Antidepressant effects of activation of infralimbic cortex via upregulation of BDNF and β-catenin in an estradiol withdrawal model.

IF 3.5 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2024-09-01 Epub Date: 2024-05-14 DOI:10.1007/s00213-024-06610-z

Jiali Chen, Yiying Zhou, Miaojun Lai, Yanping Zhang, Yifang Hu, Dingding Zhuang, Wenhua Zhou, Yisheng Zhang

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Abstract

Rationale: Clinical and preclinical studies have demonstrated that estradiol withdrawal after delivery is one of important factors involved in the pathogenesis of postpartum depression (PPD). The infralimbic cortex (IL) is related to anxiety and mood disorders. Whether IL neurons mediate PPD is still unclear.

Objectives: This study was to observe the antidepressant effect and expression of BDNF and β-catenin in IL by allopregnanolone (ALLO) treatment or the selective activation or inhibition of IL neurons using a chemogenetic approach in a pseudopregnancy model of PPD.

Methods: Administration of estradiol combined with progesterone and the abrupt withdrawal of estradiol simulated the pregnancy and early postpartum periods to induce depression in ovariectomized rats. The relative expression levels of β-catenin and BDNF were observed by western blotting.

Results: Immobility time was significantly increased in the forced swim test and open-arm movement was reduced in the elevated plus maze test in the estradiol-withdrawn rats. After ALLO treatment, the immobility time were lower and open-arm traveling times higher than those of the estradiol-withdrawn rats. Meanwhile, the expression level of BDNF or β-catenin in the IL was reduced significantly in estradiol-withdrawn rats, which was prevented by treatment with ALLO. The hM3Dq chemogenetic activation of pyramidal neurons in the IL reversed the immobility and open-arm travel time trends in the estradiol-withdrawal rat model, but chemogenetic inhibition of IL neurons failed to affect this. Upregulated BDNF and β-catenin expression and increased c-Fos in the basolateral amygdala were found following IL neuron excitation in model rats.

Conclusions: Our results demonstrated that pseudopregnancy and estradiol withdrawal produced depressive-like behavior and anxiety. ALLO treatment or specific excitement of IL pyramidal neurons relieved abnormal behaviors and upregulated BDNF and β-catenin expression in the IL in the PPD model, suggesting that hypofunction of IL neurons may be involved in the pathogenesis of PPD.

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在雌二醇戒断模型中通过上调BDNF和β-catenin激活下边缘皮层的抗抑郁作用

理由临床和临床前研究表明，产后雌二醇的停用是产后抑郁症（PPD）发病机制的重要因素之一。下边缘皮层（IL）与焦虑和情绪障碍有关。IL神经元是否介导产后抑郁仍不清楚：本研究旨在观察异丙孕酮（ALO）治疗或在假孕PPD模型中使用化学遗传学方法选择性激活或抑制IL神经元的抗抑郁作用以及BDNF和β-catenin在IL中的表达：方法：给卵巢切除大鼠注射雌二醇和黄体酮，并突然停用雌二醇，模拟妊娠期和产后早期诱导抑郁。结果：卵巢切除大鼠的静止时间显著增加：结果：雌二醇戒断大鼠在强迫游泳试验中的不动时间明显增加，在高架加迷宫试验中的开臂运动减少。ALLO治疗后，大鼠的静止时间比雌二醇戒断大鼠低，开臂运动次数比雌二醇戒断大鼠高。同时，雌二醇致残大鼠IL中BDNF或β-catenin的表达水平明显降低，而ALLO治疗可防止这种情况的发生。hM3Dq 化学发光激活 IL 中的锥体神经元可逆转雌二醇戒断大鼠模型中的不动性和开臂行走时间趋势，但化学发光抑制 IL 神经元则无法对此产生影响。IL神经元兴奋后，模型大鼠杏仁基底外侧的BDNF和β-catenin表达上调，c-Fos增加：我们的研究结果表明，假孕和雌二醇戒断会产生抑郁样行为和焦虑。结论：我们的研究结果表明，假孕和雌二醇戒断会产生抑郁样行为和焦虑，ALLO治疗或特异性兴奋IL锥体神经元可缓解PPD模型大鼠的异常行为，并上调BDNF和β-catenin在IL中的表达，这表明IL神经元功能低下可能与PPD的发病机制有关。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.

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