The brain is complex. It’s where we sense feelings, form memories and control behavior.
Recently, three Indiana University School of Medicine researchers each received National Institutes of Health grant funding to study under-explored mechanisms and connections in the brain using animal models. Through their investigations, they hope to discover therapeutic targets to treat health conditions, including obesity, anxiety and alcohol use disorder.
The faculty investigators are members of the addiction research interest group at Stark Neurosciences Research Institute — a growing collaboration of faculty from the IU School of Medicine and the School of Science at IU Indianapolis. These researchers are interested in studying the cellular, molecular and behavioral correlations to addiction to alcohol and other substances. The addiction research group is one of nine research groups at the institute.
Intersection of alcohol and anxiety
Woody Hopf, PhD, professor of psychiatry, received a five-year, $2.6 million grant from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to study the brain’s anterior insula cortex—a feelings regulator—and its interaction with alcohol and anxiety in females and males.
According to the 2022 National Survey on Drug Use and Health, 29.5 million people — 17.4 million males and 12.2 million females — ages 12 and older had alcohol use disorder in the past year. In recent decades, drinking among women has risen dramatically, and women also have greater risk of developing alcohol problems, Hopf said. Anxiety can strongly contribute to alcohol drinking in some people, he added.
The project will look at sex differences and similarities in brain mechanisms that drive alcohol intake and the possible comorbidity of anxiety with maladaptive drinking. By studying differences between females and males in animal models, Hopf said the larger goal is to identify novel sex- and individual-specific therapeutic targets for alcohol use disorder and anxiety.
The Hopf lab has a particular eye on the anterior insula system. The anterior insula is an area of the brain located about an inch and a half in from the top of the temple that often helps people adjust to challenges, which can help them stay on track for a higher goal.
“We propose that it’s a zen center for the brain,” Hopf said. “When you’re driving a car, the cost of failing is very high, but you can’t freak out. You must stay calm. That is the secret to a good life, and that is what the anterior insula often provides, along with other brain systems.”
Because the anterior insula is so powerful, Hopf said, when the brain decides that drinking alcohol or taking drugs is most important, the insula carries out the same role that it does normally, but now it’s taken over by addiction or anxiety. A major goal of the Hopf lab is to investigate how to inhibit these harmful behaviors.
The study will focus on two types of alcohol consumption: alcohol-only drinking (drinking without explicit challenge) and compulsion-like alcohol intake (when a subject knows they shouldn’t drink, but they can’t stop themselves). Hopf said researchers will use a technique known as optogenetics, where a light shines into the brain and inhibits specific brain connections. In this way, they can discover the importance of key outputs from the insula area to other parts of the brain, including how they may differ for females and males.
The Hopf lab will also directly examine activity of the anterior insula area while the animal is in different alcohol situations and behaviors.
The central aim of the study, Hopf said, is to better understand possible sex differences in insula brain mechanisms that drive alcohol drinking and anxiety.
“Women have greater risk than men for behavioral health conditions including alcohol use disorder and anxiety comorbidity,” he said. “Our overarching goal is to discover how anterior insula regulation of emotion and arousal may contribute to this higher risk.”
Mediating alcohol-seeking behaviors
Sheketha Hauser, PhD, assistant research professor of psychiatry, received a five-year, $2.3 million grant from the NIAAA to study role of serotonin-7 receptors in the brain’s serotonin system, which could impact alcohol-seeking behaviors and offer a target for therapeutics.
The chronic relapsing nature of alcohol use disorders is one of the major challenges in treating them. Alcohol misuse over time can lead to alteration in the brain and alcohol cravings that can persist even when a person abstains from consuming alcohol.
Hauser said intense cravings for alcohol can increase as more time passes between abstinence and the last alcoholic drink, increasing the inability to stop drinking or to control drinking behavior, as well as interfering with a person's ability to maintain sobriety.
“Improving a person's behavior control could reduce alcohol cravings and recurrent relapses,” Hauser said. “While there are some pharmacological treatments for alcohol use disorder, there is still a need to find more efficacious treatments.”
The serotonin system is thought to play a role in a person developing an alcohol addiction and in emotional and behavioral inhibition processes, Hauser said. The serotonin-7 receptor — the most recently discovered serotonin receptor — is a potential therapeutic target for conditions such as anxiety, depression, neuropathic pain, Alzheimer’s disease and drug addiction.
Using animal models, this research will test if treatment with a serotonin-7 receptor agonist is a potential target in reducing alcohol cravings in alcohol use disorders. The study will use behavioral, genetic, molecular and neurochemistry techniques to investigate how serotonin-7 receptors within neurocircuits that control behavior change over time during cravings and what mechanisms underly its ability to regulate alcohol-seeking behaviors.
“Research has shown the receptor plays a role in modulating behavioral inhibitory control, with a serotonin-7 agonist improving behavior control,” Hauser said. “The development of more successful treatments for alcohol use disorders and drug cravings may involve serotonin-7 receptor activation of neuronal circuits regulating the inhibition of alcohol-seeking behaviors.”
How the brain controls energy expenditure
The National Institute of Diabetes and Digestive and Kidney Diseases awarded Jonathan Flak, PhD, assistant professor of pharmacology and toxicology, a five-year, $1.8 million grant to study how unexplored mechanisms in the brain impact energy expenditure and weight loss.
The human body is wired to survive famines, not an obesity epidemic, Flak said, and it functions to push a person back to their normal body weight and protect them from starvation. Those physiological responses, however, are counterproductive when a person wants to lose weight.
Flak said there are systems in the brain that drive adipose tissue, or body fat, and muscle function and stimulate how well the cells can metabolize excess nutrients and expend energy. When a person is trying to lose weight, that brain pathway gets turned off, he said.
“These processes make it harder to lose weight,” Flak said. “Hopefully we can understand some of these processes and turn them back on to make people lose weight better.”
Current weight loss drugs have shown promise in people losing weight, Flak said, but they’re designed for a person to take for the rest of their life to see lasting effects. If someone stops taking the drug, they will most likely return to their previous weight, like when a person stops dieting.
There’s a growing interest in how to keep weight off and maintain a healthy body weight without using expensive drugs for a lifetime. Flak said these mechanisms that control how much energy a person expends could be an answer.
“Our body’s ability to metabolize nutrients is something that’s not set in stone and can be tuned by our central nervous system,” he said. “There are key components that are not fully understood, and the goal of the grant is to investigate them.”
Although the grant does not specifically fund addiction research, Flak said this study may have future applications for addiction research.
