Chronic unpredictable stress exacerbates surgery-induced sickness behavior and neuroinflammatory responses via glucocorticoids secretion in adult rats

Abstract

Accumulated evidence indicates that stress sensitizes neuroinflammatory responses to a subsequent peripheral immune challenge. The present study investigated whether chronic unpredictable stress (CUS) aggravated surgery-induced sickness behavior and neuroinflammatory processes via glucocorticoids secretion in the adult brain.MethodsSprague-Dawley adult male rats (12–14 weeks old) were exposed to 14-day CUS and then subjected to partial hepatectomy 24 h after the last stress session. The rats were pretreated with an antagonist of the glucocorticoids (GCs) receptor RU486 (30 mg/kg, i.p.) 1 h prior to stress exposure. The behavioral changes were evaluated with open field test and elevated plus-maze test. The hippocampal cytokines interleukin (IL)-1β and IL-6 were measured on postoperative days 1, 3 and 7. Ionized calcium binding adaptor protein (Iba)-1, microglial M2 phenotype marker Arg1, brain derived neurotrophic factor (BDNF) and CD200 were also examined at each time point.ResultsCUS exacerbated surgery-induced sickness behavior. Exposure to CUS alone failed to alter the levels of pro-inflammatory cytokines in the brain. However, CUS exaggerated surgery-induced pro-inflammatory cytokines expression (e.g. IL-1β and IL-6) and upregulated the levels of Iba-1 on postoperative days 1 and 3. An additional significant decreased BDNF, CD200 and a lower level of Arg1 were also observed in the stressed rats following surgical procedure. Pretreatment with RU486 blunted the potentiating effects of CUS on surgery-induced sickness behavior and neuroinflammatory responses.ConclusionChronic unpredictable stress enhanced surgery-induced sickness behavior and neuroinflammatory responses. Stress-induced GCs played a pivotal role in enhancing surgery-induced neuroinflammatory processes by modulation of microglia functions.

Mechanisms of Stress-Induced Spermatogenesis Impairment in Male Rats Following Unpredictable Chronic Mild Stress (uCMS)

“…Rats were treated 1 h before each stressful activity with vehicle or RU486 via subcutaneous injection at a volume of 1 mg/kg/day over a six-week uCMS exposure period. The dose of RU486 and timing prior to each experience of stress were based on two previous studies [45,46].…”

Upregulation of TREM2 Ameliorates Neuroinflammatory Responses and Improves Cognitive Deficits Triggered by Surgical Trauma in Appswe/PS1dE9 Mice

“…Our previous study revealed that surgery-induced proinflammatory cytokines in the brain of aged rats play an important role in the development of POCD [2, 7, 21]. These earlier findings suggest that neuroinflammatory response may be an important underlying mechanism for POCD.…”

“…Additionally, Rosczyk et al have demonstrated that locomotor activity is not depressed in either adult or aged mice following sham operation (minor abdominal surgery), which reveals that the decrease in locomotion is not due to minor surgical procedures [20]. It is likely that a more “major” surgery (partial hepatectomy) would induce a state of neuroinflammation that could result in sickness behavior [2, 7, 21-25]. …”

Stress and aging act through common mechanisms to elicit neuroinflammatory priming

“…For example, following a single session of inescapable tail shock stress, rats exhibit elevated hippocampal IL-1β production in response to intra-peritoneal LPS (Johnson et al, 2002; Johnson et al, 2003). Although LPS is commonly used as the immune challenge, stress also potentiates pro-inflammatory cytokine responses in the CNS following other peripheral and central immune challenges such as surgery or ischemic injury (Karelina et al, 2009; Norman et al, 2010; Wang et al, 2017; Weil et al, 2008). Potentiated neuroinflammatory responses follow a diverse array of stressors including chronic variable stress (de Pablos et al, 2014; Espinosa-Oliva et al, 2011; Yue et al, 2017), social defeat (Wohleb et al, 2012), stress from shipping/travel (Holder and Blaustein, 2017), social isolation (Gaudier-Diaz et al, 2017), chronic sleep restriction (Bellesi et al, 2017), and inescapable tail shock (Frank et al, 2007; Johnson et al, 2002) suggesting that neuroinflammatory priming may be a conserved feature of the stress response.…”