MEMORY RECONSOLIDATION AND ADULT NEUROGENESIS: ARE HIPPOCAMPAL NEWBORN NEURONS NEW PLAYERS IN MEMORY STABILIZATION? – ReconsoNeuro

To investigate the role of adult-born neurons in memory reconsolidation we use a strategy of loss or gain of function. Indeed, we have generated a new tool, based on recent advances in molecular biology and the pharmacogenetic approach of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). DREADDs are a family of G-protein-coupled receptors that are designed to be insensitive to their endogenous ligands, yet can be activated by synthetic drug-like compounds. We used the human mutated muscarinic designer receptors hM3Dq, hM3Ds and the hM4Di respectively linked to the Gq, Gs and Gi proteins, and we inserted these receptors within CAG-GFP retroviruses, which only incorporate into dividing cells. The GFP labels the adult-born neurons that have incorporated the viral DNA, and they can then be selectively inhibited (retrovirus-hM4Di) or stimulated (retrovirus-hM3Dq or Ds) by an injection of Clozapine-N-Oxide (CNO)--the synthetic ligand of the DREADDs that is otherwise pharmacologically inert. The great advantage offered by this approach is that the neurons born during adulthood remain throughout the life of the animal, therefore, are present during all life experiences and can be silenced or stimulated at specific time points. Contrary to other available approaches, which decrease or ablate neurogenesis (pharmacological compounds, irradiation or transgenic tools), our approach allows us to tag and modulate specific populations of adult-born neurons without any loss of cells in the network.

We have previously demonstrated that training animals in a spatial learning task increased survival and accelerated the development of neurons generated in the hippocampus a week before learning. We concluded that learning stimulated adult neurogenesis. In this project, we sought to show that these neurons specifically selected by learning played an important role in maintaining the memory of this learning in the long term. Thanks to the pharmacogenetic method that allows us to specifically tag this population of new neurons and to stimulate them later we have shown that we could improve memory. These results show that some cells that are born in the adult brain could become a target to develop new therapeutic treatments for memory deficits.

A better understanding of the biological mechanisms underlying memory formation and memory recovery is essential to develop therapeutic targets for the treatment of cognitive diseases.
In this project we have already highlighted that by stimulating certain populations of neurons generated in adulthood, we can improve long-term memory. These results reinforce the importance of adult neurogenesis in mammals and especially in humans. There are currently many correlative studies that show the impact of drug treatments, medication but also diet and exercise, on the formation and retention of memory in humans, especially during aging. These «conditions« are known to influence the good development of adult neurogenesis in rodents. In conclusion, it remains to develop new tools that allow, in human, to specifically target neuronal populations and manipulate them.

The results have been presented in several scientific meetings. A scientific article is in preparation.

Memory formation is critical for normal adaptive functioning and is at the center of many cognitive disorders. The discovery that memory becomes labile again when reactivated, and needs to go through a process of reconsolidation to become stable, has strengthened the idea that memory stabilization is a highly plastic process. The great interest in the reconsolidation process is that it offers a window of opportunity to disrupt memories a long time after the initial encoding and suggests that memory reactivation may play a role in modulating memory strength and in the updating of memory content. The understanding of the reconsolidation process is therefore of considerable importance to provide further insights into the development of therapeutic tools for treatment of pathological memories.
To date, many studies have investigated the molecular and cellular bases of reconsolidation as well as the synaptic mechanisms underlying this process within the hippocampus in particular. Recent progress has been made towards finding the engram, in particular the populations of neurons that are active during memory encoding and retrieval (defined as “engram cells”). Surprisingly, the process of reconsolidation has not been considered in the context of ongoing adult neurogenesis, which is known to confer a new support to memory processes. Adult neurogenesis is the generation of new granular neurons in the dentate gyrus of the adult hippocampus. A decade of research has proven the role of adult neurogenesis in memory formation, specifically in processes such as spatial learning, Pattern separation, forgetting, etc…However, the role of the continuous addition of granular neurons in the reconsolidation process of established memory has not been investigated.
Thus the role of hippocampal neurogenesis in the stabilization of memory remains to be defined.
Here, I propose to demonstrate that adult-born neurons play a key role in memory reconsolidation. Preliminary data demonstrated that adult-born neurons are activated by spatial memory reconsolidation. Therefore, the first goal of this project will be to generalize the role of adult-born neurons in reconsolidation of hippocampal-dependent memories, using two different behavioral hippocampal-dependent paradigms—the water maze (WM) and the contextual fear conditioning (CFC).
Then I will demonstrate a causal relationship between adult neurogenesis and memory reconsolidation. Towards this aim, we developed a new tool to specifically modulate adult-born neurons activation at the time of reconsolidation. It is based on the pharmacogenetic approach of the DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). We developed a new retrovirus that expresses GFP and contains the DREADD coupled to either the Gi or Gs proteins. Considering retroviruses incorporate DNA into dividing cells only, this new tool allows the selective inactivation (DREADD-Gi) or stimulation (DREADD-Gs) of the GFP-tagged newly generated neurons at a specific time point.
Recently, a great deal of experimental investment is directed towards the mechanisms of memory storage. Memory engram technology allows the labeling and subsequent manipulation of cells ensembles, demonstrating that memory is indeed held in specific populations of neurons. My preliminary results suggest that a specific population of neurons that are immature, and thus not activated, at the time of learning, becomes necessary when functional maturity is reached, to stabilize the memory trace after reactivation. Therefore, the third aim of the project will be to understand how this immature population of neurons that is not activated by learning can become part of the engram, and to uncover the specific connectivity between immature adult-born neurons and “engram cells” at the time of learning.

Together, these experiments will lead to a better understanding of the reconsolidation process and the role of adult neurogenesis in the dynamics of memory.