Neuropathological and spatial transcriptome brain maps in Octodon degus, a natural Alzheimer's disease rodent model - PROJECT SUMMARY/ABSTRACT The search for a cure or treatments of Alzheimer's disease (AD) has been largely unsuccessful, which has compelled several neuroscience fields to develop novel methods to understand and treat the condition. One such approach is the discovery of new unconventional animal models that naturally present AD-like traits. As a member of Dr. Xiangmin Xu's lab, I have been able to contribute to these efforts by conducting neuropathological characterizations of the Octodon degus (degu), a long-lived rodent native to Chile. This proposal focuses on the outbred degu that, in a subset of their adult population, presents cognitive deficits accompanied by spontaneous neuropathologies similar to those seen in human AD. I propose to create neuropathological, cytoarchitectural, and spatial transcriptome maps that will be integrated with behavioral datasets to comprehensively assess AD- like profiles in the outbred degu. I hypothesize that cognitively impaired degus will manifest neuropathology, altered cytoarchitecture, and maladaptive spatial transcriptomic maps reminiscent of human AD that will reveal novel therapeutic gene targets for the disease. The overall objective of this proposal is to create a comprehensive analysis of the outbred degu's AD- like features. This will shed light on the overlap between degu-AD and human-AD, which will lay the grounds for the degu's role in future AD research. I will divide degus into two groups based on their performance in an ethologically relevant burrowing behavior test: cognitively impaired (AD-like) and cognitively healthy (Non-AD) groups. The first aim of this proposal is to conduct a neuropathological and cytoarchitectural analysis (using immunofluorescence and western blot protein quantification) in degu prefrontal cortex (PFC) and dorsal hippocampus (dHIP). This will be complemented by the production of single-cell spatial transcriptomic maps in PFC & dHIP using MERFISH (multiplexed error-robust fluorescence in situ hybridization) in aim 2. This will provide a spatially resolved look at the maladaptive gene expression profiles of the cognitively impaired degu. The proposal culminates with the integration of the data from aim 1 and aim 2 with behavioral datasets (burrowing behavior, Y-maze, and open field tests). This will result in a multi-layered analysis of the degu from the transcriptomic to the behavioral level featuring spatially correlated data. I plan to analyze these integrated datasets to identify genes highly correlated with AD-like features in the degu that could yield therapeutic targets to treat the disease. Dr. Xu and I have fleshed out a training plan to progress the development of my technical, writing, mentorship, and leadership skills. I plan to perfect my skills conducting MERFISH experiments, analyzing -omic data, writing manuscripts/grants, mentoring, and presenting research. All these will contribute towards my long- term goal of becoming an independent scientist and an eventual professor at a research university.
