Neurogenesis
Encyclopedia
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells
Neural stem cell
Neural stem cells are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone of the mouse brain . In 1992, Brent A...

. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of mammals: the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...

 and the subventricular zone
Subventricular zone
The subventricular zone is a paired brain structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition....

. Studies have indicated that hormones, such as testosterone in vertebrates and ecdysone in invertebrates, have an influence on the rate of neurogenesis.

Occurrence in adults

New neurons are continually born throughout adulthood in predominantly two regions of the brain:
  • The subventricular zone
    Subventricular zone
    The subventricular zone is a paired brain structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition....

    (SVZ) lining the lateral ventricles
    Ventricular system
    The ventricular system is a set of structures containing cerebrospinal fluid in the brain. It is continuous with the central canal of the spinal cord.-Components:The system comprises four ventricles:* right and left lateral ventricles* third ventricle...

    , where neural stem cell
    Neural stem cell
    Neural stem cells are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system. In 1989, Sally Temple described multipotent, self-renewing progenitor and stem cells in the subventricular zone of the mouse brain . In 1992, Brent A...

    s and progenitor generate new neurons (Neuroblast) that migrate to the olfactory bulb
    Olfactory bulb
    The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...

     via the rostral migratory stream
    Rostral migratory stream
    The rostral migratory stream is a pathway found in the brain of some animals along which neuronal precursors that originated in the subventricular zone of the brain migrate to reach the main olfactory bulb . This pathway has been studied in the rodent, rabbit, and both the squirrel and rheusus...

  • The subgranular zone
    Subgranular zone
    The subgranular zone is a brain region in the hippocampus where adult neurogenesis occurs. It is one of the two major sites of adult neurogenesis in the brain, along with the subventricular zone .- Structure :...

    (SGZ), part of the dentate gyrus
    Dentate gyrus
    The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...

     of hippocampus
    Hippocampus
    The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...

    .

Many of the newborn cells die shortly after they are born, but a number of them become functionally integrated into the surrounding brain tissue.

Adult neurogenesis is an example of a long-held scientific theory being overturned. Early neuroanatomists, including Santiago Ramon y Cajal
Santiago Ramón y Cajal
Santiago Ramón y Cajal ForMemRS was a Spanish pathologist, histologist, neuroscientist, and Nobel laureate. His pioneering investigations of the microscopic structure of the brain were original: he is considered by many to be the father of modern neuroscience...

, considered the nervous system fixed and incapable of regeneration. The first evidence of adult mammalian neurogenesis in the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...

 was presented by Joseph Altman
Joseph Altman
Joseph Altman discovered adult neurogenesis, the creation of new neurons in the adult brain, in the 1960s. As an independent investigator at MIT, his results were largely ignored. In the late 1990s, the fact that the brain can create new neurons even into adulthood was rediscovered, leading it to...

 in 1962, followed by a demonstration of adult neurogenesis in the dentate gyrus of the hippocampus in 1963. In 1969, Joseph Altman discovered and named the rostral migratory stream
Rostral migratory stream
The rostral migratory stream is a pathway found in the brain of some animals along which neuronal precursors that originated in the subventricular zone of the brain migrate to reach the main olfactory bulb . This pathway has been studied in the rodent, rabbit, and both the squirrel and rheusus...

 as the source of adult generated granule cell neurons in the olfactory bulb. Up until the 1980s, the scientific community ignored these findings despite use of the most direct method of demonstrating cell proliferation in the early studies, i. e. 3H-thymidine autoradiography. By that time, Shirley Bayer sparking renewed interest in the topic. Studies in the 1990s finally put research on adult neurogenesis into a mainstream pursuit. Also in the early 1990s hippocampal neurogenesis was demonstrated in non-human primates and humans. More recently, neurogenesis in the cerebellum of adult rabbits has also been characterized. Further, some authors (particularly Elizabeth Gould
Elizabeth Gould (psychologist)
Elizabeth Gould is an American neuroscientist. She is a professor of psychology at Princeton University's Department of Psychology. She was one of the first to find evidence of adult neurogenesis in the hippocampus...

) have suggested that adult neurogenesis may also occur in regions within the brain not generally associated with neurogenesis including the neocortex have questioned the scientific evidence
Scientific method
Scientific method refers to a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge. To be termed scientific, a method of inquiry must be based on gathering empirical and measurable evidence subject to specific principles of...

 of these findings, arguing that the new cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 may be of glial origin.

Role in learning

The functional relevance of adult neurogenesis is uncertain, but there is some evidence that hippocampal adult neurogenesis is important for learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...

 and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....

. Multiple mechanisms for the relationship between increased neurogenesis and improved cognition have been suggested, including computational theories to demonstrate that new neurons increase memory capacity, reduce interference between memories, or add information about time
Time
Time is a part of the measuring system used to sequence events, to compare the durations of events and the intervals between them, and to quantify rates of change such as the motions of objects....

 to memories. Experiments aimed at ablating neurogenesis have proven inconclusive, but several studies have proposed neurogenic-dependence in some types of learning, and others seeing no effect. Studies have demonstrated that the act of learning itself is associated with increased neuronal survival. However, the overall findings that adult neurogenesis is important for any kind of learning are equivocal.

Effects of stress

Adult-born neurons appear to have a role in the regulation of stress. Studies have linked neurogenesis to the beneficial actions of specific antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

s, suggesting a connection between decreased hippocampal neurogenesis and depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...

. In a subsequent paper, scientists demonstrated that the behavioral benefits of antidepressant administration in mice
MICE
-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...

 is reversed when neurogenesis is prevented with x-irradiation
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...

 techniques. In fact, new-born neurons are more excitable than older neurons due to a differential expression of GABA
Gamma-aminobutyric acid
γ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...

 receptors. A plausible model, therefore, is that these neurons augment the role of the hippocampus in the negative feedback mechanism of the HPA-axis
Hypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...

 (physiological stress) and perhaps in inhibiting the amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...

 (the region of brain responsible for fearful responses to stimuli). Indeed, suppression of adult neurogenesis can lead to an increased HPA-axis
Hypothalamic-pituitary-adrenal axis
The hypothalamic-pituitary-adrenal axis , also known as thelimbic-hypothalamic-pituitary-adrenal axis and, occasionally, as the hypothalamic-pituitary-adrenal-gonadotropic axis, is a complex set of direct influences and feedback interactions among the hypothalamus, the pituitary gland ,...

 stress response in mildly stressful situations. This is consistent with numerous findings linking stress-relieving activities (learning, exposure to a new yet benign environment, and exercise) to increased levels of neurogenesis, as well as the observation that animals exposed to physiological stress (cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...

) or psychological stress (e.g. isolation) show markedly decreased levels of new-born neurons. Strikingly, the elevation of newborn neurons by antidepressants improves, under chronic stress conditions, the hippocampal control on the stress response (including the activity of the HPA axis and of stress-integrative brain nuclei), then leading to recovery; without newborn neurons, antidepressants are unable to restore the regulation of the stress response and recovery becomes impossible.

Some studies have hypothesized that learning and memory are linked to depression, and that neurogenesis may promote neuroplasticity
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...

. One study proposes that mood may be regulated, at a base level, by plasticity, and thus not chemistry. Accordingly, the effects of antidepressant treatment would only be secondary to change in plasticity.

Effects of sleep reduction

One study has linked lack of sleep to a reduction in rodent hippocampal neurogenesis. The proposed mechanism for the observed decrease was increased levels of glucocorticoids. It was shown that two weeks of sleep deprivation
Sleep deprivation
Sleep deprivation is the condition of not having enough sleep; it can be either chronic or acute. A chronic sleep-restricted state can cause fatigue, daytime sleepiness, clumsiness and weight loss or weight gain. It adversely affects the brain and cognitive function. Few studies have compared the...

 acted as a neurogenesis-inhibitor, which was reversed after return of normal sleep and even shifted to a temporary increase in normal cell proliferation. More precisely, when levels of corticosterone are elevated, sleep deprivation inhibits this process. Nonetheless, normal levels of neurogenesis after chronic sleep deprivation return after 2 weeks, with a temporary increase of neurogenesis. (http://www.pnas.org/content/103/50/19170.full)

Possible use in treating Parkinson's disease

Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

 is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the nigrostriatal projection. Transplantation of fetal dopaminergic precursor cells has paved the way for the possibility of a cell replacement therapy that could ameliorate clinical symptoms in affected
patients. Recent years have provided evidence for the existence of neural stem cells with the potential to produce new neurons, particularly of a dopaminergic phenotype, in the adult mammalian brain. Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone. Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors. Neural stem cells have been identified in the neurogenic brain regions, where neurogenesis is constitutively ongoing, but also in the non-neurogenic zones, such as the midbrain and the striatum, where neurogenesis is not thought to occur under normal physiological conditions.
A detailed understanding of the factors governing adult neural stem cells in vivo may ultimately lead to elegant cell therapies for neurodegenerative disorders such as Parkinson's disease by mobilizing autologous endogenous neural stem cells to replace degenerated neurons.

Role in behavioral sensitization

Reinforcing
Reinforcement
Reinforcement is a term in operant conditioning and behavior analysis for the process of increasing the rate or probability of a behavior in the form of a "response" by the delivery or emergence of a stimulus Reinforcement is a term in operant conditioning and behavior analysis for the process of...

 drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

s such as amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...

s and opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...

s induce behavioral sensitization upon repeated administration by inducing dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...

 neurogenesis in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). This occurs through activation of dopamine receptor
Dopamine receptor
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....

s in these areas which produces glutamate release and subsequent elevation of local basic fibroblast growth factor
Basic fibroblast growth factor
Basic fibroblast growth factor, also known as bFGF, FGF2 or FGF-β, is a member of the fibroblast growth factor family.- Function :...

 (bFGF) concentrations. The consequences of these actions are potentiated reward
Reward system
In neuroscience, the reward system is a collection of brain structures which attempts to regulate and control behavior by inducing pleasurable effects...

 responses and therefore increased drug cravings and consumption which underlie abuse
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...

 and addiction. Whether these mechanisms could be exploited for the purpose of enhancing basal hedonic tone
Hedonism
Hedonism is a school of thought which argues that pleasure is the only intrinsic good. In very simple terms, a hedonist strives to maximize net pleasure .-Etymology:The name derives from the Greek word for "delight" ....

 is unknown.

Effects of exercise

Scientists have shown that physical activity in the form of voluntary exercise results in an increase in the number of newborn neurons in the hippocampus of aging mice. The same study demonstrates an enhancement in learning of the "runner" (physically active) mice. Other research demonstrated that exercising mice that did not produce beta-endorphin, a mood-elevating hormone, had no change in neurogenesis. Yet, mice that did produce this hormone, along with exercise, exhibited an increase in newborn cells and their rate of survival.
While the association between exercise-mediated neurogenesis and enhancement of learning remains unclear, this study could have strong implications in the fields of aging and/or Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

.

Changes in old age

Neurogenesis is substantially reduced in the hippocampus of aged animals, raising the possibility that it may be linked to age-related declines in hippocampal function. Given that neurogenesis occurs throughout life, it might be expected that the hippocampus would steadily increase in size during adulthood, and that therefore the number of granule cells would be increased in aged animals. However, this is not the case, indicating that proliferation is balanced by cell death. Thus, it is not the addition of new neurons into the hippocampus that seems to be linked to hippocampal functions, but rather the rate of turnover of granule cells..

Alzheimer's disease

Allopregnanolone
Allopregnanolone
Allopregnanolone is a prototypic neurosteroid present in the blood and also the brain. It is a metabolite of progesterone and potent modulator of GABAA receptors...

, a neurosteroid, aids the continued neurogenesis in the brain. Levels of allopregnanolone in the brain decline in old age
Old age
Old age consists of ages nearing or surpassing the average life span of human beings, and thus the end of the human life cycle...

 and Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

. Allopregnanolone has been shown through reversing impairment of neurogenesis to reverse the cognitive deficit
Cognitive deficit
Cognitive deficit, also known as cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance...

s in a mouse model of Alzheimer's disease.

Regulation

Many factors may affect the rate of hippocampal neurogenesis. Exercise and an enriched environment
Environmental enrichment (neural)
Environmental enrichment concerns how the brain is affected by the stimulation of its information processing provided by its surroundings . Brains in richer, more stimulating environments, have increased numbers of synapses, and the dendrite arbors upon which they reside are more complex...

 have been shown to promote the survival of neurons and the successful integration of newborn cells into the existing hippocampus epileptic seizures, and bacterial meningitis
Bacterial meningitis
Bacterial meningitis refers to meningitis that is caused by bacterial infection.-Signs and Symptoms:*Fever*Seizures*Meningismus*Headache*Vomiting*Photophobia*Altered mental status and coma*Anorexia...

. On the other hand, conditions such as chronic stress
Stress (medicine)
Stress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...

 and aging can result in a decreased neuronal proliferation.
Circulating factors within the blood may reduce neurogenesis. In healthy aging humans, the plasma and cerebrospinal fluid levels of certain chemokines are elevated. In a mouse model, plasma levels of these chemokines correlate with reduced neurogenesis, suggesting that neurogenesis may be modulated by certain global age-dependent systemic changes. These chemokines include CCL11
CCL11
Chemokine ligand 11 is a small cytokine belonging to the CC chemokine family that is also known as eotaxin-1. CCL11 selectively recruits eosinophils by inducing their chemotaxis, and therefore, is implicated in allergic responses. The effects of CCL11 are mediated by its binding to a...

, CCL2
CCL2
For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.Chemokine ligand 2 also known as monocyte chemotactic protein-1 or small inducible cytokine A2 is a protein that in humans is encoded by the CCL2 gene. CCL2 is a small cytokine belonging to the CC...

 and CCL12
CCL12
Chemokine ligand 12 is a small cytokine belonging to the CC chemokine family that has been described in mice. It is also known as monocyte chemotactic protein 5 and, due to its similarity with the human chemokine MCP-1, sometimes it is called MCP-1-related chemokine. CCL12 specifically...

, which are highly localized on mouse and human chromosomes, implicating a genetic locus in aging.

Adult neural stem cells

Neural stem cell
Stem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

s (NSCs) are the self-renewing, multipotent cells that generate the main phenotypes of the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...

.

Effects of Marijuana

Some studies have shown that use of cannabis results in the growth of new nerve cells in the hippocampus from both embryonic and adult stem cells. In 2005 a clinical study of rats at the University of Saskatchewan showed regeneration of nerve cells in the hippocampus. Studies have shown that a synthetic drug resembling THC, the main psychoactive ingredient in marijuana, provides some protection against brain inflammation, which might result in better memory at an older age. This is due to receptors in the system that can also influence the production of new neurons (http://www.osu.edu/news/newsitem2227) Nonetheless, a study directed at Rutgers University demonstrated how synchronization of action potentials in the hippocampus of rats was altered after THC administration. Lack of synchronization resulted in impaired performance in a standard test of memory. (http://www.physorg.com/news84048508.html) Moreover, contrary to popular belief, animal studies have revealed that marijuana could provoke fits.(http://www.livescience.com/1134-marijuana-impairs-memory.html)

External links

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