Acute social isolation alters neurogenomic state in songbird forebrain

Abstract

Prolonged social isolation has negative effects on brain and behavior in humans and other social organisms, but neural mechanisms leading to these effects are not understood. Here we tested the hypothesis that even brief periods of social isolation can alter gene expression and DNA methylation in higher cognitive centers of the brain, focusing on the auditory/associative forebrain of the highly social zebra finch. Using RNA sequencing, we first identified genes that individually increase or decrease expression after isolation and observed general repression of gene sets annotated for neurotrophin pathways and axonal guidance functions. We then pursued 4 genes of large effect size: EGR1 and BDNF (decreased by isolation) and FKBP5 and UTS2B (increased). By in situ hybridization, each gene responded in different cell subsets, arguing against a single cellular mechanism. To test whether effects were specific to the social component of the isolation experience, we compared gene expression in birds isolated either alone or with a single familiar partner. Partner inclusion ameliorated the effect of solo isolation on EGR1 and BDNF, but not on FKBP5 and UTS2B nor on circulating corticosterone. By bisulfite sequencing analysis of auditory forebrain DNA, isolation caused changes in methylation of a subset of differentially expressed genes, including BDNF. Thus, social isolation has rapid consequences on gene activity in a higher integrative center of the brain, triggering epigenetic mechanisms that may influence processing of ongoing experience.

Genes and environments, development and time

“…George et al (74) show that social isolation in the highly social zebra finch affects gene expression in the brain and that this is correlated with an increase in DNA methylation of a subset of those differentially expressed genes. Hundreds of genes located in higher forebrain centers were involved in social communication when birds were isolated in a sound chamber overnight, compared to when they were paired with a same-sex partner in the chamber.…”

Stress Varies Along the Social Density Continuum

“…It should be recognized that effects of social isolation and social crowding have also been recorded in non-mammalian social species, including in insects (Wang et al, 2008;Lihoreau et al, 2009;Ueda and Wu, 2009;Stevenson and Rillich, 2013), fish (Halperin and Dunham, 1993;Brandão et al, 2015;Shams et al, 2015), and birds (Apfelbeck and Raess, 2008;Banerjee and Adkins-Regan, 2011). Notably, a recent study found immediate effects of social isolation in the expression of several immediate early genes in the forebrain of an avian species (George et al, 2019), a finding which has implications for the field of vocal learning, which historically relies on the isolation of animals (Love et al, 2019). It is difficult to determine at present how much of the human response to social density stressors is unique to humans; do we find similar responses among distantly-related taxa that show similarity in social systems, or does genetic relatedness play a more important role in determining how the CNS modulates behavior in response to social density?…”

Social isolation-induced effects on male-specific courtship behaviours and dendritic architecture in associative forebrain areas in Zebra finches (Taeniopygia guttata)

“…However, differential gene expression in neurotrophin signaling pathway and axon guidance in response to social isolation, suggest lasting structural and functional changes in the brain. 38 Specifically, immediate early gene ERG1, associated with synaptic plasticity and BDNF, that promotes growth and differentiation of new neurons and synapses, were found to be down-regulated in caudal nido- and meso-pallial regions on social isolation and reversed on exposure to the partner. 38 While the molecular mechanisms are still being understood, including differential methylation of the BDNF gene in response to isolation and mate exposure, it is well established that social isolation induces regressive plasticity.…”