- 作者列表："Curtin C","Hyman SL","Boas DD","Hassink S","Broder-Fingert S","Ptomey LT","Gillette MD","Fleming RK","Must A","Bandini LG
:Research suggests that the prevalence of obesity in children with autism spectrum disorder (ASD) is higher than in typically developing children. The US Preventive Services Task Force and the American Academy of Pediatrics (AAP) have endorsed screening children for overweight and obesity as part of the standard of care for physicians. However, the pediatric provider community has been inadequately prepared to address this issue in children with ASD. The Healthy Weight Research Network, a national research network of pediatric obesity and autism experts funded by the US Health Resources and Service Administration Maternal and Child Health Bureau, developed recommendations for managing overweight and obesity in children with ASD, which include adaptations to the AAP's 2007 guidance. These recommendations were developed from extant scientific evidence in children with ASD, and when evidence was unavailable, consensus was established on the basis of clinical experience. It should be noted that these recommendations do not reflect official AAP policy. Many of the AAP recommendations remain appropriate for primary care practitioners to implement with their patients with ASD; however, the significant challenges experienced by this population in both dietary and physical activity domains, as well as the stress experienced by their families, require adaptations and modifications for both preventive and intervention efforts. These recommendations can assist pediatric providers in providing tailored guidance on weight management to children with ASD and their families.
: 研究表明，自闭症谱系障碍 (ASD) 儿童肥胖的患病率高于典型发育中的儿童。美国预防服务工作组和美国儿科学会 (AAP) 已经认可筛查儿童超重和肥胖作为医生护理标准的一部分。然而，儿科提供者社区没有充分准备解决 ASD 儿童的这一问题。健康体重研究网络，由美国卫生资源与服务管理局妇幼卫生局资助的儿童肥胖和自闭症专家的国家研究网络,制定了管理 ASD 儿童超重和肥胖的建议，包括对 AAP 2007 指南的适应。这些建议是从 ASD 儿童现有的科学证据中得到的，当证据不可用时，在临床经验的基础上建立共识。应当指出，这些建议不反映官方的 AAP 政策。许多 AAP 建议仍然适合初级保健从业者对 ASD 患者实施; 然而，该人群在饮食和体力活动领域面临的重大挑战,以及他们的家庭所经历的压力，需要适应和修改预防和干预工作。这些建议可以帮助儿科提供者为 ASD 儿童及其家庭提供量身定制的体重管理指导。
METHODS::The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.
METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.
METHODS::Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.