Discovery Suggests Specialized Cells Help Rewire Addicted Brain

Published online in Neuropsychopharmacology, the paper describes how glial (non-neuronal) cells regulate both cellular and behavioral responses to heroin.

By providing new insights into how addiction changes the brain, the research could lead to novel approaches to treatments and potential new targets besides neurons.

“Most therapies have focused on the blocking or activating of receptors that bind drugs like heroin,” notes Dietz, interim chair and associate professor in the Department of Pharmacology and Toxicology and a faculty member with UB’s neuroscience program.

“While that approach may be effective in the short-term, it doesn’t get to the fundamental problem of what is addiction and how to prevent it, as well as prevent relapse.”

Dietz says that not much is known about glial cells in the context of addiction.

“In the addiction field, most neuroscientists focus on neurons. Very rarely have they studied glial cells in psychiatric diseases. This work demonstrates an essential role of glia in addictive behaviors and offers us the ability to provide a new set of targets for future therapies toward the treatment of addiction,” he explains.

Dietz and his colleagues decided to study the potential role of glial cells in addiction when they found that RNA sequencing of tissue from heroin-addicted animals revealed changes in genes that are traditionally markers for a type of glial stem cell called oligodendrocyte precursor cells (OPCs).

The research is likely the first to investigate how opiates affect adult OPCs in the brain’s prefrontal cortex, which is involved in complex cognitive behaviors and is a main target of addictive drugs.

“We found that many of the genes regulated by heroin aligned with the profile of OPCs, so something was going on with them,” he says.

OPCs, he explained, are stem cells that can differentiate into myelinating oligodendrocytes, which are critical for efficient communication between neurons.

Dietz collaborated with co-author Fraser J. Sim, PhD, associate professor of pharmacology and toxicology and a faculty member with UB’s neuroscience program. In 2014, Sim identified one of the genes, SOX10, as a “master switch” for the differentiation of these stem cells towards myelination.

To determine what was happening when genes encoding OPCs were exposed to heroin, the scientists overexpressed them in addicted laboratory animals using viral gene therapy.

The result was surprising: When either of the two genes, SOX10 or BRG1, was overexpressed, the animals’ motivation to take the drug was reduced.

“To our surprise, it reduced their drug-taking behavior,” says Dietz. “It looks like the brain is trying to reconnect and possibly readapt myelin to normalize function, although that would need to be directly tested in future studies.”

One way to think of what may be happening, he explained, is to imagine that the brain is responding to exposure to drugs of abuse by attempting to reconnect with the brain’s other reward centers.

“As with any part of the body that sustains an insult, it seems that the addicted brain is trying to fix what went wrong,” he says.

“Our hypothesis is that after exposure to heroin, the brain starts to activate OPCs in an attempt to fix the altered connectivity that occurs in the addicted states. It is possible that when we facilitated OPCs, we may have reversed some of the disconnect between the prefrontal cortex and the brain’s other reward regions.”

Students in training programs of the Jacobs School of Medicine and Biomedical Sciences have opportunities to gain in-depth experience with the process of publishing in scholarly journals — often early on in their education.

Sim, who mentors undergraduates as well as master’s students and doctoral candidates, notes: “We had several student co-authors on this paper, and this is a function of the collaboration between Dr. Dietz’s lab and my lab.”

“Normally, I have as many as three trainees on each paper because I have students working on different aspects of the research that is covered by each paper,” he says.

Along with Dietz and Sim, other co-authors of “A Novel Role for Oligodendrocyte Precursor Cells (OPCs) and Sox10 in Mediating Cellular and Behavioral Responses to Heroin” are:

• Jennifer A. Martin, a fourth-year doctoral candidate in the Department of Pharmacology and Toxicology
• Aaron Caccamise, a student in Marquette University’s neuroscience doctoral program who graduated from the Department of Pharmacology and Toxicology’s BS/MS program in 2016
• Craig T. Werner, PhD, a postdoctoral fellow in the Department of Pharmacology and Toxicology
• Rathipriya Viswanathan, a second-year master’s student in the neuroscience program
• Jessie J. Polanco Garcia, a fourth-year doctoral candidate in the neuroscience program
• Andrew F. Stewart, a fourth-year student in the College of Arts and Sciences who is studying for a bachelor’s in medicinal chemistry 
• Shruthi A. Thomas, a fourth-year student in the Department of Pharmacology and Toxicology’s BS/MS program

The research was funded by the National Institute on Drug Abuse of the National Institutes of Health.