Biomedical subjects

Simon J Evans

Publications and source records attributed to Simon J Evans.

7 recordsLinked to original sources

PubMed2006

The fibroblast growth factor system and mood disorders.

Recent evidence now suggests the involvement of the fibroblast growth factor (FGF) system in mood disorders. Specifically, several members of the FGF family have been shown to be dysregulated in individuals with major depression. In this review, we will introduce the FGF system in terms of structure and function during development, in adulthood, and in various regions and cell types. We will also review the FGF system as a mediator of neural plasticity. Furthermore, this review will summarize animal as well as human studies. The majority of animal studies have focused on stress, environmental enrichment, pharmacological manipulations, and the hippocampus. By contrast, human studies have focused on volumetric measurements, antidepressant literature, and, most recently, post-mortem microarray experiments. In summary, a reduced tone in the FGF system might alter brain development or remodeling and result in a predisposition or vulnerability to mood disorders, including major depression.

Animals↗

PubMed2006

Application of microarray technology in primate behavioral neuroscience research.

Gene expression profiling of brain tissue samples applied to DNA microarrays promises to provide novel insights into the neurobiological bases of primate behavior. The strength of the microarray technology lies in the ability to simultaneously measure the expression levels of all genes in defined brain regions that are known to mediate behavior. The application of microarrays presents, however, various limitations and challenges for primate neuroscience research. Low RNA abundance, modest changes in gene expression, heterogeneous distribution of mRNA among cell subpopulations, and individual differences in behavior all mandate great care in the collection, processing, and analysis of brain tissue. A unique problem for nonhuman primate research is the limited availability of species-specific arrays. Arrays designed for humans are often used, but expression level differences are inevitably confounded by gene sequence differences in all cross-species array applications. Tools to deal with this problem are currently being developed. Here we review these methodological issues, and provide examples from our experiences using human arrays to examine brain tissue samples from squirrel monkeys. Until species-specific microarrays become more widely available, great caution must be taken in the assessment and interpretation of microarray data from nonhuman primates. Nevertheless, the application of human microarrays in nonhuman primate neuroscience research recovers useful information from thousands of genes, and represents an important new strategy for understanding the molecular complexity of behavior and mental health.

Animals↗

PubMed2005

Combining laser capture microdissection with quantitative real-time PCR: effects of tissue manipulation on RNA quality and gene expression.

Laser capture microdissection (LCM) is increasingly being used in quantitative gene expression studies of the nervous system. The current study aimed at determining the impact of various tissue manipulations on the integrity of extracted RNA in LCM studies. Our data indicate that various tissue preparation strategies prior to microdissection may decrease RNA quality by as much as 25%, thus affecting expression profiles of some genes. To circumvent this problem, we developed a strategy for reverse transcriptase real-time PCR that has considerable sensitivity and can be used to calculate relative changes in gene expression. This approach was validated in subregions of the rat cerebellum. Accordingly, expression of glial gene markers - myelin-associated glycoprotein and proteolipid protein 1 - was found 70-160-fold higher in the white matter layer of the cerebellar cortex as compared to the neuron-enriched granular layer. In contrast, expression of a specific neuronal maker, neuron-specific enolase, was found seven-fold higher in the granular layer, as compared to the white matter layer. Furthermore, this approach had high sensitivity and specificity as we were able to detect a 38% decrease in the expression of neuron-specific enolase without a change in the expression of glial markers following administration of the neurotoxin, ibotenic acid. These results demonstrate feasibility of performing accurate semi-quantitative gene expression analyses in LCM samples.

Animals↗

PubMed2004

Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain.

There are major concerns that specific agonal conditions, including coma and hypoxia, might affect ribonucleic acid (RNA) integrity in postmortem brain studies. We report that agonal factors significantly affect RNA integrity and have a major impact on gene expression profiles in microarrays. In contrast to agonal factors, gender, age, and postmortem factors have less effect on gene expression profiles. The Average Correlation Index is proposed as a method for evaluating RNA integrity on the basis of similarity of microarray profiles. Reducing the variance due to agonal factors is critical in investigating small but validated gene expression differences in messenger RNA levels between psychiatric patients and control subjects.

Adult↗

PubMed2004

Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions.

Studies of gene expression abnormalities in psychiatric or neurological disorders often involve the use of postmortem brain tissue. Compared with single-cell organisms or clonal cell lines, the biological environment and medical history of human subjects cannot be controlled, and are often difficult to document fully. The chance of finding significant and replicable changes depends on the nature and magnitude of the observed variations among the studied subjects. During an analysis of gene expression changes in mood disorders, we observed a remarkable degree of natural variation among 120 samples, which represented three brain regions in 40 subjects. Most of such diversity can be accounted for by two distinct expression patterns, which in turn are strongly correlated with tissue pH. Individuals who suffered prolonged agonal states, such as with respiratory arrest, multi-organ failure or coma, tended to have lower pH in the brain; whereas those who experienced brief deaths, associated with accidents, cardiac events or asphyxia, generally had normal pH. The lower pH samples exhibited a systematic decrease in expression of genes involved in energy metabolism and proteolytic activities, and a consistent increase of genes encoding stress-response proteins and transcription factors. This functional specificity of changed genes suggests that the difference is not merely due to random RNA degradation in low pH samples; rather it reflects a broad and actively coordinated biological response in living cells. These findings shed light on critical molecular mechanisms that are engaged during different forms of terminal stress, and may suggest clinical targets of protection or restoration.

Adult↗

PubMed2003

Microarray technology: a review of new strategies to discover candidate vulnerability genes in psychiatric disorders.

OBJECTIVE: An international effort is in progress to discover candidate genes and pathways associated with psychiatric disorders, including two of the most serious diseases, schizophrenia and mood disorders, through the use of new technology-microarrays. Instead of studying one gene at a time, microarrays provide the opportunity to analyze thousands of genes at once. METHOD: This article reviews the steps in this discovery process, including the acquisition and characterization of high-quality postmortem brain tissue, RNA extraction, and preparation and use of microarray technology. Two alternative microarray methods and factors affecting the quality of array data are reviewed. RESULTS: New analytical strategies are being developed to process the massive data sets generated by microarray studies and to define the significance of implicated genes. Array results must be validated by other methods, including in situ hybridization and real-time polymerase chain reaction. Identified genes can also be evaluated in terms of their chromosomal locations and possible overlap with regions of suggestive linkage or association identified with genome-wide linkage analysis in psychiatry and in terms of overlap with genes identified by microarray studies in animals administered psychoactive drugs. Microarray studies are only the first major step in the process. Further efforts in the investigation involve multiple strategies for studying function and gene structure, including transgenic and knockout animal studies. CONCLUSIONS: Microarrays present a methodology that can identify genes or pathways for new and unique potential drug targets, determine premorbid diagnosis, predict drug responsiveness for individual patients, and, eventually, initiate gene therapy and prevention strategies.

Brain Chemistry↗

PubMed2002

Evaluation of Affymetrix Gene Chip sensitivity in rat hippocampal tissue using SAGE analysis. Serial Analysis of Gene Expression.

DNA microarrays are a powerful tool for monitoring thousands of transcript levels simultaneously. However, the use of DNA microarrays in studying the central nervous system faces several challenges. These include the detection of low-abundance transcripts in highly complex tissue as well as estimating relatively low-magnitude changes in transcript levels in response to experimental manipulation. Many transcripts important to brain function have low expression levels or are expressed in relatively few cells, making them difficult to detect in the complex background of brain tissue. The aim of the present study is to evaluate the sensitivity of Gene Chip detection of transcripts in brain by using results from serial analysis of gene expression (SAGE) studies. The results of this comparison indicate that Affymetrix Gene Chips, like SAGE, only reliably detect medium- to high-abundance transcripts and that detection of low-abundance transcripts, many of which have great relevance to biological function in brain, is inconsistent. Specifically, we estimate that Gene Chips reliably detect no more than 30% of the hippocampal transcriptome when using a gross hippocampal dissection as the source tissue. This report provides the first broad evaluation of Affymetrix Gene Chip sensitivity relevant to studying the brain.

Animals↗