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

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到母亲生理状态和早期环境的显着影响1。母亲在怀孕期间的压力暴露会对后代的大脑进行心理上的“编程”，导致后代在以后的生活中生理和行为发生深刻的变化。在大鼠中使用社会应激范例，我们已经表明，主要的神经内分泌应激系统，下丘脑-垂体-肾上腺（HPA）轴，对产前应激暴露特别敏感：应激母鼠的成年后代显示出显着更大的应激反应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，成年产前强调后代也表现出高度焦虑样行为1。这些压力反应和焦虑样行为的变化与压力相关基因的中枢表达变化有关，然而，是什么介导了后代大脑中的这些变化尚不清楚。肠道微生物群影响压力反应，压力影响肠道微生物群：大脑和肠道之间的双向交流已经建立;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，与常规饲养的小鼠相比，无菌小鼠（没有肠道微生物群）显示出减少的焦虑样行为，并且这种行为可以通过用来自对照小鼠的微生物群定植肠道来逆转2。同样，用益生菌治疗的小鼠表现出减少的焦虑样行为和较低的皮质酮对压力的反应2。相反，用亚临床剂量的病原菌治疗小鼠会导致焦虑样行为和HPA轴激活增加2。通过操纵肠道微生物群诱导的焦虑行为和压力反应的变化与大脑中GABA受体的表达改变有关。这一点很重要，因为功能失调的GABA信号传导与焦虑和抑郁有关，GABAA受体是一些抗焦虑药物的靶点。重要的是，压力也会影响肠道微生物群的组成，例如反复的社会压力暴露会破坏成年小鼠的肠道微生物群。此外，大鼠的早期生活压力（通过产后母体分离）导致应激反应和焦虑样行为增加，并与肠道微生物组成和多样性的长期变化相关2。共生微生物群在出生后不久的早期生活中定植在哺乳动物的肠道中。肠道初始定殖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，早期生活中的肠道微生物群对于HPA轴的正常发育和晚年的适当应激反应至关重要。鉴于压力会影响肠道微生物群，有理由假设怀孕后期的社会压力暴露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。项目目的：该项目的首要目标是确定肠道微生物群的改变是否有助于产前应激（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大鼠中的不良表型是否可以通过控制肠道微生物

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.