The bed nucleus of the stria terminalis (BNST) is a forebrain region implicated in aversive responses to uncertain threat. Much of the work on the role of BNST in defensive behavior has used Pavlovian paradigms in which the subject reacts to aversive stimuli delivered in a pattern determined entirely by the experimenter. Here, we report that BNST also mediates proactive defensive responses in a task that allows subjects to prevent the delivery of an aversive outcome. In a standard two-way signaled active avoidance paradigm, male rats learned to shuttle during a tone to avoid shock. Our data demonstrate that chemogenetic inhibition (hM4Di) of BNST attenuates the expression of the avoidance response, whereas chemogenetic activation (hM3Dq) of BNST potentiates the response by extending the period of tone-evoked shuttling. This effect was specific to the BNST, as inactivation of the neighboring medial septum produced no effect on the expression of avoidance. These data support the novel conclusion that BNST mediates two-way avoidance behavior in male rats..

The bed nucleus of the stria terminalis (BNST) is a forebrain region implicated in aversive responses to uncertain threat. Much of the work on the role of BNST in defensive behavior has used Pavlovian paradigms in which the subject reacts to aversive stimuli delivered in a pattern determined entirely by the experimenter. Here, we report that BNST also mediates proactive defensive responses in a task that allows subjects to prevent the delivery of an aversive outcome. In a standard two-way signaled active avoidance paradigm, male rats learned to shuttle during a tone to avoid shock. Our data demonstrate that chemogenetic inhibition (hM4Di) of BNST attenuates the expression of the avoidance response, whereas chemogenetic activation (hM3Dq) of BNST potentiates the response by extending the period of tone-evoked shuttling. This effect was specific to the BNST, as inactivation of the neighboring medial septum produced no effect on the expression of avoidance. These data support the novel conclusion that BNST mediates two-way avoidance behavior in male rats.

Preclinical quantitative models of cognitive performance are necessary for translation from basic research to clinical studies. In rodents, non-cognitive factors are a potential influence on testing outcome and high variability in behavior requires multiple time point testing for better assessment of performance in more sophisticated tests. Thus, these models have limited translational value as most human cognitive tests characterize cognition using single digit scales to distinguish between impaired and unimpaired function. To address these limitations, we developed a cognitive index for learning based on previously described scores for strategies used by mice to escape the Barnes maze. We compared the cognitive index and circadian patterns of light-dark entrainment in young (4–6 months), middle-aged (13–14 months), and aged (18–24 months) mice as cognitive changes during aging are often accompanied by pronounced changes in sleep-wake cycle. Following continuous analysis of circadian wheel-running activity (30–40 days), the same cohorts of mice were tested in the Barnes maze. Aged mice showed significant deficits in the learning and memory portions of the Barnes maze relative to young and middle-aged animals, and the cognitive index was positively correlated to the memory portion of the task (probe) in all groups. Significant age-related alterations in circadian entrainment of the activity rhythm were observed in the middle-aged and aged cohorts. In middle-aged mice, the delayed phase angle of entrainment and increased variability in the daily onsets of activity preceded learning and memory deficits observed in aged animals. Interestingly, learning-impaired mice were distinguished by a positive relationship between the extent of Barnes-related cognitive impairment and variability in daily onsets of circadian activity. While it is unclear whether changes in the sleep-wake cycle or other circadian rhythms play a role in cognitive impairment during aging, our results suggest that circadian rhythm perturbations or misalignment may nevertheless provide an early predictor of age-related cognitive decline.