Project description:The aim of this study was to investigate whether the differences in memory decline associated with aging are a result of differences in gene expression. We first categorized age-unimpaired and age-impaired rats based on their performance in the Morris water maze, when compared to young rats. Then we isolated messenger RNA from the dentate gyrus of the hippocampus of each animal to interrogate Affymetrix RAE 230A rat genome microarrays. Supervised statistical analysis of the different groups of aged animals recognized 85 genes (p<0.005) that were significantly different in the dentate gyrus of aged rats that had learned the Morris water maze (MWM) paradigm when compared to learning impaired and a number of controls for stress, exercise and non-spatial learning. In addition, statistical analysis of the microarray data that included young and aged rats identified 1129 genes (p<0.005) that were differentially expressed between aged and young rats independent of behavior, but due to aging alone. Experiment Overall Design: a total of 80 samples were analyzed including aged and young rats for aged versus young comparisons. One chip was interrogated per animal. Supervised analysis of aged rat data (aged unimpaired (HID U) versus controls : HID I, VIS, YOKE, SIT includes 39 samples (intermediate learners were not included in the analysis). Controls include cage controls, yoke controls (no platform), visible platform controls.
Project description:The aim of this study was to investigate whether the differences in memory decline associated with aging are a result of differences in gene expression. We first categorized age-unimpaired and age-impaired rats based on their performance in the Morris water maze, when compared to young rats. Then we isolated messenger RNA from the dentate gyrus of the hippocampus of each animal to interrogate Affymetrix RAE 230A rat genome microarrays. Supervised statistical analysis of the different groups of aged animals recognized 85 genes (p<0.005) that were significantly different in the dentate gyrus of aged rats that had learned the Morris water maze (MWM) paradigm when compared to learning impaired and a number of controls for stress, exercise and non-spatial learning. In addition, statistical analysis of the microarray data that included young and aged rats identified 1129 genes (p<0.005) that were differentially expressed between aged and young rats independent of behavior, but due to aging alone. Keywords: behavior comparison, age comparison
Project description:The aim of this study was to investigate whether the differences in memory decline associated with aging are a result of differences in gene expression. We first categorized age-unimpaired and age-impaired rats based on their performance in the Morris Water Maze and then isolated messenger RNA from the CA1 hippocampal region of each animal to interrogate Affymetrix microarrays. Microarray analysis (p<0.005) identified a set of 50 genes that were transcribed differently in age-unimpaired animals that had successfully learned a spatial task compared to aged learning-impaired animals and a variety of groups designed to control for all non-learning aspects of exposure to the water maze paradigm. Experiment Overall Design: a total of 79 samples were analyzed including aged and young rats. One chip was interrogated per animal. Analysis of aged rat data includes 44 samples. Controls include cage controls, yoked controls (no platform), visible platform controls.
Project description:The dentate gyrus of the hippocampus is a brain region involved in learning, memory formation, and spatial coding. We performed single-cell RNA-sequencing of the dentate gyrus of young and old mice to identify the age-induced changes.
Project description:We inhibited RNA polymerase I by genetic ablation of the basal transcription factor TIF-IA in adult hippocampal neurons. Nucleolar stress resulted in progressive neurodegeneration, although with a differential vulnerability within the CA1, CA3 and dentate gyrus. Here, we investigate the consequences of nucleolar stress on learning and memory. The mutant mice do not show any impairment in the behavioral memory tests, suggesting the activation of adaptive mechanisms. In fact, we observe a significantly enhanced learning and re-learning corresponding to the initial inhibition of rRNA transcription and accompanied by aberrant synaptic plasticity. To explore the putative molecular mechanisms underlying these adaptative changes we profiled global gene expression of control and TIFIACaMKCreERT2 mutant mice (5-6 mice/genotype) 4 weeks after induction of the mutation (injection of tamoxifen).
Project description:The current study employed next-generation RNA sequencing to examine gene expression related to brain aging and cognitive decline. Young and aged rats were trained on a spatial episodic memory task. Hippocampal regions CA1, CA3 and the dentate gyrus (DG) were isolated. Poly-A mRNA was examined using two different platforms, Illumina and Ion Proton. The Illumina platform was used to generate lists of genes that were differentially expressed across regions, ages, and in association with cognitive function. The gene lists were then retested using the Ion Proton platform. The results describe regional differences in gene expression and point to regional differences in vulnerability to aging. Aging was associated with increased expression of immune response related genes, particularly in the dentate gyrus. Finally, for the memory task used, impaired performance of aged animals was linked to the regulation of Ca2+ and synaptic function in region CA1.
Project description:Aging is often associated with cognitive decline, but many elderly individuals maintain a high level of function throughout life. Here we studied outbred rats, which also exhibit individual differences across a spectrum of outcomes that includes both preserved and impaired spatial memory. Previous work in this model identified the CA3 subfield of the hippocampus as a region critically affected by age and integral to differing cognitive outcomes. Earlier microarray profiling revealed distinct gene expression profiles in the CA3 region, under basal conditions, for aged rats with intact memory and those with impairment. Because prominent age-related deficits within the CA3 occur during neural encoding of new information, here we used microarray analysis to gain a broad perspective of the aged CA3 transcriptome under activated conditions. Behaviorally induced CA3 expression profiles differentiated aged rats with intact memory from those with impaired memory. In the activated profile, we observed substantial numbers of genes (greater than 1000) exhibiting increased expression in aged unimpaired rats relative to aged impaired, including many involved in synaptic plasticity and memory mechanisms. This unimpaired aged profile also overlapped significantly with a learning induced gene profile previously acquired in young adults. Alongside the increased transcripts common to both young learning and aged rats with preserved memory, many transcripts behaviorally-activated in the current study had previously been identified as repressed in the aged unimpaired phenotype in basal expression. A further distinct feature of the activated profile of aged rats with intact memory is the increased expression of an ensemble of genes involved in inhibitory synapse function, which could control the phenotype of neural hyperexcitability found in the CA3 region of aged impaired rats. These data support the conclusion that aged subjects with preserved memory recruit adaptive mechanisms to retain tight control over excitability under both basal and activated conditions. RNA profiles from cognitively unimpaired and impaired aged rats were compared under 2 conditions: spatial learning task and a non-spatial learning task.
Project description:Chemotherapy treatment for breast cancer can induce cognitive impairments often involving oxidative stress. The brain, as a whole, is susceptible to oxidative stress due to its high-energy requirements, limited anaerobic respiration capacities, and limited antioxidant defenses. The goal of the current study was to determine if the manganese porphyrin SOD mimetic MnTnBuOE-2-PyP (MnBuOE) could ameliorate the effects of doxorubicin, cyclophosphamide, and paclitaxel (AC-T) on mature dendrite morphology and cognitive function. Four-month-old female C57BL/6 mice received intraperitoneal injections of chemotherapy followed by subcutaneous injections of MnBuOE. Four weeks following chemotherapy treatment, mice were tested for hippocampus-dependent cognitive performance in the Morris water maze. After testing, brains were collected for Golgi staining and molecular analyses. MnBuOE treatment preserved spatial memory during the Morris water-maze. MnBuOE/AC-T showed spatial memory retention during all probe trials. AC-T treatment significantly impaired spatial memory retention in the first and third probe trial (no platform). AC-T treatment decreased dendritic length in the Cornu Ammonis 1 (CA1) and dentate gyrus (DG) areas of the hippocampus while AC-T/MnBuOE maintained dendritic length. Comparative proteomic analysis revealed affected protein networks associated with cell morphology and behavior functions in both the AC-T and AC-T/MnBuOE treatment groups
Project description:The aim of this study was to investigate whether the differences in memory decline associated with aging are a result of differences in gene expression. We first categorized age-unimpaired and age-impaired rats based on their performance in the Morris Water Maze and then isolated messenger RNA from the CA1 hippocampal region of each animal to interrogate Affymetrix microarrays. Microarray analysis (p<0.005) identified a set of 50 genes that were transcribed differently in age-unimpaired animals that had successfully learned a spatial task compared to aged learning-impaired animals and a variety of groups designed to control for all non-learning aspects of exposure to the water maze paradigm. Keywords: behavior comparison, age comparison
Project description:Although immediate early genes (IEGs) such as Bdnf, Arc and Egr1, have been implicated in plasticity, the larger pathways related to memory and memory disorders are not well understood. Here, we combined statistical Affymetrix microarray and behavioral analyses to identify key genes and pathways associated with aging-related cognitive impairment. Aged rats were separated into cognitively unimpaired (AU) or impaired (AI) groups, based on their Morris water maze performance relative to young-adult (Y) animals. Hippocampal gene expression was assessed in Y, AU and AI on the fifth (last) day of maze training or 21 days posttraining, and in non-trained aged and young animals (eight groups, overall n = 78, one chip/animal). ANOVA, linear contrasts, and overrepresentation analyses identified genes and pathways that differed from Y generally with aging (in both AU and AI) or selectively with cognitive status (only in AI or AU). Plasticity pathways, including insulin/cAMP/IEG signaling, and glycogenolytic and lipogenic pathways, were selectively downregulated (5 days) in AI, whereas Notch2 (regulating oligodendrocyte differentiation) and myelination pathways were upregulated (particularly at 21 days). Downregulation with general aging occurred in signal transduction and axonal growth/transport pathways, whereas upegulation occurred in immune/inflammatory, lipid metabolism/transport (e.g., Lxr-Srebf1), and lysosomal pathways. In AU, receptor/signal transduction genes were selectively upregulated, suggesting possible compensatory mechanisms. Immunohistochemistry confirmed and extended results to the protein level. Thus, this study identified novel cognition-linked processes, suggesting a new model in which energy-intensive, plasticity/lipogenic processes and energy-generating pathways necessary for learning are coordinately downregulated during training, while myelinogenic programs that impair cognition are concurrently activated. Experiment Overall Design: Aged rats were separated into cognitively unimpaired (AU) or impaired (AI) groups, based on their Morris water maze performance relative to young-adult (Y) animals (NT, 5D, and 21D, N=10/group). Hippocampal gene expression was assessed in Y, AU and AI on the fifth (last) day of maze training or 21 days posttraining, and in non-trained aged and young animals (eight groups, overall n = 78, one chip/animal)