Glutamatergic stimulation of the left dentate gyrus abolishes depressive-like behaviors in a rat learned helplessness paradigm

Abstract

BackgroundEpisodic experiences of stress have been identified as the leading cause of major depressive disorder (MDD). The occurrence of MDD is profoundly influenced by the individual’s coping strategy, rather than the severity of the stress itself. Resting brain activity has been shown to alter in several mental disorders. However, the functional relationship between resting brain activity and coping strategies has not yet been studied. In the present study, we observed different patterns of resting brain activity in rats that had determined either positive (resilient to stress) or negative (vulnerable to stress) coping strategies, and examined whether modulation of the preset resting brain activity could influence the behavioral phenotype associated with negative coping strategy (i.e., depressive-like behaviors). MethodsWe used a learned helplessness paradigm—a well-established model of MDD—to detect coping strategies. Differences in resting state brain activity between animals with positive and negative coping strategies were assessed using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glutamatergic stimulation was used to modulate resting brain activity. ResultsAfter exposure to repeated uncontrollable stress, seven of 23 rats exhibited positive coping strategies, while eight of 23 rats exhibited negative coping strategies. Increased resting brain activity was observed only in the left ventral dentate gyrus of the positive coping rats using FDG-PET. Furthermore, glutamatergic stimulation of the left dentate gyrus abolished depressive-like behaviors in rats with negative coping strategies. ConclusionIncreased resting brain activity in the left ventral dentate gyrus helps animals to select positive coping strategies in response to future stress.