Prolonged partner separation erodes nucleus accumbens transcriptional signatures of pair bonding in male prairie voles

Abstract

The loss of a spouse is often cited as the most traumatic event in a person's life. However, for most people, the severity of grief and its maladaptive effects subside over time via an understudied adaptive process. Like humans, socially monogamous prairie voles (Microtus ochrogaster) form opposite-sex pair bonds, and upon partner separation, show stress phenotypes that diminish over time. We test the hypothesis that extended partner separation diminishes pair bond-associated behaviors and causes pair bond transcriptional signatures to erode. Pairs were cohoused for 2 weeks and then either remained paired or were separated for 48hrs or 4wks before collecting fresh nucleus accumbens tissue for RNAseq. In a separate cohort, we assessed partner-directed affiliation at these time points. We found that these behaviors persist despite prolonged separation in both same-sex and opposite-sex paired voles. Opposite-sex pair bonding led to changes in accumbal transcription that were stably maintained while animals remained paired but eroded following prolonged partner separation. Eroded genes are associated with gliogenesis and myelination, suggesting a previously undescribed role for glia in pair bonding and loss. Further, we pioneered neuron-specific translating ribosomal affinity purification in voles. Neuronally-enriched transcriptional changes revealed dopaminergic-, mitochondrial-, and steroid hormone signaling-associated gene clusters sensitive to acute pair bond disruption and loss adaptation. Our results suggest that partner separation erodes transcriptomic signatures of pair bonding despite core behavioral features of the bond remaining intact, revealing potential molecular processes priming a vole to be able to form a new bond.

Cholinergic interneurons in the nucleus accumbens are a site of cellular convergence for corticotropin release factor and estrogen regulation

“…during estrus) drive to explore the environment is suppressed in order to mate and reproduce successfully. Furthermore, there is evidence that more prolonged stressors can negatively affect accumbal-dependent reproductive and pair-bonding behaviors 65,66 . This relationship may also be more or less prominent with age with a heightened interaction during adolescence and reproductive age and a diminishing interaction during reproductive senescence 67 .…”

Single nucleus RNA-sequencing reveals transcriptional synchrony across different relationships

“…The nucleus accumbens (NAc) is involved in emotional and reward processing 13 . Neuromodulatory signaling within this region is integral for bond formation, which results in subsequent long-term changes in gene expression and physiology [14][15][16][17] . Here, we used snRNAseq to identify cell-type specific changes that support long-term social bonds.…”

“…Together, these modules may reflect proliferation of neural progenitors, neurogenesis and/or maturation of these immature neurons. In humans, retrospective birth dating of neurons that incorporated 14 C from nuclear bombs has revealed continuous generation of striatal interneurons, and migration of neural progenitors from the subventricular zone (SVZ) to the striatum and their subsequent maturation into inhibitory interneurons has been observed in mice and rats 25,26 . Additionally, in female prairie voles, neurogenesis has been observed in the striatum 25,27 .…”

Prairie voles as a model for adaptive reward remodeling following loss of a bonded partner

“…We can draw on extensive prior research about pair bonding in prairie voles to inform our understanding of loss. Loss is operationalized in prairie voles by physically separating partners 25,49,50 . Partner separation is ethologically relevant as it mirrors what happens in the wild where many voles lose their partners to predation 27 .…”