Imaging Neural Dynamics of Compulsive Behaviors

Simultaneous observation of Sapap3-KO compulsive grooming (left) and central striatum neuron activity (right) using nVista miniature microscope. Data courtesy of Susanne E. Ahmari Lab — University of Pittsburgh.

Imagine a mind caught in an endless loop of obsessions, anxiety, and ritualistic behaviors; welcome to the world of obsessive-compulsive disorder (OCD), a neuropsychiatric condition characterized by uncontrollable and recurring thoughts and repetitive behaviors. Research has linked OCD symptoms to hyperactivity in the striatum, a crucial brain region for motor control and decision-making. But how does this hyperactivity lead to such compulsive behaviors? The precise mechanisms remain unknown.

One prominent hypothesis is that OCD symptoms are caused by an imbalance of parallel striatal circuits, with increased activity in direct pathway-projecting spiny projection neurons (dSPN) and/or decreased activity in indirect pathway-projecting neurons (iSPNs). While this theory has some support from other models of repetitive behaviors, it has not been tested in the context of OCD-specific behaviors until now.

Working in the laboratory of Susanne E. Ahmari at the University of Pittsburgh, Sean C. Piantadosi, Elizabeth E. Manning, Britt L. Chamberlain et al., in their recent Nature Communications paper entitled, Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior, directly examined SPN activity in freely moving Sapap3-knockout (Sapap3-KO) mice, which exhibit OCD-relevant behaviors like compulsive grooming. Using cutting-edge techniques like in vivo calcium (Ca2+) imaging with Inscopix nVista™ miniscopes, they found that central striatum activity significantly increased at the onset of grooming and persisted throughout grooming bouts in Sapap3-KO mice compared to wild-type (WT) mice. This hyperactivity was specific to grooming behavior, with no changes observed during non-grooming periods.

Further analysis revealed that the hyperactivity was driven by dopamine D2-receptor expressing neurons (iSPNs), not D1-receptor expressing neurons (dSPNs). Optogenetic inhibition of these iSPNs reduced excessive grooming in KO mice, highlighting their critical role in compulsive behavior. Additionally, chronic treatment with a first-line treatment for OCD, the serotonin reuptake inhibitor (SRI) fluoxetine, reduced both the hyperactivity of iSPNs and compulsive grooming, suggesting a potential mechanism for the therapeutic effects of SRIs in treating OCD.

These findings emphasize the importance of targeting specific neural pathways to develop effective treatments for OCD. The results suggest that indirect pathway striatopallidal SPN hyperactivity contributes to the generation of excessive grooming behavior, and strategies aimed at reducing such hyperactivity could be beneficial for treating compulsive behaviors in disorders like OCD. The study also highlights the potential of circuit-based therapies, such as transcranial magnetic stimulation (TMS) and deep-brain stimulation (DBS), which can selectively alter the activity of specific neural circuits. This circuit-specific approach, which could potentially be translated into humans, could provide new hope for people with severe OCD.

Understanding the intricate workings of the brain is crucial for developing effective treatments. This research provides new insights into the neural mechanisms underlying OCD and opens promising avenues for treatment by identifying the specific role of iSPNs in driving compulsive behavior and mediating treatment response. By modulating this neural pathway, targeted therapies could provide significant relief for those living with OCD, breaking the relentless cycle of distress and repetitive actions.

Yasaman Akhavan-Farshchi is our Inscopix Product Manager with an MBA and MSc in Biomedical Engineering. With a passion for innovation, Yasaman is committed to delivering exceptional customer experience through product development and cross-functional team collaboration.

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