Adult neurogenesis is the process in which neurons are generated from neural stem cells in the adult. This process differs from prenatal neurogenesis.
In most mammals, new neurons are born throughout adulthood in two regions of the brain: The subgranular zone (SGZ), part of the dentate gyrus of the hippocampus, where neural stem cells give birth to granule cells (implicated in memory formation and learning). The subventricular zone (SVZ) of the lateral ventricles, which can be divided into three microdomains: lateral, dorsal and medial. Neural stem cells migrate to the olfactory bulb through the rostral migratory stream where they differentiate into interneurons participating in the sense of smell. In humans, however, few if any olfactory bulb neurons are generated after birth.
More attention has been given to the neurogenesis in the dentate gyrus than in the striatum. In rodents, many of the newborn dentate gyrus neurons die shortly after they are born, but a number of them become functionally integrated into the surrounding brain tissue. Adult neurogenesis in rodents is reported to play a role in learning and memory, emotion, stress, depression, response to injury, and other conditions.
The numbers of neurons born in the human adult hippocampus remains controversial; some studies have reported that in adult humans about 700 new neurons are added in the hippocampus every day, while more recent studies show that adult hippocampal neurogenesis does not exist in humans, or, if it does, it is at undetectable levels. Recent evidence shows that adult neurogenesis is essentially extinct in humans. The experiments advocating for the presence of adult neurogenesis have focused on how dual antigen retrieval finds that DCX antibodies are staining many cells within the adult human dentate gyrus. This finding is not as clear though as supporters of adult neurogenesis suggest; the dentate gyrus cells stained with DCX have been shown to have a mature morphology, contrasting the idea that novel neurons are being generated within the adult brain. The role of new neurons in human adult brain function thus remains unclear.
Mechanism
Adult neural stem cells
Neural stem cells (NSCs) are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system.
Lineage reprogramming (trans-differentiation) Emerging evidence suggests that neural microvascular pericytes, under instruction from resident glial cells, are reprogrammed into interneurons and enrich local neuronal microcircuits. This response is amplified by concomitant angiogenesis.
Model organisms of neurogenesis
Planarian Planarian are one of the earliest model organisms used to study regeneration with Pallas as the forefather of planarian studies. Planarian are a classical invertebrate model that in recent decades have been used to examine neurogenesis. The central nervous system of a planarian is simple, though fully formed with two lobes located in the head and two ventral nerve cords. This model reproduces asexually producing a complete and fully functioning nervous system after division allowing for consistent examination of neurogenesis.
Axolotl The axolotl is less commonly used than other vertebrates, but is still a classical model for examining regeneration and neurogenesis. Though the axolotl has made its place in biomedical research in terms of limb regeneration, the model organism has displayed a robust ability to generate new neurons following damage. Axolotls have contributed as a bridge organism between invertebrates and mammals, as the species has the regenerative capacity to undergo complete neurogenesis forming a wide range of neuronal populations not limited to a small niche, yet the complexity and architecture is complex and analogous in many ways to human neural development.
Zebrafish Zebrafish have long been a classical developmental model due to their transparency during organogenesis and have been utilized heavily in early development neurogenesis. The zebrafish displays a strong neurogenerative capacity capable of regenerating a variety of tissues and complete neuronal diversity (with the exception of astrocytes, as they have yet to be identified within the zebrafish brain) with continued neurogenesis through the life span. In recent decades the model has solidified its role in adult regeneration and neurogenesis following damage. The zebrafish, like the axolotl, has played a key role as a bridge organism between invertebrates and mammals. The zebrafish is a rapidly developing organism that is relatively inexpensive to maintain, while providing the field ease of genetic manipulation and a complex nervous system.
Chick Though avians have been used primarily to study early embryonic development, in recent decades the developing chick has played a critical role in the examination of neurogenesis and regeneration as the young chick is capable of neuronal-turnover at a young age, but loses the neurogenerative capacity into adulthood. The loss of neuroregenerative ability over maturation has allowed investigators to further examine genetic regulators of neurogenesis.
Rodents
Rodents, mice and rats, have been the most prominent model organism since the discovery of modern neurons by Santiago Ramon y Cajal. Rodents have a very similar architecture and a complex nervous system with very little regenerative capacity similar to that found in humans. For that reason, rodents have been heavily used in pre-clinical testing. Rodents display a wide range of neural circuits responsible for complex behaviors making them ideal for studies of dendritic pruning and axonal shearing. While the organism makes for a strong human analog, the model has its limitations not found in the previous models: higher cost of maintenance, lower breeding numbers, and the limited neurogenerative abilities.
To some extent, adult neurogenesis in rodents may be induced by selective disruption of Notch signalling in astrocytes: this produces novel neurons which functionally integrate into the striatal circuit.
Adult neurogenesis in the subventricular zone and dentate gyrus of rodents generates oxidative stress and production of reactive oxygen species that can damage both DNA and lipids. The oxidative stress caused by postnatal neurogenesis may significantly contribute to the reduced learning and memory that occurs with increasing age.
Octopus
A cephalopod also known as the common octopus, this organism has an intricate nervous system that demonstrates the brain's capacity to produce new cells. In this case and in other taxa when compared, these organisms adapt to unpredictable environments by using newly formed brain cells. This is over a short life-span (female about one year) where wild common octopuses focus most of their energy on mating and offspring care. Findings suggest that the octopus vulgaris like other short-lived species have a complex hippocampal proliferation, needed for spatial/navigation, and short and long-term memory.Hippocampus
Chickadees
Black-capped chickadees are a well-known model species in the field of neuroscience for their neural mechanisms in song vocalization, plasticity, and memory. Black-capped chickadees are different from other species in the larger group of songbirds because they are characterized by food-caching behaviors. Due to this behavior, chickadees can be described through their remarkable spatial memory. Seasonal changes in hippocampal densities have been described since 1994 where neuronal survival peaks during the fall (October), measured by thymidine (see tracking neurogenesis below) labeled cells, weeks after injection. When compared to non-food caching birds such as the house sparrow, chickadees had significantly more hippocampal neuron recruitment from fall to spring. The changes in hippocampal density is directly associated with increased hoarding behavior, especially during the winter when better spatial memory maximizes their survival.
Over the 2 decades since the initial discovery, the specific role of chickadee hippocampus in memory has gained wide attention. In an experimental setting, hippocampal lesions affect memory for locations, validating previous notions for this specific role. Further, experimentally inhibiting neuronal proliferation decreases scores on spatial memory tasks, supporting that new neurons hold the same role as pre-existing ones. The specific function of the hippocampus, coupled with seasonal changes in their volume, point towards their temporary advantages for spatial memory consolidation. Taken all together, adult neurogenesis in the hippocampus of black-capped chickadees suggest a selective mechanisms for neuronal survival in direct correlation with seasonal food caching behavior.
Developmentally, progenitor cells called radial glial cells are thought to mitigate newly born neurons to their destinations. Radial glial cells extend processes from their soma in the avian ventricular zone to the parenchyma of the adult forebrain. These new neurons have been observed as early as 3 days after thymidine administration in the HVC and as early as 7 days before reaching the hippocampus. Avian migration of new neurons are analogous to mammalian species, providing a future direction in exploring neurogenesis in mammalian species and beyond. However, captivity has been shown to reduce hippocampal volumes when compared to wild counterparts. Reduced neurogenesis in captive birds may be caused by stress, lack of exercise, diminished social interaction, and limited caching opportunities.
Tracking neurogenesis The creation of new functional neurons can be measured in several ways, summarized in the following sections.
DNA labelling Labelled DNA can trace dividing cell's lineage, and determine the location of its daughter cells. A nucleic acid analog is inserted into the genome of a neuron-generating cell (such as a glial cell or neural stem cell). Thymine analogs (3H) thymidine and BrdU are commonly used DNA labels, and are used for radiolabelling and immunohistochemistry respectively.
Fate determination via neuronal lineage markers DNA labeling can be used in conjunction with neuronal lineage markers to determine the fate of new functional brain cells. First, incorporated labeled nucleotides are used to detect the populations of newly divided daughter cells. Specific cell types are then determined with unique differences in their expression of proteins, which can be used as antigens in an immunoassay. For example, NeuN/Fox3 and GFAP are antigens commonly used to detect neurons, glia, and ependymal cells. Ki67 is the most commonly used antigen to detect cell proliferation. Some antigens can be used to measure specific stem cell stages. For example, stem cells requires the sox2 gene to maintain pluripotency and is used to detect enduring concentrations of stem cells in CNS tissue. The protein nestin is an intermediate filament, which is essential for the radial growth of axons, and is therefore used to detect the formation of new synapses.
Cre-Lox recombination
Some genetic tracing studies utilize cre-lox recombination to bind a promoter to a reporter gene, such as lacZ or GFP gene. This method can be used for long term quantification of cell division and labeling, whereas the previously mentioned procedures are only useful for short-term quantification.
Viral vectors