Comparison of brain and blood gene expression in an animal model of negative symptoms in schizophrenia

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

Download Full-text

Whole blood gene expression within days after total-body irradiation predicts long term survival in Gottingen minipigs

Scientific Reports ◽

10.1038/s41598-021-95120-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sunita Chopra ◽

Maria Moroni ◽

Jaleal Sanjak ◽

Laurel MacMillan ◽

Bernadette Hritzo ◽

...

Keyword(s):

Gene Expression ◽

Total Body Irradiation ◽

Whole Blood ◽

Radiation Effects ◽

Expression Profiles ◽

Mass Casualty ◽

Machine Learning Algorithms ◽

Term Survival ◽

Blood Gene Expression ◽

Total Body

AbstractGottingen minipigs mirror the physiological radiation response observed in humans and hence make an ideal candidate model for studying radiation biodosimetry for both limited-sized and mass casualty incidents. We examined the whole blood gene expression profiles starting one day after total-body irradiation with increasing doses of gamma-rays. The minipigs were monitored for up to 45 days or time to euthanasia necessitated by radiation effects. We successfully identified dose- and time-agnostic (over a 1–7 day period after radiation), survival-predictive gene expression signatures derived using machine-learning algorithms with high sensitivity and specificity. These survival-predictive signatures fare better than an optimally performing dose-differentiating signature or blood cellular profiles. These findings suggest that prediction of survival is a much more useful parameter for making triage, resource-utilization and treatment decisions in a resource-constrained environment compared to predictions of total dose received. It should hopefully be possible to build such classifiers for humans in the future.

Download Full-text

Interaction of clozapine with metformin in a schizophrenia rat model

Scientific Reports ◽

10.1038/s41598-021-96478-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

G. Horvath ◽

G. Kis ◽

G. Kekesi ◽

A. Büki ◽

L. G. Adlan ◽

...

Keyword(s):

Gene Expression ◽

Cognitive Function ◽

Negative Symptoms ◽

Antipsychotic Drugs ◽

D1 Receptor ◽

Antidiabetic Drug ◽

Beneficial Effects ◽

Adjuvant Therapies ◽

Behavioral Parameters ◽

The Brain

AbstractThe low efficacy of antipsychotic drugs (e.g., clozapine) for negative symptoms and cognitive impairment has led to the introduction of adjuvant therapies. Because previous data suggest the procognitive potential of the antidiabetic drug metformin, this study aimed to assess the effects of chronic clozapine and metformin oral administration (alone and in combination) on locomotor and exploratory activities and cognitive function in a reward-based test in control and a schizophrenia-like animal model (Wisket rats). As impaired dopamine D1 receptor (D1R) function might play a role in the cognitive dysfunctions observed in patients with schizophrenia, the second goal of this study was to determine the brain-region-specific D1R-mediated signaling, ligand binding, and mRNA expression. None of the treatments affected the behavior of the control animals significantly; however, the combination treatment enhanced D1R binding and activation in the cerebral cortex. The Wisket rats exhibited impaired motivation, attention, and cognitive function, as well as a lower level of cortical D1R binding, signaling, and gene expression. Clozapine caused further deterioration of the behavioral parameters, without a significant effect on the D1R system. Metformin blunted the clozapine-induced impairments, and, similarly to that observed in the control animals, increased the functional activity of D1R. This study highlights the beneficial effects of metformin (at the behavioral and cellular levels) in blunting clozapine-induced adverse effects.

Download Full-text

A dual approach to self-stimulation and locomotor trace affected by chronic methamphetamine treatment for an animal model of schizophrenia

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y93-050 ◽

1993 ◽

Vol 71 (5-6) ◽

pp. 321-325 ◽

Cited By ~ 11

Author(s):

Morikuni Takigawa ◽

Hiroshi Maeda ◽

Kenichi Ueyama ◽

Hidefumi Tominaga ◽

Kei Matsumoto

Keyword(s):

Animal Model ◽

Negative Symptoms ◽

Disease Model ◽

Stereotyped Behavior ◽

Dependent Manner ◽

Dual Approach ◽

Reverse Tolerance ◽

Self Stimulation ◽

Dose Dependent

The effect of long-term methamphetamine (MAP) treatment on intracranial self-stimulation of the lateral hypotholamus and locomotor traces was assessed. An attempt was made to provide a useful animal model for understanding anhedonia, stereotypy, and reoccurrence of liability, which are analogous to symptoms of schizophrenia. The frequency of intracranial self-stimulation (ICSS) as used as a measure of the animals' "hedonic–anhedonic" state. Following long-term MAP treatment (3 mg/kg), rats gradually showed stereotyped behavior, and became inactive and unresponsive to ICSS. These behavioral changes and decreased ICSS lasted several weeks after cessation of chronic MAP treatment and seemed to suggest post-MAP chronic psychosis and (or) anhedonia, two of the negative symptoms of schizophrenia. The traces of rat behavior affected by chronic MAP treatment were classified into three types, peripheral, mixed, and fixed, occurring in a dose-dependent manner. Reverse tolerance, similar to the reoccurrence of schizophrenic symptoms, was observed as a fixed stereotypy associated with loss of ICSS. These abnormal phenomena were suppressed by pretreatment with haloperidol. In the present study, the combination of ICSS and locomotor trace affected by chronic MAP treatment was proposed as an animal model of schizophrenia and as a useful technique for gauging the effect of neuroleptics.Key words: self-stimulation, anhedonia, stereotypy, reverse tolerance, animal disease model, schizophrenia, methamphetamine.

Download Full-text