Neurogenesis

Model of mammalian neurogenesis[4]

During embryonic development, the mammalian central nervous system (CNS; brain and spinal cord) is derived from the neural tube, which contains NSCs that will later generate neurons.[3] However, neurogenesis doesn't begin until a sufficient population of NSCs has been achieved. These early stem cells are called neuroepithelial cells (NEC)s, but soon take on a highly elongated radial morphology and are then known as radial glial cells (RGC)s.[3] RGCs are the primary stem cells of the mammalian CNS, and reside in the embryonic ventricular zone, which lies adjacent to the central fluid-filled cavity (ventricular system) of the neural tube.[5][6] Following RGC proliferation, neurogenesis involves a final cell division of the parent RGC, which produces one of two possible outcomes. First, this may generate a subclass of neuronal progenitors called intermediate neuronal precursors (INP)s, which will divide one or more times to produce neurons. Alternatively, daughter neurons may be produced directly. Neurons do not immediately form neural circuits through the growth of axons and dendrites. Instead, newborn neurons must first migrate long distances to their final destinations, maturing and finally generating neural circuitry. For example, neurons born in the ventricular zone migrate radially to the cortical plate, which is where neurons accumulate to form the cerebral cortex.[5][6] Thus, the generation of neurons occurs in a specific tissue compartment or 'neurogenic niche' occupied by their parent stem cells.

The rate of neurogenesis and the type of neuron generated (broadly, excitatory or inhibitory) are principally determined by molecular and genetic factors. These factors notably include the Notch signaling pathway, and many genes have been linked to Notch pathway regulation.[7][8] The genes and mechanisms involved in regulating neurogenesis are the subject of intensive research in academic, pharmaceutical, and government settings worldwide.

The amount of time required to generate all the neurons of the CNS varies widely across mammals, and brain neurogenesis is not always complete by the time of birth.[3] For example, mice undergo cortical neurogenesis from about embryonic day (post-conceptional day) (E)11 to E17, and are born at about E19.5.[9] Ferrets are born at E42, although their period of cortical neurogenesis does not end until a few days after birth.[10] In contrast, neurogenesis in humans generally begins around gestational week (GW) 10 and ends around GW 25 with birth about GW 38–40.[11]

As embryonic development of the mammalian brain unfolds, neural progenitor and stem cells switch from proliferative divisions to differentiative divisions. This progression leads to the generation of neurons and glia that populate cortical layers. Epigenetic modifications play a key role in regulating gene expression in the cellular differentiation of neural stem cells. Epigenetic modifications include DNA cytosine methylation to form 5-methylcytosine and 5-methylcytosine demethylation.[12][13] These modifications are critical for cell fate determination in the developing and adult mammalian brain.

DNA cytosine methylation is catalyzed by DNA methyltransferases (DNMTs). Methylcytosine demethylation is catalyzed in several stages by TET enzymes that carry out oxidative reactions (e.g. 5-methylcytosine to 5-hydroxymethylcytosine) and enzymes of the DNA base excision repair (BER) pathway.[12]

Neurogenesis can be a complex process in some mammals. In rodents for example, neurons in the central nervous system arise from three types of neural stem and progenitor cells: neuroepithelial cells, radial glial cells and basal progenitors, which go through three main divisions: symmetric proliferative division; asymmetric neurogenic division; and symmetric neurogenic division. Out of all the three cell types, neuroepithelial cells that pass through neurogenic divisions have a much more extended cell cycle than those that go through proliferative divisions, such as the radial glial cells and basal progenitors.[14] In the human, adult neurogenesis has been shown to occur at low levels compared with development, and in only three regions of the brain: the adult subventricular zone (SVZ) of the lateral ventricles, the amygdala and the dentate gyrus of the hippocampus.[15][16][17]

In many mammals, including rodents, the olfactory bulb is a brain region containing cells that detect smell, featuring integration of adult-born neurons, which migrate from the SVZ of the striatum to the olfactory bulb through the rostral migratory stream (RMS).[15][18] The migrating neuroblasts in the olfactory bulb become interneurons that help the brain communicate with these sensory cells. The majority of those interneurons are inhibitory granule cells, but a small number are periglomerular cells. In the adult SVZ, the primary neural stem cells are SVZ astrocytes rather than RGCs. Most of these adult neural stem cells lie dormant in the adult, but in response to certain signals, these dormant cells, or B cells, go through a series of stages, first producing proliferating cells, or C cells. The C cells then produce neuroblasts, or A cells, that will become neurons.[16]

Significant neurogenesis also occurs during adulthood in the hippocampus of many mammals, from rodents to some primates, although its existence in adult humans is debated.[19][20][21] The hippocampus plays a crucial role in the formation of new declarative memories, and it has been theorized that the reason human infants cannot form declarative memories is because they are still undergoing extensive neurogenesis in the hippocampus and their memory-generating circuits are immature.[22] Many environmental factors, such as exercise, stress, and antidepressants have been reported to change the rate of neurogenesis within the hippocampus of rodents.[23][24] Some evidence indicates postnatal neurogenesis in the human hippocampus decreases sharply in newborns for the first year or two after birth, dropping to "undetectable levels in adults."[19]