Evolution of brain-wide activity in the awake behaving mouse after acute fear by longitudinal manganese-enhanced MRI

Life threatening fear after a single exposure evolves in a subset of vulnerable individuals to anxiety, which may persist for their lifetime. Yet neither the whole brain9s response to innate acute fear nor how brain activity evolves over time is known. Sustained neuronal activity may be a factor in the development of anxiety. We couple two experimental protocols to obtain a fear response leading to anxiety. Predator stress (PS) is a naturalistic approach that induces fear in rodents; and the serotonin transporter knockout (SERT-KO) mouse responds to PS with sustained defensive behavior. Behavior was monitored before, during and at short and long times after PS in WT and SERT-KO mice. Both genotypes responded to PS with defensive behavior, and SERT-KO retained defensive behavior for 23 days, while wild type (WT) mice return to baseline exploratory behavior by 9 days. Thus, differences in neural activity between WT and SERT-KO at 9 days after PS will identify neural correlates of persistent defensive behavior. We used longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) to identify brain-wide neural activity between behavioral sessions. Mn2+ accumulation in active neurons occurs in awake behaving mice and is retrospectively imaged. To confirm expected effects of PS, behavior was monitored throughout. Following the same two cohorts of mice, WT and SERT-KO, longitudinally allowed unbiased quantitative comparisons of brain-wide activity by statistical parametric mapping (SPM). During natural behavior in WT, only low levels of activity-induced Mn2+-accumulation were detected, while much more accumulation appeared immediately after PS in both WT and SERT-KO, and evolved at 9 days to a new activity pattern at p