Determining face, predictive, construct validity and novel receptor targets in a spontaneous compulsive-like mouse model

Abstract

Obsessive-compulsive disorder (OCD) is one of the most prevalent neuropsychiatric disorders with no known etiology. Genetic variation, sex differences and physiological stages, such as pregnancy, postpartum and menopause in females, are important factors that are thought to modulate the pathophysiology of the disorder. Deeper understanding of these factors and their role in modulating behaviors is essential to unraveling the complex clinical heterogeneity of OCD. Using a novel mouse model that exhibits a spontaneous compulsive-like phenotype, I investigated the role of strain differences, sex differences, ovarian sex hormones and postpartum lactation in influencing compulsive-like and affective behaviors. Due to the lack of definite neural substrates and first line therapeutic options for treatment resistant patients, I also probed into the role of positive allosteric modulation of nicotinic acetylcholine receptor subtype as a therapeutic target for translational prospects. The thesis showed several significant and novel findings. Strain and sex comparisons of the compulsive-like mouse strains (BIG1 and BIG2) showed that the behavioral outcomes and HPA axis response can be influenced by sex, genotype and sex by genotype interactions. Acute ovariectomy and behavioral assessments after one week, which mimics surgical menopause in humans, increased the compulsive-like behaviors in the BIG strains only. Acute ovariectomy also exacerbated anxiety-like behaviors in the compulsive-like BIG strains. This exacerbation of compulsive-like behaviors was restored only by estrogen and not progesterone, while estrogen and progesterone both restored anxietylike behaviors based on the strain and the type of behavioral assessments. Lactating postpartum compulsive-like female mice were protected against compulsive-like behaviors and showed enhanced responsiveness to selective serotonin reuptake inhibitors (SSRIs) compared to the non-lactating and the nulliparous females. Finally, acute and chronic administration of desformylflustrabromine (dFBr), a positive allosteric modulator of α4β2 nicotinic acetylcholine receptors, resulted in the attenuation of compulsive-like behaviors in the mouse model, while not affecting anxiety-like behaviors. The current thesis work therefore provides a foundation for further exploration of factors like strain, sex, physiological status and cholinergic receptor subtypes in mouse models to understand the neurobiology and behavioral correlates of OCD in humans.