Behavior and pro-inflammatory cytokine variations among submissive and dominant mice engaged in aggressive encounters: moderation by corticosterone reactivity.

Abstract

Psychosocial stressors contribute to the pathophysiology of affective disorders and variations of cytokine functioning have been implicated in this process. The present investigation demonstrated, in mice, the impact of stressful aggressive encounters on activity levels, plasma corticosterone and cytokine concentrations, and on cytokine mRNA expression within the prefrontal cortex (PFC) and hippocampus. As glucocorticoids have been tied to cytokine variations, mice were subdivided into low or high corticosterone responders, defined in terms of circulating hormone levels 75 min post-confrontation. Interestingly, stressor-induced effects among low and high responders varied as a function of whether mice were submissive or dominant during the aggressive bout. Agonistic encounters elicited subsequent hyperactivity, particularly among low corticosterone responders and among dominant mice. Plasma levels of corticosterone and interleukin (IL)-6 concomitantly increased after aggressive encounters and varied with dominance status and with the low versus high corticosterone response. Among the low responders corticosterone and IL-6 increases were modest and only apparent among submissive mice, whereas among high responders these elevations were more pronounced and comparable in submissive and dominant mice. Aggressive episodes also increased IL-1β and IL-6 mRNA brain expression. The IL-1β rise was greater in the PFC and hippocampus of submissive mice that were low responders. Among high responders IL-1β and IL-6 increased in both groups, although in the PFC this effect was specific to dominant mice. The data are discussed in terms of their relevance to the impact of aggressive encounters on affective behaviors, and to the role that cytokines might play in this regard.

Social status, glucocorticoids, immune function, and health: Can animal studies help us understand human socioeconomic-status-related health disparities?

“…CRP and IL-6 levels were elevated in lower SES humans (Demakakos et al, 2008;Friedman and Herd, 2010;Gimeno et al, 2007Gimeno et al, , 2008Gruenewald et al, 2009;Hagger-Johnson et al, 2012;Maksimović et al, 2008;McDade et al, 2011;Nazmi and Victora, 2007;Petersen et al, 2008;Saijo et al, 2008;Schafer et al, 2011;Seeman et al, 2008;Tabassum et al, 2008), while circulating and splenic IL-6 and IL-1β levels were elevated in subordinate mice living in unstable social groups (Audet et al, 2010;Avitsur et al, 2007;Savignac et al, 2011). These trends suggest that this pro-inflammatory bias may only be observed in subordinates during unstable social situations or periods of chronic social stress.…”

“…IL-1β, IL-6, TNF-α) was one of the few responses that was stronger in subordinates than dominants (see Table 2). In stable groups of mice and rhesus macaques, social rank did not relate to splenic or circulating IL-6 levels (Avitsur et al, 2007;Hoffman et al, 2011;Merlot et al, 2004), but in three studies that subjected animals to social disruption or otherwise unstable social hierarchies, submissive mice exhibited greater splenic or circulating IL-1β and IL-6 levels most likely mediated by glucocorticoid resistance (Audet et al, 2010;Avitsur et al, 2007;Savignac et al, 2011). Anti-inflammatory cytokine production was not found to relate to social status (Bartolomucci et al, 2001;de Groot et al, 2001;Merlot et al, 2004;Savignac et al, 2011).…”

“…Despite this, a study investigating the dynamics of IL-10 levels over time indicated that dominant mice had faster rises and falls in this anti-inflammatory cytokine after exposure to an infectious, live antigen, demonstrating the importance of measuring these biomarkers at multiple time points to best estimate potentially relevant temporal dynamics of immune responses (Merlot et al, 2004). There have been a few studies that investigated brain levels of inflammatory cytokines with respect to social rank, but too few to make any clear conclusions (e.g., Audet et al, 2010).…”

Astrocytic Hypertrophy in Anterior Cingulate White Matter of Depressed Suicides

“…In particular, it has been well documented that patients suffering from depression have significantly higher levels of circulating pro-inflammatory cytokines (Miller et al, 2009), and that administration of interferon-a leads to depressive-like symptoms (Malaguarnera et al, 1998;reviewed by Horsmans, 2006) that are accompanied by increased ACC activation (Capuron et al, 2005). Expression of brain cytokines seems altered in suicides (Tonelli et al, 2008), and pro-inflammatory cytokines have been implicated in the development of stress-induced depressive symptoms (Audet et al, 2010;Goshen et al, 2008). The differences between cortical gray and white matter astrocytes highlighted in the present study need to be explored further, but may have to do with an increased facility of cytokines to diffuse within the brain along white matter tracts (Konsman et al, 2000).…”

Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment

“…It is worth noting that in the stressful condition, microglial IL-6 expression is affected by treatment in an opposite fashion as compared to the expression of other pro-inflammatoryrelated genes. Previous studies have already found unique IL-6 expression profile compared to that of other pro-inflammatory cytokines in response to stressful (Audet et al, 2010) or immunogenic stimuli (Skelly et al, 2013). In addition, IL-6 has been reported to produce unexpected effects when used to modulate a variety of physiological processes, such as memory function (Arnold et al, 2002;Yirmiya and Goshen, 2011).…”