Biphasische Expression plastizitätsvermittelnder Gene und die Stabilisierung von Ensembles des Furchtgedächtnisses in hippocampalen und neocorticalen Netzwerken.
Zusammenfassung der Projektergebnisse
This research project was targeted at elucidating molecular and cellular mechanisms that regulate fear memory formation as well as at uncovering cellular processes associated with aging-dependent cognitive decline. Although fear memories are critical to survival, severe aversive events can also lead to the formation of strong maladaptive memories that trigger disproportionate and generalized fear responses that are resistant to extinction and can give rise to psychiatric conditions such as post-traumatic stress disorder (PTSD). Although mechanisms that constrain memory formation have been described, it is still not understood whether the salience of the fearful experience activate processes that limit the storage of this information. Such a process could represent a biological strategy to prevent abnormally salient stimuli to give rise to strong memories that could compromise adaptive behavior. In one of our studies, we uncovered a mechanism regulated by the salience of a fearful experience that gates the strength of fear memory and associated maladaptive responses. We showed that, unlike low salience experiences, highly salient experiences induced two phases of Npas4 expression in the CA1 region of the mouse hippocampus. Using pharmacological and genetic approaches we showed that the late Npas4 expression constraints the consolidation of fear memory and prevents the formation of maladaptive behavior, namely the contextual generalization of the fear response and resistance to suppression by extinction. Finally, we found that this effect is associated with increased cholecystokinin (CCK)-expressing interneurons-dependent inhibitory input onto CA1 pyramidal neurons. Overall, our study uncovered a biological mechanism that modulates the strength of memories of highly salient fearful experiences, which may also play a role in regulating resilience to adverse life events. In another study, we investigated possible cellular dysfunctions associated with agingdependent cognitive decline. It is now well accepted that memory traces (or engrams) are encoded within the neuronal population activated during learning and that the recall of those memories requires the reactivation of the same subset of cells. However, whether cognitive deficits in aging are associated with alterations in neuronal activation during learning and/or reactivation during recall is not understood. In our work we characterized a cohort of aged mice according to their cognitive performance in an object-place recognition task into aged impaired (AI) and aged unimpaired (AU). Next, we identified the dentate gyrus population activated by learning and assessed their reactivation during the recall of the object location memory. We found that although the size of the population activated by learning or recall was identical in AI and AU, AI mice had impaired reactivation of learning-activated neurons (i.e. reactivation rate). Moreover, we found a significant correlation between aged mice cognitive performance and reactivation rates. Taken together this study suggested that age-related impairments may emerge at least in part from impaired stabilization of engram cells.
Projektbezogene Publikationen (Auswahl)
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MeCP2 gates spatial learning-induced alternative splicing events in the mouse hippocampus. Molecular Brain, 13(1).
Brito, David V. C.; Gulmez, Karaca Kubra; Kupke, Janina; Frank, Lukas & Oliveira, Ana M. M.
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Engram reactivation during memory retrieval predicts long-term memory performance in aged mice. Neurobiology of Aging, 101, 256-261.
Gulmez, Karaca Kubra; Brito, David V.C.; Kupke, Janina; Zeuch, Benjamin & Oliveira, Ana M.M.
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Molecular and cellular mechanisms of engram allocation and maintenance. Brain Research Bulletin, 170, 274-282.
Gulmez, Karaca Kubra; Kupke, Janina & Oliveira, Ana M.M.
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Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice. Cold Spring Harbor Laboratory.
Brito, David V.C.; Kupke, Janina; Sokolov, Rostilav; Cambridge, Sidney; Both, Martin; Bengtson, C. Peter; Rozov, Andrei & Oliveira, Ana M.M.
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Dnmt3a1 regulates hippocampus-dependent memory via the downstream target Nrp1. Cold Spring Harbor Laboratory.
Kupke, Janina; Klimmt, Julien; Mudlaff, Franziska; Schwab, Maximilian; Lutsik, Pavlo; Plass, Christoph; Sticht, Carsten & Oliveira, Ana M.M.
