New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult-born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult-born neurons impairs the animal's ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.

Increased consumption of high-fat diet (HFD) leads to obesity and adverse neurocognitive outcomes. Childhood and adolescence are important periods of brain maturation shaping cognitive function. These periods could consequently be particularly sensitive to the detrimental effects of HFD intake. In mice, juvenile and adulthood consumption of HFD induce similar morphometric and metabolic changes. However, only juvenile exposure to HFD abolishes relational memory flexibility, assessed after initial radial-maze concurrent spatial discrimination learning, and decreases neurogenesis. Our results identify a critical period of development covering adolescence with higher sensitivity to HFD-induced hippocampal dysfunction at both behavioral and cellular levels.

Neurogenesis in the hippocampus is characterized by the birth of thousand of cells that generate neurons throughout life. The fate of these adult newborn neurons depends on life experiences. In particular, spatial learning promotes the survival and death of new neurons. Whether learning influences the development of the dendritic tree of the surviving neurons (a key parameter for synaptic integration and signal processing) is unknown. Here we show that learning accelerates the maturation of their dendritic trees and their integration into the hippocampal network. We demonstrate that these learning effects on dendritic arbors are homeostatically regulated, persist for several months, and are specific to neurons born during adulthood. Finally, we show that this dendritic shaping depends on the cognitive demand and relies on the activation of NMDA receptors. In the search for the structural changes underlying long-term memory, these findings lead to the conclusion that shaping neo-networks is important in forming spatial memories.adult neurogenesis | memory | spatial learning | hippocampus | dendrite I n the search for the mechanisms underlying long-term memory formation, structural changes have been proposed to play a major role (1). Adult neurogenesis, a novel form of structural plasticity, occurs in the dentate gyrus (DG), a key structure in processing spatial relational memory (2). Adult neurogenesis in the DG is a complex, multistep process that starts with the proliferation of neural precursors residing in the dentate subgranular layer (2). At least 50% of the daughter cells die within a few days after their birth. The adult-born cells that survive this initial period of cell death differentiate mainly into granule neurons. These new mature neurons are synaptically integrated into the dentate network, where they receive functional inputs (3) and form functional synapses with their target cells (4).Adult-born neurons contribute to the formation of memories, particularly spatial memory as measured in the water maze (5, 6). Reciprocally, spatial learning has been shown to influence adult neurogenesis (7). We have shown that during spatial learning and similar to the selective stabilization process observed during brain development, neuronal networks are sculpted by a tightly regulated selection and suppression of different populations of newly born neurons (8). This homeostatic regulation of the numbers of newly born neurons is important for spatial memory, because its alteration leads to memory deficits (8, 9).One of the requirements for the new neurons to process information is the development of extensive dendritic arbors capable of receiving and integrating complex spatiotemporal patterns of synaptic inputs (4). Whether learning influences such a dendritic development is unknown. To address this issue, we used doublecortin (Dcx) and retroviral labeling to examine to what extent spatial learning in the water maze affects the dendritic morphology of adult-born neurons. Furthermore, we investigated whether the ...

VGF is a neurotrophin-inducible, activity-regulated gene product that is expressed in CNS and PNS neurons, in which it is processed into peptides and secreted. VGF synthesis is stimulated by BDNF, a critical regulator of hippocampal development and function, and two VGF C-terminal peptides increase synaptic activity in cultured hippocampal neurons. To assess VGF function in the hippocampus, we tested heterozygous and homozygous VGF knock-out mice in two different learning tasks, assessed long-term potentiation (LTP) and depression (LTD) in hippocampal slices from VGF mutant mice, and investigated how VGF C-terminal peptides modulate synaptic plasticity. Treatment of rat hippocampal slices with the VGF-derived peptide TLQP62 resulted in transient potentiation through a mechanism that was selectively blocked by the BDNF scavenger TrkB-Fc, the Trk tyrosine kinase inhibitor K252a (100 nM), and tPA STOP, an inhibitor of tissue plasminogen activator (tPA), an enzyme involved in pro-BDNF cleavage to BDNF, but was not blocked by the NMDA receptor antagonist APV, anti-p75 NTR function-blocking antiserum, or previous tetanic stimulation. Although LTP was normal in slices from VGF knock-out mice, LTD could not be induced, and VGF mutant mice were impaired in hippocampal-dependent spatial learning and contextual fear conditioning tasks. Our studies indicate that the VGF C-terminal peptide TLQP62 modulates hippocampal synaptic transmission through a BDNF-dependent mechanism and that VGF deficiency in mice impacts synaptic plasticity and memory in addition to depressive behavior.

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.

Although there is growing knowledge about intracellular mechanisms underlying neuronal plasticity and memory consolidation and reconsolidation after retrieval, information concerning the interaction among brain areas during formation and retrieval of memory is relatively sparse and fragmented. Addressing this question requires simultaneous monitoring of activity in multiple brain regions during learning, the post-acquisition consolidation period, and retrieval and subsequent reconsolidation. Immunoreaction to the immediate early gene c-fos is a powerful tool to mark neuronal activation of specific populations of neurons. Using this method, we are able to report, for the first time, post-training activation of a network of closely related brain regions, particularly in the frontal cortex and the basolateral amygdala (BLA), that is specific to the learning of an odor-reward association. On the other hand, retrieval of a well-established associative memory trace does not seem to differentially activate the same regions. The amygdala, in particular, is not engaged after retrieval, whereas the lateral habenula (LHab) shows strong activation that is restricted to animals having previously learned the association. Although intracellular mechanisms may be similar during consolidation and reconsolidation, this study indicates that different brain circuits are involved in the two processes, at least with respect to a rapidly learned olfactory task.

A new memory is initially labile and becomes stabilized through a process of consolidation, which depends on gene expression. Stable memories, however, can again become labile if reactivated by recall and require another phase of protein synthesis in order to be maintained. This process is known as reconsolidation. The functional significance of the labile phase of reconsolidation is unknown; one hypothesis proposes that it is required to link new information with reactivated memories. Reconsolidation is distinct from the initial consolidation, and one distinction is that the requirement for specific proteins or general protein synthesis during the two processes occurs in different brain areas. Here, we identified an anatomically distinctive molecular requirement that doubly dissociates consolidation from reconsolidation of an inhibitory avoidance memory. We then used this requirement to investigate whether reconsolidation and consolidation are involved in linking new information with reactivated memories. In contrast to what the hypothesis predicted, we found that reconsolidation does not contribute to the formation of an association between new and reactivated information. Instead, it recruits mechanisms similar to those underlying consolidation of a new memory. Thus, linking new information to a reactivated memory is mediated by consolidation and not reconsolidation mechanisms.

These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at ␤ receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory discrimination. They were injected with a ␤ adrenergic receptor antagonist into the PL 5 min or 2 h after training and tested 48 h later. Rats injected at 2 h showed amnesia, whereas those injected at 5 min had good retention, equivalent to saline-injected controls. Monitoring extracellular noradrenaline efflux in PL by in vivo microdialysis during the first hours after training revealed a significant increase shortly after training, with a rapid return to baseline, and then another increase around the 2-h posttraining time window. Pseudo-trained rats showed a smaller early efflux and did not show the second wave of efflux at 2 h. These results confirm earlier pharmacological and immunohistochemical studies suggesting a delayed role of noradrenaline in a late phase of long-term memory consolidation and the engagement of the PL during these consolidation processes.There is a growing body of evidence from behavioral studies suggesting that the prelimbic (PL) and infralimbic regions of rat frontal cortex are involved in executive functions requiring attentional shift and behavioral flexibility, and in working memory (Kesner 1989;Birrell and Brown 2000; deBruin et al. 2000;Jodo et al. 2000;Mulder et al. 2000). Recent experiments in our laboratory suggest that this region is not only involved in these higher 'executive functions,' but is also important in the posttraining consolidation of memory of a simple odor-reward association. The task used is a three-way discrimination among odors, one of which is associated with a palatable reward. Taking advantage of the spontaneous foraging behavior of the rat, reliable learning is achieved in only three trials massed over a few minutes. The memory endures for at least 1 wk without showing any decline. Immunoreactivity to c-fos antibody has been used as a marker for neuronal activation after training and after a control condition in which rats were exposed to all of the elements of the training but not the odor-reward association. Not surprisingly, many regions were equally activated by both the control and trained conditions. Nevertheless, there were three regions which stood out as differentially activated specifically by the associative training. These were the basolateral amygdala, the ventral orbital cortex, and the PL of the prefrontal cortex (Tronel and Sara 2002). These experiments show that these regions are activated as a result of the training, but they do not prove that they are necessary to the learning or memory process. Subsequent experiments added further support for this notion; injections of the NMDA receptor antagonist APV into the PL immediately after training induced a robust and enduring amnesia expressed when the rats were ...