Dissertation Defense: On the Analysis of Mouse Behavior

About this Dissertation

Behavior results from complex interactions between brain regions and neurotransmitter systems. Accurate and high throughput measurement of animal behavior is critical for many branches of neuroscience, allowing for mechanistic studies and pre-clinical drug testing. Methodological limitations contribute to narrow investigations, which may overlook the interplay between distinct but related behaviors, like affective behaviors and executive function (EF). To prevent this, researchers can perform multiple assessments in one study, termed a test battery. However, test batteries often exclude cognitive or goal-directed behaviors due to the lengthy testing period needed to perform traditional operant tests. This dissertation first reviews current evidence related to the investigation and relation of affective, pain-like, and goal-directed behaviors, with a focus on rodent models. Then, I demonstrate the use of traditional and novel test batteries to investigate these behavioral changes in multiple mouse models.

First, I investigated affective and pain-like behavior in mice lacking Nape-pld, a key enzyme for the synthesis of lipid mediators that can activate receptors in the endocannabinoid system. I found that these mice displayed reduced sucrose preference but otherwise normal anxiety- and depression-like behavior and had baseline differences in thermal nociception and inflammation response. Then, I investigated the affective, pain-like, and operant effects of chronic vapor exposure (CVE) to vehicle or nicotine (NIC). Regardless of NIC content, acute abstinence from CVE increased mechanical sensitivity and self-grooming, while chronic abstinence from NIC CVE resulted in motor stimulation. Other traditional anxiety- and depression-like behaviors were unchanged by CVE. In an operant test battery, acute abstinence from NIC CVE impaired acquisition, decreased sucrose motivation, and impaired an inhibitory response to aversive rewards. Finally, I developed a protocol for the high throughput analysis of 6 operant tests which can be completed in as few as 19 sessions. This battery investigates multiple aspects of goal-directed behavior and EF including operant acquisition, cognitive flexibility, reward devaluation, motivation via response to increased instrumental effort, cue devaluation or the extinction of learned behavior, and reacquisition. I validated this test by demonstrating that lesions to the orbitofrontal cortex impaired cognitive flexibility, as in traditional operant tests. I then used this battery to investigate the effects of the P129T mutation, which results in a mutated version of the Fatty Acid Amide Hydrolase (FAAH) enzyme that is associated with problem drug use in humans. Knock-in animals displayed reduced activity in response to increasing instrumental effort, and reduced activity on the first day of an extinction test. Then, to encourage others to use this new operant battery I outlined how to efficiently collect data, shared a database for customizable analysis, and described common issues and how to solve them. This protocol has potential implications for many aspects of neuroscience including the investigation of novel therapeutics and the neural circuitry underlying behaviors.

Together, the information in this dissertation demonstrates the utility of multi-faceted behavioral assays and the combination of traditional and novel approaches to collect more comprehensive behavioral data, which will allow researchers to better investigate neural circuitry underlying behaviors or the behavioral changes associated with novel therapeutics.

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