Touched or detached: neurobiological mechanisms of loneliness

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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.