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Neural correlates of conceptual-level fear generalization in posttraumatic stress disorder.


  • 影响因子:6.22
  • DOI:10.1038/s41386-020-0661-8
  • 作者列表:"Morey RA","Haswell CC","Stjepanović D","Mid-Atlantic MIRECC Workgroup.","Dunsmoor JE","LaBar KS
  • 发表时间:2020-03-28

:Posttraumatic stress disorder (PTSD) may develop when mechanisms for making accurate distinctions about threat relevance have gone awry. Generalization across conceptually related objects has been hypothesized based on clinical observation in PTSD, but the neural mechanisms remain unexplored. Recent trauma-exposed military veterans (n = 46) were grouped into PTSD (n = 23) and non-PTSD (n = 23). Participants learned to generalize fear across conceptual categories (animals or tools) of semantically related items that were partially reinforced by shock during functional magnetic resonance imaging. Conditioned fear learning was quantified by shock expectancy and skin conductance response (SCR). Relative to veteran controls, PTSD subjects exhibited a stronger neural response associated with fear generalization to the reinforced object category in the striatum, anterior cingulate cortex, amygdala, occipitotemporal cortex, and insula (Z > 2.3; p < 0.05; whole-brain corrected). Based on SCR, both groups generalized the shock contingency to the reinforced conceptual category, but learning was not significantly different between groups. We found that PTSD was associated with an enhanced neural response in fronto-limbic, midline, and occipitotemporal regions to a learned representation of threat that is based on previously established conceptual knowledge of the relationship between basic-level exemplars within a semantic category. Behaviorally, veterans with PTSD were somewhat slower to differentiate threat and safety categories as compared with trauma-exposed veteran controls owing in part to an initial overgeneralized behavioral response to the safe category. These results have implications for understanding how fear spreads across semantically related concepts in PTSD.


: 当准确区分威胁相关性的机制出错时,创伤后应激障碍 (PTSD) 可能会发展。基于 PTSD 的临床观察,假设跨概念相关对象的泛化,但神经机制仍未被探索。近期暴露于创伤的退伍军人 (n = 46) 分为 PTSD (n = 23) 和非 PTSD (n = 23)。参与者学会了在功能磁共振成像过程中通过休克部分强化的语义相关项目的概念类别 (动物或工具) 中概括恐惧。条件性恐惧学习通过休克期望和皮肤传导反应 (SCR) 进行量化。相对于退伍军人对照组,PTSD 受试者在纹状体、前扣带皮层、杏仁核、枕颞皮层中表现出与恐惧泛化相关的更强的神经反应。和脑岛 (z> 2.3; P <0.05; 全脑校正)。基于 SCR,两组均将休克偶然性推广到强化的概念类别,但学习在组间无显著差异。我们发现,创伤后应激障碍与额边缘、中线和枕颞区的神经反应增强有关,这种反应是基于对语义范畴内的基本级别范例之间关系的先前建立的概念性知识而形成的对威胁的习得表征。行为上,与创伤暴露的退伍军人对照相比,PTSD 退伍军人区分威胁和安全类别的速度稍慢,部分原因是对安全类别的初始过度泛化行为反应。这些结果对理解恐惧如何在 PTSD 中跨语义相关概念传播有影响。



来源期刊:Molecular psychiatry
作者列表:["Li C","Meng F","Garza JC","Liu J","Lei Y","Kirov SA","Guo M","Lu XY"]

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.

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作者列表:["Torretta S","Rampino A","Basso M","Pergola G","Di Carlo P","Shin JH","Kleinman JE","Hyde TM","Weinberger DR","Masellis R","Blasi G","Pennuto M","Bertolino A"]

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.

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作者列表:["Chadha R","Meador-Woodruff JH"]

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.

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