Stress-induced alterations in anxiety-like behavior and adaptations in plasticity in the bed nucleus of the stria terminalis

Abstract

In vulnerable individuals, exposure to stressors can result in chronic disorders such as generalized anxiety disorder (GAD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). The extended amygdala is critically implicated in mediating acute and chronic stress responsivity and anxiety-like behaviors. The bed nucleus of the stria terminalis (BNST), a subregion of the extended amygdala, serves as a relay of corticolimbic information to the paraventricular nucleus of the hypothalamus (PVN) to directly influence the stress response. To investigate the influence of the corticosteroid milieu and housing conditions on BNST function, adult C57Bl/6J were either acutely or chronically administered corticosterone (CORT, 25mg/kg in sesame oil) or vehicle (sesame oil) or were group housed or socially isolated for 1 day (acute) or 6-8 weeks (chronic). To ascertain whether these stressors could influence anxiety-like behavior, studies were performed using the novel open-field (NOF) and the elevated zero maze (EZM) tests. To investigate potential associated changes in plasticity, alterations in BNST function were assessed using ex vivo extracellular field potential recordings in the (dorsal-lateral) dlBNST and a high frequency stimulus protocol to induce long-term potentiation (LTP). Our results suggest that chronic CORT injections and chronic social isolation housing conditions lead to an increase in anxiety-like behavior on the EZM and NOF. Chronically stressed mice also displayed a parallel blunting of LTP in the dlBNST. Conversely, acute social isolation housing had no effect on anxiety-like behavior but still resulted in a blunting of LTP in the dlBNST. Collectively, our results suggest acute and chronic stressors can have a distinct profile on plasticity in the BNST that is not uniformly associated with an increase in anxiety-like behavior.

Figure 1. Anxiety-like Behavior is decreased in chronic corticosterone treated mice

A. Time spent on the open arm of the EZM (seconds). All mice were tested 20–24 hours after the final injection of vehicle or CORT. Chronic CORT treated mice spent significantly less time in the open arm of the EZM compared to all other groups (n=9–12 per group), *p<0.05. Data are represented as mean ± SEM. B. Number of open arm entries on the EZM. No significant differences were found on number of open arm entries. (n=9–12 per group). Data are represented as mean ± SEM. C. Time spent in the center zone of the NOF. All mice were tested 20–24 hours after the final injection of vehicle or CORT. Chronic CORT treated mice spent significantly less time in the center zone compared to acute vehicle treated mice (n=9–12 per group), *p<0.05. Data are represented as mean ± SEM. D. Distance Traveled on the NOF. No differences were found in the distance traveled on the NOF. (n=9–12 per group). Data are represented as mean ± SEM.

Figure 2. Anxiety-like Behavior is decreased in chronically socially isolated mice compared to group housed mice

A. Time spent on the open arm of the EZM (seconds). All mice were tested after being group housed or socially isolated for 24 hours or 5–6 weeks. Chronic socially isolated mice spent significantly less time in the open arm of the EZM compared to group housed mice (n=7–13 per group), *p<0.05. Data are represented as mean ± SEM. B. Number of open arm entries on the EZM. No significant differences were found on number of open arm entries. (n=7–13 per group). Data are represented as mean ± SEM. C. Time spent in the center zone of the NOF. Chronic socially isolated mice spent significantly less time in the center zone of the NOF compared to group housed mice (n=7–13 per group), *p<0.05. Data are represented as mean ± SEM. D. Distance Traveled on the NOF. No differences were found in the distance traveled on the NOF. (n=7–13 per group). Data are represented as mean ± SEM.

Figure 3. Chronic Corticosterone group displays blunted LTP in the dlBNST

A. 0–5 minutes after administering tetanus, N2 amplitude was significantly blunted in the chronic CORT group compared to chronic vehicle and acute CORT. B. 55–60 minutes after administering tetanus, N2 amplitude was lower in the chronic CORT group compared to acute vehicle and acute CORT groups. C. Representative traces from: i) acute vehicle, ii) acute CORT, iii) chronic vehicle, and iv) chronic CORT. D. ▴ Time of tetanus [two trains (20 sec interstimulus interval); 100 Hz, 1 sec]. Inset) Input [stimulation intensity(v)] – Output [Amplitude of N2 (mV)] curves taken at start of each experiment.

Figure 4. Socially isolated mice display blunted LTP in the dlBNST compared to group housed mice

A. 0–5 minutes after administering tetanus, there was no significant difference in N2 amplitude in any group. B. 55–60 minutes after administering tetanus, N2 amplitude was lower in the isolated compared to group housed mice. C. Representative traces from: i) acute (1 Day) socially isolated, ii) chronic (6–8 weeks) socially isolated, and iii) group housed. D. ▴ Time of tetanus [two trains (20 sec interstimulus interval); 100 Hz, 1 sec]. Inset) Input [stimulation intensity(v)] – Output [Amplitude of N2 (mV)] curves taken at start of each experiment.