The fluctuations of metabotropic glutamate receptor subtype 5 (mGluR5) in the Amygdala in fear conditioning model of male Wistar rats following sleep deprivation, reverse circadian and napping.
睡眠剥夺、反向昼夜节律和打盹后雄性 Wistar 大鼠恐惧条件反射模型杏仁核代谢型谷氨酸受体亚型 5 (mGluR5) 的波动。
- 作者列表："Kordestani-Moghadam P","Nasehi M","Khodagholi F","Vaseghi S","Zarrindast MR","Khani M
:Sleep is involved in metabolic system, mental health and cognitive functions. Evidence shows that sleep deprivation (SD) negatively affects mental health and impairs cognitive functions, including learning and memory. Furthermore, the metabotropic glutamate receptor subtype 5 (mGluR5) is a metabolic biomarker, which is affected by various conditions, including stress, sleep deprivation, and cognitive and psychiatric disorders. In this research, we investigated the effect of SD and reverse circadian (RC), and two models of napping (continuous and non-continuous) combined with SD or RC on fear-conditioning memory, anxiety-like behavior and mGluR5 fluctuations in the amygdala. 64 male Wistar rats were used in this study. The water box apparatus was used to induce SD/RC for 48 hours, and fear-conditioning memory apparatus was used to assess fear memory. The results showed, fear-conditioning memory was impaired following SD and RC, especially in contextual stage. However, anxiety-like behavior was increased. Furthermore, mGluR5 was increased in the left amygdala more than the right amygdala. Additionally, continuous napping significantly improved fear-conditioning memory, especially freezing behavior. In conclusion, following SD and RC, fear-conditioning memory in contextual stage is more vulnerable than in auditory stage. Furthermore, increase in anxiety-like behavior is related to increase in the activity of left amygdala and mGluR5 receptors.
: 睡眠参与代谢系统、精神卫生和认知功能。有证据表明，睡眠剥夺 (SD) 对精神卫生产生负面影响，损害认知功能，包括学习和记忆。此外，代谢型谷氨酸受体亚型 5 (mGluR5) 是一种代谢生物标志物，受各种条件的影响，包括压力、睡眠剥夺以及认知和精神疾病。在这项研究中，我们调查了 SD 和反向昼夜节律 (RC)，以及两种打盹模型 (连续和非连续) 与 SD 或 RC 结合对恐惧条件记忆的影响, 焦虑样行为和杏仁核 mGluR5 波动。本研究采用雄性 Wistar 大鼠 64 只。使用水箱装置诱导 SD/RC 48 小时，使用恐惧条件记忆装置评估恐惧记忆。结果显示，恐惧条件记忆在 SD 和 RC 之后受损，尤其是在情境阶段。然而，焦虑样行为增加。此外，mGluR5 在左侧杏仁核中的增加多于右侧杏仁核。此外，持续午睡显著改善了恐惧调节记忆，尤其是冻结行为。总之，遵循 SD 和 RC，情境阶段的恐惧条件记忆比听觉阶段更脆弱。此外，焦虑样行为的增加与左杏仁核和 mGluR5 受体活性的增加有关。
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.