Novel Quantitative Analyses in Mouse Models of Neurological and Psychiatric Disorders
Numerous efforts have been made to illuminate the mechanisms underlying neurological and psychiatric disorders, in order to develop treatments for these diseases. With the advantage of transgenic mouse models to recapitulate human pathological alterations and to support drug screening, promising discoveries have been made over the past century. In this dissertation, I am focusing on Alzheimer’s disease (AD), which is a neurodegenerative disorder with significant public health concern. Using one of the newest mouse models of AD, the AppNL-F mouse model, I have investigated synaptic, network, and cognitive alterations related to this disease, with techniques from in vitro and in vivo electrophysiology for examining abnormalities in the brain to behavior tests for assessing the cognitive functions of the animals. In the meantime, novel quantitative approaches have been developed and applied to objectively interpret the experimental data. In AppNL-F homozygous mice, we have found synaptic alterations consistent with deficits in parvalbumin-expressing interneurons (PV INs). Moreover, through long-term in vivo local field potential (LFP) recording, we have discovered perturbed network activities associated with disrupted sleep patterns, which happened during a critical period in the disease progression and may lead to further cognitive deficits in these animals.
Besides well-known cognitive dysfunctions such as loss of memory and reasoning as well as language difficulties, there is a second group of non-cognitive symptoms including psychiatric disorders and behavioral disturbances, such as depression, hallucination, delusions, and agitations(Burns et al., 1990; Burns and Iliffe, 2009). Therefore, I have also investigated into the mouse forced-swim test (FST), which is widely used in the screening of antidepressants. By quantitative analyses on this test, we have discovered a new confounding factor, and developed novel methods to determine the important parameters in the mouse FST, which could be applied to mouse AD models to study depression and the effect of antidepressants in AD.
In conclusion, the application of quantitative approaches in neuroscience studies have led to the discovery of intriguing results and provided ground for exciting future research.