Dopaminergic Dual Gating of Obsessive-Compulsive Behaviors
Post by Lincoln Tracy
The takeaway
In an animal model of obsessive-compulsive disorder, dopamine neurons in the substantia nigra were found to control repetitive behaviors through a dual gating mechanism involving both striatal and cortical projections.
What's the science?
Obsessive-compulsive disorder (OCD) is a chronic mental health condition in which patterns of unwanted thoughts and fears (obsessions) lead to repetitive behaviors (compulsions). Dopamine – the brain chemical responsible for allowing us to feel pleasure, satisfaction, and motivation – has been implicated in OCD-like behavior. Studies in mice have shown that excess dopamine results in an increase in OCD-like behaviors while knocking out dopamine receptors reduces such behaviors. While dopamine antagonists are frequently prescribed to people with OCD, the exact role of dopamine receptors and the specific parts of the brain in controlling the repetitive behaviors in OCD is unknown. This week in PNAS, Xue and colleagues used pharmacological and optogenetic manipulation of dopaminergic activity in OCD-like mice to identify the brain circuits involved in the dopaminergic control of the repetitive behaviors in OCD.
How did they do it?
First, the authors used an established method of repeated optogenetic stimulation to generate mice displaying OCD-like repetitive self-grooming behaviors. After establishing an OCD mouse model, the authors again used optogenetic stimulation to manipulate dopaminergic neurons from the substantia nigra and the ventral tegmental area to investigate their potential role in regulating excessive self-grooming behaviors in OCD-like mice. Next, alternative neuronal pathways starting in the substantia nigra were explored using anterograde and retrograde tracing of neuronal pathways, as dopaminergic neurons in the substantia nigra project to multiple brain regions. Finally, they injected the OCD-like mice with antagonists specific to two different types of dopamine receptors to examine the roles of dopamine receptors in mediating the substantia nigra pathways that regulate OCD-like behaviors.
What did they find?
Inhibiting dopaminergic activity from the substantia nigra, but not from the ventral tegmental area to ventromedial striatum, suppressed excessive grooming behaviors in OCD-like mice. These results suggest dopaminergic inputs from the substantia nigra, but not the ventral tegmental area, facilitate OCD-like repetitive behaviors in mice. The authors identified a novel projection between the substantia nigra and the lateral orbitofrontal cortex. Stimulating this neuronal pathway reduced excessive grooming behaviors in OCD-like mice, while inhibiting this connection increased grooming behaviors. This suggests OCD-like behaviors are regulated by two distinct dopaminergic neural pathways projecting from the substantia nigra. Finally, activity in the two dopaminergic neural pathways affected the compulsive grooming behaviors differently. Activity of the substantia nigra-ventromedial striatum pathway promotes grooming behaviors via D1 receptors, but activity of the substantia nigra-orbitofrontal cortex pathway suppresses grooming behaviors via D2 receptors. This implies the distinct pathways have distinct dopaminergic signaling profiles.
What's the impact?
This study is the first to show that the projection between the substantia nigra and the lateral orbitofrontal cortex not only exists but plays a vital role in the modulation of repetitive behaviors in OCD. This projection is part of a dual gating mechanism through which dopaminergic neurons from the substantia nigra modulate repetitive behaviors. These findings suggest that dopamine-focused treatment strategies may be beneficial to individuals with OCD.
