Summary: Dopamine receptors in the ventral hippocampus play a central role in regulating the balance between approach and avoidance behaviors, broadening our understanding of dopamine beyond its established roles in reward and motivation. By examining neurons that express D1 and D2 receptors in mice, researchers revealed how these receptor-defined cells produce opposing emotional responses under stress, with implications for anxiety, depression, and addiction.
Unexpectedly, stimulating D2-expressing neurons reduced fear-like behavior in mice, a finding that highlights new therapeutic possibilities for mood and anxiety disorders. This research points to dopamine circuits in the hippocampus as influential modulators of emotional decision-making under stress.
Key Facts
- Dopamine and emotion: D1 and D2 receptors in the ventral hippocampus regulate approach versus avoidance decisions when animals face stressful or uncertain contexts.
- Opposing functions: Neurons expressing D1 and D2 receptors drive opposite behavioral responses; activation of D2 neurons in particular led to reduced fear behaviors in mice.
- Clinical relevance: These results reveal an underappreciated role for hippocampal dopamine signaling and suggest new targets for treating anxiety, depression, and addiction.
Source: Mount Sinai Hospital
Mount Sinai researchers have identified distinct functions for two dopamine receptor-expressing cell types in the part of the brain that mediates approach and avoidance behavior.
These receptor-defined neurons appear to influence circuits linked to anxiety and mood disorders, offering insight into neurobiological mechanisms that have been difficult to pinpoint.
The team focused on D1 and D2 dopamine receptors within the ventral hippocampus (vHipp) of male mice, a region known to coordinate emotional responses, stress reactivity, and decisions that weigh potential rewards against potential threats.
Their work extends knowledge of dopamine signaling beyond classic reward-related brain regions and positions hippocampal dopaminergic modulation as a key factor in decision-making under stress and uncertainty.
The study was published in the May 7 issue of Nature.
“Healthy and disrupted emotional processing depends on the brain’s ability to resolve conflicts between approach and avoidance on a moment-to-moment basis, and the hippocampus has long been implicated in that computation,” said senior author Eric J. Nestler, MD, PhD, 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.
“This is the first comprehensive functional analysis of D1- and D2-expressing neurons in the ventral hippocampus. We show that dopamine plays a larger role in this region than previously appreciated and that it conveys decision-related information when animals face stressful choices.”
The hippocampus helps animals decide in anxiety-provoking situations—for example, whether to approach a food source when potential threats are nearby. These approach/avoidance dilemmas, where a goal has both attractive and risky elements, can produce excessive fear and anxiety in humans.
Using molecular and functional approaches, the Mount Sinai team demonstrated that D1- and D2-expressing neurons are transcriptionally distinct, occupy specific locations across vHipp subfields, and are engaged differently during anxiogenic exploration. Both cell types are recruited during investigation, but they contribute separate signals related to exploration and behavioral choice.
Crucially, the two populations mediate opposite approach–avoidance responses and are differentially modulated by local dopamine transmission. The researchers were surprised to find that cells typically associated with the striatum’s motor and reward systems are also functionally significant within the hippocampus.
An unexpected behavioral result was that activating D2-expressing cells made mice notably less fearful, suggesting D2 signaling in the vHipp can suppress avoidance and promote approach under certain conditions.
“These findings emphasize dopamine as a meaningful neuromodulator in hippocampal circuits,” Dr. Nestler added. “Dopamine signaling should be reconsidered in brain regions traditionally overlooked when studying learning, memory, and emotional behavior.”
The next steps for the researchers are to map exactly how the dopamine–hippocampus circuit is altered in stress-related conditions, including anxiety disorders and major depressive disorder—which commonly involve heightened avoidance—as well as in addiction, where individuals pursue rewards despite adverse consequences.
“By delineating the neuromodulatory circuits that govern approach and avoidance, we move closer to addressing leading causes of disability worldwide,” said Dr. Nestler.
Funding: This research was supported by grants from the National Institute on Drug Abuse, the National Institute of Mental Health, and the Hope for Depression Research Foundation.
About this dopamine and anxiety research news
Author: Elizabeth Dowling
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mount Sinai Hospital
Image: The image is credited to Neuroscience News
Original Research: Closed access. “Dopamine D1–D2 signalling in hippocampus arbitrates approach and avoidance” by Eric J. Nestler et al., Nature.
Abstract
Dopamine D1–D2 signalling in hippocampus arbitrates approach and avoidance
The hippocampus and dopaminergic circuits coordinate decision-making in situations that elicit anxiety. How dopamine modulates hippocampal representations of emotionally salient stimuli to resolve conflicts between approach and avoidance is not well understood.
This study examined dopaminoceptive neurons in the male mouse ventral hippocampus, distinguishing cells by expression of D1 or D2 receptors. These neuron populations are transcriptionally distinct and show topographic organization across ventral hippocampal subfields and cell types.
In the ventral subiculum, where both D1 and D2 neurons are enriched, they are recruited during anxiogenic exploration but exhibit different activity profiles tied to investigation and behavioral selection. The two populations mediate opposing approach–avoidance behaviors and are differentially influenced by dopamine transmission in that region.
Together, these results indicate that ventral hippocampal dopamine dynamics gate exploratory behaviors under contextual uncertainty and implicate dopaminoception in the complex computations the hippocampus uses to govern emotional states.