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. 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 substantia nigra. 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. newer research has shown that there in fact is neurogenesis in the striatum. 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. traumatic brain injury traumatic brain injuries vary in their mechanism of injury, producing a blunt or penetrating trauma resulting in a primary and secondary injury with excitotoxicity and relatively wide spread neuronal death. due to the overwhelming number of traumatic brain injuries as a result of the war on terror, tremendous amounts of research have been placed towards a better understanding of the pathophysiology of traumatic brain injuries as well as neuroprotective interventions and possible interventions prompting restorative neurogenesis. hormonal interventions, such as progesterone, estrogen, and allopregnanolone have been examined heavily in recent decades as possible neuroprotective agents following traumatic brain injuries to reduce the inflammation response stunt neuronal death. in rodents, lacking the regenerative capacity for adult neurogenesis, the activation of stem cells following administration of α7 nicotinic acetylcholine receptor agonist, pnu-282987, has been identified in damaged retinas with follow-up work examining activation of neurogenesis in mammals after traumatic brain injury. currently, there is no medical intervention that has passed phase-iii clinical trials for use in the human population. factors affecting 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. for example, the rate of neurogenesis in aged animals is predictive of memory. however, new born cells in aged animals are functionally integrated. 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. effects of exercise main article: neurobiological effects of physical exercise § neuroplasticity 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 mice and rats. these and other studies have shown that learning in both species can be enhanced by physical exercise. recent research has shown that brain-derived neurotrophic factor and insulin-like growth factor 1 are key mediators of exercise-induced neurogenesis. exercise increases the production of bdnf, as well as the nr2b subunit of the nmda receptor. exercise increases the uptake of igf-1 from the bloodstream into various brain regions, including the hippocampus. in addition, igf-1 alters c-fos expression in the hippocampus. when igf-1 is blocked, exercise no longer induces neurogenesis. 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. effects of cannabinoids some studies have shown that the stimulation of the 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 (cbd), 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. a few studies have reported a positive association between thc and hippocampal neurogenesis. some of them hypotethize a biphasic effect, some of them express that part of the negative effects could be attributable to neuroadaptation due to exposure at a specific period of life, and that it could be reversed. regulation summary of the signalling pathways in the neural stem cell microenvironment. 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, viral infection 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. another study implicated the cytokine, il-1beta, which is produced by glia. that study found that blocking il-1 could partially prevent the severe impairment of neurogenesis caused by a viral infection. 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. ephrin-a2 and ephrin-a3 have been showed to negatively regulate adult neurogenesis. history 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.