Neurobiological Consequences and Mechanisms of Early Social Rejection Experiences in an Animal Model with relevance for Borderline Personality Disorder

本提案的主要目的是进一步阐明与BPD相关的啮齿动物模型中社会排斥的分子后果和机制。社会排斥是痛苦的一个主要来源，并与包括BPD在内的各种精神疾病的发展有关。在第一个资助期内，我们建立了一种新的动物模型，用于研究实验室大鼠早期不良社会经历的持续后果（相关项目1）。通过剥夺动物在童年和青春期的特定社会需求，我们能够在成年雌性大鼠中引起持续的行为变化，这些行为变化类似于BPD的核心方面（例如，社会互动和识别障碍，以及疼痛敏感性降低），以及内源性大麻素系统（ECS）的改变，例如内源性大麻素anandamide（AEA）的区域增强水平。与社会排斥相关的神经生物学后果和机制在很大程度上仍然未知。在这里，我们的目标是进一步研究这些过程中，通过调查的后果，剥夺社会要求在青春期大鼠单独，并结合早期的变化，在母婴互动的质量。我们的研究将集中在涉及社会行为和疼痛处理的调制的神经化学系统：ECS，中央催产素和内源性阿片系统。在这里，我们计划利用成像技术（正电子发射断层扫描），使未来的翻译方法与人类研究。此外，我们将应用分子和神经化学技术，并评估行为变化。基于我们以前的研究结果，我们现在还打算更密切地监测整个青春期社会排斥经历的神经生物学后果的时间过程，以便阐明调节成年期持续行为和神经生物学变化的机械过程的时间过程。此外，为了获得一个给定的分子变化和特定的BPD样行为特征之间的因果关系，我们将使用区域病毒介导的基因转移方法在额外的救援实验。第一个目标将是增强的杏仁核AEA水平的正常化和由此预期的疼痛感知和社会障碍的正常化。其他鉴定的持续性分子变化也将通过病毒介导的基因转移选择性靶向。这种方法不仅将为BPD提供机制性见解，还将为我们的CRU提供新的干预策略。

The major aim of the present proposal is to further elucidate the molecular consequences and mechanisms of social rejection in a rodent model with relevance to BPD. Social rejection is a major source of distress and has been implicated in the development of various psychiatric disorders including BPD. During the first funding period, we established a novel animal model for persistent consequences of early adverse social experiences in laboratory rats (Associated Project 1). By depriving animals of specific social requirements during childhood and adolescence we were able to evoke persistent behavioral changes in adult female rats that resemble core aspects of BPD (e.g. disturbed social interaction and recognition, and decreased pain sensitivity), as well as alterations in the endocannabinoid system (ECS), such as regionally enhanced levels of the endocannabinoid anandamide (AEA). The neurobiological consequences and mechanisms linked to social rejection are still largely unknown. Here, we aim to further examine these processes by investigating the consequences of deprivation of social requirements in adolescent rats ¿ alone, and in combination with early variances in the quality of mother-infant interaction. Our investigations will focus on neurochemical systems involved in the modulation of social behavior and pain processing: the ECS, the central oxytocin and the endogenous opioid system. Here, we plan to utilize imaging techniques (positron emission tomography) to enable a future translational approach with human studies. Additionally, we will apply molecular and neurochemical techniques and assess behavioral changes. Based on our previous findings, we now also intend to monitor the time course of neurobiological consequences of social rejection experiences throughout adolescence more closely, in order to shed light on the time course of the mechanistic processes mediating the persistent behavioral and neurobiological changes in adulthood. Furthermore, in order to gain a causal link between a given molecular change and a specific BPD-like behavioral feature we will use a regional viral-mediated gene transfer approach in an additional rescue experiment. A first target will be the normalization of enhanced amygdalar AEA levels and the hereby expected normalization of pain perception and social impairments. Other identified persistent molecular changes will be also selectively targeted by viral-mediated gene transfer. This approach will not only provide a mechanistical insight for BPD but will also deliver new intervention strategies for our CRU.