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），即重大抑郁症（MDD）和躁郁症（BD）是遗传和环境风险因素贡献的表型。这些因素相互作用以及它们如何对大脑结构和功能发挥影响的潜在神经生物学机制尚未理解。 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。在第一个资金期间，我们获得了CACNA1C +/-大鼠多种行为改变的大量证据，包括焦虑相关的行为升高，在Apomorphine挑战下对声学的抑制作用，在Apomorphine挑战下抑制声学的缺陷，逆转学习障碍，空间导航任务中的逆转学习障碍，以及社会行为行为和声学交流和声学交流缺陷。与BD特别相关，锂在抑制苯丙胺唤起的躁狂样表型中的有效性几乎在Cacna1c +/-大鼠中被钝化。在神经生物学测量，免疫激活和表观遗传修饰的水平上，GXE相互作用与行为表型的环境调节相似。例如，在Cacna1c+/+大鼠的海马中检测到成熟的microRNA（miRNA）水平的广泛降低，以响应于断奶后的社会隔离（SI），作为虐待模型。有趣的是，这种作用在Cacna1c +/-大鼠中大大钝化。具体而言，绝大多数miRNA（> 80％）受GXE相互作用的影响，表明大多数海马miRNA受遗传和环境因素的结合（合作WP3）的结合受到调节。此外，虽然断奶后的SI引起的免疫反应性为特征，其特征是Cacna1c+/+大鼠促促炎性细胞因子的升高，但在Cacna1c +/-大鼠中未见这种反应性，表明抗韧性（合作WP4）。在第二个融资期内，我们将在我们已建立的GXE CACNA1C大鼠模型中遵循五项研究。我们将（1）确定社会行为和声学交流缺陷的生物心理学机制； （2）为BD样情感循环开发一种新型的行为测定； （3）将前额叶皮层和海马中钙信号成分的改变与与AD相关的行为表型。与WP3一起，我们将（4）通过脑内注射重组腺相关病毒颗粒（RAAV）进一步探索miRNA操纵在前额叶皮层和海马中的影响，旨在挽救通过恢复miRNA生物发生后恢复液后的SI后与AD相关的行为表型。最后，使用WP3和WP4，我们（5）将评估这种miRNA生物发生操纵对免疫特征的影响，反之亦然，免疫挑战对与AD相关的表型的影响。通过这种高度相互联系的方法，该项目承诺在AD病因和治疗中有关miRNA生物发生和免疫系统的新见解。