Synaptosomal proteomics in hippocampus from a PD model
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ABSTRACT: SWATH-MS proteomics was used to study protein composition in isolated hippocampal synapses derived from A53T-mutated hα-syn rats respect to WT rats.
Project description:Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We imposed ELA by rearing rat pups in simulated poverty, assessed hippocampal memory, and probed changes in gene expression, their transcriptional regulation and the consequent changes in hippocampal neuronal structure. ELA rats had poor hippocampal memory and stunted hippocampal pyramidal neurons, associated with ~140 differentially expressed genes. Upstream regulators of the altered genes included glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributed critically to the memory deficits because blocking its function transiently following ELA rescued spatial memory and restored the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augmented dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function.
Project description:With the criterion of 2-fold cutoff, 7 miRNAs were upregulated and 7 miRNAs were downregulated in APP/PS1 hippocampal tissues compared with WT hippocampal tissues Microarray analysis of miRNAs was performed on pooled hippocampal tissues from WT (n=16) and APP/PS1 mice (n=16) at E14
Project description:With the criterion of 2-fold cutoff, 7 miRNAs were upregulated and 7 miRNAs were downregulated in APP/PS1 hippocampal tissues compared with WT hippocampal tissues
Project description:Transcriptional profiling of rat hippocampus 4.5h post intracranial self-stimulation (ICSS) show that this treatment, which improves learning and memory processes in a variety of paradigms of implicit and explicit memory, regulates gene expression of genes related to cAMP-mediated signaling and regulation of synaptic plasticity, among others. Rats were implanted with a monopolar stainless steel electrode aimed at the lateral hypothalamus in the right hemisphere. Hippocampal gene expression was analyzed 4.5h post treatment comparing rats subjected to acute self-stimulation (2500 stimulation trains; ICSS group) with sham-operated rats (with electrode placement but placed in the ICSS without stimulation during 40 min.; Sham group). Two-condition experiment, ICSS and Sham. Every sample consisted of pooled hippocampi ipsilateral to the electrode from three rats. Slices between Bregma levels -2 and -4 were used for dissections of the hippocampi. Common reference design, comparing every condition versus a brain pooled tissue consisting of pooled hippocampal tissue ipsilateral to the electrode of sham-operated (n=3) and stimulated (n=3) rats. Biological replicates: 4 DBS and 4 sham. One replicate per array.
Project description:Diabetes is one of the major risk factors for Alzheimer’s disease (AD) development. The role of elevated levels of glucose, methylglyoxal (MGO), and advanced glycation end products (AGEs) in diabetes in the pathogenesis of the AD is not well understood. In this pursuit, we studied the role of methylglyoxal in the pathogenesis of AD in rat models. The elevated plus-maze (EPM) behavioural study indicated that MGO induces anxiety. Treatment of telmisartan (RAGE expression inhibitor) and aminoguanidine (MGO quencher) attenuated MGO induced anxiety. Further, hippocampal proteomics demonstrated that MGO treated rats differentially regulate proteins involved in calcium homeostasis, mitochondrial functioning, and apoptosis which may affect neurotransmission and neuronal plasticity. Hippocampal tau phosphorylation level was increased in MGO treated rats which was reduced in presence in aminoguanidine and telmisartan. Plasma fructosamine level was increased upon MGO treatment. Hippocampal histochemistry showed vascular degeneration and neuronal loss upon MGO treatment. This study provides mechanistic insight into the role of MGO in the diabetes-associated development of AD.
Project description:The hippocampal formation is a brain structure essential for higher-order cognitive functions. It has exquisite differences in anatomical organization and cellular composition, and hippocampal sub-regions have different properties and functional roles. Areas CA1 and CA3 in particular, are key sub-regions for learning and memory formation that fulfill complementary but specific functions. The molecular basis for such specific properties and the link to learning and memory remain unknown. Here using a SWATH-MS proteomic approach and bioinformatic tools, we identify a selective proteomic signature in area CA1 and CA3, and reveal their specific dynamics during memory formation. We show that 30% of all quantifiable proteins are differentially expressed in area CA1 and CA3 at baseline, and that each proteome responds differently during the formation of memory for object or object location. Using clustering and cross-correlational analyses, we outline specific temporal proteomic profiles and an increased correlation between both forms of memory within area CA1, but not within area CA3. These results provide new insight into a proteomic basis for hippocampal sub-region molecular and functional specificity.
Project description:The study determined whether there were gender differences in the <br>expression of hippocampal genes in adult rats in association with dissimilarity <br>in their behavior, and how these were affected by prenatal stress. Pregnant <br>Wistar rats were subjected to varied stress once daily on days 14-20 of <br>gestation.<br>
Project description:The present study was conducted to identify relevant genes that could be involved in the action of androgens in rat hippocampus. We compared hippocampal gene expression between controls and orchidectomized male rats.
Project description:This project aims to assess the transcriptomic signature of FUS∆NLS/+ (FUS) vs FUS+/+ (WT) mice, by identifying differentially expressed genes in basal conditions and also during learning. Cytoplasmic mislocalization of the nuclear Fused in Sarcoma (FUS) protein is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS accumulation is recapitulated in the frontal cortex and spinal cord of heterozygous Fus∆NLS/+ mice. We show that in these mice, the hippocampus, a critical structure involved in learning and memory, paradoxically displays nuclear FUS accumulation. FUS binds to a set of genes characterized by the presence of an ETS/ELK-binding motifs, and involved in RNA metabolism, transcription, ribosome/mitochondria and chromatin organization. Importantly, hippocampal nuclei showed a decompaction of the neuronal chromatin at highly expressed genes and an inappropriate transcriptomic response was observed after spatial training of Fus∆NLS/+ mice. Furthermore, these mice lacked precision in hippocampal-dependent spatial memory task. These studies shows that mutated FUS affects epigenetic regulation of the chromatin landscape in hippocampal neurons, which could participate in FTD/ALS pathogenic events.
Project description:Study the effect of fetal alcohol exposure (FAE) on hippocampal development; Compare the pattern of gene expression in the hippocampus of FAE and control rats fed either an isocaloric diet or a normal diet, at post-natal day 5 of development. FAE will delay the maturation of the hippocampus; Rats were fed one of three diet, a liquid diet with 5% ethanol (FAE group), an isocaloric liquid diet (Isocalorc group) or nomal lab chao (normal group)