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.Rôle de la neurogénèse hippocampique dans la reconsolidation de la mémoireDissection des mécanismes hypothalamiques impliqués dans la détection du statut nutritionnel et régulation de la prise alimentaire via les interactions entre mTORC1, les mélanocortines et les endocannabinoïdes

Functional heterogeneity of POMC neurons relies on mTORC1 signaling.

Hypothalamic pro-opiomelanocortin (POMC) neurons are known to trigger satiety. However, these neuronal cells encompass heterogeneous subpopulations that release γ-aminobutyric acid (GABA), glutamate, or both neurotransmitters, whose functions are poorly defined. Using conditional mutagenesis and chemogenetics, we show that blockade of the energy sensor mechanistic target of rapamycin complex 1 (mTORC1) in POMC neurons causes hyperphagia by mimicking a cellular negative energy state. This is associated with decreased POMC-derived anorexigenic α-melanocyte-stimulating hormone and recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Electrophysiology and optogenetic studies further reveal that pharmacological blockade of mTORC1 simultaneously activates POMC/GABAergic neurons and inhibits POMC/glutamatergic ones, implying that the functional specificity of these subpopulations relies on mTORC1 activity. Finally, POMC neurons with different neurotransmitter profiles possess specific molecular signatures and spatial distribution. Altogether, these findings suggest that mTORC1 orchestrates the activity of distinct POMC neurons subpopulations to regulate feeding behavior

Assessing the action of GluK1 overexpression on synaptic strength and plasticity in a mouse model of Down syndrome

Kainate receptors belong to one subfamily of the glutamatergic receptors. This receptor family is composed by homo- or heterodimers of five different types of subunits named GluK1 to GluK5. The human gene coding for the kainate receptor subunit GluK1 (GRIK1) is located on the human chromosome 21 that triplicates in Down syndrome. In animal models of this disease, Grik1 is situated on the short triplicated segment of chromosome 16, the orthologous of human chromosome 21. Previous work on trisomic models has found an imbalance between excitatory and inhibitory hippocampal synaptic activity. In this study, we used Ts2Cje mouse model to investigate a putative link between a GluK1 excess of function and altered synaptic properties in the hippocampus of trisomic mice. Trisomic animals were differentiated from their diploid littermates (DLM) by multiplex qPCR. RTqPCR analysis revealed that Grik1 mRNA levels are increased by more than 50% in different structures of the trisomic brain. Despite the lack of GluK1 specific antibody, we found in electrophysiological experiments that the extra gene-copy produces an increase of GluK1 functional protein at the membrane of trisomic neurons. Hippocampal patch clamp recordings from CA1 neurons revealed significant increase in basal and evoked inhibitory drive onto pyramidal cells and interneurons from trisomic mice. Ts2Cje animals also presented impaired synaptic plasticity in hippocampal CA1 pyramidal cells. We also observed that GluK1 selective drugs may rescue the over-inhibition phenotype observed in trisomic mice. Our data support the implication of GluK1-containing kainate receptors in the control of network activity in the area CA1 of the hippocampus which is altered in Down syndrome. Further molecular and pharmacological experiments will reveal more details about the effect of GluK1 overexpression on synaptic physiology and pathophysiology of this disease

Unbalanced dendritic inhibition of CA1 neurons drives spatial-memory deficits in the Ts2Cje Down syndrome model

Overinhibition is assumed one of the main causes of cognitive deficits (e.g. memory impairment) in mouse models of Down syndrome (DS). Yet the mechanisms that drive such exaggerated synaptic inhibition and their behavioral effects remain unclear. Here we report the existence of bidirectional alterations to the synaptic inhibition on CA1 pyramidal cells in the Ts2Cje mouse model of DS which are associated to impaired spatial memory. Furthermore, we identify triplication of the kainate receptor (KAR) encoding gene Grik1 as the cause of these phenotypes. Normalization of Grik1 dosage in Ts2Cje mice specifically restored spatial memory and reversed the bidirectional alterations to CA1 inhibition, but not the changes in synaptic plasticity or the other behavioral modifications observed. We propose that modified information gating caused by disturbed inhibitory tone rather than generalized overinhibition underlies some of the characteristic cognitive deficits in DS.The authors gratefully acknowledge the financial support received from the Spanish Agency of Research (AEI) under the grant BFU2015-64656-R (to J.L.), co-financed by the European Regional Development Fund (ERDF), and the “Severo Ochoa” Program for Centres of Excellence in R&D (SEV-2013-0317 and SEV-2017-0723). This work was also supported by the Generalitat Valenciana through the program PrometeoII/2015/012 (to J.L.), the FPI fellowship program (to S.V. and A.G.), and the SyMBaD – Marie Curie ITN (agreement # 238608) (to W.M.)Peer reviewe

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

International audienc

mTORC1 pathway disruption abrogates the effects of the ciliary neurotrophic factor on energy balance and hypothalamic neuroinflammation

Ciliary neurotrophic factor (CNTF) potently decreases food intake and body weight in diet-induced obese mice by acting through neuronal circuits and pathways located in the arcuate nucleus (ARC) of the hypothalamus. CNTF also exerts pro-inflammatory actions within the brain. Here we tested whether CNTF modifies energy balance by inducing inflammatory responses in the ARC and whether these effects depend upon the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which regulates both energy metabolism and inflammation. To this purpose, chow- and high fat diet (HFD)- fed mice lacking the S6 kinase 1 (S6K1?/?), a downstream target of mTORC1, and their wild-type (WT) littermates received 12 days continuous intracerebroventricular (icv) infusion of the CNTF analogue axokine (CNTFAx15). Behavioral, metabolic and molecular effects were evaluated. Central chronic administration of CNTFAx15 decreased body weight and feed efficiency in WT mice only, when fed HFD, but not chow. These metabolic effects correlated with increased number of iba-1 positive microglia specifically in the ARC and were accompanied by significant increases of IL-1? and TNF-? mRNA expression in the hypothalamus. Hypothalamic iNOS and SOCS3 mRNA, molecular markers of pro-inflammatory response, were also increased by CNTFAx15. All these changes were absent in S6K1?/? mice. This study reveals that CNTFAx15 requires a functional S6K1 to modulate energy balance and hypothalamic inflammation in a diet-dependent fashion. Further investigations should determine whether S6K1 is a suitable target for the treatment of pathologies characterized by a high neuroinflammatory state

Mol Psychiatry

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.Bordeaux Region Aquitaine Initiative for NeuroscienceInnovations instrumentales et procédurales en psychopathologie expérimentale chez le rongeurDissection des mécanismes hypothalamiques impliqués dans la détection du statut nutritionnel et régulation de la prise alimentaire via les interactions entre mTORC1, les mélanocortines et les endocannabinoïdes.Développment d'une infrastructure française distribuée coordonné