Early life bladder inflammatory events in female mice lead to subsequent LUTS in adulthood

项目总结 下尿路症状(LUT)是看泌尿科医生的最常见原因之一。 而且往往伴随着焦虑和抑郁等心理后果。 LUTS患者可能会出现膀胱-大脑对话中断；他们可能会说，我甚至没有任何感觉 直到我浑身湿透。更好的治疗选择可以从对基础大脑的更好理解中出现 对LUT和膀胱-大脑通讯有贡献的电路和细胞。潜在的LUT 值得深入研究的病原学是早期尿路感染(UTI)。对女性(有 尿路感染的发生率是男性的4倍)，表明早年尿路感染预示着晚年的下尿路感染。城市交通信息系统及其他基础研究 成年时的膀胱侮辱表明炎症是急性下尿路感染和心理后果的基础。为 例如，成人全身注射环磷酰胺(CYP)--最常见的非侵入性(无导管) 模拟尿路感染相关炎症的方法-导致膀胱和心理行为功能障碍。然而，还有 关于早年尿路感染在晚年尿路感染和心理后果中的作用的研究显着缺乏。 在这里，我们第一次展示了在CYP后经历反复的早期生命膀胱炎的雌性小鼠 成年后的膀胱和心理行为障碍。这些数据支持我们的假设：早期生命 CYP诱导的膀胱炎引起膀胱和大脑的炎症，从而扰乱了膀胱-大脑的对话和引导 导致终生LUTS和心理行为后果；这种晚年生活中的膀胱和大脑功能障碍可能是 在成年后，大脑关键回路的操纵逆转了这一趋势。在目标1中，我们将定义由CYP诱导的早期生命 生命周期中膀胱和大脑中的炎症指数。在目标2中，我们将确定早期生命 从我们的试验数据开始，CYP在整个生命周期中诱导了膀胱和大脑的功能变化： 反复发生的早期CyP诱导的膀胱炎会导致成年后排尿功能障碍和焦虑样行为。我们 将使用药理学工具来解决这些功能变化的机制和特异性，并测试 终生焦虑和抑郁的表型。在目标3中，我们将映射和操纵关键点 参与膀胱-大脑对话的大脑回路的组成部分。使用我们经过验证的能力来评估 在这种对话的中心脑区(蓝斑、巴林顿核、额叶皮质)的神经元活动， 我们将在早期记录排尿事件前后自由活动小鼠神经元的活动 生活CYP模型。我们假设，早期生命膀胱炎扰乱了这些神经元类型对 来自膀胱的感觉，从而区分排尿周期阶段。然后，我们将尝试反转 光遗传操作对早期膀胱炎所致膀胱和晚年心理行为功能障碍的影响 成年期相关神经元的活动，就像我们已经在成人模型中所做的那样。鉴于……的流行 LUT，这里提出的基本实验具有巨大的潜力，可以扩大我们对 新生儿膀胱炎会影响一生中的膀胱-大脑对话。

PROJECT SUMMARY Lower Urinary Tract Symptoms (LUTS) are among the most common reasons to see a urologist across the lifespan and are often accompanied by psychological consequences, such as anxiety and depression. Patients with LUTS may have a disrupted bladder–brain dialogue; they may say “I don’t even feel anything until I am wet”. Better therapeutic options can emerge from a better understanding of the fundamental brain circuits and cells that contribute to LUTS and that contribute to bladder–brain communication. A potential LUTS etiology that merits closer study is early life urinary tract infection (UTI). Clinical studies in females (who have UTIs 4x more often than males) show early life UTIs predict later life LUTS. Basic research on UTIs and other bladder insults in adulthood suggest inflammation underlies acute LUTS and psychological consequences. For example, adult systemic injection of cyclophosphamide (CYP) — the most common noninvasive (catheter-free) way to model UTI-linked inflammation — leads to bladder and psychobehavioral dysfunction. However, there is a striking absence of research on the role of early life UTIs in later life LUTS and psychological consequences. Here we show for the first time that female mice experiencing repeated, early life cystitis after CYP have bladder and psychobehavioral dysfunction in adulthood. These data fuel our hypotheses: Early life CYP-induced cystitis induces bladder and brain inflammation, which disrupts bladder-brain dialogue and leads to lifelong LUTS and psychobehavioral consequences; this later life bladder and brain dysfunction can be reversed by manipulation of key brain circuits in adulthood. In Aim 1, we will define early life CYP-induced inflammatory indices in bladder and brain across the lifespan. In Aim 2, we will determine early-life CYP-induced functional changes in bladder and brain across the lifespan, launching off from our pilot data: repeated, early-life CYP-induced cystitis leads to adulthood voiding dysfunction and anxiety-like behavior. We will use pharmacologic tools to address the mechanism and specificity of these functional changes, and test for anxiety- and depression-like phenotypes throughout life. In Aim 3, we will map and manipulate key components of the brain circuits that contribute to bladder-brain dialogue. Using our proven abilities to assess neuron activity in brain regions central to this dialogue (locus coeruleus, Barrington’s nucleus, frontal cortex), we will record the activity of sets of neurons in freely-moving mice before and after voiding events in our early life CYP model. We hypothesize that early life cystitis disrupts the ability of these neuron types to respond to sensation from the bladder and thus discriminate voiding cycle stages. We will then attempt to reverse the early life cystitis-induced bladder and psychobehavioral dysfunction in later life by optogenetically manipulating the activity of relevant neurons in adulthood, as we have already done in adult models. Given the prevalence of LUTS, the basic experiments proposed here have enormous potential to expand our understanding of how neonatal cystitis influences the bladder-brain dialogue throughout the lifespan.