新生儿脂多糖免疫攻击动物模型:性别对幼年小鼠行为和免疫/神经营养改变影响的研究

IF 2.2 4区 医学 Q3 ENDOCRINOLOGY & METABOLISM
Larissa Maria Frota Cristino, Adriano José Maia Chaves Filho, Charllyany Sabino Custódio, Silvânia Maria Mendes Vasconcelos, Francisca Cléa F de Sousa, Lia Lira O Sanders, David Freitas de Lucena, Danielle S Macedo
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引用次数: 4

摘要

产前/围产期暴露于感染可能引发神经发育改变,导致神经精神障碍,如自闭症谱系障碍(ASD)。先前的证据指出了长期的行为后果,例如在关键的神经发育时期暴露于脂多糖(LPS)产前和产后(PN)诱导的啮齿动物的自闭症样行为。此外,性别也会影响自闭症的患病率和症状。尽管如此,人们对这种影响背后的机制知之甚少。我们的目的是研究性别对雏鼠在接近人类ASD诊断年龄时暴露于LPS引发的行为和神经营养/炎症改变的影响。方法:试验第5、7天,瑞士雄性、雌性小鼠每日单次注射大肠杆菌LPS或无菌生理盐水500 μg/kg(对照组)。我们对使用PN25的动物(相当于3-5岁的人类)进行了运动活动、重复行为、焦虑样行为、社会互动和工作记忆的行为测定。为了确定前额皮质和海马中的BDNF水平,我们使用了PN8(相当于人类足月婴儿)和PN25的动物。此外,我们还评估了iba-1(小胶质细胞标志物)、TNFα和细小蛋白在PN25上的表达。结果:雄性幼年小鼠出现重复行为、焦虑和工作记忆缺陷。女性表现出社交障碍和工作记忆缺陷。在神经化学分析中,我们发现雌性小鼠大脑区域的BDNF水平较低,在幼年小鼠中更为明显。只有lps刺激的雌性小鼠海马小胶质细胞激活标志物iba-1表达明显,tnf - α水平升高,同时小蛋白表达降低。讨论/结论:雄性和雌性小鼠表现出明显的行为改变。然而,lps挑战的年轻女性表现出与自闭症相关的最显著的神经生物学改变,如小胶质细胞激活增加和小白蛋白损伤。由于这些性别敏感的改变似乎与年龄有关,因此,更好地了解一生中暴露于特定风险因素所引起的变化,是制定自闭症预防和精确治疗策略的重要目标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Animal Model of Neonatal Immune Challenge by Lipopolysaccharide: A Study of Sex Influence in Behavioral and Immune/Neurotrophic Alterations in Juvenile Mice.

Introduction: The prenatal/perinatal exposure to infections may trigger neurodevelopmental alterations that lead to neuropsychiatric disorders such as autism spectrum disorder (ASD). Previous evidence points to long-term behavioral consequences, such as autistic-like behaviors in rodents induced by lipopolysaccharide (LPS) pre- and postnatal (PN) exposure during critical neurodevelopmental periods. Additionally, sex influences the prevalence and symptoms of ASD. Despite this, the mechanisms underlying this influence are poorly understood. We aim to study sex influences in behavioral and neurotrophic/inflammatory alterations triggered by LPS neonatal exposure in juvenile mice at an approximate age of ASD diagnosis in humans.

Methods: Swiss male and female mice on PN days 5 and 7 received a single daily injection of 500 μg/kg LPS from Escherichia coli or sterile saline (control group). We conducted behavioral determinations of locomotor activity, repetitive behavior, anxiety-like behavior, social interaction, and working memory in animals on PN25 (equivalent to 3-5 years old of the human). To determine BDNF levels in the prefrontal cortex and hippocampus, we used animals on PN8 (equivalent to a human term infant) and PN25. In addition, we evaluated iba-1 (microglia marker), TNFα, and parvalbumin expression on PN25.

Results: Male juvenile mice presented repetitive behavior, anxiety, and working memory deficits. Females showed social impairment and working memory deficits. In the neurochemical analysis, we detected lower BDNF levels in brain areas of female mice that were more evident in juvenile mice. Only LPS-challenged females presented a marked hippocampal expression of the microglial activation marker, iba-1, and increased TNFα levels, accompanied by a lower parvalbumin expression.

Discussion/conclusion: Male and female mice presented distinct behavioral alterations. However, LPS-challenged juvenile females showed the most prominent neurobiological alterations related to autism, such as increased microglial activation and parvalbumin impairment. Since these sex-sensitive alterations seem to be age-dependent, a better understanding of changes induced by the exposure to specific risk factors throughout life represents essential targets for developing strategies for autism prevention and precision therapy.

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来源期刊
Neuroimmunomodulation
Neuroimmunomodulation 医学-免疫学
CiteScore
3.60
自引率
4.20%
发文量
35
审稿时长
>12 weeks
期刊介绍: The rapidly expanding area of research known as neuroimmunomodulation explores the way in which the nervous system interacts with the immune system via neural, hormonal, and paracrine actions. Encompassing both basic and clinical research, ''Neuroimmunomodulation'' reports on all aspects of these interactions. Basic investigations consider all neural and humoral networks from molecular genetics through cell regulation to integrative systems of the body. The journal also aims to clarify the basic mechanisms involved in the pathogenesis of the CNS pathology in AIDS patients and in various neurodegenerative diseases. Although primarily devoted to research articles, timely reviews are published on a regular basis.
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