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Corticosterone Treatment and Incubation Time After Contextual Fear Conditioning Synergistically Induce Fear Memory Generalization in Neuropeptide S Receptor-Deficient Mice.

ABSTRACT: Fear memory generalization is a learning mechanism that promotes flexible fear responses to novel situations. While fear generalization has adaptive value, overgeneralization of fear memory is a characteristic feature of the pathology of anxiety disorders. The neuropeptide S (NPS) receptor (NPSR) has been shown to be associated with anxiety disorders and has recently been identified as a promising target for treating anxiety disorders. Moreover, stress hormones play a role in regulating both physiological and pathological fear memories and might therefore also be involved in anxiety disorders. However, little is known about the interplay between stress hormone and the NPS system in the development of overgeneralized fear. Here, we hypothesize that NPSR-deficient mice with high corticosterone (CORT) levels during the fear memories consolidation are more prone to develop generalized fear. To address this hypothesis, NPSR-deficient mice were submitted to a contextual fear conditioning procedure. Immediately after conditioning, mice received CORT injections (2.5 or 5 mg/kg). One day and 1 month later, the mice were tested for the specificity and strength of their fear memory, their anxiety level, and their startle response. Moreover, CORT blood levels were monitored throughout the experiment. Using this protocol, a specific contextual fear memory was observed in all experimental groups, despite the 5-mg/kg CORT-treated NPSR-deficient mice. This group of mice showed a generalization of contextual fear memory and a decreased startle response, and the females of this group had significantly less body weight gain. These findings indicate that interplay between CORT and the NPS system during the consolidation of fear memories is critical for the generalization of contextual fear.

SUBMITTER: Kolodziejczyk MH

PROVIDER: S-EPMC7081924 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A fundamental question in neuroscience is how memories are stored and retrieved in the brain. Many neurological, psychiatric and neurodevelopmental disorders are associated with cognitive deficits. Therefore characterizing the biological basis of these processes is critical for understanding normal and abnormal brain function. It is known that long-term memory formation requires transcription and translation as well as epigenetic processes that control gene expression. In this study we examined genome-wide gene expression changes during memory consolidation and after memory retrieval. We observe the largest changes in gene expression 30 minutes after memory acquisition and retrieval, and several novel genes were found to be affected by both. Interestingly, acquisition and retrieval of memory down-regulate different processes. Chromatin assembly is down-regulated after memory acquisition whereas RNA processing is down-regulated so after retrieval. Histone variant H2AB levels are reduced following acquisition, while splicing factor Rbfox1 and NMDA receptor-dependent microRNA miR-219 are down-regulated following retrieval. We also show that miR-219 down-regulation after retrieval is accompanied by up-regulation of its target protein CAMKIIÎ³. Our study highlights for the first time the differential involvement of epigenetic mechanisms that control gene expression, such as histone variants and post-transcriptional RNA processing, during memory acquisition and retrieval. 72 total samples were analyzed, including animals trained in a contexual conditioning paradigm (FC) and controls. Tissue was collected at 30 minutes (FC30), 4 hours (FC4), 12 hours (FC12) and 24 hours after FC (FC24) as well as 30 minutes after testing for retrieval of the memory (RT30). Testing was performed at 24 hours after training over a 5-minute interval. Animals that were handled but not trained were dissected at the same time of day to control for variations due to circadian rhythms (CC30, CC4 andCC12). The protocol was repeated over the course of 2 weeks to obtain 9 animals (2 hippocampi) per group, so that 9 independent FC experiments were represented in each time point and all animals for each group were dissected at the exactly the same time of day.

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Corticosterone Treatment and Incubation Time After Contextual Fear Conditioning Synergistically Induce Fear Memory Generalization in Neuropeptide S Receptor-Deficient Mice.

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