FoxO6 regulates memory consolidation and synaptic function.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE42097 | GEO | 2012/11/08
SECONDARY ACCESSION(S): PRJNA179129
REPOSITORIES: GEO
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Project description:We used microarrays to assess gene expression differences in the hippocampus between FoxO6 mutant and wild-type siblings before (basal) or after novel object learning. The cohort of basal mice were housed individually for at least 3 days prior to tissue harvesting. The mice used to collect hippocampal samples after the object learning task were handled daily in the procedure room, prior to the object learning task. 24 hours before the object learning task, each mouse was individually habituated to the empty novel object arena for 10 min. On the days of the novel object learning task and the empty arena habituation, the mice were transferred to the procedure room and acclimatized for 60 min. For the novel object learning task, the mice were allowed to explore two identical and novel objects for 10 min in a 70 x 70 x 70 cm black plastic arena with a white PVC vinyl material on the base. After the object exploration, mice were transferred to an empty cage, and were euthanized after 60 min. The brains were dissected and incubated in ice-cold RNAlater (Ambion) for 24 hours at 4M-BM-:C. The brains were then rapidly frozen in O.C.T. Tissue-Tek (Sakura) at -80M-BM-:C. Coronal brain sections (300 M-BM-5m) were made using a microtome (Microm), the hippocampus was finely dissected and collected into M-bM-^@M-^XRNA lysis bufferM-bM-^@M-^Y (Ambion), and homogenized for 30 sec using a rotar-stat homogenizer. Total RNA was extracted using the RNAqueous column (Ambion) following the manufacturerM-bM-^@M-^Ys protocol.
2012-11-08 | E-GEOD-42097 | biostudies-arrayexpress
Project description:The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.
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Project description:We performed an RNA Sequencing experiment on dorsal hippocampal tissue from four groups of animals: Baf53b+/- homecage (Baf53b+/- HC); Baf53b+/- behavior (Baf53b+/- Beh); wildtype homecage (WT HC); and wildtype behavior (WT Beh). Homecage animals were sacrificed directly from the animal's cage. Behavior animals were sacrificed thirty minutes following Object Location Memory training. The objective of this study was to examine activity regulated gene expression following a learning event (HC vs Beh) in wildtype and Baf53b+/- mutant mice. Examination of gene expression following a learning event in wildtype and Baf53b+/- mutant mice in dorsal hippocampus.
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Project description:We report a bulk transcriptomic dataset of mouse dorsal hippocampus to identify gene expression changes of spatial object recognition training. We report a spatial transcriptomics dataset of mouse brain tissue generated with the 10x Genomics Visium platform to identify gene expression profiles of spatial object recognition training. We report a single nuclei ATAC-seq and a Single nuclei RNA-sequencing using SPLiT-pool barcoding datasets of mouse dorsal hippocampus to identify chromatin and gene expression changes of spatial object recognition training.
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Project description:The histone lysine demethylase KDM5B has been implicated in recessive intellectual disability disorders and heterozygous, protein truncating variants in KDM5B are associated with reduced cognitive function in the normal adult population. To help distinguish between developmental and demethylase-dependent functions of KDM5B in hippocampus-dependent learning and memory, we studied mice homozygous for a Kdm5bDARID allele that lacks demethylase activity. Demethylase-deficient Kdm5bDARID/DARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in mice in the home cage (baseline) and hyperactivated upon learning stimulus compared to wildtype mice. The expression of other learning-associated genes was also significantly altered in the Kdm5bDARID/DARID hippocampus. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on learning and memory mechanisms.
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Project description:The forkhead transcription factor FoxO6 is prominently expressed during development of the murine neocortex. However, its function in cortical development is as yet unknown. We now demonstrate that cortical development is altered in FoxO6+/- and FoxO6-/- mice, showing migrating neurons halted in the intermediate zone. Using a FoxO6-directed siRNA approach, we substantiate the requirement of FoxO6 for a correct radial migration in the developing neocortex. Subsequent genome-wide transcriptome analysis reveals altered expression of genes involved in cell adhesion, axon guidance, and gliogenesis upon silencing of FoxO6 We then show that FoxO6 binds to DAF-16-binding elements in the Plexin A4 (Plxna4) promoter region and affects Plxna4 expression. Finally, ectopic Plxna4 expression restores radial migration in FoxO6+/- and siRNA-mediated knockdown models. In conclusion, the presented data provide insights into the molecular mechanisms whereby transcriptional programs drive cortical development.
2016-11-11 | GSE71954 | GEO
Project description:Purpose: We investigated Nr4a effector genes following a hippocampus dependent learning task using a dominant mouse model of Nr4a. Method: We performed total RNA sequencing after training for hippocampus-dependent memory from Nr4ADN and control littermates Results: Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we found that Nr4a transcription factors regulate expression of specific effector genes encoding endoplasmic reticulum (ER) chaperones that drive protein folding, enabling membrane proteins to more efficiently traffic to the cell surface. Conclusion: This study identified the effector genes of Nr4a transcription factors involved in learning and memory.
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Project description:FoxO6 is expressed in the brain, craniofacial region and somite, but the precise role of FoxO6 in craniofacial development remain unknown. We found that FoxO6 is expressed specifically in craniofacial tissues and FoxO6-/- mice undergo expansion of the face, frontal cortex, olfactory component and skull. Our gene expression array data demonstrated that Lats1, an important component of Hippo signaling pathway, was decresed in FoxO6-/- mice. Our in vitro and in vivo data further validated that FoxO6 activates Lats1 expression, thereby increasing Yap phosphorylation and activation of Hippo signaling.
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Project description:Myotonic dystrophy type I (DM1) patients demonstrate visuospatial dysfunction and impaired performance in tasks requiring recognition or memory of figures and objects. In DM1, CUG expansion RNAs inactivate the Muscleblind-like (MBNL) proteins. We show that constitutive Mbnl2 inactivation in Mbnl2ΔE2/ΔE2 mice, selectively impairs object recognition memory in the novel object recognition test. When exploring the context of a novel arena in which the objects are later encountered, the Mbnl2ΔE2/ΔE2 dorsal hippocampus responds with a lack of enrichment for learning and memory related pathways, mounting instead transcriptome alterations predicted to impair growth and neuron viability. In Mbnl2ΔE2/ΔE2 mice, saturation effects may prevent deployment of a functionally relevant transcriptome response during novel context exploration. Post-novel context exploration alterations in genes implicated in tauopathy and dementia are observed in the Mbnl2ΔE2/ΔE2 dorsal hippocampus. Thus MBNL2 inactivation in DM1 patients may alter novel context processing in the dorsal hippocampus and impair object recognition memory.
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