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A General Method for Evaluating Deep Brain Stimulation Effects on Intravenous Methamphetamine Self-Administration
Published on: January 22, 2016
A comprehensive study to delineate the role of an extracellular vesicle-associated microRNA-29a in chronic
Subhash Chand1, Austin Gowen1, Mason Savine1
1Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, Nebraska, USA.
Abstract:
Extracellular vesicles (EVs), which express a repertoire of cargo molecules (cf. proteins, microRNA, lipids, etc.), have been garnering a prominent role in the modulation of several cellular processes. Here, using both non-human primate and rodent model systems, we provide evidence that brain-derived EV (BDE) miRNA, miR-29a-3p (mir-29a), is significantly increased during chronic methamphetamine (MA) exposure. Further, miR-29a levels show significant increase both with drug-seeking and reinstatement in a rat MA self-administration model. We also show that EV-associated miR-29a is enriched in EV pool comprising of small EVs and exomeres and further plays a critical role in MA-induced inflammation and synaptodendritic damage. Furthermore, treatment with the anti-inflammatory drug ibudilast (AV411), which is known to reduce MA relapse, decreased the expression of miR-29a and subsequently attenuated inflammation and rescued synaptodendritic injury. Finally, using plasma from MUD subjects, we provide translational evidence that EV-miR29a could potentially serve as a biomarker to detect neuronal damage in humans diagnosed with MA use disorder (MUD). In summary, our work suggests that EV-associated miR-29a-3p plays a crucial role in MUD and might be used as a potential blood-based biomarker for detecting chronic inflammation and synaptic damage.
Insights
Brain-derived extracellular vesicle microRNA-29a-3p increases with chronic methamphetamine exposure, driving inflammation and neuronal damage. This microRNA may serve as a biomarker for methamphetamine use disorder.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Extracellular vesicles (EVs) mediate intercellular communication through their cargo.
- Chronic methamphetamine (MA) exposure causes significant neuroinflammation and synaptodendritic damage.
- MicroRNAs (miRNAs) are key regulators of gene expression and cellular processes.
Purpose of the Study:
- To investigate the role of brain-derived EV miRNA, specifically miR-29a-3p, in chronic methamphetamine use disorder (MUD).
- To determine if miR-29a-3p levels correlate with drug-seeking behavior and neuroinflammation.
- To evaluate the potential of EV-miR29a as a biomarker for neuronal damage in MUD.
Main Methods:
- Utilized non-human primate and rodent models for chronic MA exposure.
- Measured miR-29a-3p levels in brain-derived EVs during MA self-administration and reinstatement.
- Analyzed EV composition and treated animals with ibudilast (AV411).
- Assessed plasma EV-miR29a in human subjects with MUD.
Main Results:
- Chronic MA exposure significantly increased brain-derived EV miR-29a-3p levels in animal models.
- Elevated miR-29a-3p correlated with drug-seeking behavior and MA-induced inflammation and synaptodendritic damage.
- Ibudilast treatment reduced miR-29a-3p, inflammation, and neuronal injury.
- Plasma EV-miR29a levels were elevated in human MUD subjects, indicating potential as a biomarker.
Conclusions:
- EV-associated miR-29a-3p plays a critical role in mediating MA-induced neuroinflammation and synaptodendritic damage.
- miR-29a-3p is a potential blood-based biomarker for detecting chronic inflammation and synaptic damage in MUD.
- Targeting EV-miR29a may offer therapeutic strategies for MUD.
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