Stressful experiences induce the release of stress hormones, such as glucocorticoids, which is important for memory consolidation, but can come at the cost of losing memory specificity. Sylvie Lesuis and her colleagues demonstrate that mice that receive corticosterone treatment immediately after contextual fear conditioning show a fear response in an novel environment where the mice never had an aversive experience. As it is known that contextual fear memories are encoded by sparsely distributed neurons in the hippocampal dentate gyrus (DG) that become activated during learning (Rao-Ruiz et al., 2019), so called engram cells, they next determined whether corticosterone affects the formation of an engram cell population.

Although fear conditioning reduces the excitability of learning-activated DG neurons, corticosterone selectively increases the excitability of these cells. This is accompanied by a stable increase in the size of the engram cell population and these cells become reactivated when mice are exposed to a neutral context, suggesting that this drives the generalized fear response after elevated corticosterone levels. To confirm this, Michel van den Oever and colleagues used a viral-TRAP approach to express an inhibitory DREADD selectively in the corticosterone-enhanced engram cell population. Chemogenetic suppression of these specific neurons abolished the generalized fear response when mice were exposed to the novel environment.

These findings give insight into the cellular substrate of reduced memory specificity induced by glucocorticoids, which is relevant for our understanding of disorders that are characterized by generalized fear, such as post-traumatic stress disorder and anxiety disorders.
 
Read the publication in Biological Psychiatry: Glucocorticoids promote fear generalization by increasing the size of a dentate gyrus engram cell population

Source: Center for Neurogenomics and Cognitive Research
Image: Osamu Shimomura and Jeff Lichtman, Harvard University