Chronic unpredictable stress during adolescence protects against adult traumatic brain injury-induced affective and cognitive deficits

Abstract

Pre-clinical early-life stress paradigms model early adverse events in humans. However, the long-term behavioral consequences of early-life adversities after traumatic brain injury (TBI) in adults have not been examined. In addition, endocannabinoids may protect against TBI neuropathology. Hence, the current study assessed the effects of adverse stress during adolescence on emotional and cognitive performance in rats sustaining a TBI as adults, and how cannabinoid receptor 1 (CB1) activation impacts the outcome. On postnatal days (PND) 30-60, adolescent male rats were exposed to four weeks of chronic unpredictable stress (CUS), followed by four weeks of no stress (PND 60-90), or no stress at any time (Control), and then anesthetized and provided a cortical impact of moderate severity (2.8 mm tissue deformation at 4 m/s) or sham injury. TBI and Sham rats (CUS and Control) were administered either arachidonyl-2'-chloroethylamide (ACEA; 1 mg/kg, i.p.), a CB1 receptor agonist, or vehicle (VEH; 1 mL/kg, i.p.) immediately after surgery and once daily for 7 days. Anxiety-like behavior was assessed in an open field test (OFT) and learning and memory in novel object recognition (NOR) and Morris water maze (MWM) tasks. No differences were revealed among the Sham groups in any behavioral assessment and thus the groups were pooled. In the ACEA and VEH-treated TBI groups, CUS increased exploration in the OFT, enhanced NOR focus, and decreased the time to reach the escape platform in the MWM, suggesting decreased anxiety and enhanced learning and memory relative to the Control group receiving VEH (p < 0.05). ACEA also enhanced NOR and MWM performance in the Control + TBI group (p < 0.05). These data suggest that 4 weeks of CUS provided during adolescence may provide protection against TBI acquired during adulthood and/or induce adaptive behavioral responses. Moreover, CB1 receptor agonism produces benefits after TBI independent of CUS protection.

Keywords: Cannabinoid receptor 1 (CB1); Chronic unpredictable stress (CUS); Controlled cortical impact (CCI); Early life stress (ELS); Endocannabinoids; Traumatic brain injury (TBI).

Fig. 1

AB. Mean (± S.E.M.) body weight recorded at baseline (before any manipulations) and once weekly to evaluate the effect of stress on weight gain and to monitor recovery after Sham injury (A) or TBI (B). For panel A, *p<0.05 vs. Control + Sham + VEH and Control + Sham + ACEA. For panel B, *p<0.05 vs. Control + TBI + VEH and Control + TBI + ACEA. No other comparisons were significant.

Fig. 2.

Mean (± S.E.M.) percent-time spent in the center zone in the open-field test. *p<0.05 vs. Control + TBI + VEH, Control + TBI + ACEA, and SHAM. There was no difference between the CUS + TBI + VEH and CUS + TBI + ACEA groups (p>0.05). The Control groups, regardless of treatment (VEH or ACEA) did not differ from SHAM (p>0.05). No other comparisons were significant.

Fig. 3.

Mean (± S.E.M.) anxiety-like behavior quantified as the total time spent in the periphery vs. the center zone during a 5-min session. *^{, #}p<0.05 vs. Control + TBI + VEH. While not statistically significant, the CUS + TBI + ACEA group trended (p=0.07) toward greater improvement relative to the Control + TBI + ACEA group (65.2 ± 2.2 vs. 57.9 ± 2.2). No other comparisons were significant.

Fig. 4.

Mean (± S.E.M.) time (s) to locate a hidden and visible platform in the Morris water maze after TBI or SHAM injury. For the hidden platform assessments, *p<0.05 vs. Control + TBI + VEH and ^#p<0.05 vs. all TBI groups. The Control + TBI group treated with ACEA performed at the same level as the CUS groups. No other comparisons reached significance. No differences were observed among the groups on the visible platform assessment (p>0.05).