Substance use disorders create persistent changes in the brain that often make long-term recovery challenging. While neuroscientists have historically focused on neurons — the primary nerve cells responsible for transmitting electrical signals — to understand and treat addiction, a new research project at The University of Texas at San Antonio is turning its attention to an often-overlooked “support cell” in the brain: astrocytes.
Supported by a new two-year, $368,392 grant from the National Institute on Drug Abuse (NIDA) at the National Institutes of Health (NIH), researchers are investigating how astrocytes in the midbrain (the uppermost portion of the brainstem) may act as a natural brake against drug-seeking behavior. By mapping and manipulating the molecular programs within these non-neuronal cells, the team aims to uncover therapeutic targets capable of combating addiction to stimulants like cocaine and opioids like fentanyl.
Looking beyond neurons
Addiction research has historically focused on neurons within the mesolimbic dopamine system — the brain’s primary reward and motivation network. Astrocytes, the star-shaped glial cells that regulate the environment around neurons, were traditionally seen as structural or nutrient support cells. But recently, they have gained recognition as active partners in neural function.
“Astrocytes have traditionally been thought of as ‘support cells’ for neurons,” said Matthew J. Wanat, PhD, professor in the Department of Neuroscience, Developmental and Regenerative Biology in the College of Sciences at UT San Antonio and co-principal investigator on the award. “However, a growing body of research highlights that astrocytes are not necessarily playing second fiddle to neurons but rather are in a partnership with neurons and can directly impact neuronal activity.”
While prior research mainly analyzed astrocytes in the striatum, the UT San Antonio team is focusing upstream on the ventral tegmental area (VTA), a core midbrain region that supplies dopamine to the rest of the reward circuit. Preliminary observations suggest that exposure to certain substances causes long-lasting adaptations in VTA astrocytes that naturally work to suppress future drug intake.
“The big picture idea is that astrocytes are different from neurons,” Wanat explained. “By looking at how drugs affect astrocytes, we might find new targets to reduce drug intake.”
Decoding the molecular switches of the epigenome
To understand how drugs leave lasting marks on brain tissue, the researchers are studying epigenetics — the layer of biological instructions that controls how genes are turned on or off without altering the underlying DNA sequence.
In every cell, DNA is packaged into a complex structure called chromatin. When chromatin is open or “accessible,” genes can be read and expressed into cellular messages; when tightly compacted, those genes remain silent.
“You can think of these 23,000 genes as instructions, and every cell essentially makes sequential choices about which instructions it needs to follow,” said Alexey A. Soshnev, MD, PhD, assistant professor in the Department of Neuroscience, Developmental and Regenerative Biology in the College of Sciences and co-principal investigator. “Here, we are studying both abundance of gene ‘message’ — a proxy for gene activity — and structure of the gene itself.”
The project evaluates both psychostimulants (cocaine) and opioids (fentanyl) to determine if different drug classes induce a shared molecular signature within VTA astrocytes.
“The drugs and their pharmacological mechanisms of action are pretty well understood at this point — and are indeed different,” Soshnev noted. “However, there is a fundamental similarity between the two: they both hijack the dopamine-producing brain circuit, which is, ultimately, the mechanism of disease. When two different actors cause similar outcomes, it is logical that there must be some fundamental similarity between the two, and our studies are designed to uncover any such ‘overlap.’”
Reprogramming gene activity
To move beyond simply observing these genetic changes to proving they directly cause changes in behavior, the team is deploying advanced gene-control technology known as “epigenetic editing.”
At the heart of this approach is dCas9, an enzyme derived from the bacterial gene-editing system, CRISPR. Unlike regular CRISPR/Cas9, which cuts specific DNA sequences, dCas9 is modified to bind to a precise location in the genome without damaging the underlying DNA. By attaching transcriptional activators or repressors to the dCas9 protein, researchers can selectively dial gene activity up or down without altering the host genetic code.
“The first part of our study will describe the changes associated with drug-seeking behavior, but this is a correlation,” Soshnev explained. “So, we need to establish causality — and the way to do that would be to manipulate the activity of these genes and test whether this would either ‘rescue’ or exacerbate the behavioral phenotypes.”
A potential path toward broad-spectrum addiction therapies
If the two-year exploratory discovery phase successfully identifies high-confidence gene targets altered by both cocaine and fentanyl, the project will be eligible to advance into a three-year functional validation phase supported by the NIH.
While clinical applications remain a long-term goal, establishing an astrocyte-specific therapeutic target could provide a new avenue for developing substance use disorder treatments that target astrocytes rather than neurons.
“The dream would be to find a silver bullet where there is a drug-induced change in astrocytes within the ventral tegmental area that is controlling cravings,” Wanat said.
