Israeli, US researchers find brain’s signals that make OCD behaviors hard to stop

Hebrew University of Jerusalem and SUNY Stony Brook scientists discover linked chemicals in pre-clinical trials in mice, potentially helping treat obsessive compulsive disorder

In a groundbreaking study, researchers from the Hebrew University of Jerusalem and SUNY Stony Brook University said they found that one chemical signaling system in the brain can effectively “take the wheel” of another.

The peer-reviewed findings offer a new perspective on the origins of chemical imbalances that underlie numerous debilitating neurological and psychiatric disorders such as Parkinson’s disease, obsessive-compulsive disorder (OCD), anxiety, and depression.

The research team, led by Prof. Joshua Goldberg of Hebrew University and Stony Brook’s Prof. Joshua Plotkin, focused on the brain region central to learning and moving, the dorsal striatum, and the way the coordination between cells may go into overdrive.

“Compulsions, such as repetitive checking or washing, are thought to arise from abnormal activity in circuits of the dorsal striatum that control habitual behaviors,” said Goldberg, speaking to The Times of Israel.

Using AI and cutting-edge imaging techniques in pre-clinical trials on mice in the laboratory, the team explored the effect of a brain chemical called acetylcholine, which can directly trigger the release of serotonin, a neurotransmitter long linked to mood and psychiatric disorders.

The findings, recently published in Nature Communications, could help explain why certain behaviors become “so difficult to stop” in conditions such as OCD, the researchers said.

“Understanding these interactions may help us better understand the circuit dysfunction underlying these disorders and could eventually point toward new ways of treating them,” Goldberg said.

A psychiatric disease affecting people worldwide

Speaking to The Times of Israel, Plotkin said that OCD is one of the most common psychiatric disorders in the world, affecting up to three percent of the global population.

“The disorder doesn’t really discriminate between nationality, race, or gender,” Plotkin said.

In Israel, a study found direct evidence that acute trauma can also trigger or worsen OCD symptoms.

Four to six months after witnessing the bloody October 7, 2023, Hamas assault, nearly 40 percent of survivors exposed to the violence met the criteria for probable OCD, compared to just seven percent of a matched control group elsewhere in Israel.

The symptoms included compulsive cleaning, ordering, and checking locks, windows, and doors, often tied to fears of invasion or safety.

The brain decides which action is appropriate

Plotkin’s lab explores how the brain carries on with the “daunting task of sorting through a plethora of potential actions that can be performed.”

Some of these actions are useful and appropriate, Plotkin said, while others are inappropriate.

“The inability to properly do this is at the crux of many neurological disorders, perhaps most notably, OCD,” he explained.

“While many scientists focus on genes or molecules, we focus on how the activity of brain circuits changes in disease,” said Goldberg.

The two scientists have been friends since 2009, when they worked in the same lab at Northwestern University. They have had a joint research grant since 2017.

The link between brain systems

The part of the brain most intimately associated with habit learning and action selection is the basal ganglia.

The striatum acts as the main intake center for the basal ganglia. It is in charge of receiving massive amounts of information from widely diverse parts of the brain. The striatum sorts all this information like a processing center before deciding on movements or actions.

Within this system is acetylcholine, a neurotransmitter that sends signals between nerve cells.

“For about 30 years, neuroscientists have known that a special interaction exists in the brain between the acetylcholine system and the dopamine system,” Goldberg said. “Dopamine is a signaling chemical that plays a central role in reward and learning.”

The interaction was written about in hints in scientific literature, or what Plotkin described as “little breadcrumbs.”

“At the time these breadcrumbs dropped, we didn’t really know,” he said. “We didn’t have enough information to make a connection. So this is really a credit to Josh Goldberg’s lab. He really connected the dots, and then we pursued it rigorously.”

The study followed the “classic path of scientific discovery,” Goldberg explained. The researchers started with a hypothesis based on these earlier findings and tested it directly.

“That does not always happen in science,” he said. “Many discoveries occur more accidentally.”

The link between the acetylcholine and dopamine systems

In their research, the team used a technology called optogenetics, which allowed the scientists to control specific brain cells using flashes of light.

When they activated the cells that released acetylcholine, the nearby serotonin fibers responded almost instantly by releasing their own chemical signals.

“This showed that acetylcholine does not just talk to serotonin,” Plotkin said. “It can actually take the wheel.”

When the researchers looked at brain states linked to OCD, they found the system running in overdrive.

The acetylcholine cells were overactive, which forced a massive surge of serotonin. This suggests that the symptoms of OCD might not just be about having too much of one chemical, but rather a breakdown in the brain’s coordination system.

“What our work suggests is that in these pre-clinical models of OCD behaviors, acetylcholine is elevated,” Plotkin said. “It’s very, very high.”

Goldberg explained that “the real surprise” was discovering the interaction between acetylcholine and serotonin in the part of the brain where serotonin input is relatively sparse.

“Yet this may play an important role in disorders of compulsive behavior,” he said.

The study is “quite novel,” said Jun Ding, a neurology professor in Stanford University’s neurosurgery department. Ding was not involved in the study.

He said the research discovered that specific neurons using acetylcholine can directly trigger the release of serotonin, a key chemical involved in mood and behavior.

“In addition, it showed that this interaction becomes much stronger in a mouse model of OCD,” Ding said.

The interaction opens “the door to many new questions about how these circuits function and malfunction,” Goldberg said.

Plotkin’s lab has already started working with other scientists at Stony Brook on some of the groundwork to begin clinical trials on acetylcholine’s influence.

“At the moment, treatment options for OCD, along with nearly all psychiatric disorders, are incomplete,” Plotkin said. “Current pharmacological treatments for OCD only benefit a fraction of patients, and cure even fewer.”

“Better targets around which to develop treatments are desperately needed, and these insights offer important mechanistic clues in the search for such targets,” he said.