| Abstract: | In pathological or artificial conditions, memory can be formed as silenced engrams that are unavailable for retrieval by presenting conditioned stimuli but can be artificially switched into the latent state so that natural recall is allowed. However, it remains unclear whether such different states of engrams bear any physiological significance and can be switched through physiological mechanisms. Here, we show that an acute social reward experience switches the silent memory engram into the latent state. Conversely, an acute social stress causes transient forgetting via turning a latent memory engram into a silent state. Such emotion-driven bidirectional switching between latent and silent states of engrams is mediated through regulation of Rac1 activity–dependent reversible forgetting in the hippocampus, as stress-activated Rac1 suppresses retrieval, while reward recovers silenced memory under amnesia by inhibiting Rac1. Thus, data presented reveal hippocampal Rac1 activity as the basis for emotion-mediated switching between latent and silent engrams to achieve emotion-driven behavioral flexibility.Animals are required to flexibly retrieve memories according to their emotional states for achieving optimal behaviors in an ever-changing environment. To understand the underlying mechanisms of such regulation, extensive effort has been devoted to studying the impact of emotion on memory processes (1–5). For instance, stress can block memory retrieval through hormones, neuroinflammation, or depression of synapses in both human and animal models (6–12), while reward and novelty can facilitate both the formation and maintenance of memories (13, 14). However, how emotion might directly impact the memory engram remains elusive. The proposed theory and experimental demonstrations have revealed the presence of multiple states of memory engrams, such as silent, latent, and active states (15–17). In the silent state, only artificial activation of engram cells is capable of inducing memory expression, whereas latent engram cells can be activated by a natural conditioned stimulus to drive the engram into the active state for memory retrieval. It is intriguing to note that training either mouse models of Alzheimer’s disease or protein synthesis-inhibited mice are reported to yield only silent engrams, and such silent engrams could be turned into a latent state (18–22) through artificial manipulations of either optical stimulation–induced long-term potentiation (LTP) or virus-driven overexpression of activated PAK1. However, the physiological significance of the different states of engrams, particularly the silent engram, remains unclear. In the course of studying the functions of reversible forgetting (23, 24), we became interested in testing the idea that the emotional impact on memory retrieval could be mediated through switching the engram between latent and silent states, while reversible forgetting may play a role in making such switching.To investigate this idea, we tested the effects of acute social reward (SR) and social stress (SS) on memory retrieval. Since mating and fighting are widely perceived and used as behavioral stimuli for evoking feelings of reward and stress, respectively (25–27), we adopted a modified short procedure for evoking acute emotion through social interactions. For SR treatment, a single experimental male mouse is exposed to two females brought from different home cages for 10 min. Such a subtle positive experience is sufficient to enhance retrieval of contextual fear memory (28). For SS treatment, a single experimental male mouse is exposed to a group of five male littermates for 10 min. This is a hostile social environment in which the experimental mouse fights with other littermates during this time window. Such a subtle stressful experience is sufficient to significantly reduce 24-h contextual fear memory (28). Based on these two paradigms of acute social experiences, we investigated how emotion affects memory retrieval through alterations in engram states. |
