SSA: Investigating a role for the gut microbiota in stress axis dysfunction and anxiety behaviour in prenatally stressed rats

SSA：研究肠道微生物群在产前应激大鼠应激轴功能障碍和焦虑行为中的作用

• 批准号: 1959126
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1959126
• 关键词: SSA; Investigating; role; gut; microbiota

Importance of the early life environment: The development and neuronal organisation of the fetal/neonatal brain is significantly influenced by the physiological status of the mother and the early environment1. Maternal stress exposure during pregnancy detrimentally 'programmes' the offspring's brain resulting in profound alterations in physiology and behaviour in later life. Using a social stress paradigm in rats we have shown that the principal neuroendocrine stress system, the hypothalamo-pituitary-adrenal (HPA) axis, is particularly sensitive to prenatal stress exposure: the adult offspring of stressed dams display markedly greater stress responses1. HPA axis dysfunction is involved in the neurobiology of a range of mood disorders, including anxiety and depression. Indeed, adult prenatally stressed offspring also exhibit heightened anxiety-like behaviour1. These changes in stress responsivity and anxiety-like behaviour have been linked with changes in the central expression of stress-related genes, however what mediates these changes in the offspring's brain is not known.The gut microbiota influences stress responses and stress influences the gut microbiota: Bidirectional communication between the brain and the gut is well established; however recent studies have highlighted the importance of the gut microbiota in influencing stress responses and related behaviours2. For example, germ free mice (with no commensal microbiota) display reduced anxiety-like behaviour compared with conventionally-reared mice and this behaviour can be reversed by colonization of the gut with microbiota from control mice2. Similarly mice treated with probiotics display reduced anxiety-like behaviour and lower corticosterone responses to stress2. In contrast treatment of mice with subclinical doses of pathogenic bacteria results in increased anxiety-like behaviour and activation of the HPA axis2. Changes in anxiety behaviour and stress responsiveness induced by manipulating the gut microbiota are associated with altered expression of GABA receptors in the brain3. This is important given dysfunctional GABA signalling has been linked to anxiety and depression and the GABAA receptor is a target for some anxiolytic drugs. Importantly, stress also influences the composition of the gut microbiota e.g. repeated social stress exposure disrupts commensal microbial populations in adult mice. Moreover early life stress (via post-natal maternal separation) in rats results in increased stress reactivity and anxiety-like behaviour and is associated with long-term changes in the composition and diversity of the gut microbiota2. Commensal microbiota colonise the mammalian gut in early postnatal life, shortly after birth. The predominant source of microbes for the initial colonisation of the gut are the maternal microbiota. Studies using germ free mice have clearly demonstrated that the gut microbiota in early life is critical for the normal development of the HPA axis and appropriate stress responses in later life. Given that stress affects the gut microbiota, it is reasonable to hypothesise that social stress exposure during late pregnancy may alter the maternal microbiota and subsequently influence the composition/diversity of the gut microbiota of her offspring. Whether this may influence stress responsiveness and behaviour in the offspring is not known.Project Aims: The overarching aim of this project is to establish whether alterations in the gut microbiota contributes to HPA axis dysfunction and anxiety-like behaviour in prenatally stressed (PNS) rats, whether there are any sex differences in the contribution of the gut microbiota and whether the adverse phenotypes in PNS rats can be reversed by manipulating the gut microbiota.

早期生活环境的重要性：胎儿/新生儿大脑的发育和神经元组织受母亲的生理状态和早期环境的显着影响1。母亲在怀孕期间承受的压力会对后代的大脑进行有害的“编程”，导致以后生活中生理和行为的深刻改变。使用大鼠的社会压力范例，我们发现主要的神经内分泌压力系统，下丘脑-垂体-肾上腺（HPA）轴，对产前压力暴露特别敏感：压力母鼠的成年后代表现出明显更大的压力反应1。 HPA 轴功能障碍涉及一系列情绪障碍的神经生物学，包括焦虑和抑郁。事实上，成年产前应激的后代也会表现出高度的焦虑样行为1。压力反应性和焦虑样行为的这些变化与压力相关基因的中心表达的变化有关，然而，尚不清楚是什么在后代大脑中介导这些变化。肠道微生物群影响应激反应，压力影响肠道微生物群：大脑和肠道之间的双向通讯已建立；然而，最近的研究强调了肠道微生物群在影响应激反应和相关行为方面的重要性2。例如，与传统饲养的小鼠相比，无菌小鼠（没有共生微生物群）表现出较少的焦虑样行为，并且这种行为可以通过在肠道中定植来自对照小鼠的微生物群来逆转。同样，用益生菌治疗的小鼠表现出焦虑样行为减少和皮质酮对压力的反应降低2。相比之下，用亚临床剂量的病原菌治疗小鼠会导致焦虑样行为增加和 HPA 轴2激活。操纵肠道微生物群引起的焦虑行为和压力反应的变化与大脑中 GABA 受体表达的改变有关。鉴于 GABA 信号传导功能失调与焦虑和抑郁有关，并且 GABAA 受体是某些抗焦虑药物的靶标，这一点非常重要。重要的是，压力也会影响肠道微生物群的组成，例如肠道菌群。反复的社会压力会扰乱成年小鼠的共生微生物群。此外，大鼠的早期生活压力（通过产后母体分离）会导致应激反应性和焦虑样行为增加，并与肠道微生物群的组成和多样性的长期变化相关。共生微生物群在出生后不久即出生后不久就定居在哺乳动物肠道中。肠道最初定植的微生物的主要来源是母体微生物群。使用无菌小鼠的研究清楚地表明，生命早期的肠道微生物群对于 HPA 轴的正常发育和晚年适当的应激反应至关重要。鉴于压力会影响肠道微生物群，因此可以合理地假设，怀孕后期暴露于社会压力可能会改变母体微生物群，并随后影响其后代肠道微生物群的组成/多样性。这是否会影响后代的应激反应和行为尚不清楚。 项目目标：该项目的总体目标是确定肠道微生物群的改变是否会导致产前应激 (PNS) 大鼠的 HPA 轴功能障碍和焦虑样行为，肠道微生物群的贡献是否存在任何性别差异，以及 PNS 大鼠的不良表型是否可以通过肠道微生物群的影响来消除。 通过操纵肠道微生物群来逆转。