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Machine Learning Analysis of the Orbitofrontal Cortex Transcriptome of Human Opioid Users Identifies Shisa7 as a
Randall J Ellis1, Jacqueline-Marie N Ferland1, Tanni Rahman2
1Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Addiction Institute of Mount Sinai, New York, New York.
Background:
Identifying neurobiological targets predictive of the molecular neuropathophysiological signature of human opioid use disorder (OUD) could expedite new treatments. OUD is characterized by dysregulated cognition and goal-directed behavior mediated by the orbitofrontal cortex (OFC), and next-generation sequencing could provide insights regarding novel targets.
Methods:
Here, we used machine learning to evaluate human postmortem OFC RNA sequencing datasets from heroin users and control participants to identify transcripts that were predictive of heroin use. To determine a causal link to OUD-related behaviors, we examined the effects of overexpressing the top target gene in a translational rat model of heroin seeking and behavioral updating. Additionally, we determined the effects of overexpression on the rat OFC transcriptome compared with that of human heroin users. Co-immunoprecipitation/mass spectrometry (co-IP/MS) from the rat OFC elucidated the protein complex of the novel target.
Results:
Our machine learning approach identified SHISA7 as predictive of human heroin users. Shisa7 is understudied but appears to be an auxiliary protein of GABAA (gamma-aminobutyric acid A) or AMPA receptors. In rats, Shisa7 expression positively correlated with heroin-seeking behavior. Overexpressing Shisa7 in the OFC augmented heroin seeking and impaired behavioral updating for sucrose-based operant contingency. RNA sequencing of rat OFC revealed gene coexpression networks regulated by Shisa7 overexpression similar to human heroin users. Finally, co-IP/MS showed that heroin influenced Shisa7 binding to glutamatergic and GABAergic receptor subunits. Both gene expression signatures and Shisa7 protein complex emphasized perturbations of neurodegenerative and neuroimmune processes.
Conclusions:
Our findings suggest that OFC Shisa7 is a critical driver of neurobehavioral pathology related to drug-seeking behavior and behavioral updating, thus identifying a potential therapeutic target for OUD.
Insights
Researchers identified SHISA7 in the orbitofrontal cortex as a key driver of opioid use disorder (OUD) behaviors. Targeting SHISA7 may offer a new therapeutic strategy for OUD by modulating drug-seeking and cognitive functions.
Area of Science:
- Neuroscience
- Genomics
- Pharmacology
Background:
- Opioid use disorder (OUD) presents significant challenges due to dysregulated cognition and goal-directed behavior.
- The orbitofrontal cortex (OFC) plays a crucial role in mediating these OUD-related behaviors.
- Identifying novel neurobiological targets is essential for developing effective OUD treatments.
Purpose of the Study:
- To identify neurobiological targets in the OFC predictive of the molecular signature of OUD.
- To investigate the causal role of identified targets in OUD-related behaviors using a translational rat model.
- To elucidate the molecular mechanisms underlying the identified target's function in the OFC.
Main Methods:
- Machine learning analysis of human postmortem OFC RNA sequencing data from heroin users and controls.
- Overexpression of the top identified gene (SHISA7) in a rat model to assess effects on heroin seeking and behavioral updating.
- RNA sequencing of rat OFC to compare gene expression with human heroin users.
- Co-immunoprecipitation/mass spectrometry (co-IP/MS) to identify the SHISA7 protein complex.
Main Results:
- SHISA7 was identified as a transcript predictive of heroin use in humans.
- SHISA7 overexpression in rats augmented heroin seeking and impaired behavioral updating.
- SHISA7 regulates gene coexpression networks in the rat OFC similar to those in human heroin users.
- SHISA7 interacts with glutamatergic and GABAergic receptor subunits, implicating neurodegenerative and neuroimmune pathways.
Conclusions:
- OFC SHISA7 is a critical driver of neurobehavioral pathology in OUD.
- SHISA7 modulates drug-seeking behavior and behavioral updating, representing a potential therapeutic target for OUD.
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