for the in vitro muscular differentiation assay. Myofibers were isolated from the soleus of NG2-CreERT/Rosa-tdTomato mice by using a collagenase-containing medium. Isolated myofibers were incubated in DMEM-containing 10% FBS and Tam (2 µM) for three days to label NG2+ PCs. The medium was then changed to a differentiation medium containing 2% horse serum. After six days of induction, the myogenesis of NG2+ PCs was observed. Fig. S4. In vitro myogenic potency of NG2+ PCs from soleus muscles. A. Myofibers isolated from the soleus of NG2-CreERT/Rosa-tdTomato mice, which were incubated in DMEM-containing hydroxy tamoxifen (Tam) for three days to label NG2+ PCs. After six days of differentiation induction, myogenesis was determined by immunostaining with myosin heavy chain (MyHC) and myosin heavy chain (MYH) isoform 2 and 7. Isolated soleus myofibers were used for control for immunostaining. Scale bars = 100 µm. Fig. S5. Tam treatment induces deletion of NG2+ cells. A. In vitro effects of 4-hydroxytamoxifen (4-HT) on NG2+ cells isolated from subcutaneous adipose tissues of NG2-CreERT/Rosa26-DTA mice. Cells at confluent were incubated in medium containing hydroxy-Tam for 5 days, and the number of cells were counted. B. Gene expression of NG2 in NG2+ cells with Tam was esteemed by qPCR. Fig. S6. Microarray enrichment analysis in response to PC deletion. After induction of NG2+ PC deletion for one month, microarray analysis of the soleus of PC-deletion and control mice was performed. The top 20 upregulated and downregulated pathway-related gene sets are listed