Scratching the surface. Preclinical studies on cognitive flexibility and deep-brain stimulation in obsessive-compulsive disorder.

TY - THES

T1 - Scratching the surface.

T2 - Preclinical studies on cognitive flexibility and deep-brain stimulation in obsessive-compulsive disorder.

AU - Van den Boom, B.

PY - 2024

Y1 - 2024

N2 - While most of us can identify with obsessive-compulsive disorder (OCD) patients, our understanding of the disorder and potential treatments remains insufficient. We set out to explore the relationship between various OCD-like symptoms, the role of cognitive flexibility in OCD, and the therapeutic mechanism of deep-brain stimulation (DBS) using SAPAP3 knockout mice (SAPAP3-/-), a mouse model for OCD. At the core of this model is compulsive-like self-grooming, which continues despite negative consequences such as loss of fur or even skin lesions. Therefore, in chapter 2, we developed a versatile, open-source grooming classifier that reliably and under various conditions can detect grooming behavior. In chapter 3, we assessed cognitive deficits in SAPAP3-/- and found reduced behavioral flexibility, a core symptom of OCD, accompanied by an imbalance in sign- and goal-tracking behavior. Surprisingly, OCD-like behaviors (i.e., grooming, anxiety, behavioral inflexibility, and hypoactivity) did not correlate. To further explore the relationship between balanced sign and goal tracking and behavioral flexibility, we validated these findings in chapter 4 and found that sign and goal tracking before reversal learning could predict behavioral flexibility, suggesting a robust relationship. By altering reward-cue salience, we were able to induce balanced sign and goal tracking, which resulted in rescued behavioral flexibility. To better understand the neurobiology of compulsive-like grooming, we developed and validated a novel open-source single-photon miniaturized fluorescent microscope for calcium imaging in collaboration with Dr. Tycho Hoogland in chapter 5. The so-called NINscope allows real-time in vivo dual-site imaging, while manipulating distal regions. This technique records large datasets that provide many challenges to analyze due to the large size, many neurons, and substantial out-of-focus signals. In collaboration with the Levelt lab, we developed a novel preprocessing pipeline for calcium-imaging data in chapter 6. Direct comparison between our pipeline and a widely used pipeline revealed comparable results. In chapter 7, we compared ventral striatum and internal capsule (IC) DBS, and found IC-DBS to be more effective at reducing excessive grooming. Both DBS targets recruited similar prefrontal cortex regions. To better understand the therapeutic mechanism of IC-DBS, we employed calcium imaging in cortical and striatal regions in freely behaving animals in chapter 8, while varying clinically relevant parameters. We identified a number of general DBS principles, accompanied by specific involvement of the medial orbitofrontal cortex, which was validated by optogenetics. In conclusion, although our research only scratched the surface of this complex disorder, we gained a better understanding of OCD and its treatment, DBS.

AB - While most of us can identify with obsessive-compulsive disorder (OCD) patients, our understanding of the disorder and potential treatments remains insufficient. We set out to explore the relationship between various OCD-like symptoms, the role of cognitive flexibility in OCD, and the therapeutic mechanism of deep-brain stimulation (DBS) using SAPAP3 knockout mice (SAPAP3-/-), a mouse model for OCD. At the core of this model is compulsive-like self-grooming, which continues despite negative consequences such as loss of fur or even skin lesions. Therefore, in chapter 2, we developed a versatile, open-source grooming classifier that reliably and under various conditions can detect grooming behavior. In chapter 3, we assessed cognitive deficits in SAPAP3-/- and found reduced behavioral flexibility, a core symptom of OCD, accompanied by an imbalance in sign- and goal-tracking behavior. Surprisingly, OCD-like behaviors (i.e., grooming, anxiety, behavioral inflexibility, and hypoactivity) did not correlate. To further explore the relationship between balanced sign and goal tracking and behavioral flexibility, we validated these findings in chapter 4 and found that sign and goal tracking before reversal learning could predict behavioral flexibility, suggesting a robust relationship. By altering reward-cue salience, we were able to induce balanced sign and goal tracking, which resulted in rescued behavioral flexibility. To better understand the neurobiology of compulsive-like grooming, we developed and validated a novel open-source single-photon miniaturized fluorescent microscope for calcium imaging in collaboration with Dr. Tycho Hoogland in chapter 5. The so-called NINscope allows real-time in vivo dual-site imaging, while manipulating distal regions. This technique records large datasets that provide many challenges to analyze due to the large size, many neurons, and substantial out-of-focus signals. In collaboration with the Levelt lab, we developed a novel preprocessing pipeline for calcium-imaging data in chapter 6. Direct comparison between our pipeline and a widely used pipeline revealed comparable results. In chapter 7, we compared ventral striatum and internal capsule (IC) DBS, and found IC-DBS to be more effective at reducing excessive grooming. Both DBS targets recruited similar prefrontal cortex regions. To better understand the therapeutic mechanism of IC-DBS, we employed calcium imaging in cortical and striatal regions in freely behaving animals in chapter 8, while varying clinically relevant parameters. We identified a number of general DBS principles, accompanied by specific involvement of the medial orbitofrontal cortex, which was validated by optogenetics. In conclusion, although our research only scratched the surface of this complex disorder, we gained a better understanding of OCD and its treatment, DBS.

M3 - PhD thesis

ER -