神经胶质蛋白-3基因敲除小鼠对吗啡敏感性的性别差异。

IF 3.5 3区 医学 Q2 NEUROSCIENCES Psychopharmacology Pub Date : 2024-07-31 DOI:10.1007/s00213-024-06660-3
Dieter D Brandner, Mohammed A Mashal, Nicola M Grissom, Patrick E Rothwell
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引用次数: 0

摘要

性别对包括自闭症谱系障碍在内的脑部疾病的发病率和病程有很大影响。人们对这些性别差异的机理基础仍然知之甚少,部分原因是生物医学研究中偏向于分析男性受试者和排除女性受试者的历史偏见。例如,对携带自闭症相关神经胶质蛋白-3突变的雄性小鼠的研究在文献中占很大比例,包括我们自己之前的研究,结果显示雄性神经胶质蛋白-3基因敲除小鼠对慢性吗啡暴露的反应减弱。因此,我们研究了神经ligin-3的组成型基因敲除和条件型基因敲除如何影响雌性小鼠对吗啡的敏感性,并以运动活动作为阿片类药物敏感性差异的替代物,这种差异可能与自闭症谱系障碍的病理生理学和治疗有关。与雄性小鼠相反,雌性神经ligin-3基因敲除小鼠在长期接触吗啡后表现出正常的精神运动敏感性。然而,在没有神经ligin-3表达的情况下,雌性和雄性小鼠在吗啡产生的运动刺激拓扑图上表现出相似的变化。多巴胺神经元中神经ligin-3的条件性基因缺失增加了雌性小鼠对高剂量吗啡的运动反应,而对雄性小鼠进行同样的操作则会降低其精神运动敏感性。总之,我们的数据显示,敲除神经胶质蛋白-3对雌性和雄性小鼠的吗啡敏感性既有共同的影响,也有不同的影响。这些结果也支持了这样一种观点,即雌性小鼠可以抵御自闭症相关基因变异的影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Sex differences in morphine sensitivity of neuroligin-3 knockout mice.

Sex has a strong influence on the prevalence and course of brain conditions, including autism spectrum disorders. The mechanistic basis for these sex differences remains poorly understood, due in part to historical bias in biomedical research favoring analysis of male subjects, and the exclusion of female subjects. For example, studies of male mice carrying autism-associated mutations in neuroligin-3 are over-represented in the literature, including our own prior work showing diminished responses to chronic morphine exposure in male neuroligin-3 knockout mice. We therefore studied how constitutive and conditional genetic knockout of neuroligin-3 affects morphine sensitivity of female mice, using locomotor activity as a proxy for differences in opioid sensitivity that may be related to the pathophysiology and treatment of autism spectrum disorders. In contrast to male mice, female neuroligin-3 knockout mice showed normal psychomotor sensitization after chronic morphine exposure. However, in the absence of neuroligin-3 expression, both female and male mice show a similar change in the topography of locomotor stimulation produced by morphine. Conditional genetic deletion of neuroligin-3 from dopamine neurons increased the locomotor response of female mice to high doses of morphine, contrasting with the decrease in psychomotor sensitization caused by the same manipulation in male mice. Together, our data reveal that knockout of neuroligin-3 has both common and distinct effects on morphine sensitivity in female and male mice. These results also support the notion that female sex can confer resilience against the impact of autism-associated gene variants.

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来源期刊
Psychopharmacology
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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