School of Pharmacy researcher publishes work on social isolation, drug abuse

LAWRENCE — Since the COVID-19 pandemic, University of Kansas researcher Zijun Wang has studied social isolation and how it affects mental health and substance abuse disorders. Her research article, titled “Prelimbic cortex to ventral tegmental area projection regulates early social isolation stress-potentiated heroin seeking in mice,” appears in the Oct. 29 edition of the open access journal Nature Communications.

Wang, associate professor of pharmacology & toxicology in the School of Pharmacy, is exploring how early-life adversities increase vulnerability to substance abuse disorders. Her research in mouse models has found that the stress of early social isolation (ESI) increases heroin-seeking behavior, and combined ESI and heroin abuse altered gene expression in the brain that appears to lead to heroin relapse.

One in six children have severe exposure to four or more adverse experiences, according to Wang. Stress from these experiences is detrimental to brain development, especially the prefrontal cortex that controls self-regulation.

“Any stress that challenges the maturation of the brain can disrupt brain development or rewire the brain leading to behavior abnormalities and impaired mental health,” Wang said. “Depression, anxiety and drug addiction significantly impair mental health, and early life adversity can increase risk for these mental illnesses and even for early aging and neurodegenerative disorders such as Alzheimer’s disease.”

Wang’s research is exploring the reasons why early life adversity, such as ESI, alters the brain and makes people susceptible to drug addiction. Potentially, her research will help inform therapeutic approaches by discovering novel molecular targets in key brain circuits to circumvent these vulnerabilities. Social isolation, she said, can alter the function and gene expression within the prefrontal cortex to the ventral tegmental area circuit, in a way similar to drug abuse, and lead to potentiated drug-seeking behavior.

“The combined factors of early life stress and later drug exposure induce a deleterious effect on this brain circuitry,” Wang said, “and we want to further understand impact of these factors.”

In a deeper dive, her lab is identifying individual molecules, triggered by isolation stress and drug abuse, that are impacting neuron function to make the situation worse and that can lead to increased drug-seeking behavior.

Wang’s research team is using CRISPR-Cas9 gene editing technology to specifically manipulate the expression of target genes within the affected brain circuit. Theoretically, the gene would be edited to alter the negative behavior and reduce or eliminate the impact of stress and drug addiction in the brain. Potentially, this type of research could lead to therapies and drug discovery that could interrupt the destructive effects of stress and drug abuse.

“I want people to know that early stress has a big impact on the brain,” Wang said. “Some people are really vulnerable to mental illness, not because they choose to, but because environmental factors, and in some cases genetic predisposition, have put them in that position. I believe we can always find a cure or at least ways to mitigate this stress-induced effect, either through modifying the behavior or through pharmacological interventions. This is the focus of our science and research.”

Over the past five years, Wang has received over $3 million in grants from the National Institutes of Health to fund her research.