A collaborative study by members of the Memory Circuits team together with the lab of Harm Krugers and Sylvie Lesuis (UvA) reveals that elevated levels of the stress hormone corticosterone induce an increase in the size of a hippocampal fear engram and this change underlies generalized expression of fear in a neutral environment. Their findings were published in Biological Psychiatry.
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. Lesuis et al. 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, 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.
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