Does mobile DNA impact memory formation? (2016–2018)
Neuroplasticity, the ability of neurons to reorganize and create new connections in response to external stimuli, is critical for learning and memory formation. The molecular and cellular basis of this special property of neurons, however, is not completely understood. The retrotransposon LINE-1 (L1) is a type of ¿¿¿jumping gene¿¿¿ that can move to new locations in the genome. L1 has been demonstrated to mobilize and create genomic diversity in the mammalian brain, and preferentially integrates within neuronally expressed genes. Intriguingly, neuronal L1 activity appears to be a property of physiologically normal, healthy brains, but little is known about the relationship between L1 mobilization and brain function. We hypothesize that L1 mobilizes in response to neuronal activity, and influences neuronal circuitry involved in memory formation. To address this hypothesis, we will use retrotransposon capture sequencing (RC-seq) to quantify and examine the localization pattern of endogenous L1 insertions in the brains of mice routinely exposed to environmental stimuli, compared to control mice, using both wild-type and MeCP2-mutant (Rett syndrome) animals. We will also employ optogenetic techniques to directly stimulate neurons in mice equipped with an engineered L1 reporter transgene, to observe the correlation between neuronal stimulation and L1 mobilisation. Finally, using a system wherein neurons receiving an engineered L1 insertion during a memory-forming exercise can be reactivated, we will investigate a direct link between neuronal L1 mobilisation and memory formation. The experiments proposed here will greatly elucidate the relationship between L1 activity and brain function in normal and abnormal neurobiological contexts.