The atypical Rho GTPase Rnd2 is critical for dentate granule neuron development and anxiety-like behavior during adult but not neonatal neurogenesis.

Despite the central role of Rho GTPases in neuronal development, their functions in adult hippocampal neurogenesis remain poorly explored. Here, by using a retrovirus-based loss-of-function approach in vivo, we show that the atypical Rho GTPase Rnd2 is crucial for survival, positioning, somatodendritic morphogenesis, and functional maturation of adult-born dentate granule neurons. Interestingly, most of these functions are specific to granule neurons generated during adulthood since the deletion of Rnd2 in neonatally-born granule neurons only affects dendritogenesis. In addition, suppression of Rnd2 in adult-born dentate granule neurons increases anxiety-like behavior whereas its deletion in pups has no such effect, a finding supporting the adult neurogenesis hypothesis of anxiety disorders. Thus, our results are in line with the view that adult neurogenesis is not a simple continuation of earlier processes from development, and establish a causal relationship between Rnd2 expression and anxiety.

Corticosteroid-Binding Globulin Deficiency Specifically Impairs Contextual and Recognition Memory Consolidation in Male Mice.

BACKGROUND/AIMS: Glucocorticoids are essential in modulating memory processes of emotionally arousing experiences and we have shown that corticosteroid-binding globulin (CBG) influences glucocorticoid delivery to the brain. Here, we investigated the role of CBG in contextual and recognition long-term memory according to stress intensity. METHOD: We used adult male mice totally deficient in CBG (Cbg KO) or brain-specific Cbg KO (CbgCamk KO) to examine their performance in contextual fear conditioning (CFC) and au-ditory fear conditioning, both at short (1 h) and long-term (24 h). Long-term memory in Cbg KO was further analyzed in conditioned odor aversion and in novel object recognition task (NORT) with different paradigms, that is, with and without prior habituation to the context, with a mild or strong stressor applied during consolidation. In the NORT experiments, total and free glucocorticoid levels were measured during consolidation. RESULTS: Impaired memory was observed in the Cbg KO but not in the CbgCamk KO in the CFC and the NORT without habituation when tested 24 h later. However, Cbg KO displayed normal behavior in the NORT with previous habituation and in the NORT with a mild stressor. In condition of the NORT with a strong stressor, Cbg KO retained good 24 h memory performance while controls were impaired. Total and free glucocorticoids levels were always higher in controls than in Cbg KO except in NORT with mild stressor where free glucocorticoids were equivalent to controls. CONCLUSIONS: These data indicate that circulating but not brain CBG influences contextual and recognition long-term memory in relation with glucocorticoid levels.

Genetic labeling of embryonically-born dentate granule neurons in young mice using the PenkCre mouse line.

The dentate gyrus (DG) of the hippocampus is a mosaic of dentate granule neurons (DGNs) accumulated throughout life. While many studies focused on the morpho-functional properties of adult-born DGNs, much less is known about DGNs generated during development, and in particular those born during embryogenesis. One of the main reasons for this gap is the lack of methods available to specifically label and manipulate embryonically-born DGNs. Here, we have assessed the relevance of the PenkCre mouse line as a genetic model to target this embryonically-born population. In young animals, PenkCre expression allows to tag neurons in the DG with positional, morphological and electrophysiological properties characteristic of DGNs born during the embryonic period. In addition, PenkCre+ cells in the DG are distributed in both blades along the entire septo-temporal axis. This model thus offers new possibilities to explore the functions of this underexplored population of embryonically-born DGNs.

Chemogenetic stimulation of adult neurogenesis, and not neonatal neurogenesis, is sufficient to improve long-term memory accuracy.

Hippocampal adult neurogenesis is involved in many memory processes from learning, to remembering and forgetting. However, whether or not the stimulation of adult neurogenesis is a sufficient condition to improve memory performance remains unclear. Here, we developed and validated, using ex-vivo electrophysiology, a chemogenetic approach that combines selective tagging and activation of discrete adult-born neuron populations. Then we demonstrated that, in rats, this activation can improve accuracy and strength of remote memory. These results show that stimulation of adult-born neuron activity can counteract the natural fading of memory traces that occurs with the passage of time. This opens up new avenues for treating memory problems that may arise over time.

Adult-born neurons immature during learning are necessary for remote memory reconsolidation in rats.

Memory reconsolidation, the process by which memories are again stabilized after being reactivated, has strengthened the idea that memory stabilization is a highly plastic process. To date, the molecular and cellular bases of reconsolidation have been extensively investigated particularly within the hippocampus. However, the role of adult neurogenesis in memory reconsolidation is unclear. Here, we combined functional imaging, retroviral and chemogenetic approaches in rats to tag and manipulate different populations of rat adult-born neurons. We find that both mature and immature adult-born neurons are activated by remote memory retrieval. However, only specific silencing of the adult-born neurons immature during learning impairs remote memory retrieval-induced reconsolidation. Hence, our findings show that adult-born neurons immature during learning are required for the maintenance and update of remote memory reconsolidation.