https://doi.org/10.24839/2325-7342.JN23.5.376 Are All Chronic Social Stressors the Same? Behavioral, Physiological, and Neural Responses to Two Social Stressors in a Female Mouse Model of Anxiety and Depression Michael R. Jarcho*, Siena College and Loras College; Madeline R. Avery, Loras College; Kelsey B. Kornacker , Danielle Hollingshead, and David Y. Lo*, Coe College ABSTRACT. Chronic stress has been associated with several negative health outcomes and psychopathological conditions, and social stressors (e.g., exclusion from a group, loss of a loved one) can be particularly problematic with regard to psychopathological conditions. Social isolation or instability can result in both behavioral and physiological stress responses. The present study attempted to assess whether the behavioral and physiological markers of stress would follow similar patterns in response to both social isolation and instability. By employing both of these models of social stress in female mice, we hoped to determine which might serve as a more appropriate model of stress-induced anxiety or depression in women. One behavioral index of anxiety, rearing behavior, was elevated only in animals experiencing social instability, F(2, 351) = 6.91, p = .001, η2 = .04, (1-b) = 0.94. Despite small sample sizes, gene expression of proinflammatory markers interleukin one beta receptor and tumor necrosis factor alpha were significantly elevated in hippocampal samples from mice that experienced either social stressor compared to controls, IL1-beta receptor, F(2, 6) = 5.65, p = .045, η2 = .85, (1-b) = 0.99, TNF alpha, F(2, 6) = 8.89, p = .042, η2 = .86, (1-b) = 0.99, with the highest levels in mice that experienced social instability. Glial fibrillary acidic protein gene expression, conversely, was significantly lower in mice of either stress group, F(2, 6) = 13.37, p = .006, η2 = .82, (1-b) = 0.99. Mice that were subjected to either social stressor showed elevated hair corticosterone compared to baseline levels and as compared to controls: Group x Time interaction, F(4, 63) = 3.47, p = .013, η2 = .18, (1-b) = 0.89. These results suggest that chronic social stress might increase the expression of symptoms of depression and anxiety, and that social instability is a more potent stressor than social isolation in mice. ndividuals under chronic stress suffer anxiety insights into the behavioral, physiological, and and depression at higher rates than sex- and neurological consequences associated with chronic Iage-matched controls (O’Donovan et al., social stressors. In addition, using these models 2010; Slavich & Irwin, 2014). In modern society, to demonstrate how individuals respond to the some of the primary sources of chronic stress termination of those same stressors may provide WINTER 2018 are social in nature, relating to relationships and insight into potential therapeutic applications to conflicts with other people (McEwen, 2003, 2004; mitigate symptoms associated with chronic stress PSI CHI Slavich & Irwin, 2014). As such, the development with specific implications for anxiety and depressive JOURNAL OF PSYCHOLOGICAL of appropriate animal models could provide disorders. RESEARCH 376 COPYRIGHT 2018 BY PSI CHI, THE INTERNATIONAL HONOR SOCIETY IN PSYCHOLOGY (VOL. 23, NO. 5/ISSN 2325-7342) *Faculty mentor Jarcho, Avery, Kornacker, Hollingshead, and Lo | Comparing Chronic Social Stressors Historically, the most common rodent model in female subjects (Herzog et al., 2009; Jarcho, that has been utilized to investigate chronic social Massner, Eggert, & Wichelt, 2016). This paradigm stress is the social defeat model (a.k.a. “resident- is characterized by frequent and unpredictable intruder” model; Golden, Covington, Berton, & changes to the subjects’ social environments includ- Russo, 2011; Hollis & Kabbaj, 2014; Iñiguez et al., ing social isolation and social crowding. 2014; Kinsey, Bailey, Sheridan, Padgett, & Avitsur, The social instability model described above 2007; Watt, Burke, Renner, & Forster, 2009). This was designed to accurately translate to frequent model involves a male rodent subject (i.e., the and substantial changes to one’s social environment “intruder”) being introduced to a larger and more in humans. Given that social stressors may last aggressive male’s cage (i.e., the “resident”). The for weeks to months (e.g., family disagreements, subject is often attacked repeatedly by the aggressive feeling excluded from a group), or longer (e.g., resident, eventually resulting in the subject express- end of a marriage, loss of a loved one), assess- ing behavioral and physiological symptoms that ing glucocorticoid responses over a comparable resemble human populations experiencing clinical timeline is ideal. Common methods of sampling anxiety and depression (e.g., social withdrawal, glucocorticoids involve the collection of either anhedonia; Hollis and Kabbaj, 2014; Iñiguez et al., blood plasma or saliva. Additionally, urinary and 2014; Kinsey et al., 2007; Watt et al., 2009; Zhang, fecal samples provide insight to HPA functioning Yuan, Shao, & Wang, 2016). over the preceding hours (Harper & Austad, 2015; For at least two reasons, the social defeat Shamim, Yousufuddin, Bakhai, Coats, & Honour, paradigm has been insufficient for providing a 2000). These methods give “point” values that are complete picture of the neuroendocrine correlates highly variable within the same individual, and of depression and anxiety. First, the social defeat within a given day. A number of variables are known model involves both physical (i.e., attacks by resi- to affect plasma and salivary samples in particular dent male) and psychological (i.e., being placed (e.g., food intake, exercise, time of day/year) and into an unfamiliar cage) stressors, whereas the most need to be controlled for or taken into account, common sources of social stress in modern human and repeated samples are required for an accurate populations are psychological. Physical stressors understanding of HPA regulation (Davenport, certainly exist, even in Western societies (e.g., Tiefenbacher, Lutz, Novak, & Meyer, 2006). malnutrition, infectious diseases), but psychosocial Sampling glucocorticoids (i.e., corticosterone in stressors are recognized as frequent precursors to rodents, cortisol in primates) in hair, however, is onset of depressive and anxiety disorders (Juster, a newer method that allows for the noninvasive McEwen, & Lupien, 2010; McEwen, 2004, 2005; assessment of glucocorticoids over a longer period Slavich & Irwin, 2014). Second, the social defeat of time with a single sample and has been shown model is typically only effective with male rodents to accurately reflect individual responses to various (although, see Harris et al., 2018; Takahashi et al., social stressors in rhesus macaques (Davenport et 2017; Williams et al., 2018) because males tend to al., 2006; Dettmer, Novak, Meyer, & Suomi, 2014; be more aggressive than females (Solomon, 2017). Dettmer, Novak, Novak, Meyer, & Suomi, 2009; However, women report experiencing depressive or Dettmer, Novak, Suomi, & Meyer, 2012). Further, anxiety symptoms two times more frequently than because the hair samples reflect HPA activity over men (McLean, Asnaani, Litz, & Hofmann, 2011; the entire period that the hair has been growing Silverstein, 2002). Therefore, a rodent model that (5 weeks in the current study), variables like stage involves a primarily psychological stress and is effec- of estrous cycle and time of day are inherently tive with females might provide insights that have controlled. been missed when using the social defeat paradigm. Previous work in this lab (Jarcho et al., 2016) One alternative model has been developed has shown that female mice exposed to social insta- in which male mice either experience or witness bility experience an increase in hair corticosterone, social defeat (Warren et al., 2013). Although indicating that HPA activity is elevated in these this testing paradigm allows for the assessment animals throughout the time that they experience of strictly psychological stress (in the witnesses), social instability. However, we were unable to it still employs male subjects. Recently, a social determine whether our effects were unique to social WINTER 2018 instability paradigm was developed and found to be instability stress itself, or whether they would be PSI CHI effective at eliciting the predicted behavioral and common across other social stressors. In addition, JOURNAL OF hypothalamic-pituitary-adrenal (HPA) responses previous work by this lab was limited because we did PSYCHOLOGICAL RESEARCH COPYRIGHT 2018 BY PSI CHI, THE INTERNATIONAL HONOR SOCIETY IN PSYCHOLOGY (VOL. 23, NO. 5/ISSN 2325-7342) 377 Comparing Chronic Social Stressors | Jarcho, Avery, Kornacker, Hollingshead, and Lo not include a measure of neuronal consequences of elevated brain TNFa and IL-1bR were also observed the stressor, an important measure possibly linking in our social stress paradigms. physiological and behavioral patterns. The current Our third marker, GFAP, is an intermediate study attempted to address both of those questions filament component of astrocytes and is often used by incorporating both social instability and social as an indicator of astrocyte activity and function isolation stressors, and by quantifying mRNA (Hol & Pekny, 2015). In relation to stress, decreased concentrations in hippocampal tissue samples GFAP expression has been shown to occur in the in an attempt to elucidate the mechanisms that brains of stressed animals