Impact of NEIL DNA glycosylases on the brain’s GPS
NEIL DNA glycosylases play a key role in base excision repair (BER), which is the major pathway for repair the oxidative DNA damage. Recent findings identified that loss of DNA glycosylases responsible for repair of oxidized bases results in impaired brain development, cognition and behavior. Moreover, the transcriptomic analysis in the hippocampus of those DNA glycosylase-deficient transgenic mice showed patterned perturbation of genetic and epigenetic programming. Hippocampal networks encode episodic memories as sequence of events and places according to individual experiences, among which spatial memory is the important one that relates to spatial locations. The identification of place cells in the hippocampus and grid cells in the entorhinal cortex that respond to the animal’s self-localization in any novel environment has been well characterized, which indicates that space information can be encoded and manipulated in the firing pattern of particular neurons. However, the molecular and cellular mechanism underlying how genetic and epigenetic programming affects hippocampal spatial memory remains largely unknown. In this project, I will use different NEIL-deficient mouse models (e.g. Neil1-/-, Neil2-/-, Neil3-/- and Neil1-/-Neil2-/-) to explore the impact of the NEIL DNA repair system on neuronal functions during spatial cognition, and unravel NEIL-dependent molecular underpinnings of functionally distinct neurons and neural networks contributing to memory formation.
To minimize the distress of animals and improve animal well-being, I will provide enriched housing conditions, careful handling and close monitoring during the whole experimental procedure. Wildtype mice (C57/Bl6N) will be used as a control for all KO models. The same animal will be tested in different behavioural tasks, but the groups for measuring long-term and short-term memory must be separated. The same animals used for behavior studies will be used for neuronal recording and in vitro experiments for DNA/RNA/protein analysis. In total, we plan to use 200 of wildtype control mice and 200 of Neil3-/- mice for both young (3-6-month) and old (12-18-month) age groups. As for Neil1-/-, Neil2-/- and Neil1-/-Neil2-/- mice, we will work with young mice, thus the total number is 270 with 90 mice for each KO models. We will try to use as few animals as possible to achieve the goal.
To minimize the distress of animals and improve animal well-being, I will provide enriched housing conditions, careful handling and close monitoring during the whole experimental procedure. Wildtype mice (C57/Bl6N) will be used as a control for all KO models. The same animal will be tested in different behavioural tasks, but the groups for measuring long-term and short-term memory must be separated. The same animals used for behavior studies will be used for neuronal recording and in vitro experiments for DNA/RNA/protein analysis. In total, we plan to use 200 of wildtype control mice and 200 of Neil3-/- mice for both young (3-6-month) and old (12-18-month) age groups. As for Neil1-/-, Neil2-/- and Neil1-/-Neil2-/- mice, we will work with young mice, thus the total number is 270 with 90 mice for each KO models. We will try to use as few animals as possible to achieve the goal.