Touched or detached: neurobiological mechanisms of loneliness

社会孤立与对身心健康的破坏性影响有关。与COVID-19大流行影响相关的新证据表明，与检疫相关的社会隔离是精神疾病的一个风险因素。此外，即使是被称为“孤独”的社会孤立，也会增加患冠心病、中风、抑郁症、认知能力下降和痴呆症的风险。因此，了解社会孤立的有害影响背后的生物学机制将是非常有益的，并将有助于设计干预措施，以增强许多个人所经历的有限社会互动的影响。考虑到社会联系是一种天生的需要，它可能涉及行为、生理和分子适应。然而，支持社会联系的神经和荷尔蒙系统尚未被识别和描述。下丘脑神经肽催产素在社会隔离和社会联系的界面上起着核心作用，它的释放受社会互动的功能调节，特别是由社交触摸传递的体感刺激。该转化项目旨在通过在动物和人类社会隔离模型上开展一套互补实验（WPs 1-5），探索社会隔离的行为、神经和分子后遗症。在动物模型（大鼠）中，社会隔离包括物理隔离，而在人类中，我们将把孤独作为一种主观的隔离体验来关注。在大鼠中，我们的目标是通过无偏倚的转录组学和蛋白质组学分析以及系统和单细胞水平的体内电生理（WP1）来揭示在社会隔离和再社会化期间大脑中发生的分子和神经变化。具体来说，我们的目的是揭示在社会隔离和再社会化（WP2）过程中催产素系统诱导的解剖、电生理和分子修饰。此外，我们将通过将动物对之间的这些变化作为脑间耦合的代理，来探索群体层面上社会隔离的影响。至关重要的是，我们将评估通过化学发生操作和社会接触（WP3）增强内源性催产素系统活性来逆转这些变化的可能性。在大鼠模型中进行这些详细分析之后，我们将通过比较经历高孤独感和低孤独感的个体的脑间耦合、社会联系和催产素水平来探索孤独感对人类的影响（WP4）。具体来说，我们将利用最先进的双功能近红外光谱（fNIRS）的高时间分辨率来研究由高孤独和低孤独参与者组成的二人组在现实生活中的相互作用如何重新配置脑间网络。

Social isolation is associated with devastating effects on mental and physical health. Emerging evidence related to the effects of the COVID-19 pandemic implicates quarantine-related social isolation as a risk factor for psychiatric disorders. Moreover, even perceived social isolation, termed “loneliness”, increases the risk for coronary heart disease, stroke, depression, cognitive decline and dementia. Therefore, understanding the biological mechanisms underlying the detrimental effects of social isolation will be extremely beneficial and will facilitate the design of interventions that can augment the influence of the limited social interactions experienced by many individuals. Considering that social connectedness is as an innate need, it is likely to involve behavioral, physiological and molecular adaptations. Yet, the neural and hormonal systems that support social connectedness have yet to be identified and described. A central player at the interface of social isolation and connectedness is the hypothalamic neuropeptide oxytocin, the release of which is regulated as a function of social interactions, especially somatosensory stimuli delivered by social touch. This translational project is aimed at probing the behavioral, neural and molecular sequelae of social isolation by carrying out a set of complementary experiments (WPs 1-5) on animal and human models of social isolation. While social isolation includes physical isolation in the animal model (rats), in humans, we will focus on loneliness as a subjective experience of isolation. In rats, we aim to reveal the molecular and neural changes that take place in the brain during social isolation and resocialization by using unbiased transcriptomic and proteomic analyses as well as in vivo electrophysiology at both the system and single cells levels (WP1). Specifically, we aim to reveal anatomical, electrophysiological and molecular modifications induced in the oxytocin system during social isolation and resocialization (WP2). Additionally, we will explore the effects of social isolation at the group level by correlating these modifications across pairs of animals as a proxy for inter-brain coupling. Critically, we will evaluate the possibility of reversing these changes by enhancing endogenous oxytocin system activity using chemogenetic manipulations as well as social touch (WP3). Following these detailed analyses in the rat model, we will explore the effects of loneliness in humans by comparing inter-brain coupling, social connectedness and oxytocin levels of individuals experiencing states of either high or low loneliness (WP4). Specifically, we will take advantage of the high temporal resolution of state-of-the-art dual-functional Near-Infrared Spectroscopy (fNIRS) to examine how inter-brain networks reconfigure during real-life interactions of dyads composed of high loneliness and low loneliness participants.