Differential transcriptome expression in human nucleus accumbens as a function of loneliness

Abstract

Loneliness is associated with impaired mental and physical health. Studies of lonely individuals reported differential expression of inflammatory genes in peripheral leukocytes and diminished activation in brain reward regions such as nucleus accumbens, but could not address gene expression in the human brain. Here, we examined genome-wide RNA expression in postmortem nucleus accumbens from donors (N = 26) with known loneliness measures. Loneliness was associated with 1 710 differentially expressed transcripts from 1 599 genes (DEGs; FDR p < 0.05, fold-change ≥ |2|, controlling for confounds) previously associated with behavioral processes, neurological disease, psychological disorders, cancer, organismal injury, and skeletal and muscular disorders, as well as networks of upstream RNA regulators. Furthermore, a number of DEGs were associated with Alzheimer's disease genes (which was correlated with loneliness in this sample, although gene expression analyses controlled for AD diagnosis). These results identify novel targets for future mechanistic studies of gene networks in nucleus accumbens and gene regulatory mechanisms across a variety of diseases exacerbated by loneliness.Loneliness has been defined as a negative emotional state of unfulfilled intimate and social needs (1). It can also be considered as a behavioral trait, because it is stable over time (2, 3), difficult to alter with interventions (4), and heritable (5). Loneliness is a subjective perception of social isolation and therefore independent of objective measures such as social network size (1), making it a challenge to study in non-human animals.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Supplementary information is available at Molecular Psychiatry's website. Conflict of InterestThe authors declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptLoneliness has a profoundly negative impact on psychological/behavioral processes including mental health, particularly in aging populations. For example, loneliness is associated with depression and anxiety (6-8). Longitudinal studies of cognition reported that loneliness at baseline predicted cognitive decline in recall memory over a 4-year period (9), was associated with lower levels of perceptual processing and memory at baseline (10), overall cognitive decline (11) and incident dementia (12), as well as a decline in motor function (13). The underlying molecular-genetic mechanisms of these associations are currently unknown, in part because gene expression as a function of loneliness has not yet been examined in the human brain.Loneliness is also associated with increased risk for neurological and neurodegenerative diseases such as Alzheimer's disease (AD) (10), as well as cancer (17,18), and organismal and muscular diseases and...

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