Summary: Researchers have identified a specific brain circuit that can switch behavior into a compulsive “repeat mode,” causing mice to persistently dig and sniff even when rewards are available. The circuit connects neurons in the nucleus accumbens through the hypothalamus to the lateral habenula, a brain region known for processing aversive or unpleasant experiences.
Repeated activation of this pathway produces a progressively negative internal state that biases animals toward repetitive actions and away from natural, reward-driven behaviors. Interrupting the relay from the hypothalamus to the lateral habenula abolishes the compulsive actions, offering new mechanistic insight that is relevant to conditions such as obsessive-compulsive disorder (OCD) and addiction.
Key Facts:
- Repetitive trigger: Stimulation of the nucleus accumbens → hypothalamus → lateral habenula circuit forces animals into repetitive behaviors.
- Negative internal state: Repeated activation produces an aversive state that overrides normal motivations for food or social interaction.
- Therapeutic insight: Blocking the hypothalamus → habenula relay stops the compulsive behaviors, suggesting a target for further research into compulsivity.
Source: Karolinska Institute
Background: Both animals and humans can become locked into repetitive or compulsive behaviors, but the specific brain mechanisms that drive and maintain such patterns have been unclear. This study maps a discrete neural pathway that can impose a compulsive-like state on behavior, demonstrating how a defined circuit overrides competing motivations.
The research team focused on a pathway beginning in the nucleus accumbens, a central hub of the brain’s reward circuitry. From there, the pathway projects to a subset of neurons in the lateral hypothalamic area (LHA), which in turn send outputs to the lateral habenula (LHb), a structure associated with processing aversive signals and negative outcomes.
Using cell-type-specific genetic methods together with optogenetics — a technique that uses light to control genetically targeted neurons — the scientists activated this ACB→LHA→LHb pathway. Repeated activation gradually produced an aversive internal state in mice, and the animals responded by performing stereotyped, repetitive actions such as digging and sniffing. Importantly, these behaviors persisted even when food or other rewards were available, indicating that the induced state competed with and overrode normal goal-directed drives.
The investigators identified a specific subtype of striosomal neurons in the nucleus accumbens (characterized by markers Tac1, Tshz1 and Oprm1) that project to Esr1-expressing neurons in the LHA. Those LHA neurons then project to the lateral habenula. Activating the D1+ accumbens projections or inhibiting LHA→LHb neurons influenced behavior in ways that produced reward-independent, compulsive-like patterns across different contexts.
Crucially, when the researchers blocked the relay from the hypothalamus to the habenula, the compulsive behaviors stopped. This finding demonstrates that the LHA→LHb leg of the circuit is required for sustaining the aversive state that drives repetitive actions. The work provides a clear circuit-level mechanism showing how certain behaviors can be prioritized by the brain even when they are no longer functional or rewarding.
The experiments combined multiple complementary approaches: genetic targeting to label and manipulate specific neuron types, recordings of brain activity, precise optogenetic control of defined pathways, and standardized behavioral assays. Together these methods allowed the team to directly link compulsive-like behaviors to a distinct, anatomically defined circuit.
Funding: This research was supported by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Wenner-Gren Foundations, StratNeuro, and the Swedish Brain Foundation. The authors report no conflicts of interest.
Key Questions Answered:
A: A pathway from the nucleus accumbens to the hypothalamus, relayed to the lateral habenula, can shift behavior into repetitive patterns.
A: Mice display compulsive digging and sniffing even when rewards are available, reflecting a progressively negative internal state.
A: Yes. Inhibiting the hypothalamus→habenula relay abolishes the repetitive behaviors induced by circuit activation.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full by the editorial team.
- Additional explanatory context was added by staff to clarify methods and implications.
About this neuroscience research news
Author: Press Office, Karolinska Institute
Source: Karolinska Institute
Contact: Press Office – Karolinska Institute
Image: The image is credited to Neuroscience News
Original Research: Open access. “A striosomal accumbens pathway drives stereotyped behavior through an aversive Esr1+ hypothalamic-habenula circuit” by Konstantinos Meletis et al., published in Science Advances (DOI: 10.1126/sciadv.adx9450).
Abstract (condensed):
The lateral hypothalamic area integrates external cues and internal states to select between competing innate or value-driven behaviors. This study defines a striosomal Tac1+/Tshz1+/Oprm1+ neuron subtype in the nucleus accumbens that targets Esr1+ LHA neurons projecting to the lateral habenula. Cell type–specific and input-output-defined optogenetic activation of the ACB→LHA→LHb pathway progressively induces an aversive behavioral state that depends on Esr1+ LHA→LHb activity. Activation of D1+ ACB→LHA projections or inhibition of LHA→LHb neurons defined by ACB inputs can produce reward-independent, compulsive-like behaviors that generalize across contexts, overriding drives for natural rewards and social interactions. These results identify a discrete Tac1+ striosomal ACB projection to an aversive Esr1+ LHA→LHb pathway as a circuit that promotes stereotyped and compulsive-like behaviors over goal-directed actions.