Beneficial effects of physical activity on depressive and OCD-like behaviors in the male offspring of morphine-abstinent rats.
- 作者列表："Nouri Zadeh-Tehrani S","Sadat-Shirazi MS","Akbarabadi A","Aghadokht-Mamaghani A","Soltani H","Mokri A","Zarrindast MR
:The role of parental morphine exposure before gestation on mood disorder in the offspring was well described. Besides, physical activity can improve the symptoms of mood disorders. So, the current study aimed to investigate the role of physical activity on depressive and OCD-like behaviors induced by parental morphine exposure. 40 male and 40 female Wistar rats (60-days old) received morphine for consecutive 10 days and were drug-free for 10 days. They were prepared for mating either with a morphine-abstinent or with a drug-naïve rat. The adult male offspring were divided into two groups as follows: (1) those that were subjected to treadmill exercise for three weeks (3-days each week), and (2) those without exercise. Also, the offspring were subjected to forced swimming and marble-burying tests. The levels of 5-HT3 receptor (R), D1, and D2 dopamine receptor (DR) were evaluated as well as the level of monoamine oxidase-B (MAO-B) in the prefrontal cortex (PFC). Results showed that exercise improved depressive and OCD-like behaviors in the offspring of morphine-abstinent rats. Western blotting data revealed that the levels of 5-HT3R, D1DR, D2DR, and MAO-B in the PFC increased in the offspring of morphine-abstinent rats compared to the control. However, it was shown that treadmill exercise decreases the levels of 5-HT3R, MAO-B, and D2DR. Morphine exposure, even before conception, could affect the behaviors in the offspring. Besides, the molecular changes were also detected in the brain. We found that mild physical activity might modulate OCD and depressive-like behavior in the offspring of morphine-abstinent rats by decreasing the levels of 5-HT3R, D2DR, and MAO-B located in the PFC.
: 很好地描述了妊娠前父母吗啡暴露对后代情绪障碍的作用。此外，身体活动可以改善情绪障碍的症状。因此，本研究旨在探讨体力活动对父母吗啡暴露诱导的抑郁和强迫症样行为的作用。40 只雄性和 40 只雌性 Wistar 大鼠 (60 日龄) 接受吗啡连续 10 天，10 天无药。他们准备与吗啡戒断者或药物初治大鼠交配。成年雄性后代分为以下两组 :( 1) 进行为期三周的踏车运动 (每周 3 天)，和 (2) 那些没有锻炼的人。此外，后代还接受了强迫游泳和大理石掩埋试验。评估 5-HT3 受体 (R) 、 D1 和 D2 多巴胺受体 (DR) 水平以及单胺氧化酶-B (MAO-B) 水平在前额叶皮层 (PFC)。结果表明，运动改善了吗啡戒断大鼠子代的抑郁和强迫症样行为。Western blotting 数据显示，与对照组相比，吗啡戒断大鼠子代 PFC 中 5-HT3R 、 D1DR 、 D2DR 和 MAO-B 水平升高。然而，结果表明，跑台运动降低了 5-HT3R 、 MAO-B 和 D2DR 的水平。吗啡暴露，即使在受孕之前，也会影响后代的行为。此外，在大脑中也检测到分子变化。我们发现轻度体力活动可能通过降低位于 PFC 的 5-HT3R 、 D2DR 和 MAO-B 水平来调节吗啡戒断大鼠后代的强迫症和抑郁样行为。
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.