An Animal Model of a Behavioral Intervention for Depression

Abstract

Although conditioned inhibition of fear (or learned safety) is a learning process critical for preventing chronic stress, a predisposing factor for depression and other psychopathologies, little is known about its functional purposes or molecular mechanisms. To obtain better insight into learned safety, we investigated its behavioral and molecular characteristics and found that it acts as a behavioral antidepressant in two animal models. Learned safety promotes the survival of newborn cells in the dentate gyrus of the hippocampus, while its antidepressant effect is abolished in mice with ablated hippocampal neurogenesis. Learned safety also increases the expression of BDNF in the hippocampus and leads to downregulation of genes involved in the dopaminergic and neuropeptidergic but not the serotonergic system in the basolateral amygdala. These data suggest that learned safety is an animal model of a behavioral antidepressant that shares some neuronal hallmarks of pharmacological antidepressants but is mediated by different molecular pathways.

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

“…Safety learning was tested using an explicitly unpaired training procedure previously described for mice (Pollak et al, 2008;Rogan et al, 2005). Unpaired training took place after a 60-to 80-s acclimation period in Cxt A (as above) over three daily sessions.…”

“…Successful CS safety learning was probed using two tests: conditioned inhibition of contextual fear and retarded acquisition of new fear learning (Pollak et al, 2008;Rogan et al, 2005). One day after the final training session, conditioned inhibition was tested by measuring freezing in Cxt A during a 60-s baseline followed by a 20-s CS presentation (Pollak et al, 2008).…”

“…One day after the final training session, conditioned inhibition was tested by measuring freezing in Cxt A during a 60-s baseline followed by a 20-s CS presentation (Pollak et al, 2008). Conditioned inhibition was expressed as the reduction in freezing during the 20-s CS relative to the 20 s before the CS.…”

“…Fear retardation was expressed as the decrease in freezing to the CS in the 'safety' group relative to the previously naive fear group. Since fear retardation can be overcome by additional training (Pollak et al, 2008;Rescorla, 1969), we conducted a second round of explicitly paired training and testing. The effects of strain and training-type (unpaired vs paired) on retardation were analyzed using two-factor ANOVA.…”

Learning not to Fear: Neural Correlates of Learned Safety

“…Learned safety and learned fear are opposite associative processes that are important for survival and well-being (Pollak et al, 2008(Pollak et al, , 2010b. In humans, pathological forms of learned fear are hallmarks of severe psychopathologies, such as anxiety disorders, post-traumatic stress disorders (PTSD), and depression (Pollak et al, 2008).…”