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Region-specific transcriptional response to chronic nicotine in rat brain.

ABSTRACT: Even though nicotine has been shown to modulate mRNA expression of a variety of genes, a comprehensive high-throughput study of the effects of nicotine on the tissue-specific gene expression profiles has been lacking in the literature. In this study, cDNA microarrays containing 1117 genes and ESTs were used to assess the transcriptional response to chronic nicotine treatment in rat, based on four brain regions, i.e. prefrontal cortex (PFC), nucleus accumbens (NAs), ventral tegmental area (VTA), and amygdala (AMYG). On the basis of a non-parametric resampling method, an index (called jackknifed reliability index, JRI) was proposed, and employed to determine the inherent measurement error across multiple arrays used in this study. Upon removal of the outliers, the mean correlation coefficient between duplicate measurements increased to 0.978+/-0.0035 from 0.941+/-0.045. Results from principal component analysis and pairwise correlations suggested that brain regions studied were highly similar in terms of their absolute expression levels, but exhibited divergent transcriptional responses to chronic nicotine administration. For example, PFC and NAs were significantly more similar to each other (r=0.7; P<10(-14)) than to either VTA or AMYG. Furthermore, we confirmed our microarray results for two representative genes, i.e. the weak inward rectifier K(+) channel (TWIK-1), and phosphate and tensin homolog (PTEN) by using real-time quantitative RT-PCR technique. Finally, a number of genes, involved in MAPK, phosphatidylinositol, and EGFR signaling pathways, were identified and proposed as possible targets in response to nicotine administration.

SUBMITTER: Konu O

PROVIDER: S-EPMC3098570 | biostudies-literature | 2001 Aug

REPOSITORIES: biostudies-literature

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Region-specific transcriptional response to chronic nicotine in rat brain.

Konu O Kane J K JK Barrett T T Vawter M P MP Chang R R Ma J Z JZ Donovan D M DM Sharp B B Becker K G KG Li M D MD

Brain research 20010801 1-2

Even though nicotine has been shown to modulate mRNA expression of a variety of genes, a comprehensive high-throughput study of the effects of nicotine on the tissue-specific gene expression profiles has been lacking in the literature. In this study, cDNA microarrays containing 1117 genes and ESTs were used to assess the transcriptional response to chronic nicotine treatment in rat, based on four brain regions, i.e. prefrontal cortex (PFC), nucleus accumbens (NAs), ventral tegmental area (VTA), ...[more]

PMID: 11478936

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Project description:IntroductionClinical studies suggest that HIV-1-infected patients are more likely to use or abuse addictive drugs than is the general population. We hypothesized that HIV-1 proteins impact novelty-seeking behavior and enhance the transcriptional response to nicotine in genes implicated in both novelty-seeking behavior and drug addiction.MethodsWe assessed the effects of HIV-1 proteins on novelty-seeking behavior by comparing baseline activity differences of HIV-1Tg and F344 control rats in the open-field test. One day after behavioral testing, all rats began daily subcutaneous injections of either nicotine (0.4 mg/kg, base) or saline (the same for each rat) for 27 days. At the end of treatment, the prefrontal cortex, nucleus accumbens, and ventral tegmental area were collected for RNA expression analysis of genes in the receptor families for dopamine, GABA, glutamate, and serotonin.ResultsSignificant strain difference was detected in the distance moved in the center, such that HIV-1Tg rats traveled greater distance in the center of the arena than did F344 rats. Quantitative RT-PCR analysis showed that mRNA from Drd3 and Grm2 in the prefrontal cortex and Drd5 and Gabra6 in the ventral tegmental area was significantly upregulated, whereas that of Drd5 in the nucleus accumbens was downregulated in HIV-1Tg rats compared with F344 rats. Further, more addiction-related genes were significantly modulated by nicotine in each brain region in the HIV-1Tg rats than in the control animals.ConclusionsHIV-1 proteins may affect novelty-seeking behavior and modulate the expression of genes related to drug addiction and novelty-seeking behavior.ImplicationsHIV-1 viral proteins and chronic nicotine treatment impact the expression of genes involved in novelty-seeking behavior and addiction in three brain regions of the HIV-1 transgenic rat. These findings implicate that HIV-1 proteins may be involved in novelty-seeking behavior and in modulating the expression of genes related to drug addiction and novelty seeking.

Project description:Microglia are resident macrophages of the brain, performing roles related to brain homeostasis, including modulation of synapses, trophic support, phagocytosis of apoptotic cells and debris, as well as brain protection and repair. Studies assessing morphological and transcriptional features of microglia found regional differences as well as sex differences in some investigated brain regions. However, markers used to isolate microglia in many previous studies are not expressed exclusively by microglia or cannot be used to identify and isolate microglia in all contexts. Here, fluorescent activated cell sorting was used to isolate cells expressing the microglia-specific marker TMEM119 from prefrontal cortex (PFC), striatum, and midbrain in mice. RNA-sequencing was used to assess the transcriptional profile of microglia, focusing on brain region and sex differences. We found striking brain region differences in microglia-specific transcript expression. Most notable was the distinct transcriptional profile of midbrain microglia, with enrichment for pathways related to immune function; these midbrain microglia exhibited a profile similar to disease-associated or immune-surveillant microglia. Transcripts more highly expressed in PFC isolated microglia were enriched for synapse-related pathways while microglia isolated from the striatum were enriched for pathways related to microtubule polymerization. We also found evidence for a gradient of expression of microglia-specific transcripts across the rostral-to-caudal axes of the brain, with microglia extracted from the striatum exhibiting a transcriptional profile intermediate between that of the PFC and midbrain. We also found sex differences in expression of microglia-specific transcripts in all 3 brain regions, with many selenium-related transcripts more highly expressed in females across brain regions. These results suggest that the transcriptional profile of microglia varies between brain regions under homeostatic conditions, suggesting that microglia perform diverse roles in different brain regions and even based on sex.

Dataset Information

Region-specific transcriptional response to chronic nicotine in rat brain.

Publications

Region-specific transcriptional response to chronic nicotine in rat brain.

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