Discovery of dopamine receptors in overlooked brain region sheds light on complex circuitry for anxiety and depression

Mount Sinai researchers have discovered distinct roles for two dopamine receptors located on nerve cells within the portion of the brain that controls approach vs. avoidance behavior. These receptors potentially influence anxiety and mood disorders whose origins are still unclear.

The team characterized the function of D1 and D2 dopamine receptors in the ventral hippocampus of mice, a region involved in the regulation of emotions and stress responses. Their work expands the field’s knowledge of dopamine signaling beyond its well-known actions in other brain regions that influence reward and motivation, and sets the stage for future research into dopamine dysregulation in a range of anxiety and depressive disorders.

The results of the study appear in Nature.

“Healthy and dysregulated emotional processing related to an individual’s ability to resolve conflict between approach and avoidance when making decisions on a moment-by-moment basis have long implicated the hippocampus,” says senior author Eric J. Nestler, MD, Ph.D., Nash Family Professor of Neuroscience and Director of The Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai, and Chief Scientific Officer of the Mount Sinai Health System.

“Ours is the first comprehensive, functional study of newly discovered D1 and D2 expressing cells in the ventral hippocampus. We demonstrate that dopamine is more important in that area of the brain than previously believed, and moreover, that it conveys information related to decision-making under stressful conditions.”

The hippocampus coordinates decision-making in anxiety-inducing situations, like when an individual has to choose whether to obtain food or drink in threatening situations. Such approach/avoidance dilemmas, where a particular goal has both desirable and potentially undesirable consequences, can cause excessive fear, confusion, and anxiety in humans.

The Mount Sinai team investigated the influence of dopamine signaling within the ventral hippocampus on approach/avoidance behavior in male mice. Researchers learned that D1 and D2 dopamine receptors expressed in different neuronal populations are called into play to help execute approach/avoidance decisions. These receptors and the cells that express them mediate opposite approach/avoidance responses, and are differentially impacted by dopamine transmission in that region of the brain.

The team was surprised to learn that the neuronal cells that express D1 and D2 receptors, which are most highly enriched in the striatum—a critical part of the motor and reward system—are also relevant in the hippocampus. Another unexpected behavioral observation was that mice whose D2 cells were artificially activated became much less fearful.

“These discoveries underscored for us that dopamine is an important component of the hippocampal circuitry and that dopamine signaling should be reconsidered in many brain regions where it was previously overlooked, especially those associated with learning, memory, and emotional behavior,” notes Dr. Nestler, whose considerable research over the years has been designed to better understand the molecular mechanisms of drug addiction and depression. “Our work further implicates dopamine dysregulation in anxiety and mood disorders.”

Dr. Nestler credits the study’s two co-first authors, Arthur Godino, Ph.D., a graduate student and later postdoctoral fellow, and Marine Salery, Ph.D., a postdoctoral fellow, and the rest of the large research team for the creative advances made in this investigation.

The next step for Dr. Nestler and his team is to show precisely how the dopamine-hippocampus circuit that modulates approach/avoidance is dysregulated in several stress-related conditions, such as anxiety disorders and major depressive disorders (which involve increased avoidance) and in drug addiction (where individuals seek drug rewards despite harmful consequences).

“By helping to delineate the neuromodulatory circuits that govern these disorders,” says Dr. Nestler, “we’re taking an essential step toward addressing a leading cause of disability in humans worldwide.”