Mechanisms of Cognitive Aging in Caenorhabditis elegans: Normal aging, insulin signaling, and sexual dimorphism

Abstract

Cognitive aging has become a serious public health concern in our aging society. Molecular, cellular, and connectivity changes occur with age in the brain, leading to behavioral changes, including the decline in learning and memory abilities. Here, we used the model organism Caenorhabditis elegans to study the molecular, morphological, and behavioral changes that occur during neuronal aging. We first characterized the transcriptomic changes that occur in neurons during aging, and then we characterized how the daf-2 Insulin/IGF-1 receptor mutant exhibits a significant DAF-16-dependent extension of learning and memory span with age compared to wild-type worms. Using RNA sequencing, we discovered that aged IIS/FOXO pathway mutants exhibit distinct neuronal transcriptomic alterations in response to cognitive aging, including the upregulation of stress response genes whose homologs have been found to be neuroprotective. Second, in addition to assessing hermaphrodite aging, we also characterized the male neuronal aging process. Besides sex-shared neuronal aging genes, males differentially downregulate mitochondrial metabolic genes and upregulate GPCR genes with age, while the X chromosome exhibits increased gene expression in hermaphrodites and altered dosage compensation complex expression with age. Third, we identified neuron-type-specific targets of the daf-2 mutant that were overshadowed in bulk neuronal sequencing using single-nucleus sequencing. We found that chemosensory neurons exhibit the biggest changes between daf-2 mutants and wild-type neurons. We validated the neuron-type-specific expression changes in daf-2 using promoter-GFP constructs and identified AWC-specific gene expression changes in daf-2 neurons that control the learning and memory improvements in daf-2 worms through behavioral validation. Combining deep single-neuron transcriptomics, genetic manipulation, and behavioral analyses, this thesis enabled us to identify conserved genes that function in specific adult neurons to control behaviors such as learning and memory, elucidating possible pathways for further study, and shedding light on intervention development.