Chronic Hippocampal Abnormalities and Blunted HPA Axis in an Animal Model of Repeated Unpredictable Stress

Abstract

Incidence of post-traumatic stress disorder (PTSD) ranges from 3 to 30% in individuals exposed to traumatic events, with the highest prevalence in groups exposed to combat, torture, or rape. To date, only a few FDA approved drugs are available to treat PTSD, which only offer symptomatic relief and variable efficacy. There is, therefore, an urgent need to explore new concepts regarding the biological responses causing PTSD. Animal models are an appropriate platform for conducting such studies. Herein, we examined the chronic behavioral and neurobiological effects of repeated unpredictable stress (RUS) in a mouse model. 12 weeks-old C57BL/6J male mice were exposed to a 21-day RUS paradigm consisting of exposures to a predator odor (TMT) whilst under restraint, unstable social housing, inescapable footshocks and social isolation. Validity of the model was assessed by comprehensive examination of behavioral outcomes at an acute timepoint, 3 and 6 months post-RUS; and molecular profiling was also conducted on brain and plasma samples at the acute and 6 months timepoints. Stressed mice demonstrated recall of traumatic memories, passive stress coping behavior, acute anxiety, and weight gain deficits when compared to control mice. Immunoblotting of amygdala lysates showed a dysregulation in the p75NTR/ProBDNF, and glutamatergic signaling in stressed mice at the acute timepoint. At 6 months after RUS, stressed mice had lower plasma corticosterone, reduced hippocampal CA1 volume and reduced brain-derived neurotrophic factor levels. In addition, glucocorticoid regulatory protein FKBP5 was downregulated in the hypothalamus of stressed mice at the same timepoint, together implicating an impaired hypothalamus-pituitary-adrenal-axis. Our model demonstrates chronic behavioral and neurobiological outcomes consistent with those reported in human PTSD cases and thus presents a platform through which to understand the neurobiology of stress and explore new therapeutic interventions.

Neurobiological Trajectories Involving Social Isolation in PTSD: A Systematic Review

“…Total plasma [45,48,49] as well as adrenal CORT levels [46] were decreased in animals exposed to both SI and trauma compared to controls. In Cheng et al [49] corticosterone levels were higher if compared to neonatally isolated (NI) animals with no stress exposure, but lower compared to the levels of animals exposed only to SPS and not neonatal isolation (NI).…”

“…Lower plasma corticosterone levels six months after RUS was associated with a two-fold increase of proinflammatory cytokines IL-1β and IFN-γ in socially isolated animals of the Algamal et al study [45].…”

“…Eight studies concerned animal research and two investigated human subjects. Four out of the eight animal studies [42][43][44][45] used mice as experimental subjects and four studies [46][47][48][49] used rats, divided in socially isolated (experimental) and group-housed animals (controls). Face-validity [33,50] was established in all animal studies, since they phenomenologically resembled the human setting of PTSD with inescapable electric foot shock serving as the most common traumatic experience (male intruder, predator odor, restraint, and forced swimming were, moreover, used in parallel or independently).…”

“…Construct validity [33,50] was served in terms of the effort to identify common underlying mechanisms with the human disorder, whereas predictive validity [33,50] was present in three of the animal studies [42,44,47] in terms of providing predictions concerning therapeutic responses and novel pharmacological targets. Hippocampal and amygdala involvement was investigated in seven of the studies [42,43,[45][46][47][48][49], the role of the HPA-axis and its products in four studies [45,46,48,49], while the endocannabinoid system in three [44,47,48]. The immune profile of stressed animals and upregulation of proinflammatory cytokines was examined in one of the studies [45].…”

“…Hippocampal and amygdala involvement was investigated in seven of the studies [42,43,[45][46][47][48][49], the role of the HPA-axis and its products in four studies [45,46,48,49], while the endocannabinoid system in three [44,47,48]. The immune profile of stressed animals and upregulation of proinflammatory cytokines was examined in one of the studies [45]. In the two human longitudinal studies conducted by the same research group [51,52], the telomere length of prisoners of war with PTSD was examined 42 years (T 2 ) after war captivity (T 0 ) with an intermediate survey of perceived social isolation (T 1 ) 18 years after trauma occurrence.…”