Background Coping strategy impacts susceptibility to psychosocial stress. The locus coeruleus (LC) and dorsal raphe (DR) are monoamine nuclei that are implicated in stress-related disorders. This study was designed to identify genes in these nuclei that distinguish active and passive coping strategies in response to social stress. Methods Rats were exposed to repeated resident-intruder stress and coping strategy determined. Gene and protein expression in the LC and DR were determined by PCR array, ELISA, and compared between active and passive stress coping and unstressed rats. The effect of daily IL-1 receptor antagonist (IL-1ra, ICV) prior to stress on anhedonia was also determined. Results Rats exhibited passive or active coping strategies based on a short (SL) or longer latency (LL) to assume a defeat posture, respectively. Stress differentially regulated 19 and 26 genes in the LC and DR of SL and LL rats, respectively, many of which encoded for inflammatory factors. Notably, IL1β was increased in SL and decreased in LL rats in both the LC and DR. Protein changes were generally consistent with a proinflammatory response to stress in SL rats selectively. Stress produced anhedonia selectively in SL rats and this was prevented by IL-1ra, consistent with a role for IL1β in stress vulnerability. Conclusions This study highlighted distinctions in gene expression related to coping strategy in response to social stress. Passive coping was associated with a bias towards pro-inflammatory processes, particularly IL1β, whereas active coping and resistance to stress-related pathology was associated with suppression of inflammatory processes.

Social stress is a risk factor for psychiatric disorders, however only a subset of the population is susceptible while others remain resilient. Inflammation has been linked to the pathogenesis of psychosocial disorders in humans and may underlie these individual differences. Using a resident-intruder paradigm capable of revealing individual differences in coping behavior and inflammatory responses, the present study determined if resveratrol (RSV; 0, 10, 30mg/kg/day) protected against persistent stress-induced inflammation in socially defeated rats. Furthermore, the antidepressant efficacy of RSV was evaluated using the sucrose preference test. Active coping rats were characterized by more time spent in upright postures and increased defeat latencies versus passive coping rats. Five days after defeat, flow cytometry revealed enhanced stimulation of inflammatory proteins (IL-β, TNF-α) in spleen cells of passive rats as compared to active coping and controls, an effect that was blocked by both doses of RSV. Furthermore, only passive coping rats exhibited increased proinflammatory proteins (IL-1β, TNF-α, GM-CSF) in the locus coeruleus (LC), a noradrenergic brain region implicated in depression. Notably, only 30mg/kg RSV blocked LC neuroinflammation and importantly, was the only dose that blocked anhedonia. Alternatively, while stress had minimal impact on resting cytokines in the dorsal raphe (DR), RSV dose-dependently reduced DR cytokine expression. However, this did not result in changes in indoleamine 2,3-dioxygenase activity or serotonin levels. Taken together, these data suggest that social stress-induced depressive-like behavior evident in passive coping rats may be driven by stress-induced neuroinflammation and highlight natural anti-inflammatory agents to protect against social stress-related consequences.

Repeated exposure to social stress can precipitate the development of psychosocial disorders including depression and comorbid cardiovascular disease. While a major component of social stress often encompasses physical interactions, purely psychological stressors (i.e. witnessing a traumatic event) also fall under the scope of social stress. The current study determined whether the acute stress response and susceptibility to stress-related consequences differed based on whether the stressor consisted of physical versus purely psychological social stress. Using a modified resident-intruder paradigm, male rats were either directly exposed to repeated social defeat stress (intruder) or witnessed a male rat being defeated. Cardiovascular parameters, behavioral anhedonia, and inflammatory cytokines in plasma and the stress-sensitive locus coeruleus were compared between intruder, witness, and control rats. Surprisingly intruders and witnesses exhibited nearly identical increases in mean arterial pressure and heart rate during acute and repeated stress exposures, yet only intruders exhibited stress-induced arrhythmias. Furthermore, re-exposure to the stress environment in the absence of the resident produced robust pressor and tachycardic responses in both stress conditions indicating the robust and enduring nature of social stress. In contrast, the long-term consequences of these stressors were distinct. Intruders were characterized by enhanced inflammatory sensitivity in plasma, while witnesses were characterized by the emergence of depressive-like anhedonia, transient increases in systolic blood pressure and plasma levels of tissue inhibitor of metalloproteinase. The current study highlights that while the acute cardiovascular responses to stress were identical between intruders and witnesses, these stressors produced distinct differences in the enduring consequences to stress, suggesting that witness stress may be more likely to produce long-term cardiovascular dysfunction and comorbid behavioral anhedonia while exposure to physical stressors may bias the system towards sensitivity to inflammatory disorders.

Together these data suggest that ovarian hormones play a critical role in the behavioral, inflammatory, and cardiovascular susceptibility to social stress in female rats and reveal putative systems that are sensitized to stress in an ovarian hormone-dependent manner.

Psychosocial stress precipitates psychiatric disorders and cardiovascular disease in vulnerable individuals. The locus coeruleus (LC), a major source of norepinephrine in the brain is implicated in depressive disorders and indirectly increases sympathetic activity. We previously identified two distinct phenotypic responses to social defeat (SD) in rats, characterized by either passive coping (PC, submissive postures) or active coping (AC, upright postures, resistance to defeat). PC was associated with endocrine and behavioral adaptations resembling depression and enhanced inflammation and decreased heart rate variability indicating greater cardiovascular disease risk. Using cardiac telemetry the present study investigated the impact of DSP4 (400ug/rat, icv), a noradrenergic neurotoxin that selectively lesions the LC, compared with vehicle on the cardiovascular response to SD or control manipulations (30 min/day, 7 days) and persistent changes in resting cardiovascular parameters in PC and AC rats. Blood pressure and heart rate significantly increased in AC and PC rats during SD vs controls (day 1). This cardiovascular response to SD was reduced by day 7 in the AC rats, but not PC rats. Interestingly, DSP4 treatment decreased the SD‐induced pressor response in the PC rats. Furthermore, 24 hr telemetry indicated a significant pressor response in PC vs AC rats that persisted for at least 5 days after the 7th and final defeat. Chronic elevations in blood pressure evident in PC rats were also blocked by DSP4 treatment. These data implicate a role for the LC in the enhanced cardiovascular susceptibility evident following social stress in passive coping individuals. Supported by 13BGIA14370026

Psychosocial stress is linked to psychiatric disorders such as depression. Using a social stressor in rats (resident‐intruder model) we previously identified two phenotypic responses to social stress. One population (45%) exhibited a passive coping response and assumed a defeat posture within a short latency (SL, <300s). The other phenotype (55%) exhibited proactive coping behaviors and a longer defeat latency (LL, >300s). Furthermore, SL rats developed endocrine and behavioral characteristics resembling depression, while the LL phenotype remains resilient. As the locus coeruleus (LC) is a stress‐sensitive brain region that is implicated in the stress coping response, it may mediate individual differences in the response to social stress and resulting pathology. Therefore the present study utilized the neurotoxin DSP‐4 to selectively lesion the noradrenergic LC prior to social stress. DSP‐4 treated rats exhibited decreased active coping behaviors upon the first exposure to social stress (upright posture: veh; 124±40, DSP‐4; 56±42). Furthermore, 5 days after the 5th exposure to social stress, DSP‐4 rats exhibited a reduction in sucrose intake compare with controls (Con: 84%, Veh: 80%, DSP‐4, 72%). These data suggest that lesioning the LC shifted rats towards a passive coping response and increase anhedonic behaviors. Therefore, the LC may mediate a protective effect over consequences of social stress. Grant Funding Source: Supported by NARSAD 17830 and 13BGIA 14370026

Women are more than twice as likely to suffer from depression and anxiety compared with men. This enhanced susceptibility begins at puberty and ends at menopause suggesting that cycling ovarian hormones are likely a contributing factor to this phenomenon. However, the mechanism by which ovarian hormones contribute to this enhanced susceptibility to stress remains unknown. Using a modified social defeat model in which a female repeatedly bears witness to an aggressive social defeat encounter, we have previously shown that cycling females exhibit anxiety‐like burying and depressive‐like anhedonia that was associated with enhanced peripheral inflammatory sensitivity. Furthermore, witness stress in intact females produced enhanced expression of high mobility group box 1 (HMGB‐1), a marker of neuroinflammatory priming, within the central amygdala (CeA). Increased HMGB‐1 expression suggests that exposure to a subsequent stressor would result in a faster and greater neuroinflammatory response and likely a sensitized behavioral response. Importantly, these behavioral and inflammatory consequences were attenuated or absent in ovariectomized (OVX) females, suggesting that the presence of ovarian hormones are critical in these stress‐induced effects. The current studies build upon these initial findings to further implicate neuroinflammatory priming, and HMGB‐1 as a putative target to reduce susceptibility.METHODSStudy 1 evaluated the effect of a history of witness stress on the behavioral and neuroinflammatory response to the Porsolt forced swim test (FST) in intact and OVX females. Study 2 evaluated whether treatment with an HMGB‐1 antagonist could inhibit the emergence of anxiety‐ and depressive‐like behaviors and neuroinflammation induced by witness stress in intact females. Finally, study 3 determined the involvement of estrogen in these processes by comparing anxiety‐like burying, depressive‐like anhedonia, cytokine and HMGB‐1 levels in OVX females that received 17β‐estradiol (17β‐E) or placebo replacement.RESULTSFindings from these studies indicated that 1) a previous history of witness stress produced behavioral sensitization in intact females as evidence by enhanced behavioral despair in the FST, 2) administration of the HMGB‐1 antagonist was unable to block the emergence of anxiety‐ and depressive‐like behaviors, and 3) constant levels of 17β‐E selectively contributed to the anxiety‐like behaviors evoked by witness stress. Findings from study 3 further indicated that witness stress evoked HMGB‐1 was directly dependent upon the presence of 17β‐E. Cytokine data are still being evaluated; however, it is expected that exposure to a novel stressor will produce sensitization of CeA inflammation and that this priming can be blocked by the HMGB‐1 antagonist. While the current studies suggest that CeA neuroinflammatory priming may be a putative ovarian hormone dependent mechanism associated with stress susceptibility in intact females, targeting this neuroinflammation globally using an HMBG‐1 inhibitor does not provide therapeutic benefit for the behavioral effects of psychosocial stress.Support or Funding Information17PRE33670106 NARSAD26809 15SDG22430017 I21BX002085 1101BX001374This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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