Gene Expression In Cerebral Cortex Research Articles

Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer's Disease Model Mice

AbstractBackgroundDefining cellular mechanisms that drive Alzheimer's disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre‐symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD.MethodTo identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2‐/‐) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA‐Seq and Ribo‐Seq (ribosome profiling). Identical starting pools of bulk RNA were used for RNA‐Seq and Ribo‐Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels to disentangle genes specifically regulated at the translation level. Regulated genes were functionally evaluated by gene ontology tools.ResultCompared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to APP metabolism associated with neurotoxicity and neuroprotection.ConclusionThis work represents the first genome‐wide study of brain translatome regulation in animal models of AD, and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

Transcriptome and Translatome Regulation of Pathogenesis in Alzheimer’s Disease Model Mice

Background: Defining cellular mechanisms that drive Alzheimer’s disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD. Objective: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI;NOS2 -/- ) and Tg2576 (APPSw), and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling). Methods: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools. Results: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection. Conclusion: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain.

Effect of Artesunate vs Memantine in Aluminum Chloride Induced Model of Neurotoxicity in Rats

Alzheimer disease is one of the commonest neurological diseases which is characterized by amyloid plaques accumulation in multiple brain regions. This study investigated the potential neuroprotective effect of artesunate on aluminum induced neurotoxicity vs memantine in rats. 40 male albino Wistar rats were divided randomly into 4 groups as follow: Group 1 negative control, group 2 positive control group induced by ammonium chloride, group 3 rats treated by NH4Cl + artesunate solution, group 4 rats treated by NH4Cl + memantine S.C. spatial Memory and Learning were evaluated using Morris Water Maze (MWM) test. Malondialdehyde (MDA) and reduced glutathione (GSH) levels were measured in cerebral cortex tissue homogenate. Tumor necrosis factor-α (TNFα) and interleukin-1 beta (IL-1β) concentrations were measured in rat cerebral cortex tissue homogenate using rat enzyme linked immunosorbent assay (ELISA) kits. Real-time quantitative reverse transcription-polymerase chain reaction (Real-time qRT-PCR) for Caspase-3, Bcl-2 and iNOS gene expression was measured in rat cerebral cortex. Slices from cerebral cortex were studied by histopathological examination. Artesunate significantly decreased MDA level and inhibited iNOS, caspase and upregulated Bcl-2 gene expression in cerebral cortex. ART increased significantly antioxidant level GSH, and decreased significantly TNF-alpha and IL-B levels. It reduced significantly 1ry retention latency, 2ry retention latency and initial acquisition latency. It also improved brain histopathology and decreased amyloid plaque deposition. ART exerted neuroprotective effect through oxidative stress correction and enhancement of antiapoptotic markers in neuronal cells of the cerebral cortex.

Maternal immune activation alters behavior in adult offspring, with subtle changes in the cortical transcriptome and epigenome

Maternal immune activation during prenatal development, including treatment with the viral RNA mimic, polyriboinosinic–polyribocytidilic acid (poly IC), serves as a widely used animal model to induce behavioral deficits reminiscent of schizophrenia and related disease. Here, we report that massive cytokine activation after a single dose of poly IC in the prenatal period is associated with lasting working memory deficits in adult offspring. To explore whether dysregulated gene expression in cerebral cortex, contributes to cognitive dysfunction, we profiled the cortical transcriptome, and in addition, mapped the genome-wide distribution of trimethylated histone H3-lysine 4 (H3K4me3), an epigenetic mark sharply regulated at the 5′ end of transcriptional units. However, deep sequencing-based H3K4me3 mapping and mRNA profiling by microarray did not reveal significant alterations in mature cerebral cortex after poly IC exposure at embryonic days E17.5 or E12.5. At a small set of genes (including suppressor of cytokine signaling Socs3), H3K4me3 was sensitive to activation of cytokine signaling in primary cultures from fetal forebrain but adult cortex of saline- and poly IC-exposed mice did not show significant differences. A limited set of transcription start sites (TSS), including Disrupted-in-Schizophrenia 1 (Disc1), a schizophrenia risk gene often implicated in gene–environment interaction models, showed altered H3K4me3 after prenatal poly IC but none of these differences survived after correcting for multiple comparisons. We conclude that prenatal poly IC is associated with cognitive deficits later in life, but without robust alterations in epigenetic regulation of gene expression in the cerebral cortex.

Dynamic Gene Expression in the Human Cerebral Cortex Distinguishes Children from Adults

In comparison with other primate species, humans have an extended juvenile period during which the brain is more plastic. In the current study we sought to examine gene expression in the cerebral cortex during development in the context of this adaptive plasticity. We introduce an approach designed to discriminate genes with variable as opposed to uniform patterns of gene expression and found that greater inter-individual variance is observed among children than among adults. For the 337 transcripts that show this pattern, we found a significant overrepresentation of genes annotated to the immune system process (pFDR≅0). Moreover, genes known to be important in neuronal function, such as brain-derived neurotrophic factor (BDNF), are included among the genes more variably expressed in childhood. We propose that the developmental period of heightened childhood neuronal plasticity is characterized by more dynamic patterns of gene expression in the cerebral cortex compared to adulthood when the brain is less plastic. That an overabundance of these genes are annotated to the immune system suggests that the functions of these genes can be thought of not only in the context of antigen processing and presentation, but also in the context of nervous system development.

Significance of F3/Contactin gene expression in cerebral cortex and nigrostriatal development

F3/Contactin is a neuronal surface glycoprotein, which plays a general role in neural development and, in particular, in neuronal and oligodendrocyte differentiation. In a previous study using the F3/EGFP transgenic mice, which express an EGFP reporter under control of the regulatory region from the mouse F3/Contactin gene, the activation of the F3/Contactin promoter was found to correlate with granule and Purkinje neuron differentiation in developing cerebellar cortex. Here we report that in developing cerebral cortex and basal ganglia the F3/Contactin gene is mostly activated during early commitment of neuronal precursors, thus indicating a region-specific profile of its developmental activation. We also report that, in the same structures of F3/EGFP mice, a downregulation of the endogenous F3/Contactin gene occurs, which correlates with upregulation of the dopaminergic phenotype and with locomotor pattern abnormalities. Therefore, F3/EGFP transgenic mice exhibit morphological and functional phenotypes recapitulating those arising from imbalance of the striatal dopaminergic pathway. As for the underlying mechanisms, we postulate that in F3/EGFP mice F3/Contactin downregulation results from the ability of transgene promoter sequences to interfere with the activation of the endogenous gene, thus realizing an F3/Contactin knockdown model, while dopaminergic upregulation is consistent with a general F3/Contactin inhibitory effect on the neuronal phenotype.

Role of antioxidants on Na+,K+-ATPase activity and gene expression in cerebral cortex of hyperprolinemic rats

Considering that Na(+),K(+)-ATPase is an embedded-membrane enzyme and that experimental chronic hyperprolinemia decreases the activity of this enzyme in brain synaptic plasma membranes, the present study investigated the effect of chronic proline administration on thiobarbituric acid-reactive substances, as well as the influence of antioxidant vitamins E plus C on the effects mediated by proline on Na(+),K(+)-ATPase activity in cerebral cortex of rats. The expression of Na(+),K(+)-ATPase catalytic subunits was also evaluated. Results showed that proline increased thiobarbituric acid-reactive substances, suggesting an increase of lipid peroxidation. Furthermore, concomitant administration of vitamins E plus C significantly prevented the increase of lipid peroxidation, as well as the inhibition of Na(+),K(+)-ATPase activity caused by proline. We did not observe any change in levels of Na(+),K(+)-ATPase mRNA transcripts after chronic exposure to proline and vitamins E plus C. These findings provide insights into the mechanisms through which proline exerts its effects on brain function and suggest that treatment with antioxidants may be beneficial to treat neurological dysfunctions present in hyperprolinemic patients.

CDNA microarray analysis of gene expression in the cerebral cortex and hippocampus of BALB/c mice subjected to chronic mild stress.

Depressive disorders are devastating metal illness that can lead to deterioration in the social and occupational functioning of affected individuals. The etiology and pathophysiology of depression remain unknown. Present study was performed to better understand the underlying causes of depression. An experimental animal depression was induced in male BALB/c mice subjected to a chronic mild stress (CMS) procedure involving different stressor for consecutive 4weeks. A cDNA microarray was employed to study the effects of CMS on the gene expression in cerebral cortex and hippocampus. 4-week CMS caused a significant reduction of 2% sucrose consumption. Morris water maze procedure showed impairment in cognitive function in stressed mice. Results of microarray showed that there were 102 and 60 genes were markedly affected by CMS treatment in cerebral cortex and hippocampus regions, respectively, including DNA damage/repair-related enzymes, anti-oxidant enzyme, and cyclin and cyclin-dependent kinase (CDK). These findings suggest that multiple biochemical effects play an important role the etiology of depression.

Thyroid Hormone-Regulated Mouse Cerebral Cortex Genes Are Differentially Dependent on the Source of the Hormone: A Study in Monocarboxylate Transporter-8- and Deiodinase-2-Deficient Mice

Thyroid hormones influence brain development through the control of gene expression. The concentration of the active hormone T(3) in the brain depends on T(3) transport through the blood-brain barrier, mediated in part by the monocarboxylate transporter 8 (Mct8/MCT8) and the activity of type 2 deiodinase (D2) generating T(3) from T(4). The relative roles of each of these pathways in the regulation of brain gene expression is not known. To shed light on this question, we analyzed thyroid hormone-dependent gene expression in the cerebral cortex of mice with inactivated Mct8 (Slc16a2) and Dio2 genes, alone or in combination. We used 34 target genes identified to be controlled by thyroid hormone in microarray comparisons of cerebral cortex from wild-type control and hypothyroid mice on postnatal d 21. Inactivation of the Mct8 gene (Mct8KO) was without effect on the expression of 31 of these genes. Normal gene expression in the absence of the transporter was mostly due to D2 activity because the combined disruption of Mct8 and Dio2 led to similar effects as hypothyroidism on the expression of 24 genes. Dio2 disruption alone did not affect the expression of positively regulated genes, but, as in hypothyroidism, it increased that of negatively regulated genes. We conclude that gene expression in the Mct8KO cerebral cortex is compensated in part by D2-dependent mechanisms. Intriguingly, positive or negative regulation of genes by thyroid hormone is sensitive to the source of T(3) because Dio2 inactivation selectively affects the expression of negatively regulated genes.

Progesterone Differentially Regulates Pro- and Anti-Apoptotic Gene Expression in Cerebral Cortex Following Traumatic Brain Injury in Rats

Although the administration of progesterone has been shown to be neuroprotective in experimental models of traumatic brain injury (TBI), the mechanisms for this beneficial effect are still poorly understood. The present study examined the effects of progesterone on mRNA and protein levels of the Bcl-2 apoptosis regulatory genes, bax, bad, bcl-2, and bcl-x(L), in cerebral cortex after TBI. Male Sprague-Dawley rats were subjected to either sham surgery or lateral fluid percussion brain injury of moderate severity (2.4-2.6 atm). Within 1 h post-surgery, progesterone (4 mg/kg) or vehicle (corn oil) administration was initiated for 1-7 days postoperatively. Our results indicate that bax and bad mRNA levels and Bax and Bad protein expression in the ipsilateral, injured cerebral cortex were significantly elevated post-TBI, while mRNA levels of bcl-2 and bcl-x(L) or Bcl-2 and Bcl-x(L) protein expression were not changed. Under the sham-treated condition, progesterone significantly increased mRNA levels of the anti-apoptotic gene, bcl-2, but down-regulated pro-apoptotic gene expression (bax and bad) in cerebral cortex. After TBI, progesterone treatment reduced bax and bad mRNA levels in the ipsilateral cerebral cortex of TBI rats, and decreased Bax and Bad protein levels. In addition, bcl-2 and bcl-x(L) mRNA levels, as well as Bcl-2 and Bcl-x(L) protein expression, were increased by progesterone in TBI injured cortex. These data indicate that one of the neuroprotective mechanisms of progesterone may be related to its differential regulation of apoptotic signals.

Erratum to “The novel monoamine reuptake inhibitor and potential antidepressant, S33005, induces Arc gene expression in cerebral cortex” [Eur. J. Pharmacol. 489(2004)179–185

Erratum to “The novel monoamine reuptake inhibitor and potential antidepressant, S33005, induces Arc gene expression in cerebral cortex” [Eur. J. Pharmacol. 489(2004)179–185

O4-05-02 Pleiotropic effects of statins on gene expression in cerebral cortex of mice

O4-05-02 Pleiotropic effects of statins on gene expression in cerebral cortex of mice

The novel monoamine reuptake inhibitor and potential antidepressant, S33005, induces Arc gene expression in cerebral cortex

Recent data show that corticolimbic expression of the effector immediate early gene Arc is up-regulated by standard antidepressant drugs. Here, we tested the effect upon Arc expression of a novel antidepressant and selective 5-hydroxytryptamine/noradrenaline reuptake inhibitor (SNRI), (−)1-(1-dimethylaminomethyl) 5-methoxybenzocyclobutan-1-yl) cyclohexanol (S33005). Arc mRNA abundance in frontal, cingulate, orbital and parietal cortices, hippocampus (CA1 pyramidal layer) and striatum was elevated in rats treated daily for 14 but not 7 days with 10 mg/kg i.p. S33005 compared to saline. Fourteen but not 7 days treatment with 10 mg/kg i.p. venlafaxine, the prototypical SNRI, also elevated Arc mRNA, but its effects were not as pronounced and detected in fewer regions, compared to S33005. Neither S33005 nor venlafaxine altered Arc mRNA after acute injection nor altered brain derived neurotrophic factor mRNA after repeated administration. These data demonstrate that sustained treatment with SNRIs increases Arc expression in corticolimbic regions, and underpin previous neurochemical and behavioural evidence that S33005 is efficacious in models predictive of antidepressant action.

Immediate-early gene expression in cerebral cortex following exposure to chronic-intermittent hypoxia

Chronic-intermittent hypoxia (CIH) was postulated to evoke c- fos expression in cortical regions that modulate sympathetic discharge. Animals exposed to CIH for 30 days exhibited c- fos labeling in medial prefrontal, cingulate, retrosplenial, and insular cortices. Our findings strongly suggest activation of cortical circuits that adaptively regulate sympathetic and cardiovascular activities.

Decrease of adenosine A-1 receptor gene expression in cerebral cortex of aged rats

Changes of adenosine A-1 receptor (A1-AR) gene expression in aging were investigated in cerebral cortex using the rat aged from 2 months (adult) to 24 months (aged). Quantification of A1-AR protein level by immunoblotting analysis showed an age-related decrease of A1-AR in cerebral cortex of Wistar rats. Compared to the preparations from 2-month-old animals, the levels of A1-AR in the 6-, 12-, and 24-month-old rats were reduced by 14.3±5.2, 32.5±4.5 and 28.2±5.7%, respectively. Similar decrease of mRNA level in A1-AR was also obtained using Northern blotting analysis. Two representative spots of mRNA, a 3.4-kb transcript and a 5.6-kb transcript, were observed in X-ray film from cerebral cortex of rat hybridized with rat A1-AR cDNA probe. Compared to the 2 month-old rats, levels of the 5.6-kb transcript were decreased by 17.9±2.5, 27.4±3.2 and 23.1±2.1% in the 6-, 12- and 24-month-old rats, respectively. These results indicated an age-related decrease of A1-AR in cerebral cortex of the rat that seems responsible for the change of response to adenosine.

Selegiline enhances NGF synthesis and protects central nervous system neurons from excitotoxic and ischemic damage

It has been previously demonstrated that selegiline, an irreversible monoamine oxidase B (MAO-B) inhibitor, potentiates glial reaction to injury and possesses some ‘trophic-like’ activities which do not depend on the inhibition of MAO-B and which are probably associated with the induction of astrocyte-derived neurotrophic substances. Based on these findings, we tried to find out whether selegiline is able to modify the expression of nerve growth factor (NGF) and to protect central nervous system (CNS) neurons from excitotoxic and ischemic damage. Selegiline (10 pM–1 nM) induced NGF messenger RNA (mRNA) expression in cultured rat cortical astrocytes as determined by reverse transcription-polymerase chain reaction (RT-PCR) followed by a corresponding increase in NGF protein content measured by two-site NGF-enzyme-linked immunosorbent assay (ELISA) in astrocyte-conditioned medium. Additionally, exposure of hippocampal cultures containing neuronal and glial cells to this drug at the same concentrations enhanced significantly the content of NGF measured in the culture medium after 6 h of incubation. We hypothesize that selegiline could rescue hippocampal neurons from injury by induction of astrocyte-derived NGF in this cell culture system. To test this hypothesis, an excitotoxic damage was induced in the same type of cells by exposure to 0.5 mM l-glutamate for 1 h. Selegiline (10 pM–1 nM) present in the growth medium 6 h before until 18 h after induction of injury (the point of glutamate-toxicity measurement) protected hippocampal neurons from excitotoxic death. Furthermore, administered intraperitoneally (i.p.) (8 × 15 mg/kg per day) this drug enhanced the expression of NGF message in intact rat cerebral cortex and protected rat cortical tissue from ischemic insult due to permanent occlusion of the middle cerebral artery (MCA). The neuroprotective activity of selegiline (5 × 10 mg/kg per day i.p.) was also demonstrated in a mouse model of focal cerebral ischemia. The present data show that selegiline induced NGF expression in cultured rat cortical astrocytes. In mixed primary cultures of hippocampal neuronal and glial cells, selegiline increased NGF protein content and protected hippocampal neurons from excitotoxic degeneration. In vivo, this drug induced NGF gene expression in cerebral cortex from intact rats and protected rat and mouse cortical tissue from ischemic insult after occlusion of the MCA. Our results indicate that the induction of astrocyte-derived NGF could contribute to the neuroprotective activity of selegiline demonstrated both in vivo and in vitro and can explain, in part, the ‘trophic-like’ properties of this compound which has been observed by others.