Closed-loop recruitment of striatal interneurons prevents compulsive-like grooming behaviors
Obsessive-compulsive behaviors have long been associated with overactivation of the striatum. The GABA-ergic parvalbumin-positive interneurons (PVIs) in the striatum play a crucial role in regulating striatal activity and inhibiting inappropriate motivated behaviors. To investigate the potential role of striatal PVIs in regulating obsessive-compulsive behaviors, researchers evaluated excessive grooming behavior (a behavioral index for assessing compulsive-like behaviors) in Sapap3 knockout (Sapap3-KO) mice.
Research Background: Compulsive behaviors are core symptoms of various neuropsychiatric disorders (such as obsessive-compulsive disorder), and increasing evidence suggests that they are associated with dysfunctions in the cortico-striatal circuits. Previous studies have found that the density of PVIs in the striatal region is reduced in obsessive-compulsive disorder patients and animal models exhibiting pathological repetitive behaviors. PVIs are believed to play an important role in regulating behavioral output through their robust feed-forward inhibition of projection neurons in the striatum. However, the causal relationship between PVIs and compulsive behaviors remains unclear.
Source of the paper:
This study was jointly conducted by Sirenia Lizbeth Mondragon-Gonzalez, Christiane Schreiweis, and Eric Burguiere from the Brain and Spine Institute in Paris, France, and the results were published in the journal Nature Neuroscience.
Research Procedure and Results: (a) Research Procedure: Researchers bilaterally injected the AAV5-hChR2-mCherry virus into Sapap3-KO mice, specifically expressing the light-sensitive cation channel rhodopsin2, enabling optogenetic activation of PVIs. Optical fibers were bilaterally implanted in the striatal region receiving input from the lateral orbitofrontal cortex for optogenetic manipulation.
The study consisted of two main parts: 1) Sustained optogenetic activation: Continuous optical activation of PVIs (5ms pulses at 20Hz, 10mW power) to observe changes in grooming behavior of the mice. 2) Closed-loop optogenetic activation: By recording local field potentials (LFPs) from the lateral orbitofrontal cortex, a transient increase in the 1-4Hz delta band power was observed preceding grooming bouts, serving as a biomarker for grooming behavior. Based on this, an online monitoring and classification system using an artificial neural network was established to trigger brief (4s) optical activation of striatal PVIs upon detection of the LFP biomarker.
(b) Main Results: 1) Sustained optogenetic activation of PVIs reduced the number and duration of grooming bouts in Sapap3-KO mice by 55.8% and 46.25%, respectively, restoring them to normal levels, without significantly affecting other behaviors (such as walking or scratching). 2) In Sapap3-KO mice, the lateral orbitofrontal cortex LFP exhibited a transient increase in the 1-4Hz delta band power approximately 1 second before the onset of grooming bouts, which could be used to predict grooming behavior. 3) The closed-loop optogenetic activation system could detect the LFP biomarker in real-time and promptly activate PVIs, effectively preventing grooming bouts, reducing their number and duration by 59.37% and 70.54%, respectively, comparable to sustained activation but requiring only 13% of the stimulation time.
Research Significance and Innovations: 1) This study is the first to demonstrate the crucial role of striatal PVIs in regulating compulsive-like grooming behavior, providing new insights into the neural circuit mechanisms underlying compulsive behaviors. 2) The discovery of the grooming behavior biomarker in the lateral orbitofrontal cortex LFP lays the foundation for real-time prediction and intervention of compulsive behaviors. 3) The establishment of an innovative machine learning-based closed-loop optogenetic activation system enables real-time detection and on-demand regulation of behaviors, offering a new approach for precise symptom control in clinical settings. 4) Compared to sustained stimulation, closed-loop activation significantly reduces unnecessary stimulation time, providing advantages in reducing power consumption and avoiding potential side effects.
Overall, this study combines state-of-the-art techniques such as electrophysiological recording, optogenetic manipulation, and artificial intelligence, achieving breakthrough progress in elucidating the neural circuit basis of compulsive behaviors, behavior prediction, and regulation methods. It has important implications for exploring the pathological mechanisms of obsessive-compulsive disorder and developing novel therapeutic strategies.