Optogenetic modulation of TrkB signaling and study of the role in remote memory

Abstract

Optogenetic activation of receptors has advantages compared to chemical or ligand treatment with high spatial and temporal precision. Especially in the brain, using genetically expressed light tunable receptors is superior to direct infusion or systemic drug treatment. In chapter 1, we applied light activatable TrkB receptor, Opto-cytTrkB(E281A), in mouse brain with reducing basal activity by recruiting Cry2PHR(E281A) mutant and deleting extracellular domain to prevent it from unexpected activation by endogenous ligand. This form was sufficiently expressed in the mouse hippocampus and the cortex via viral gene delivery with highly sensitive toward blue light even non-invasive light stimulation fulfilling canonical signal transduction. Also, we demonstrated Opto-cytTrkB(E281A) can locally induce TrkB signaling in axon terminals in the MEC-HPC circuit. From these results, we suggest that Opto-cytTrkB(E281A) will be useful to elucidate the time- and region-specific role of TrkB signaling from cellular function to neural circuit mechanisms. It takes a long-time for the memory to be remote memory. The frontal cortex is thought to be the region where the old memory is recalled. However, the TrkB underlie the neural circuit remains to be elucidated. In chapter 2, we suggest that TrkB in neurons projecting the entorhinal cortex to prefrontal cortex is required to consolidate remote memory by increasing reactivity of mPFC cells. Furthermore, TrkB deletion devastated the experience-dependent maturation of oligodendroglia in the prefrontal cortex resulting in defect of remote memory, which was restored by clemastine administration. Together, our data suggest TrkB in the intercortical circuits served the remote memory consolidation.