Gene expression following acute methamphetamine administration in selectively bred mice
Ontology highlight
ABSTRACT: This study examined NAc gene expression in a pair short-term selected lines bred for high or low response to methamphetamine (MA). We sought to identify candidate genes preferentially expressed among individuals showing either large or small acute responses to MA. Additionally, we sought to identify genes and networks differentially expressed by MA exposure within these divergent lines. Keywords: Short-term selected lines (STSLs), saline (SAL), methamphetamine (MA), nucleus acumbens (NAc)
Project description:This study examined NAc gene expression in a pair short-term selected lines bred for high or low response to methamphetamine (MA). We sought to identify candidate genes preferentially expressed among individuals showing either large or small acute responses to MA. Additionally, we sought to identify genes and networks differentially expressed by MA exposure within these divergent lines. Experiment Overall Design: STSLs generated from C57BL/6J x DBA/2J stock were bred for high (HMACT) or low (LMACT) acute MA response. Mice were given a challenge injection of MA or SAL, and decapitated 1 hr later. NAc gene expression was assessed.
Project description:Transcriptome profiling can broadly characterize drug effects and risk for addiction in the absence of drug exposure. Modern large-scale molecular methods, including RNA-sequencing (RNA-Seq), have been extensively applied to alcohol-related disease traits, but rarely to risk for methamphetamine (MA) addiction. We used RNA-Seq data from selectively bred mice with high or low risk for voluntary MA intake to construct coexpression and cosplicing networks for differential risk. Three brain reward circuitry regions, the nucleus accumbens (NAc), prefrontal cortex (PFC) and ventral midbrain (VMB), were explored. With respect to differential gene expression and wiring, the VMB was more strongly affected than either the PFC or NAc. Coexpression network connectivity was higher in the low line than the high line in the VMB, oppositely affected in the NAc, and little impacted in the PFC. Gene modules protected from the effects of selection may help to eliminate certain mechanisms from significant involvement in risk for MA intake. One such module was enriched in genes with dopamine-associated annotations. Overall, the data suggest that mitochondrial function and glutamate-mediated synaptic plasticity have key roles in the outcomes of selective breeding for high versus low levels of MA intake.
Project description:Two wild house mice lines were genetically selected for short and long attack latency. Mice with an attack latency <50s or >600s were considered short attack latency mice (SAL) and long attack latency mice(LAL) respectively. RNA from the hippocampus of 14 SAL or 14 LAL mice was pooled and used as input material for the SAGE libraries. Keywords: other
Project description:Two wild house mice lines were genetically selected for short and long attack latency. Mice with an attack latency <50s or >600s were considered short attack latency mice (SAL) and long attack latency mice(LAL) respectively. RNA from the hippocampus of 14 SAL or 14 LAL mice was pooled and used as input material for the SAGE libraries. Keywords: other
Project description:Genome wide DNA methylation profiling of normal and methamphetamine (MA) abusers with different addiction susceptibility. The Illumina Infinium HumanMethylation450 Beadchip was used to obtain DNA methylation profiles in peripheral blood lymphocytes (PBLs). Samples included 8 health controls, 8 high MA addiction susceptibility (HMAS) abusers, and 8 high MA addiction susceptibility (LMAS) abusers.
Project description:To identify molecular effects of chronic drug treatment, heroin and methamphetamine treated animals were compared with saline treated animals at multiple time-points using microarray technology. Gene expression profile was assessed 14 h after the last dose of 1, 3, 6 or 12 days drug treatment and after 13, 15, 18 or 24 days of withdrawal. Animals were injected intraperitoneally with saline (SAL) (Polfa, Lublin, Poland), heroin (synthesized from morphine in Institute of Pharmacology PAS, Krakow, Poland) or D-methamphetamine (Sigma-Aldrich, Poznan, Poland) twice a day for consecutive 12 days in increasing doses. The Methamphetamine last dose (8 mg/kg) was four times greater than the first dose (2 mg/kg). It was also the case for heroin (40 and 10 mg/kg respectively). Mice were sacrificed by decapitation after 1, 3, 6 or 12 days of treatment or after 13, 15, 18 or 24 days of withdrawal.
Project description:The GASH/Sal hamster (Genetic audiogenic seizure, Salamanca) is a model of audiogenic seizures with the epileptogenic focus localized in the inferior colliculus (IC). The sound-induced seizures exhibit a short latency (7-9 seconds), which implies innate protein disturbances in the IC as a basis for seizure susceptibility and generation. Here, we aim to study the protein profile in the GASH/Sal IC in comparison to controls. Protein samples from the IC were processed for enzymatic digestion and then analyzed by mass spectrometry in Data-Independent Acquisition mode. After identifying the proteins using the UniProt database, we selected those with differential expression. We identified 5254 proteins, of which 184 were differentially expressed, 126 upregulated and 58 downregulated. Moreover, a small number of proteins were uniquely found in the GASH/Sal or the control. The resuls indicated a protein profile alteration in the epileptogenic nucleus that might underlie the innate occuring audiogenic seizures in the GASH/Sal model.
Project description:To inform the mechanism of hnRNP H dysfunction in methamphetamine-induced dopamine release and behavior, we surveyed mRNA targets of hnRNP H via cross-linking immunoprecipitation coupled with high-throughput sequencing (CLIP-seq) in striatal tissue at baseline and at 30 min post-MA (2 mg/kg, i.p.). To integrate identification of hnRNP H targets with the impact of methamphetamine on downstream gene expression and splicing, we analyzed the transcriptome of the parallel samples used in CLIP-seq.
Project description:Methamphetamine use disorder (MUD) is a chronic, relapsing disease that is characterized by repeated drug use despite negative consequences for which there are currently no FDA approved cessation therapeutics. Repeated methamphetamine (METH) use induces long-term gene expression changes in brain regions associated with reward processing and drug-seeking behavior, and recent evidence suggests that methamphetamine-induced neuroinflammation may also shape behavioral and molecular responses to the drug. Microglia, the resident immune cells in the brain, are principal drivers of neuroinflammatory responses and contribute to the pathophysiology of substance use disorders. Here, we investigated transcriptional and morphological changes in striatal microglia in response to methamphetamine-taking and during methamphetamine abstinence, as well as their functional contribution to drug-taking behavior. We show that methamphetamine self-administration induces transcriptional changes related to protein folding, mRNA processing, immune signaling, and neurotransmission in striatal microglia. Importantly, many of these transcriptional changes persist through abstinence, a finding supported by morphological analysis. Functionally, we report that microglial ablation increases methamphetamine-taking, possibly involving neuroimmune and neurotransmitter regulation. In contrast, microglial depletion did not alter methamphetamine-seeking behavior following 21 days of abstinence, highlighting the complexity of drug-seeking behaviors. Taken together, these results suggest that methamphetamine induces both short and long-term changes in striatal microglia that contribute to altered drug-taking behavior and may be leveraged for preclinical development of methamphetamine cessation therapeutics.
Project description:Two large-scale outbreaks of streptococcal toxic shock-like syndrome (STSLS) have revealed Streptococcus suis 2 (SS2) to be a severe, evolving pathogen in humans. We investigated the mechanism by which SS2 causes STSLS. The transcriptional regulator TstS up-regulated during experimental infection. Compared with the wild type 05ZY strain, the tstS deletion mutant (∆tstS) elicited reduced cytokine secretion in macrophages. In mice, tstS deletion decreased virulence, bacterial load, and cytokine production. Moreover, TstS expression in P1/7 strain led to induction of STSLS in the infected mice. This is noteworthy because although virulent, P1/7 does not normally induce STSLS. Through microarray-based comparative transcriptomics analysis, we found that TstS regulates multiple metabolism related genes and several virulence-related genes associated with immune evasion.