Neuroendocrine and Immunocytochemical Demonstrations of Decreased Hypothalamo-Pituitary-Adrenal Axis Responsiveness to Restraint Stress after Long-Term Social Isolation¹

Abstract

We have studied the effects of long-term social isolation of male Wistar rats, after early weaning (16 days), on the activity of the hypothalamo-pituitary-adrenal (HPA) axis. In addition to studying basal HPA activity, the response of the HPA axis to 15 min of immobilization stress was examined. Plasma corticosterone concentrations were measured, and the relative weights of adrenal glands, thymus, and testes were obtained, the latter to check whether gonadal function was affected by the isolation paradigm. Moreover, we carried out a quantitative immunohistochemical study of pituitary ACTH and its hypothalamic secretagogues: CRF, arginine vasopressin (AVP), and oxytocin (OT), both at the level of the synthesizing cell bodies in the hypothalamic paraventricular nucleus and of the releasing fibers in the median eminence (ME). Body weight and daily consumption of food and water were not altered, but social isolation caused a reduction in plasma corticosterone levels, both under basal and stress-stimulated conditions; this was correlated with an increased thymus weight, without affecting adrenal or testicular weights. The immunohistochemical study revealed that isolation caused a smaller increase in the number of ACTH-immunoreactive cells in the pars distalis of the anterior pituitary after exposure to restraint stress, as compared with control animals. This result indicates that fewer corticotrophs were activated by restraint stress in isolated animals, such cells being smaller and exhibiting a smaller ACTH-immunoreactive area than in control animals. Isolated animals also showed an increase in the content of CRF-ir fibers in the ME and a smaller decrease in the neuropeptide immunoreactivity after stress than that observed in control animals. This result could indicate a reduced release of CRF into the portal vasculature in response to acute stress and may partially explain the reduced activation of corticotrophs observed in the pituitary of isolated animals. However, no changes were found in the content of CRF, AVP, or OT within the paraventricular nucleus, nor of the AVP or OT content in the ME. The results of this study show that long-term social isolation after early weaning caused a hypofunction of the HPA axis in the adult rat. This hypofunction was particularly evident after exposure to an acute stressor, suggesting a desensitization of this axis to stressful stimuli.

Social Isolation in Adolescence Disrupts Cortical Development and Goal-Dependent Decision-Making in Adulthood, Despite Social Reintegration

“…Temporarily high CORT concentrations occupy low-affinity GRs and high-affinity MRs, coordinating high rates of cortical dendritic spine turnover and pruning during adolescence (Liston and Gan, 2011). We found that social isolation caused CORT insufficiency early in the wake cycle, when levels should be high (see also Sánchez et al, 1998), and concurrently, previously isolated adult mice retained adolescent-like spine densities. Further, PSD95, a marker of mature synapses, was elevated, suggesting that overabundant spines contained functional synapses (Berry and Nedivi, 2017).…”

Prolonged Social Isolation, Started Early in Life, Impairs Cognitive Abilities in Rats Depending on Sex

“…The scientific literature concerning the changes in rat basal blood CORT level (without additional acute stress) under early social isolation for considerably shorter periods includes controversial data. A reduction in the basal blood CORT concentration was reported after 8-week and 6-week social isolation in male Wistar rats [36,40]. Thirteen-day social isolation in male and female Sprague Dawley rats also caused a decline in the blood CORT level [29].…”

“…However, this approach does not always allow one to determine the effect of social isolation [32]. In a previous study [40], social isolation stress decreased plasma CORT concentration, the subsequent acute restraint stress increased blood CORT levels in both group-housed and socially isolated rats. However, CORT concentration remained diminished in the single-housed rats when compared with the group-housed animals.…”

“…Adrenal glands (the adrenal cortex) secrete CORT into the blood and regulate basal and functional hormonal levels [101]. The changes in their relative weight in socially isolated rats are sex-dependent: In male rats, there were no differences in adrenal gland weights (after 5, 6, and 8 weeks of social isolation in Wistar and Sprague Dawley rat lines) [36][37][38][39][40], while in females, the weights of the adrenal glands increased (13 and 14 weeks of social isolation in hooded and Wistar rats) [35,37]. Our results are in good agreement with these data.…”

Does stress exacerbate liver diseases?

“…In contrast to the previously mentioned HPA axis activation by stressful stimuli, evidence of stress‐induced HPA axis hyporesponsiveness has been observed in several rodent strains and certain human diseases 50–55 . Interestingly, rats with chronic cholestatic liver injury displayed reduced HPA axis responsiveness to ether stress 56 .…”