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 further studied. Early neuroanatomists, including Santiago Ramón y Cajal, considered the nervous system fixed and incapable of regeneration. The first evidence of adult mammalian neurogenesis in the cerebral cortex was presented by Joseph Altman 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 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 (and Michael Kaplan) again showed that adult neurogenesis exists in mammals (rats), and Nottebohm showed the same phenomenon in birds 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) have suggested that adult neurogenesis may also occur in regions within the brain not generally associated with neurogenesis including the neocortex. However, others have questioned the scientific evidence of these findings, arguing that the new cells may be of glial origin. Recent research has elucidated the regulatory effect of GABA on neural stem cells. GABA's well-known inhibitory effects across the brain also affect the local circuitry that triggers a stem cell to become dormant. They found that diazepam (Valium) has a similar effect.
Role in learning
The functional relevance of adult neurogenesis is uncertain, but there is some evidence that hippocampal adult neurogenesis is important for learning and 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 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 antidepressants, suggesting a connection between decreased hippocampal neurogenesis and depression. In a pioneer study, scientists demonstrated that the behavioral benefits of antidepressant administration in mice is reversed when neurogenesis is prevented with x-irradiation techniques. In fact, newborn neurons are more excitable than older neurons due to a differential expression of GABA receptors. A plausible model, therefore, is that these neurons augment the role of the hippocampus in the negative feedback mechanism of the HPA-axis (physiological stress) and perhaps in inhibiting the amygdala (the region of brain responsible for fearful responses to stimuli).[vague] Indeed, suppression of adult neurogenesis can lead to an increased HPA-axis 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) or psychological stress (e.g. isolation) show markedly decreased levels of newborn neurons. Interestingly, under chronic stress conditions, the elevation of newborn neurons by antidepressants improves the hippocampal-dependent control on the stress response; 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. 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 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) While this is recognized, overlooked is the blood glucose demand exhibited during temporary diabetic hypoglycemic states. The American Diabetes Association amongst many documents the pseudosenilia and agitation found during temporary hypoglycemic states. Much more clinical documentation is needed to competently demonstrate the link between decreased hematologic glucose and neuronal activity and mood.
Possible use in treating Parkinson's disease
Parkinson's disease 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. In recent years, scientists 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.
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.
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.
Many factors may affect the rate of hippocampal neurogenesis. Exercise and an enriched environment have been shown to promote the survival of neurons and the successful integration of newborn cells into the existing hippocampus. Another factor is central nervous system injury since neurogenesis occurs after cerebral ischemia,epileptic seizures, and bacterial meningitis. On the other hand, conditions such as chronic stress 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, CCL2 and CCL12, which are highly localized on mouse and human chromosomes, implicating a genetic locus in aging.
Epigenetic regulation also plays a large role in neurogenesis. DNA methylation is critical in the fate-determination of adult neural stem cells in the subventricular zone for post-natal neurogenesis through the regulation of neuronic genes such as Dlx2, Neurog2, and Sp8. Many microRNAs such as miR-124 and miR-9 have been shown to influence cortical size and layering during development.
Some studies have shown that the use of cannabinoids 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. 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 corresponded with impaired performance in a standard test of memory. Recent studies indicate that a natural cannabinoid of cannabis, cannabidiol, increases adult neurogenesis while having no effect on learning. THC however impaired learning and had no effect on neurogenesis. A greater CBD to THC ratio in hair analyses of cannabis users correlates with protection against gray matter reduction in the right hippocampus. CBD has also been observed to attenuate the deficits in prose recall and visuo-spatial associative memory of those currently under the influence of cannabis, implying neuroprotective effects against heavy THC exposure. Neurogenesis might play a role in its neuroprotective effects, but further research is required.
^Altman, J. (1963). "Autoradiographic investigation of cell proliferation in the brains of rats and cats". The Anatomical record145 (4): 573–591. doi:10.1002/ar.1091450409. PMID14012334. edit
^Altman, J. (1969). "Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb". The Journal of Comparative Neurology137 (4): 433–457. doi:10.1002/cne.901370404. PMID5361244. edit
^Bayer, S. A. (1982). "Changes in the total number of dentate granule cells in juvenile and adult rats: a correlated volumetric and 3H-thymidine autoradiographic study". Experimental brain research. Experimentelle Hirnforschung. Experimentation cerebrale46 (3): 315–323. PMID7095040. edit
^Shankle; Rafii, M. S.; Landing, B. H.; Fallon, J. H. (1999). "Approximate doubling of numbers of neurons in postnatal human cerebral cortex and in 35 specific cytoarchitectural areas from birth to 72 months". Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society2 (3): 244–259. doi:10.1007/s100249900120. PMID10191348. edit
^Rakic P (February 2002). "Adult neurogenesis in mammals: an identity crisis". J. Neurosci.22 (3): 614–8. PMID11826088.Cite uses deprecated parameters (help)
^Wiskott L, Rasch MJ, Kempermann G (2006). "A functional hypothesis for adult hippocampal neurogenesis: avoidance of catastrophic interference in the dentate gyrus". Hippocampus16 (3): 329–43. doi:10.1002/hipo.20167. PMID16435309.
^Aimone JB, Wiles J, Gage FH (June 2006). "Potential role for adult neurogenesis in the encoding of time in new memories". Nat Neurosci.9 (6): 723–7. doi:10.1038/nn1707. PMID16732202.Cite uses deprecated parameters (help)
^Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E (2002). "Neurogenesis may relate to some but not all types of hippocampal-dependent learning". Hippocampus12 (5): 578–84. doi:10.1002/hipo.10103. PMID12440573.
^Meshi D, Drew MR, Saxe M, et al. (June 2006). "Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment". Nat Neurosci.9 (6): 729–31. doi:10.1038/nn1696. PMID16648847.Cite uses deprecated parameters (help)
^Gould, E.; Beylin, A.; Tanapat, P.; Reeves, A.; Shors, T. J. (1999). "Learning enhances adult neurogenesis in the hippocampal formation". Nature Neuroscience2 (3): 260–265. doi:10.1038/6365. PMID10195219. edit
^Arias-Carrión O, Verdugo-Díaz L, Feria-Velasco A, et al. (October 2004). "Neurogenesis in the subventricular zone following transcranial magnetic field stimulation and nigrostriatal lesions". J Neurosci Res.78 (1): 16–28. doi:10.1002/jnr.20235. PMID15372495.Cite uses deprecated parameters (help)
^Arias-Carrión O, Hernández-López S, Ibañez-Sandoval O, Bargas J, Hernández-Cruz A, Drucker-Colín R (November 2006). "Neuronal precursors within the adult rat subventricular zone differentiate into dopaminergic neurons after substantia nigra lesion and chromaffin cell transplant". J Neurosci Res.84 (7): 1425–37. doi:10.1002/jnr.21068. PMID17006899.Cite uses deprecated parameters (help)
^Van Praag, H.; Kempermann, G.; Gage, F. (1999). "Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus". Nature Neuroscience2 (3): 266–270. doi:10.1038/6368. PMID10195220. edit
^Bjørnebekk A, Mathé AA, Brené S (September 2005). "The antidepressant effect of running is associated with increased hippocampal cell proliferation". Int J Neuropsychopharmacol8 (3): 357–68. doi:10.1017/S1461145705005122. PMID15769301.Cite uses deprecated parameters (help)
^Demirakca, T.; Sartorius, A.; Ende, G.; Meyer, N.; Welzel, H.; Skopp, G.; Mann, K.; Hermann, D. (2010). "Diminished gray matter in the hippocampus of cannabis users: Possible protective effects of cannabidiol". Drug and Alcohol Dependence114 (2–3): 242–245. doi:10.1016/j.drugalcdep.2010.09.020. PMID21050680. edit
^Morgan, C. J. A.; Schafer, G.; Freeman, T. P.; Curran, H. V. (2010). "Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: Naturalistic study". The British Journal of Psychiatry197 (4): 285–290. doi:10.1192/bjp.bp.110.077503. PMID20884951. edit
Aimone JB, Jessberger S, and Gage FH (2007) Adult Neurogenesis. Scholarpedia, p. 8739
Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (March 1999). "Learning enhances adult neurogenesis in the hippocampal formation". Nat Neurosci.2 (3): 260–5. doi:10.1038/6365. PMID10195219.Cite uses deprecated parameters (help)
Moghadam KS, Chen A, Heathcote RD (August 2003). "Establishment of a ventral cell fate in the spinal cord". Dev. Dyn.227 (4): 552–62. doi:10.1002/dvdy.10340. PMID12889064.Cite uses deprecated parameters (help)
Rakic P (January 2002). "Neurogenesis in adult primate neocortex: an evaluation of the evidence". Nature Reviews Neuroscience3 (1): 65–71. doi:10.1038/nrn700. PMID11823806.Cite uses deprecated parameters (help)
Rolls, E.T & Treves, A. (1998). Neural Networks and Brain Function. Oxford: OUP. ISBN 0-19-852432-3.
Shankle, WR, Rafii, MS, Landing, BH, and Fallon, JH (1999) Approximate doubling of the numbers of neurons in the postnatal human cortex and in 35 specific cytoarchitectonic areas from birth to 72 months. Pediatric and Developmental Pathology 2:244-259.