The role of the ventral striatum in inflammatory-induced approach toward support figures
Introduction
As part of the innate immune response, an organism will exhibit a multitude of symptoms, termed “sickness behavior,” in response to infection or illness. Symptoms of sickness are triggered by the release of proinflammatory cytokines, which act as chemical messengers to signal the brain to change behavior. The most commonly observed inflammatory-induced change in social behavior has been withdrawal from others. Thus, animal research has shown that an acute inflammatory challenge leads to reduced social exploration of others (Bluthe et al., 1996, Bluthe et al., 1994, Marvel et al., 2004). Similarly, humans exposed to an experimental inflammatory challenge report increased feelings of social disconnection (Eisenberger et al., 2010) and greater threat-related neural activity to negatively-valenced pictures of unknown others (Inagaki et al., 2012). Though unpleasant in the short-term, changes in social behavior such as social withdrawal are thought to be adaptive responses in promoting rest and recuperation from illness or infection (Dantzer et al., 2008, Hart, 1988).
Despite this literature linking inflammation and social withdrawal, animal models have shown that, under certain circumstances, animals will engage in more rather than less social behavior during sickness (Aubert, 1999, Hennessy et al., 2014). This is particularly true when given the chance to affiliate with a familiar other. For instance, after being injected with lipopolysaccharide (LPS), which elicits an inflammatory response, rats spend more time huddling with familiar cage-mates as compared to responses of placebo-injected controls (Yee and Prendergast, 2010). Increases in affiliative social behavior during sickness have also been observed in non-human primates. At a relatively low dose, LPS-treated rhesus monkeys (vs. saline-treated control monkeys) show significantly more close social contact with cage-mates and, at the higher dose, proximal social contact (defined as passively sitting near a companion) is positively correlated with levels of interleukin-6 (IL-6), an inflammatory cytokine and well-known mediator of sickness behavior (Dantzer, 2001, Willette et al., 2007). Thus, depending on the target of the social behavior, sickness can lead to increased approach toward others.
In fact, increasing interactions with close, supportive individuals may confer a survival advantage should those close individuals provide care and protection to the sick (Cole, 2006, Hennessy et al., 2014). In other words, just as it may be important to withdraw from strangers or signs of threat during sickness, it may be just as important to approach close others in order to obtain care. Indeed, sickness increases social approach behavior toward close others in young children, such that infants or children who are sick become more clingy, spend more time in proximity with their caregivers, and become more upset following separation from their caregivers (Ainsworth, 1973, Bowlby, 1988, Mikulincer and Shaver, 2007). However, the effect of inflammation on the motivation to approach support figures has not yet been explored in humans.
In addition, the neural regions underlying motivations to approach loved ones during times of sickness are currently unknown. Results from studies of the neurobiology of close social relationships suggest that regions related to reward processing, especially the ventral striatum (VS), underlie feelings of social connection in close relationships (Aron et al., 2005, Acevedo et al., 2012, Inagaki and Eisenberger, 2013). For instance, reminders of close others in the neuroimaging environment, such as loving messages from close others (Inagaki and Eisenberger, 2013) or pictures of a loved one (Acevedo et al., 2012, Strathearn et al., 2009, Strathearn et al., 2008) robustly activate the VS. In addition, the VS is particularly sensitive to the motivation to approach highly pleasing rewards such as money or sweet tastes (Berridge et al., 2009, Knutson and Cooper, 2005). Thus it appears as if the VS is sensitive both to the motivation to approach rewards as well as close support figures and therefore may be associated with social approach during sickness as well.
The current study assessed the effect of an experimentally induced inflammatory challenge on the motivation to approach a support figure. Based on results from the animal literature, we expected inflammation (vs. placebo) to lead to a greater self-reported desire to be around support figures. We also investigated whether inflammation altered neural activity in a key reward-related brain region in response to viewing photographs of a social support figure, but not to photographs of an unknown stranger. We hypothesized that individuals exposed to an inflammatory challenge (vs. a placebo) would show greater neural activity in the VS in response to viewing pictures of their support figure, but would show no differences in response to viewing pictures of a stranger. Finally, we explored the association between endotoxin-induced changes in the proinflammatory cytokines, IL-6 and TNF-α, and VS activity to viewing support figures with the hypothesis that increases in cytokines would be associated with greater VS activity.
Section snippets
Overview
Detailed descriptions of similar methods have been published elsewhere (Eisenberger et al., 2010, Eisenberger et al., 2009, Inagaki et al., 2012), but are summarized here. Participants were deemed eligible to participate after being evaluated for psychiatric conditions (via the Structure Clinical Interview for DSM Axis I Disorders; First et al., 2012), scanner-safety (claustrophobia and for the females, pregnancy), and general health (vitals, BMI, blood draw). Following screening, eligible
Behavioral results
Replicating previous work using a similar paradigm (Eisenberger et al., 2009, Eisenberger et al., 2010), endotoxin (vs. placebo) led to significantly greater increases in IL-6 (F(1, 61) = 210.66, p < .001). Specifically, there was a bigger increase in IL-6 from baseline (M = 3.09 pg/mL, SD = 4.73 (values reported here are raw values)) to post-scan (M = 144.34 pg/mL, SD = 142.30) for the endotoxin participants (t(31) = 17.21, p < .001) than for the placebo participants (baseline: M = 2.00 pg/mL, SD = 1.82, post-scan: M =
Discussion
Although a prominent symptom of sickness behavior is social withdrawal, individuals may respond differently to social support figures – approaching, rather than withdrawing, from them during times of sickness. In support of this hypothesis, endotoxin (vs. placebo) led to a greater reported desire to be around a support figure and greater ventral striatum activity to images of a support figure. Furthermore, increases in IL-6 responses (from baseline to post-scan) were associated with increased
Acknowledgments
The authors extend their thanks to the Staglin IMHRO Center for Cognitive Neuroscience, the staff and support of UCLA’s Clinical and Translational Science Institute (CTSI: UL1TR000124), and the participants in the study. In addition, this work was supported by funding from the Wendell Jeffrey & Bernice Wenzel Term Chair in Behavioral Neuroscience to NIE and by R01-AG034588; R01-AG026364; R01 CA160245-01; R01-CA119159; R01 HL095799; R01 DA032922-01; P30-AG028748 to MRI, and the Cousins Center
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