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Adult Neurogenesis in the Mammalian Brain: Significant Answers and Significant Questions Guo-li Ming, Hongjun Song

Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. 

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Queensland Brain Institute: What is neurogenesis?

Neurogenesis is the process by which new neurons are formed in the brain. Neurogenesis is crucial when an embryo is developing, but also continues in certain brain regions after birth and throughout our lifespan.  

The mature brain has many specialised areas of function, and neurons that differ in structure and connections. The hippocampus, for example, which is a brain region that plays an important role in memory and spatial navigation, alone has at least 27 different types of neurons.

The incredible diversity of neurons in the brain results from regulated neurogenesis during embryonic development. During the process, neural stem cells differentiate—that is, they become any one of a number of specialised cell types—at specific times and regions in the brain.

Stem cells can divide indefinitely to produce more stem cells, or differentiate to give rise to more specialised cells, such as neural progenitor cells. These progenitor cells themselves differentiate into specific types of neurons. As seen in the diagram below, neural stem cells can also differentiate into glial progenitor cells, which give rise to glial cells such as astrocytes, oligodendrocytes and microglia.

Until recently, neuroscientists believed that the central nervous system, including the brain, was incapable of neurogenesis and unable to regenerate. However, stem cells were discovered in parts of the adult brain in the 1990s, and adult neurogenesis is now accepted to be a normal process that occurs in the healthy brain.

[Neural stem cells can produce new neural cells of any type. When stem cells from the brain are isolated and grown in a dish, they continuously divide and create large spherical masses of cells, similar to the two shown here. Each spherical mass, called a neurosphere, is produced by a single stem cell. When exposed to different chemicals, the cells turn into either neurons (red) or glia (cyan). Cell nuclei are shown in dark blue. ]

[Neural stem cells have the potential to generate all neural cell types. They differentiate into neuronal progenitor cells, which give rise to neuron, or glial progenitors, which give rise to glial cells.]

https://qbi.uq.edu.au/brain-basics/brain-physiology/what-neurogenesis

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About memory:Adult Neurogenesis  Dr. McPherson

Neurogenesis occurs in two main areas in the adult brain: the hippocampus and the olfactory bulb.

The transformation of a new cell into a neuron appears to crucially involve a specific protein called WnT3, that's released by support cells called astrocytes.

A chemical called BDNF also appears critical for the transformation into neurons.

Most recently, T-cells have also been revealed as important for neurogenesis to occur.

The extent and speed of neurogenesis can also be enhanced by various chemicals. Nerve growth factors appear to enhance the proliferation of precursor cells (cells with the potential to become neurons), and the prionprotein that, damaged, causes mad cow disease, appears in its normal state to speed the rate of neurogenesis.

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What is neurogenesis?

Neurogenesis — the creation of new brain cells — occurs of course at a great rate in the very young. For a long time, it was not thought to occur in adult brains — once you were grown, it was thought, all you could do was watch your brain cells die!

Adult neurogenesis (the creation of new brain cells in adult brains) was first discovered in 1965, but only recently has it been accepted as a general phenomenon that occurs in many species, including humans (1998).

Where does adult neurogenesis occur?

It's now widely accepted that adult neurogenesis occurs in the subgranular zone of the dentate gyrus within the hippocampus and the subventricular zone(SVZ) lining the walls of the lateral ventricles within the forebrain. It occurs, indeed, at a quite frantic rate — some 9000 new cells are born in the dentate gyrus every day in young adult rat brains — but under normal circumstances, at least half of those new cells will die within one or two months.

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How does neurogenesis occur?

New neurons are spawned from the division of neural precursor cells — cells that have the potential to become neurons or support cells. How do they decide whether to remain a stem cell, turn into a neuron, or a support cell.

Observation that neuroblasts traveled to the olfactory bulb from the SVZ through tubes formed by astrocytes has led to an interest in the role of those support cells. It's now been found that astrocytes encourage both precursor cell proliferation and their maturation into neurons — precursor cells grown on gliadivide about twice as fast as they do when grown on fibroblasts, and are about six times more likely to become neurons.

http://www.memory-key.com/memory/neurogenesis

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Understanding neurogenesis in the adult human brain Anil Gulati

The process of neurogenesis is most active during embryonic development and continues after birth for a year or 2 in humans. In the first stage (42 embryonic days), neural progenitor cells, which are mitotic are formed in a symmetrical fashion, after which the mode of cell division shifts from symmetrical to asymmetrical. During asymmetrical division, 1 neural progenitor and 1 neuron is produced.[1] Neurogenesis mostly occurs in the ventricular zone, and the newly formed progenitor neurons remain in the proliferative zone, while the neurons migrate radially out to the neocortex. The cortical neurogenesis completes by about 108 embryonic days.[2] A nonpathological process that is essential in the establishment of complex networks of the developing brain involves loss of about 50% of the neurons. There are approximately 100 billion neurons in a mature human brain.[3] The naturally occurring neuronal cell death occurs prenatally, and elimination of about 50% of unwarranted connections among neurons occurs postnatally. Each neuron can make connections with more than 1000 other neurons, thus an adult brain has approximately 60 trillion neuronal connections.

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It is now known that neurogenesis persists throughout the human lifespan, and new neurons are being formed in the adult brain. The first direct evidence for adult neurogenesis in humans was provided in 1998, when a thymidine analog, bromodeoxyuridine (BrdU) was administered to 5 cancer patients, and their postmortem brain tissue was obtained and compared to a similar patient without BrdU treatment. It was found that new neurons are being formed from dividing progenitor cells in the dentate gyrus of adult humans.[8] Follow-up studies could not be carried out because injecting BrdU in humans is not an option anymore, because of safety concerns of injecting a chemical that incorporates into the DNA of dividing brain cells. A landmark study was then conducted by measuring the 14C concentration in the DNA of brain cells of deceased patients that were previously exposed to atmospheric 14C released due to above-ground nuclear tests, and it showed significant neurogenesis in the human hippocampus.

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It can be concluded that angiogenesis and neurogenesis can be pharmacologically induced in the adult damaged brain. Therefore, pharmacological neurorestoration is likely to become a priority area of research for diseases such as stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and brain and spinal cord injuries.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4689008/

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Adult neurogenesis: mechanisms and functional significance Simon M. G. Braun, Sebastian Jessberger

New neurons are generated throughout life in distinct regions of the mammalian brain. This process, called adult neurogenesis, has been implicated in physiological brain function, and failing or altered neurogenesis has been associated with a number of neuropsychiatric diseases. Here, we provide an overview of the mechanisms governing the neurogenic process in the adult brain and describe how new neurons may contribute to brain function in health and disease.

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Contrary to the long-held belief that neurogenesis tapers off with the end of early postnatal development, the mammalian brain retains the capacity to generate new neurons throughout life. Adult neural stem/progenitor cells (NSPCs) are responsible for the generation of new neurons and reside in two main locations in the adult brain: the subventricular zone (SVZ) lining the lateral ventricles, and the hippocampal dentate gyrus (DG) (reviewed by Gage, 2000).

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The finding that neurogenesis persists throughout adulthood has initiated tremendous efforts to (1) characterize how new neurons differentiate and integrate into adult neural circuitries, (2) understand the implications of failing neurogenesis in neuropsychiatric disease processes, and (3) analyze whether endogenous NSPCs may be harnessed for brain repair. However, we are only just beginning to understand the cellular and molecular mechanisms that regulate the neurogenic process in the adult brain, and how this may contribute to neurological disease.

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NSPCs reside primarily in the DG and the SVZ, where they are maintained in a largely quiescent state (Doetsch et al., 1999; Bonaguidi et al., 2011). Upon activation by niche-derived and/or intrinsic signals, they undergo proliferation, which leads to the birth of new neurons. Newborn cells then undergo differentiation predominantly into neuronal cells before they mature and integrate over the course of several weeks into the pre-existing circuitries (Zhao et al., 2008). In the DG, newborn cells differentiate into excitatory granule cells, the principal neurons of the DG. NSPCs in the SVZ generate restricted neural progenitor cells that migrate through a glial cell scaffold via the rostral migratory stream (RMS) towards the olfactory bulb (OB) (Lepousez et al., 2013). Here, neurogenesis continues as the cells differentiate into distinct types of olfactory neurons. Thus, although NSPCs mainly reside in two locations (the SVZ and the DG), the neurogenic process continues in the OB where newborn olfactory neurons mature and functionally integrate. In addition to these main sites of neurogenesis, the generation of new neurons has also been observed in the hypothalamus.

http://dev.biologists.org/content/141/10/1983.eLetters

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https://www.artofthecell.com/

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