Abstract
BackgroundAdult hippocampal neurogenesis, the process of formation of new neurons, occurs throughout life in the hippocampus. New neurons have been associated with learning and memory as well as mood control, and impaired neurogenesis has been linked to depression, schizophrenia, autism and cognitive decline during aging. Thus, understanding the biological properties of adult neurogenesis has important implications for human health. Computational models of neurogenesis have attempted to derive biologically relevant knowledge, hard to achieve using experimentation. However, the majority of the computational studies have predominantly focused on the late stages of neurogenesis, when newborn neurons integrate into hippocampal circuitry. Little is known about the early stages that regulate proliferation, differentiation, and survival of neural stem cells and their immediate progeny.ResultsHere, based on the branching process theory and biological evidence, we developed a computational model that represents the early stage hippocampal neurogenic cascade and allows prediction of the overall efficiency of neurogenesis in both normal and diseased conditions. Using this stochastic model with a simulation program, we derived the equilibrium distribution of cell population and simulated the progression of the neurogenic cascade. Using BrdU pulse-and-chase experiment to label proliferating cells and their progeny in vivo, we quantified labeled newborn cells and fit the model on the experimental data. Our simulation results reveal unknown but meaningful biological parameters, among which the most critical ones are apoptotic rates at different stages of the neurogenic cascade: apoptotic rates reach maximum at the stage of neuroblasts; the probability of neuroprogenitor cell renewal is low; the neuroblast stage has the highest temporal variance within the cell types of the neurogenic cascade, while the apoptotic stage is short.ConclusionAt a practical level, the stochastic model and simulation framework we developed will enable us to predict overall efficiency of hippocampal neurogenesis in both normal and diseased conditions. It can also generate predictions of the behavior of the neurogenic system under perturbations such as increase or decrease of apoptosis due to disease or treatment.
Highlights
IntroductionThe process of formation of new neurons, occurs throughout life in the hippocampus
Adult hippocampal neurogenesis, the process of formation of new neurons, occurs throughout life in the hippocampus
Adult neurogenesis generates new neurons throughout life in two distinct regions of the mammalian brain: the subventricular zone, involved in olfactory processes, and the sub-granular zone (SGZ) of the dentate gyrus [1,2,3,4], where new neurons have been associated with learning and memory as well as mood control [5,6,7]
Summary
The process of formation of new neurons, occurs throughout life in the hippocampus. The majority of the computational studies have predominantly focused on the late stages of neurogenesis, when newborn neurons integrate into hippocampal circuitry. Little is known about the early stages that regulate proliferation, differentiation, and survival of neural stem cells and their immediate progeny. Most research on the neurogenic regulatory mechanisms has centered on the factors that regulate NPC proliferation and integration of newborn neurons into the dentate circuitry during the late stages of neurogenic cascade [30, 31]. Early stages of neurogenesis are very complex, as mechanisms that determine cell proliferation, differentiation, and death are active at the same time. Understanding the early stages of neurogenesis is critical if we are to manipulate this process to enhance the number of viable newborn neurons as treatment modalities
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