Individuals demonstrate marked differences in behavioral responses. Even within genetically similar inbred mouse strains, individuals vary in their responses to behavioral tasks and stressors. Underlying this behavioral variation is tremendous diversity at the neuronal level. There may be as many as 10,000 different types of neurons, which can differ in structure, molecular make-up (e.g., expression of different combinations of ion channels), and connections to other neurons. This heterogeneity arises from only ~30,000 genes and determines how neuronal circuits operate;however, the source of such neuronal diversity remains unclear. DNA recombination has been proposed as one source of such diversity. LINE-1 (Long Interspersed Nuclear Elements 1;"L1") retrotransposons are active elements in the genome that can mobilize in germ cells and neuronal precursor cells. When mobilized, L1 retrotransposons may alter gene expression, potentially supporting neuronal heterogeneity and individual variations;however, the functional role of L1 retrotransposition remains largely undetermined. Focusing on both embryonic and adult L1 insertions, this proposal will address the hypothesis that L1 retrotransposition contributes to individual differences in behavioral and neuronal phenotypes.
Aim 1 will determine how environmental experience may modulate L1 activity.
Aim 2 will develop transgenic and pharmacological approaches to attenuate L1 activity. And finally, Aim 3 will investigate how attenuating L1 retrotransposition influences behavioral responses and neuronal phenotypes in response to salient environmental experiences.
This project will determine the functional importance of mobile elements in the genome by testing the effects of L1 retrotransposition on behavioral responses and neuronal phenotypes in mice. The results of this project will contribute to our understanding of individual variation in behavioral responses and individual differences in susceptibility to neurological and psychiatric diseases.
|Bedrosian, Tracy A; Linker, Sara; Gage, Fred H (2016) Environment-driven somatic mosaicism in brain disorders. Genome Med 8:58|