The regulatory role of endocannabinoid signaling on social fear

大麻是世界上最常用的消遣性毒品，因为它有放松的作用。大麻和大麻的主要精神活性成分-德尔塔-9-四氢大麻酚（THC）具有深刻的亲社会影响，但其作用机制在很大程度上是未知的。植物衍生的大麻素，如四氢大麻酚或大麻二酚，以及合成类似物在德国越来越多地用于治疗精神病理、厌食症或慢性疼痛，但在医学上使用精神活性成分治疗社交功能障碍的情况较少。在这里，我们的目的是研究内源性内源性大麻素（eCB）系统在社会偏好行为和社会恐惧中的作用，使用已建立的小鼠社会恐惧模型，即社会恐惧条件反射（SFC）范式。在这个模型中，社会恐惧是由操作性条件反射引起的，即老鼠在接近和调查同性同种动物时受到轻微的电击。先前的数据强调了大脑催产素在促进社会恐惧消除方面的强大参与，并具体涉及大脑边缘系统的外侧隔膜区域。我们的初步数据表明，中隔内的eCB信号对于社会恐惧的消除也是必不可少的。为了详细研究脑电图在社交恐惧消退和社会偏好恢复中的作用，我们将药理学上操纵脑隔脑电图系统的活性，包括大麻素受体介导的作用和阿南达胺的合成，并监测其对社交恐惧消退的影响。我们将进一步揭示相关的eCB通路，并表征可能来自海马体的eCB信号潜在目标的间隔传入事件。然后，这些神经通路将被化学遗传学沉默或其大麻素受体（CB1）的合成将被选择性抑制，并监测其对社会恐惧获得和消除的影响。由于eCB/THC和催产素似乎都发挥亲社会效应，促进社会恐惧的消除和社会功能的恢复，它们在社会恐惧背景下的双向互动是可能的。因此，eCB和中隔内催产素系统之间的相互作用将通过包括微透析、血液采样、免疫组织化学、药理学和化学遗传学方法在内的互补方法进行研究。最后，作为一种转化方法，我们将测试四氢大麻酚和大麻二酚急性或慢性应用对社会恐惧获得和消除的影响，以及这些影响是否-至少部分-通过催产素系统介导。通过这一系列的实验，我们的目标是促进关于大麻素的作用机制的知识仍然有限，特别是在社会功能障碍的背景下，如社会恐惧。

Cannabis is the most commonly used recreational drug worldwide due to its relaxing effects. Profound pro-social effects of cannabis and delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been described, but mechanisms of action are largely unknown. Plant-derived cannabinoids, such as THC or cannabidiol, and synthetic analogs are increasingly prescribed in Germany to treat psychopathologies, anorexia or chronic pain, but the medical use of psychoactive components for treating social dysfunctions is less characterized. Here, we aim to investigate the involvement of the endogenous endocannabinoid (eCB) system in social preference behaviour versus social fear using an established mouse model of social fear, i.e. the social fear conditioning (SFC) paradigm. In this model, social fear is induced by operant conditioning, i.e. the mouse receives a mild shock when approaching and investigating a same-sex conspecific. Previous data highlight the robust involvement of brain oxytocin in promoting social fear extinction with specific involvement of the lateral septum, a region of the limbic system of the brain. Our preliminary data indicate that also eCB signaling within the septum is essential for social fear extinction. To investigate the role of eCBs in social fear extinction and reinstatement of social preference in detail, we will pharmacologically manipulate the activity of the septal eCB system including cannabinoid receptor-mediated actions and anandamide synthesis, and monitor effects on social fear extinction. We will further reveal the relevant eCB pathways and characterize septal afferents representing potential targets of eCB signaling possibly arising from the hippocampus. Then, these neuronal pathways will be chemogenetically silenced or their cannabinoid receptor (CB1) synthesis will be selectively inhibited and consequences on social fear acquisition and extinction will be monitored. As both eCB/THC and oxytocin seem to exert pro-social effects, promote social fear extinction and restore social functioning, their bidirectional interaction in the context of social fear is likely. Therefore, interactions between the eCB and the oxytocin systems within the septum will be studied using complementary methods including microdialysis, blood sampling, immunohistochemistry, pharmacological and chemogenetical approaches. Finally, as a translational approach, we will test the effects THC and cannabidiol applied either acutely or chronically on social fear acquisition and extinction, and whether these effects are - at least partly - mediated via the oxytocin system. With these series of experiments we aim to contribute to the still limited knowledge regarding the mechanisms of actions of cannabinoids especially in the context of social dysfunctions, such as social fear.