Hippocampal neurogenesis: a novel substrat for memory – MemoNeuro

1. Our aim was to determine whether “old” neurons are still plastic to respond to a learning influence and required for spatial learning (Lemaire et al., 2012).
2. Then, we asked whether these neurons generated during adulthood and also those generated at middle-age and senescence contribute to the memory abilities of aged rats. To test the hypothesis, we took advantage of the existence of inter-individual differences in spatial learning abilities during aging and visualized the recruitment of adult-born neurons into dentate memory circuits using the Immediate Early Gene (IEG) Zif268.
3. Since we have shown that adult-born neurons need to be 3-4 month old to be recruited by spatial learning (Lemaire et al., 2012), another related question is to understand which neurons are sustaining spatial learning in 2-3 month-old animals. One possibility is that spatial learning in these young adult rats is sustained by neurons born during the postnatal development of the hippocampus. A similar approach than that described above has been used to tackle this question.

1. We demonstrated that in rats there is no critical time window for experience-induced dendritic plasticity of adult-born neurons as spatial learning in the water maze sculpts the dendritic arbor of adult-born neurons even when they are several months-old. Having shown that mature adult-born neurons are still plastic, we showed that they are functionally integrated into the dentate network by analyzing the impact of their loss on spatial learning.
2. The, we showed that spatial learning ability in aged rats depends on life-long production of new hippocampal neurons.
3. We found that neurons born during development are not recruited when training young adults in the water maze.

Our objective is to uncover the specific role sustained by adult-born neurons and developmentally-generated ones

Lemaire V*, Tronel S*, Montaron MF*, Fabre A, Dugast E, Abrous DN. Long-lasting plasticity of hippocampal adult-born neurons. J Neuroscience, 2012, 32:3101-3108.

Learning & memory are fundamental processes allowing encoding, storing, and retrieving information (about space, time and emotion). These processes allow that each individual adapts to the everyday changing environment thereby contributing to species perpetuity. However this ability to “navigate in life” is lost in some individuals. Memory disorders related to aging (such as Alzheimer disease), to stress disorders and to other pathologies (depression, anxiety …) concern a large part of the population, and have a very high human and financial cost. The search for treatments to improve memory is hindered mainly because the biological basis of memory is still unclear. For this reason a better understanding of the mechanisms that underlie memory will allow the development of “memory enhancer” that may treat memory disorders and aid memory in healthy individuals.
The discovery that new neurons are created in the adult brain has generated a great interest in the field of learning and memory and of neural plasticity. Indeed, neurogenesis occurs in the dentate gyrus of the hippocampus, which is one of the main brain regions involved in memory processes. For this reason, it has been proposed that adult neurogenesis may constitute a substrate to memory processes and thus, a very promising target for curing or preventing memory disorders.
This last decade our knowledge on adult hippocampal neurogenesis has dramatically increased both at a cellular level and at a network level. In contrast, the functional role of neurogenesis remains a hotly debated topic. Over these last years, we have studied the physiological significance of hippocampal neurogenesis and its involvement in pathological memory. We have shown that: 1) adult-born neurons are required for learning and memory, and that an alteration of neurogenesis during senescence or using a transgenic approach lead to spatial memory deficits, 2) reciprocally learning regulates neurogenesis and selects a specific immature neuronal population, the survival of which it increases. This new phenomenon, which is reminiscent of the selective stabilization process occurring during development, is important for learning as its alteration leads to memory impairments in adult or in some senescent individuals. 3) We focused on prenatal stress that constitutes a developmental risk factor for the appearance of memory deficits. We have shown that prenatal stress decreased hippocampal neurogenesis throughout adulthood. Furthermore, these effects are reversible and mediated by changes occurring during the postnatal period.
Our project is in line with our previous activities. After demonstrating that adult-born neurons are a key player in learning & memory, we will attempt to understand when and how adult neurogenesis impacts memory. Three lines of research will be developed by studying: 1) the participation of mature adult-born neurons to memory processes, 2) the participation of immature adult-born neurons to memory processes, 3) the implication of neurogenesis in the pathophysiology of memory, using prenatal stress as an experimental paradigm
Our expectation is to give a relevant contribution to our knowledge of the neuronal basis of memory. We strongly believe that this field of research has therefore phenomenal potentials to be one of the main axis of research to understand and ultimately improve normal and pathological memory.