Epigenetic neuronal aging underlying cognitive decline

• Applicant: Professor Dr. Tomohisa Toda, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497658532

The goal of this proposal is to unravel a comprehensive view of epigenetic aging in a single neuronal type of the hippocampus, and to delineate its causal contributions to cognitive aging. The brain consists of thousands of different types of neurons, and this neuronal diversity underlies the complex function of the brain. Importantly, most neurons are not replaceable in the adult mammalian brain, thus, maintaining specific neuronal identity and function is critical for robust brain function throughout our life. However, brain aging compromises cognitive capability and increases risks for neurodegenerative diseases. To prevent and treat neuronal aging and age-related neurodegenerative diseases, we need a firm understanding of underlying mechanisms of neuronal aging. Deterioration of several epigenetic mechanisms have been proposed as drivers of brain aging, and the applicants also identified that levels of lamin B1, one of nuclear lamins, and DNA methylation in the hippocampus are compromised during aging. However, a comprehensive view of the functional aging of neuronal epigenome is still missing because previous studies were limited with regard to neuronal specificity, the functional interaction of diverse layers of epigenetic regulation, and mechanistic insights of specific age-related epigenetic changes in controlling neuron function and cognitive decline. In the proposed project, we will overcome these previous limitations and aim at establishing a comprehensive view of the functional aging neuronal epigenome. Our specific objectives include i) performing in-depth characterization of genome-wide age-related epigenetic changes in a purified single type of neurons, ii) establishing a functional interaction between different layers of epigenetic regulation, and iii) testing a causal role of age-related epigenetic changes in neuronal dysfunction and cognitive decline. Altogether, our data will provide a fundamental basis of functional epigenetic interactions underlying neuronal aging and cognitive decline.

• DFG Programme: Research Grants