Reduced Orexin System Function Contributes to Resilience to Repeated Social Stress

Abstract

Exposure to stress increases the risk of developing affective disorders such as depression and post-traumatic stress disorder (PTSD). However, these disorders occur in only a subset of individuals, those that are more vulnerable to the effects of stress, whereas others remain resilient. The coping style adopted to deal with the stressor, either passive or active coping, is related to vulnerability or resilience, respectively. Important neural substrates that mediate responses to a stressor are the orexins. These neuropeptides are altered in the cerebrospinal fluid of patients with stress-related illnesses such as depression and PTSD. The present experiments used a rodent social defeat model that generates actively coping rats and passively coping rats, which we have previously shown exhibit resilient and vulnerable profiles, respectively, to examine if orexins play a role in these stress-induced phenotypes. In situ radiolabeling and qPCR revealed that actively coping rats expressed significantly lower prepro-orexin mRNA compared with passively coping rats. This led to the hypothesis that lower levels of orexins contribute to resilience to repeated social stress. To test this hypothesis, rats first underwent 5 d of social defeat to establish active and passive coping phenotypes. Then, orexin neurons were inhibited before each social defeat for three additional days using designer receptors exclusively activated by designer drugs (DREADDs). Inhibition of orexins increased social interaction behavior and decreased depressive-like behavior in the vulnerable population of rats. Indeed, these data suggest that lowering orexins promoted resilience to social defeat and may be an important target for treatment of stress-related disorders.

Passive Coping Strategies During Repeated Social Defeat Are Associated With Long-Lasting Changes in Sleep in Rats

“…Many more animals were classified as passive copers than active copers. In past work, using this analysis has yielded similar segregation of groups (Chen et al, 2015;Pearson-Leary et al, 2017, 2019Grafe et al, 2018). Moreover, three additional animals had unreadable telemeter recordings (see next section).…”

“…Data are presented as the mean ± standard error of the mean (SE). For comparison of defeat latencies between the actively coping and passively coping groups, as validated in our previous studies (Wood et al, 2010;Chen et al, 2015;Pearson-Leary et al, 2017, 2019Grafe et al, 2018), we used a Student's t-test. For analysis of all other measures, a two-way repeated-measures ANOVA (Group × Time before/during/after defeat exposure) was used followed by Tukey's post hoc ttests (GraphPad Prism; GraphPad Software, La Jolla, CA, USA).…”

“…*P < 0.05, ***P < 0.001. has concluded, the experimental rat is returned to its home cage. The average defeat latency for each rat over the course of 7 days was then calculated and entered into an R script used to perform cluster analyses on average defeat latencies (code available at www.github.com/cookpa/socialdefeat) as described in Grafe et al (2018). Briefly, the bootstrap classification starts from the assumption that the average latencies are drawn from a bi-modal distribution.…”

Involvement of orexin/hypocretin in the expression of social play behaviour in juvenile rats

“…The ORX system has previously been associated with natural variation in the expression of other behaviours. For example, in adult male rodents, individual differences in extinction of conditioned fear responses (Sharko, Fadel, Kaigler, & Wilson, 2017), motivation for cocaine (Pantazis, James, Bentzley, & Aston-Jones, 2019), intrinsic spontaneous physical activity (Perez-Leighton, Boland, Billington, & Kotz, 2013), and resiliency/susceptibility in social defeat paradigms (Chung, Kim, Kim, Kim, & Yoon, 2014;Grafe, Eacret, Dobkin, & Bhatnagar, 2018) have all been associated with differences in the activation or organization of ORX system. Additionally, central administration of ORX-A reduced preference for a receptive female in sexually high-motivated but not sexually lowmotivated adult male rats (Bai, et al, 2009).…”

Psychological Adjustment and Quality of Life in Patients With Bone Tumor

“…В настоящее время проблеме психической адаптации придается особое значение в связи с возрождением интереса к теории стресса [1][2][3][4]. Изучение психической адаптации человека с позиций современной клинической психологии предполагает рассмотрение ее как сложной динамической функциональной системы, включающей биологический, психологический и социальный уровни и направленной на поддержание устойчивого взаимодействия индивида с окружающей средой, как системный процесс активного приспособления психики человека к условиям окружающей его физической и социальной среды, а также результат этого процесса [5][6][7][8].…”