The temporal origin of dentate granule neurons dictates their role in spatial memory.

The dentate gyrus is one of the only brain regions that continues its development after birth in rodents. Adolescence is a very sensitive period during which cognitive competences are programmed. We investigated the role of dentate granule neurons (DGNs) born during adolescence in spatial memory and compared them with those generated earlier in life (in embryos or neonates) or during adulthood by combining functional imaging, retroviral and optogenetic tools to tag and silence DGNs. By imaging DGNs expressing Zif268, a proxy for neuronal activity, we found that neurons generated in adolescent rats (and not embryos or neonates) are transiently involved in spatial memory processing. In contrast, adult-generated DGNs are recruited at a later time point when animals are older. A causal relationship between the temporal origin of DGNs and spatial memory was confirmed by silencing DGNs in behaving animals. Our results demonstrate that the emergence of spatial memory depends on neurons born during adolescence, a function later assumed by neurons generated during adulthood.

Long-lasting plasticity of hippocampal adult-born neurons.

Adult neurogenesis occurs in the dentate gyrus of the hippocampus, which is a key structure in learning and memory. It is believed that adult-born neurons exert their unique role in information processing due to their high plasticity during immature stage that renders them malleable in response to environmental demands. Here, we demonstrate 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 of age. By ablating neurogenesis within a specific period of time, we found that learning was disrupted when the delay between ablation and learning was extended to several months. Together, these results show that mature adult-born neurons are still plastic when they are functionally integrated into dentate network. Our results suggest a new perspective with regard to the role of neo-neurons by highlighting that even mature ones can provide an additional source of plasticity to the brain to process memory information.

Responsiveness of dentate neurons generated throughout adult life is associated with resilience to cognitive aging.

During aging, some individuals are resilient to the decline of cognitive functions whereas others are vulnerable. These inter-individual differences in memory abilities have been associated with differences in the rate of hippocampal neurogenesis measured in elderlies. Whether the maintenance of the functionality of neurons generated throughout adult life is linked to resilience to cognitive aging remains completely unexplored. Using the immediate early gene Zif268, we analyzed the activation of dentate granule neurons born in adult (3-month-old), middle-aged (12-month-old), or senescent (18-month-old) rats (n = 96) in response to learning when animals reached 21 months of age. The activation of neurons born during the developmental period was also examined. We show that adult-born neurons can survive up to 19 months and that neurons generated 4, 10, or 19 months before learning, but not developmentally born neurons, are activated in senescent rats with good learning abilities. In contrast, aged rats with bad learning abilities do not exhibit activity-dependent regulation of newborn cells, whatever their birthdate. In conclusion, we propose that resilience to cognitive aging is associated with responsiveness of neurons born during adult life. These data add to our current knowledge by showing that the aging of memory abilities stems not only from the number but also from the responsiveness of adult-born neurons.

Learning-induced survival of new neurons depends on the cognitive status of aged rats.

Aging is accompanied by an alteration of spatial memory, which has been related to an alteration in hippocampal plasticity. Within the dentate gyrus, new neurons are generated throughout the entire life of an individual. This neurogenesis seems to play a role in hippocampal-mediated learning and learning-induced changes in neurogenesis have been proposed to be involved in memory. However, in aged rats, little is known on the influence of learning on the early development of the adult-born neurons and on the possible involvement of learning-induced changes in neurogenesis in age-related memory deficits. To address this issue, we took advantage of the existence of spontaneous individual differences for performances observed in aged subjects in the water maze. In this task, learning can be divided into two phases, an early phase during which performances quickly improve, and a late phase during which asymptotic levels of performances are reached. We show that the influence of spatial learning on the survival of the newly born cells depends on their birth date and the memory abilities of the aged rats. In aged rats with preserved spatial memory, learning increases the survival of cells generated before learning whereas it decreases survival of cells produced during the early phase of learning. These results highlight the importance of learning-induced changes in adult-born cell survival in memory. Furthermore, they provide new insights on the possible neural mechanisms of aging of cognitive functions and show that an alteration to the steps leading to neurogenesis may be involved in the determination of individual memory abilities.

Upregulation of polysialylated neural cell adhesion molecule in the dorsal hippocampus after contextual fear conditioning is involved in long-term memory formation.

The role of the hippocampus in pavlovian fear conditioning is controversial. Although lesion and pharmacological inactivation studies have suggested a key role for the dorsal hippocampus in contextual fear conditioning, the involvement of the ventral part is still uncertain. Likewise, the debate is open with regard to the putative implication of each hippocampal subdivision in fear conditioning to a discrete conditioned stimulus. We explored the potential existence of dissociations occurring in the dorsal versus ventral hippocampus at the cellular level while dealing with either contextual or cued fear conditioning and focused in a molecular "signature" linked to structural plasticity, the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). We found an upregulation of PSA-NCAM expression in the dorsal (but not ventral) dentate gyrus at 24 h after contextual (but not tone) fear conditioning. Specific removal of PSA through microinfusion of the enzyme endoneuraminidase-N in the dorsal (but not ventral) hippocampus reduced freezing responses to the conditioned context. Therefore, we present evidence for a specific role of PSA-NCAM in the dorsal hippocampus in the plasticity processes occurring during consolidation of the context representation after "standard" contextual fear conditioning. Interestingly, we also found that exposing animals just to the context induced an activation of PSA-NCAM in both dorsal and ventral dentate gyrus. Altogether, these findings highlighting the distinctive occurrence of these neuroplastic processes in the dorsal hippocampus during the standard contextual fear-conditioning task enlighten the ongoing debate about the involvement of these hippocampal subdivisions in pavlovian fear conditioning.

Nicotine self-administration impairs hippocampal plasticity.

Nicotine, the neuroactive compound responsible for tobacco addiction, is primarily believed to have beneficial effects on the adult brain. However, in heavy smokers, abstinence from nicotine is accompanied by cognitive impairments that suggest adverse effects of nicotine on brain plasticity. For this reason, we studied changes in plasticity-related processes in the dentate gyrus (DG) of the hippocampal formation of animals trained to self-administer nicotine. The DG was chosen because it undergoes profound plastic rearrangements, many of which have been related to memory and learning performances. In this region, we examined the expression of the polysialylated (PSA) forms of neural cell adhesion molecule (NCAM), PSA-NCAM, neurogenesis, and cell death by measuring the number of pyknotic cells. It was found that nicotine self-administration profoundly decreased, in a dose-dependent manner, the expression of PSA-NCAM in the DG; a significant effect was observed at all the doses tested (0.02, 0.04, and 0.08 mg/kg per infusion). Neurogenesis was also decreased in the DG, but a significant effect was observed only for the two highest doses of nicotine. Finally, the same doses that decreased neurogenesis also increased cell death. These results raise an important additional concern for the health consequences of nicotine abuse and open new insight on the possible neural mechanisms of tobacco addiction.

Influence of ontogenetic age on the role of dentate granule neurons.

New neurons are continuously produced in the adult dentate gyrus of the hippocampus, a key structure in learning and memory. It has been shown that adult neurogenesis is crucial for normal memory processing. However, it is not known whether neurons born during the developmental period and during adulthood support the same functions. Here, we demonstrate that neurons born in neonates (first postnatal week) are activated in different memory processes when they are mature compared to neurons born in adults. By imaging the activation of these two different neuron generations in the same rat and using the IEG Zif268 and Fos, we show that these neurons are involved in discriminating dissimilar contexts and spatial problem solving, respectively. These findings demonstrate that the ontogenetic stage during which neurons are generated is crucial for their function within the memory network.

Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus.

During adulthood, new neurons are continuously added to the mammalian dentate gyrus (DG). An increasing number of studies have correlated changes in rates of dentate neurogenesis with memory abilities. One study based on subchronic treatment with the toxin methylazoxymethanol acetate (MAM) has provided causal evidence that neurogenesis is involved in hippocampal-dependent trace conditioning. In contrast, spatial learning is not impaired following MAM treatment. We hypothesized that this was due to the small residual number of new cells produced following MAM treatment. In the present experiment, we attempted to achieve a higher level of reduction of adult-generated cells following MAM treatment in young and aged rats. We found only a partial reduction of adult-generated cells in the DG. More importantly, independently of the age of the animals, MAM treatment at a dose necessary to reduce neurogenesis altered the overall health of the animals. In conclusion, the behavioural results obtained following subchronic treatment with high doses of MAM in adulthood must be interpreted with extreme caution.