Adult Neurogenesis

[rs_section_title title=”Cell-cell interaction in the subgranular zone (SGZ) stem cell niche.”]

In the adult hippocampal subgranular zone (SGZ), a community of various cell types resides in a spatially restricted environment called the neurogenic niche. This is a very dynamic environment, where turnover of new and old cells continues throughout life – a recent report estimates that in humans, 700 newborn neurons are generated daily. Neural stem cells (NSCs), the primary stem cells of this niche, are the sine-qua-non of this space; without them, the niche ceases to exist. These cells are very sensitive to the activity around them and respond to various stimuli by actively producing new cells. Accumulated data indicate that the formation of new neurons is not merely static or restorative; rather, this process represents an adaptive response of the brain to our environment and/or internal needs. However, this adaptive response is limited by two constraints: 1) NSCs are not renewable, and 2) the space they inhabit together with their progeny is very restricted. How then is this complex community of cells balanced?

In these sets of projects we use newly developed genetic models to elucidate the intrinsic mechanisms responsible for the molecular regulation of NSCs through stem-progeny cell communication and stem-progeny-microglia communication, distinguish cell-determined vs. niche-determined processes, and identify new transcripts participating in this control.

[rs_section_title title=”Metabolic Control of SGZ stem Cell Behavior”]

The fate of the cell, whether it divides, differentiates, enters a transient (quiescence) or permanent (senescence) growth arrest, or triggers a suicidal mechanism of death, demands a finely-tuned sequential activation and deactivation of both biosynthetic and energy generating metabolic pathways.During neurogenesis, the formation of newborn cells requires production of new membranes. Before cell division, a neuroprogenitor cell (NPC) must double its membrane content in order to maintain the size/surface ratio in daughter cells. It is not surprising, then, that there is a coordinated regulation of the fatty acid synthesis and the cell cycle. Alterations in the balance of saturated fatty acids (SFA) and mono-unsaturated fatty acids (MUFA) in the cell can influence a wide array of cellular functions – fatty acids are not only the fundamental constituents of membranes, but also vital sources of metabolic energy and important mediators that regulate many cellular activities. In stem cells, excess content of long chain fatty acids, especially SFA, triggers programmed cell death in a process known as lipid mediated toxicity or lipoapoptosis. In turn, MUFA are more preferred substrates than SFA for lipid membrane biosynthesis. Thus, the content and distribution of SFA and MUFA within the stem cells must be tightly regulated to ensure their proper function and survival.

Recently, utilizing a nuclear magnetic resonance (NMR)-based metabolomics, we have identified a lipid-based spectral signal, resonating at 1.28ppm, enriched in NPCs. In the human brain, this spectral signal was restricted to neurogenic zones, decreased with age, and responded to stimuli that increase neurogenesis, such as antidepressants and electroconvulsive therapy, implicating it as a possible biomarker for studies of neurogenesis. These data underlie the importance to further investigate the molecular identity of the signal and its relevance for adult neurogenesis.

In these sets of projects, we test the hypothesis that MUFAs are the key hub in the intertwined metabolic and transcription networks through which lipogenic and signaling pathways mutually regulate NPC proliferation and the birth of new neurons.