How Does Striatal Neuron Activity Contribute to Compulsive Behavior?

What you need to know

• Excessive activity of indirect pathway neurons in the striatum drives compulsive grooming behavior in mice
• Inhibiting these neurons reduces compulsive grooming
• The antidepressant fluoxetine reduces compulsive grooming by suppressing activity of these neurons
• This challenges previous theories about how brain circuits contribute to compulsive behaviors

A new view of compulsive behavior in the brain

Compulsive behaviors are a hallmark symptom of obsessive-compulsive disorder (OCD). These are repetitive actions that a person feels driven to perform, even when they may be excessive or harmful. For many years, scientists have been trying to understand what goes wrong in the brain to produce these behaviors.

A longstanding theory proposed that compulsive behaviors result from too much activity in a brain circuit called the “direct pathway” and/or too little activity in the “indirect pathway”. These pathways involve neurons that connect different regions involved in planning and executing movements and behaviors.

However, a new study in mice challenges this view. The research suggests that, contrary to previous theories, excessive activity in the indirect pathway may actually drive compulsive behavior.

Examining neuron activity during compulsive grooming

The researchers used a strain of mice that lack a gene called Sapap3. These mice engage in excessive self-grooming behavior that resembles the compulsive behaviors seen in OCD. The scientists were able to measure the activity of different types of neurons in a brain region called the striatum while the mice were grooming.

They found that overall, neurons in the striatum showed increased activity at the start of grooming bouts in the Sapap3 knockout mice compared to normal mice. This hyperactivity persisted throughout grooming episodes.

To dig deeper, they looked specifically at two main types of neurons in the striatum:

1. D1 neurons, which are part of the direct pathway
2. D2 neurons, which are part of the indirect pathway

Surprisingly, they found that the D2 neurons showed significantly increased activity at the start of grooming in the Sapap3 knockout mice. The D1 neurons did not show this hyperactivity. This was unexpected based on previous theories.

Inhibiting indirect pathway neurons reduces compulsive grooming

To test whether this hyperactivity of D2 neurons was actually causing the excessive grooming, the researchers used genetic techniques to selectively inhibit the activity of these neurons.

When they did this, it significantly reduced the amount of compulsive grooming behavior in the Sapap3 knockout mice. This suggests that the increased activity of these indirect pathway neurons is indeed driving the compulsive behavior.

How antidepressants may reduce compulsive behaviors

Many patients with OCD are treated with a type of antidepressant medication called selective serotonin reuptake inhibitors (SSRIs). One commonly used SSRI is fluoxetine (also known by the brand name Prozac).

The researchers treated the Sapap3 knockout mice with fluoxetine for several weeks. They found that this reduced both the compulsive grooming behavior and the hyperactivity of the indirect pathway neurons.

This provides a potential explanation for how these medications work to reduce compulsive behaviors in OCD - by dampening the excessive activity of indirect pathway neurons in the striatum.

Implications for understanding OCD

These findings challenge our previous understanding of the brain circuits involved in compulsive behaviors. Rather than resulting from an imbalance between direct and indirect pathways, with the direct pathway being overly active, it appears that hyperactivity specifically in the indirect pathway may drive these behaviors.

This new view could have important implications for developing new treatments for OCD and related conditions. It suggests that therapies aimed at reducing activity in the indirect pathway, rather than boosting the direct pathway, may be beneficial.

Conclusions

• Excessive activity of indirect pathway (D2) neurons in the striatum drives compulsive grooming in mice
• Inhibiting these neurons reduces compulsive behavior
• The antidepressant fluoxetine appears to work by suppressing activity of these neurons
• This challenges previous theories about brain circuits in OCD and compulsive behaviors

While more research is needed to confirm if the same mechanisms apply in humans with OCD, these findings open up new directions for understanding and potentially treating compulsive behaviors. They highlight the complex role of different neuron types and brain circuits in regulating behavior, and how disruptions to these systems can lead to psychiatric symptoms.

The study also demonstrates the value of using animal models to probe the neural basis of psychiatric symptoms. By combining genetic techniques, behavioral analysis, and direct measurements of brain activity, the researchers were able to uncover new insights that may ultimately translate into better treatments for patients.