Synergistic consequences of early-life social isolation and chronic stress impact coping and neural mechanisms underlying male prairie vole susceptibility and resilience

Abstract

Chronic stress can be challenging, lead to maladaptive coping strategies, and cause negative mental and physical health outcomes. Early-life adversity exposes developing young to physical or psychological experiences that risks surpassing their capacity to effectively cope, thereby impacting their lifetime physical and mental wellbeing. Sensitivity to stressful events, like social isolation, has the potential to magnify stress-coping. Chronic stress through social defeat is an established paradigm that models adverse early-life experiences and can trigger enduring alterations in behavioral and neural phenotypes. To assess the degree to which stress resilience and sensitivity stemming from early-life chronic stress impact sociability, we exposed male prairie voles to chronic social defeat stress (CSDS) during adolescence. We simultaneously exposed subjects to either social isolation (CSDS+Isol) or group housing (CSDS+Soc) during this crucial time of development. On PND41, all subjects underwent a social approach test to examine the immediate impact of isolation, CSDS, or their combined effects on sociability. Unlike the CSDS+Isol group which primarily displayed social avoidance, the CSDS+Soc group was split by individuals exhibiting susceptible or resilient stress phenotypes. Notably, the Control+Soc and CSDS+Soc animals and their cage-mates significantly gained body weight between PND31 and PND40, whereas the Control+Isol and CSDS+Isol animals did not. These results suggest that the effects of early-life stress may be mitigated by having access to social support. Vasopressin, oxytocin, and opioids and their receptors (avpr1a, oxtr, oprk1, oprm1, and oprd1) are known to modulate social and stress-coping behaviors in the lateral septum (LS). Therefore, we did an mRNA expression analysis with RT-qPCR of the avpr1a, oxtr, oprk1, oprm1, and oprd1 genes to show that isolation and CSDS, or their collective influence, can potentially differentially bias sensitivity of the LS to early-life stressors. Collectively, our study supports the impact and dimensionality of early-life adversity because the type (isolation vs. CSDS), duration (acute vs. chronic), and combination (isolation + CSDS) of stressors can dynamically alter behavioral and neural outcomes.

Chronic social defeat stress induces a depression-relevant outcome in male prairie voles

“…2 ). These stress-induced outcomes complement what has been recently reported in adolescent male prairie voles (Sailer et al, 2022) – which display increases in time to approach a social target after a similar 10-day SDS protocol. Likewise, both female prairie and mandarin voles exhibit decreases in sociability after SDS exposure, however, additional depression-related phenotypes associated with helplessness, per increases in immobility in the forced swim and tail suspension tests, are observed only after chronic (14 episodes; Wang et al, 2019) and not acute SDS protocols (3 episodes; Tickerhoof et al, 2020).…”

“…This finding is consistent with prior vole studies implementing chronic stress approaches resulting in reductions of sucrose preference after 4-weeks of social isolation (Grippo et al, 2008). Of note, previous work adopting acute stress protocols do not report anhedonia-like responses nor increases in corticosterone (Arai et al, 2016; Tickerhoof et al, 2020) – highlighting that chronic exposure to SDS is necessary to uncover anhedonia-like states, social withdrawal, and helplessness-related behavior in prairie voles (Sailer et al, 2022).…”

Effects of short-term isolation on vocal and non-vocal social behaviors in prairie voles

“…In contrast to work in mice and rats, most behaviors that we measured (USVs, non-aggressive behaviors, and huddling) were surprisingly not affected by short-term isolation. Similarly, Sailer et al (2022) found that juvenile prairie voles that experienced 9 days of social isolation engaged in social approach toward and social investigation of a conspecific behind a physical barrier at rates that were no different from animals that were not isolated. It is worth noting that combining social isolation while also exposing animals to a social stress regimen (i.e., chronic social defeat), however, reduced these behaviors [24].…”

“…In rodents, for example, social isolation increases levels of systemic inflammation and promotes anxiety-like and despair-like behaviors [21][22][23]. As in humans, social support in rodents buffers the effects of stressors, improves social investigation, and diminishes fear responses [14,15,24]. The consistent association between the quality (or absence) of social connections and psychophysiological health outcomes is a fundamental aspect of social animals across various taxa including primates, birds, fish, and invertebrates [20,25].…”

“…Although work in traditional laboratory animals has established that both long-term and shortterm isolation can impact social behavior, the relevance of such work to humans may be limited because these rodents do not demonstrate persistent and selective social bonds characteristic of humans. Species with prolonged social bonds across their lives, such as the prairie vole, may be particularly affected by social isolation [24,[39][40][41] and therefore may be more suitable to model the effects of social isolation on human social behavior. Most prairie voles will form socially monogamous pairs and engage in biparental care [42][43][44].…”