Gene x environment interactions on brain and behaviour in the Cacna1c genetic rat model: Calcium signalling, microRNAs, and immune activation

Cacna1c 遗传大鼠模型中基因 x 环境对大脑和行为的相互作用：钙信号传导、microRNA 和免疫激活

• 批准号: 250951389
• 负责人: Professor Dr. Rainer K.W. Schwarting
• 金额: --
• 依托单位: Abteilung Verhaltensneurowissenschaft
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/250951389?language=en
• 关键词: Gene; environment; interactions; brain; behaviour

Affective disorders (AD), i.e. major depressive disorder (MDD) and bipolar disorder (BD), are phenotypes to which genetic and environmental risk factors contribute. The underlying neurobiological mechanisms by which such factors interact and how they exert their influence on brain structure and function are yet poorly understood. WP2, animal backbone of the FOR2107, addresses these questions by applying a gene x environment (GxE) approach in the Cacna1c genetic rat model. In the first funding period, we obtained substantial evidence for multiple behavioural alterations in Cacna1c+/- rats, including elevated anxiety-related behaviour, deficits in pre-pulse inhibition of acoustic startle under apomorphine challenge, reversal learning impairments in a spatial navigation task, and social behaviour and acoustic communication deficits. Of particular relevance for BD, the effectiveness of lithium in inhibiting mania-like phenotypes evoked by amphetamine was almost blunted in Cacna1c+/- rats. Environmental modulation of behavioural phenotypes was paralleled by GxE interactions at the level of neurobiological measures, immune activation, and epigenetic modifications. For instance, a widespread reduction in mature microRNA (miRNA) levels was detected in the hippocampus of Cacna1c+/+ rats in response to post-weaning social isolation (SI), as a model of maltreatment. Intriguingly, this effect was largely blunted in Cacna1c+/- rats. Specifically, the vast majority of miRNAs (>80%) was affected by the GxE interaction, indicating that most hippocampal miRNAs are subject to regulation by a combination of genetic and environmental factors (collab. WP3). Moreover, while post-weaning SI evoked immune reactivity characterized by elevated pro-inflammatory cytokines in Cacna1c+/+ rats, no such reactivity was seen in Cacna1c+/- rats, suggesting resilience (collab. WP4). In the second funding period, we will follow five lines of research in our established GxE Cacna1c rat model. We will (1) identify biopsychological mechanisms underlying social behaviour and acoustic communication deficits; (2) develop a novel behavioural assay for BD-like affective cycling; and (3) link alterations in calcium signalling components in prefrontal cortex and hippocampus to behavioural phenotypes with relevance to AD. Together with WP3, we will (4) further explore the impact of miRNA manipulations in prefrontal cortex and hippocampus by means of intracerebral injection of recombinant adeno-associated virus particles (rAAV), with the aim to rescue behavioural phenotypes relevant to AD after post-weaning SI through restoring miRNA biogenesis. Finally, with WP3 and WP4, we will (5) assess the impact of such miRNA biogenesis manipulations on immune signatures and, vice versa, the impact of immune challenges on AD-relevant phenotypes. Through this highly interconnected approach, the project promises novel insight regarding miRNA biogenesis and immune system in AD aetiology and treatment.

情感障碍 (AD)，即重度抑郁症 (MDD) 和双相情感障碍 (BD)，是遗传和环境风险因素造成的表型。这些因素相互作用的潜在神经生物学机制以及它们如何对大脑结构和功能产生影响仍知之甚少。 WP2 是 FOR2107 的动物骨干，通过在 Cacna1c 遗传大鼠模型中应用基因 x 环境 (GxE) 方法来解决这些问题。在第一个资助期间，我们获得了 Cacna1c+/- 大鼠多种行为改变的实质性证据，包括焦虑相关行为升高、阿扑吗啡挑战下声惊吓的前脉冲抑制缺陷、空间导航任务中的逆转学习障碍，以及社会行为和声音沟通缺陷。与 BD 特别相关的是，锂在抑制安非他明引起的躁狂样表型方面的有效性在 Cacna1c+/- 大鼠中几乎减弱。行为表型的环境调节与神经生物学测量、免疫激活和表观遗传修饰水平上的 GxE 相互作用并行。例如，作为虐待模型，在断奶后社会隔离（SI）后，Cacna1c+/+ 大鼠的海马体中检测到成熟 microRNA (miRNA) 水平普遍下降。有趣的是，这种效应在 Cacna1c+/- 大鼠中很大程度上减弱了。具体来说，绝大多数 miRNA (>80%) 受到 GxE 相互作用的影响，表明大多数海马 miRNA 受到遗传和环境因素组合的调节（合作实验室.WP3）。此外，虽然断奶后 SI 在 Cacna1c+/+ 大鼠中引发了以促炎细胞因子升高为特征的免疫反应，但在 Cacna1c+/- 大鼠中没有观察到这种反应，这表明恢复力（collab.WP4）。在第二个资助期，我们将在已建立的 GxE Cacna1c 大鼠模型中进行五项研究。我们将（1）确定社会行为和声音沟通缺陷背后的生物心理学机制； (2) 开发一种新的类似 BD 情感循环的行为测定方法； (3) 将前额皮质和海马中钙信号传导成分的改变与 AD 相关的行为表型联系起来。我们将与WP3一起（4）通过脑内注射重组腺相关病毒颗粒（rAAV）进一步探讨miRNA操作对前额皮质和海马的影响，旨在挽救AD后的行为表型。通过恢复 miRNA 生物发生来断奶 SI。最后，通过 WP3 和 WP4，我们将 (5) 评估此类 miRNA 生物发生操作对免疫特征的影响，反之亦然，评估免疫挑战对 AD 相关表型的影响。通过这种高度互联的方法，该项目有望在 AD 病因学和治疗中提供关于 miRNA 生物发生和免疫系统的新见解。