does not require any invasive procedures or surgeries for the subjects. however, it does pose certain challenges, as these inhibitors can't be used to inhibit proliferation in specific regions, thus leading to nonspecific effects from other systems being affected. to avoid these effects, more work must be done to determine optimal doses in order to minimize the effects on systems unrelated to neurogenesis. a common pharmacological inhibitor for adult neurogenesis is methylazoxymethanol acetate (mam), a chemotherapeutic agent. other cell division inhibitors commonly used in studies are cytarabine and temozolomide. pharmacogenetics another method used to study the effects of adult neurogenesis is using pharmacogenetic models. these models provide different benefits from the pharmacological route, as it allows for more specificity by targeting specific precursors to neurogenesis and specific stem cell promoters. it also allows for temporal specificity with the interaction of certain drugs. this is beneficial in looking specifically at neurogenesis in adulthood, after normal development of other regions in the brain. the herpes simplex virus thymidine kinase (hsv-tk) has been used in studies in conjunction with antiviral drugs to inhibit adult neurogenesis. it works by targeting stem cells using glial fibrillary acidic proteins and nestin expression. these targeted stem cells undergo cell death instead of cell proliferation when exposed to antiviral drugs. cre protein is also commonly used in targeting stem cells that will undergo gene changes upon treatment with tamoxifen. irradiation irradiation is a method that allows for very specific inhibition of adult neurogenesis. it can be targeted to the brain to avoid affecting other systems and having nonspecific effects. it can even be used to target specific brain regions, which is important in determining how adult neurogenesis in different areas of the brain affects behavior. however, irradiation is more expensive than the other methods and also requires large equipment with trained individuals. inhibition of adult neurogenesis in the hippocampus many studies have observed how inhibiting adult neurogenesis in other mammals, such as rats and mice, affect their behavior. inhibition of adult neurogenesis in the hippocampus has been shown to have various affects on learning and memory, conditioning, and investigative behaviors. impaired fear conditioning has been seen in studies involving rats with a lack of adult neurogenesis in the hippocampus. inhibition of adult neurogenesis in the hippocampus has also been linked to changes in behavior in tasks involving investigation. rats also show decreased contextualized freezing behaviors in response to contextualized fear and impairment in learning spatial locations when lacking adult neurogenesis. effects on pattern separation the changes in learning and memory seen in the studies mentioned previously are thought to be related to the role of adult neurogenesis in regulating pattern separation. pattern separation is defined as, "a process to remove redundancy from similar inputs so that events can be separated from each other and interference can be reduced, and in addition can produce a more orthogonal, sparse, and categorized set of outputs." this impairment in pattern separation could explain the impairments seen in other learning and memory tasks. a decreased ability in reducing interference could lead to greater difficulty in forming and retaining new memories., although it's hard to discriminate between effects of neurogenesis in learning and pattern separation due to limitations in the interpretation behavioral results." studies show that rats with inhibited adult neurogenesis demonstrate difficulty in differentiating and learning contextualized fear conditioning. rats with blocked adult neurogenesis also show impaired differential freezing when they are required to differentiate between similar contexts. this also affects their spatial recognition in radial arm maze tests when the arms are closer together rather than when they are further apart. a meta-analysis of behavioral studies evaluating the effect of neurogenesis in different pattern separation tests has shown a consistent effect of neurogenesis ablation on performance, although there are exceptions in the literature. " effects on behavioral inhibition behavioral inhibition is important in rats and other animals in halting whatever they are currently doing in order to reassess a situation in response to a threat or anything else that may require their attention. rats with lesioned hippocampi show less behavioral inhibition when exposed to threats, such as cat odor. the disruption of normal cell proliferation and development of the dentate gyrus in developing rats also impairs their freezing response, which is an example of behavior inhibition, when exposed to an unfamiliar adult male rat. this impairment in behavioral inhibition also ties into the process of learning and memory, as repressing wrong answers or behaviors requires the ability to inhibit that response. implications 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. given that the rate of the neurogenesis does not change substantially during the adulthood, it has been proposed that unique episodic memories can be created by simply relying on the increased capacity of the young neurons of a particular age to establish stable new synapses with peers representing the unique features of an event to be memorized 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. alzheimer's disease some studies suggest that decreased hippocampal neurogenesis can lead to development of alzheimer's disease (ad). yet, others hypothesize that ad patients have increased neurogenesis in the ca1 region of ammon's horn (the principal region of ad hippocampal pathology) in order to compensate for neuronal loss. while the exact nature of the relationship between neurogenesis and alzheimer's disease is unknown, insulin-like growth factor 1-stimulated neurogenesis produces major changes in hippocampal plasticity and seems to be involved in alzheimer's pathology. allopregnanolone, a neurosteroid, aids the continued neurogenesis in the brain. levels of allopregnanolone in the brain decline in old age and alzheimer's disease. allopregnanolone has been shown through reversing impairment of neurogenesis to reverse the cognitive deficits in a mouse model of alzheimer's disease. eph receptors and ephrin signaling have been shown to regulate adult neurogenesis in the hippocampus and have been studied as potential targets to treat some symptoms of ad. molecules associated with the pathology of ad, including apoe, ps1 and app, have also been found to impact adult neurogenesis in the hippocampus. role in schizophrenia studies suggest that people with schizophrenia have a reduced hippocampus volume, which is believed to be caused by a reduction of adult neurogenesis. correspondingly, this phenomenon might be the underlying cause of many of the symptoms of the disease. furthermore, several research papers referred to four genes, dystrobrevin binding protein 1 (dtnbp1), neuregulin 1 (nrg1), disrupted in schizophrenia 1 (disc1), and neuregulin 1 receptor (erbb4), as being possibly responsible for this deficit in the normal regeneration of neurons. similarities between depression and schizophrenia suggest a possible biological link between the two diseases. however, further research must be done in order to clearly demonstrate this relationship. adult neurogenesis and major depressive disorder research indicates that adult hippocampal neurogenesis is inversely related to major depressive disorder (mdd). neurogenesis is decreased in the hippocampus of animal models of major depressive disorder, and many treatments for the disorder, including antidepressant medication and electroconvulsive therapy, increase hippocampal neurogenesis. it has been theorized that decreased hippocampal neurogenesis in individuals with major depressive disorder may be related to the high levels of stress hormones called glucocorticoids, which are also associated with the disorder. the hippocampus instructs the hypothalamic-pituitary-adrenal axis to produce fewer glucocorticoids when glucocorticoid levels are high. a malfunctioning hippocampus, therefore, might explain the chronically high glucocorticoid levels in individuals with major depressive disorder. however, some studies have indicated that hippocampal neurogenesis is not lower in individuals with major depressive disorder and that blood glucocorticoid levels do not change when hippocampal neurogenesis changes, so the associations are still uncertain. stress and depression many now believe stress to be the most significant factor for the onset of depression. as discussed above, hippocampal cells are sensitive to stress which can lead to decreased neurogenesis. this area is being considered more frequently when examining the causes and treatments of depression. studies have shown that removing the adrenal gland in rats caused increased neurogenesis in the dentate gyrus. the adrenal gland is responsible for producing cortisol in response to a stressor, a substance that when produced in chronic amounts causes the down regulation of serotonin receptors and suppresses the birth of neurons. it was shown in the same study that administration of corticosterone to normal animals suppressed neurogenesis, the opposite effect. the most typical class of antidepressants administered for this disease are selective serotonin reuptake inhibitors (ssris) and their efficacy may be explained by neurogenesis. in a normal brain, an increase in serotonin causes suppression of the corticotropin-releasing hormone (crh) through connection to the hippocampus. it directly acts on the paraventricular nucleus to decrease crh release and down regulate norepinephrine functioning in the locus coeruleus. because crh is being repressed, the decrease in neurogenesis that is associated with elevated levels of it is also being reversed. this allows for the production of more brain cells, in particular at the 5-ht1a receptor in the dentate gyrus of the hippocampus which has been shown to improve symptoms of depression. it normally takes neurons approximately three to six weeks to mature, which is approximately the same amount of time it takes for ssris to take effect. this correlation strengthens the hypothesis that ssris act through neurogenesis to decrease the symptoms of depression. some neuroscientists have expressed skepticism that neurogenesis is functionally significant, given that a tiny number of nascent neurons are actually integrated into existing neural circuitry. however, a recent study used the irradiation of nascent hippocampal neurons in non-human primates (nhp) to demonstrate that neurogenesis is required for antidepressant efficacy. 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). 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. 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. however another study has demonstrated an interaction between antidepressants and plasticity; the antidepressant fluoxetine has been shown to restore plasticity in the adult rat brain. the results of this study imply that instead of being secondary to changes in plasticity, antidepressant therapy could promote it. 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