How Compulsive Behavior Begins: Scientists Identify The Key Circuit

The study identifies a specific circuit between the nucleus accumbens and the hypothalamus that can transform normal goal-oriented behaviors into compulsive and repetitive actions. By artificially stimulating this circuit, animals began to exhibit automatic and persistent behaviors, even when natural rewards were available. This suggests that this neural pathway may be a central mechanism in human disorders such as addiction, compulsive eating, and obsessive-compulsive disorder.

To survive and function well, any animal needs to adjust its behavior to the environment. This means being able to explore, search for food, make decisions when there is danger, interact with others of the same species, and perform automatic and instinctive behaviors, such as grooming or protecting offspring.

This flexibility depends on a balance between goal-oriented behaviors, such as seeking something that brings reward, and automatic reflex behaviors.

In the brain, there is a region called the hypothalamus that acts as a regulatory center for these processes. It receives and combines internal information from the body, such as hunger, stress, available energy, and hormones, with external information from the environment, such as threats or food opportunities. From this, he decides which behavior should be prioritized.

Appropriate behavior requires the ability to interrupt repetitive actions when they do not yield results. When the brain fails in this control, compulsive and repetitive behaviors emerge, similar to what happens in disorders such as binge eating, anorexia, substance abuse, and obsessive-compulsive disorder.

Previous studies have already shown that this region of the brain, the hypothalamus, participates in these problematic behaviors.

The hypothalamus contains many different types of neurons distributed in an organized manner. Within it, there is a subregion called the lateral hypothalamic area. This area plays a direct role in regulating motivation and behaviors essential for maintaining bodily balance. There are neurons there that stimulate eating behavior and others that inhibit it.

Research shows that some neurons associated with the urge to eat can also stimulate compulsive and repetitive behaviors. This means that the neural networks linked to food motivation are connected to circuits responsible for broader behaviors related to impulse and control.

Although it is known that the lateral hypothalamic area participates in motivated behaviors, it was not yet clear how different connections and subtypes of neurons within it influence behavioral choice. This choice involves deciding between acting based on a goal, reacting instinctively, seeking rewards, or avoiding negative stimuli. The way this region connects with other areas of the brain is crucial in this balance.

For example, when certain neurons in this region send signals to the ventral tegmental area, there is an influence on the reward and motivation system, potentially generating compulsive seeking without necessarily increasing the act of eating.

However, when other neurons in the same area connect to the lateral habenula, a region related to the sensation of punishment and unpleasant experiences, the opposite occurs: aversion increases and motivation for reward decreases. These circuits have different functions and, at the same time, interact with each other.

The study investigated a specific subtype of neurons in this network, which express a molecule called Esr1 and connect to the brain's aversion center, the lateral habenula. Researchers carefully mapped which brain regions send information to these neurons and observed how this circuit functions during natural behaviors and during experimental situations.

The results show the existence of a specific group of neurons located in the nucleus accumbens, an area related to motivation, decision-making, and addiction. When these neurons are artificially stimulated, they trigger the Esr1 neuron group in the hypothalamus, which can gradually induce compulsive behaviors.

These behaviors appear even when more advantageous or pleasurable options are available, such as food or social interaction. In other words, this circuit can replace normal goal-oriented behaviors with repetitive and automatic actions.

The activation of this neural pathway produces stereotyped behaviors that vary with the environment: in an open space, the animal moves repetitively and intensely; in an environment with loose material, it digs continuously; In an environment with objects to manipulate, he repeats movements such as pushing or poking. These behaviors have no clear purpose and replace more natural actions, resembling compulsive patterns in humans.

This finding suggests the existence of a neural circuit capable of prioritizing repetition and compulsion over natural rewards. This mechanism appears similar to that observed in addictions and compulsive disorders in humans.

Previous studies have already indicated that regions related to the reward system can be altered by drugs, stress, and persistent emotional stimuli. This new study links this idea to the fundamental role of the hypothalamus and its ability to reorganize behavioral priorities.

The research also highlights the need to understand the specific types of neurons involved, their connections, and how these connections change over time, as plasticity exists, that is, the brain's ability to modify itself with experience.

In short, the work reveals that there is a precise pathway between the nucleus accumbens and a specific group of neurons in the hypothalamus that can induce compulsive behaviors, even when they are disadvantageous. This circuit may be an important target for understanding and, in the future, treating disorders linked to compulsion, addiction, and pathological repetitive behaviors.

READ MORE:

A striosomal accumbens pathway drives stereotyped behavior through an aversive Esr1+ hypothalamic-habenula circuit

THOMAS CONTESSE, MARTA GRAZIANO, CHIARA FORASTIERI, ALESSANDRO CONTESTABILE, SALOME HAHNE, FELIX JUNG, IFIGENEIA NIKOLAKOPOULO, ELEONORA RUBINO, XIAO CAO, VASILIKI SKARA, IOANNIS MANTAS, SARANTIS GIATRELLIS, MARIE CARLÉN, RICKARD SANDBERG, DANIELA CALVIGIONI, and KONSTANTINOS MELETIS

SCIENCE ADVANCES, 21 Nov 2025, Vol 11, Issue 47

DOI: 10.1126/sciadv.adx9450

Abstract:

The lateral hypothalamic area (LHA) integrates external stimuli with internal states to drive the choice between competing innate or value-driven motivated behaviors. Here, we define a striosomal Tac1+/Tshz1+/Oprm1+ neuron subtype in the nucleus accumbens (ACB) that targets Esr1+ LHA neurons that project to the lateral habenula (LHb). Intersectional cell type–specific and input-output defined optogenetic activation of this ACB-LHA-LHb pathway can progressively induce a negative behavioral state that depends on Esr1+ LHA-LHb neural activity. We found that either activation of the D1+ ACB-LHA projection or inhibition of LHA-LHb neurons defined by ACB inputs can drive reward-independent compulsive-like behaviors that generalize across contexts. We found that these complex yet stereotyped behaviors compete with highly motivated states and can override the drive for natural rewards or social interactions. Our findings reveal a discrete Tac1+ striosomal ACB projection targeting the aversive Esr1+ LHA-LHb pathway as a key circuit that promotes stereotyped and compulsive-like behaviors over goal-directed actions.