Regulation of survival and synaptic connectivity in the adult brain by cell-intrinsic excitability

Abstract

Although the lifelong addition of new neurons to the olfactory bulb and dentate gyms of mammalian brains is by now an accepted fact, the function of adult-generated neurons still largely remains a mystery. The ability of new neurons to form synapses with preexisting neurons without disrupting circuit function is central to the hypothesized role of adult neurogenesis as a substrate for learning and memory. In this doctoral thesis, I present work done in collaboration with other scientists that advance knowledge in our understanding of how the cell-intrinsic excitability of new neurons governs their incorporation into mature circuits in the adult brain. Contrary to the notion that adult neurogenesis represents continual addition of the same type of neurons that are incorporated during brain development, we have obtained data that suggests adult-born neurons have distinct characteristics and may perform a distinct function. Results we have obtained in the olfactory bulb show that an increase in cell-intrinsic activity increases survival of adult-born olfactory granule neurons and that precise spiking of these neurons is not critical for integration. Our observations in the dentate gyrus demonstrate that an increase in cell-intrinsic activity is sufficient to effect alterations in synaptic connectivity with the surrounding circuit and that input connectivity is regulated in an activity-dependent manner by Npas4 signaling. Progress in the field of adult neurogenesis is beginning to shed light on the flexibility that adult-born neurons offer to mature circuits and their potential contribution toward circuit refinement and adaptation to changing environmental demands. I am pleased to present this work as a small step towards reaching the ultimate goal of understanding the biology of lifelong learning and memory.