in the past , psychiatric diseases have been treated pharmacologically with broad - profile medication - the socalled  shotgun method .  in the same way that a shotgun fires many pellets at once , psychiatric medication can impact on many different neurotransmitter systems . due to this profile , many of these drugs , such as tricyclic antidepressants ( tcas ) or first - generation antipsychotics ( fgas ) caused severe undesirable side effects , which were held responsible for poor compliance and discontinuation of the prescribed medication . during the last two decades , new drugs have surfaced with fewer shotgun side effects because of their particular pharmacodynamic design targeted against one single and very specific molecule . in this context , selective serotonin reuptake inhibitors ( ssris ) should be mentioned here as an example of an antidepressant agent acting solely on one neurotransmitter system and within the serotonergic system on one distinct transporter molecule . the same holds true for second - generation antipsychotics ( sgas ) displaying only few side effects due to less rigid inactivation of dopamine receptor type 2 ( dr2 ) and therefore fewer extrapyramidal motor symptoms recalling parkinsonism . nevertheless , we are still struggling with inefficacious medication , since only about one third of antidepressant agents work in a given patient , meaning that one has to try on average three different medications in order to alleviate this patient 's symptoms . for schizophrenia sometimes , the individual situation seems even worse than in the field of affective disorders . as mentioned above , this article emphasizes the link between disturbed adult neurogenesis ( an ) and affective disorder . the case seems to be much more evident here than in schizophrenia , although decreased neural stem cell proliferation in the dentate gyrus ( dg ) of the hippocampus has been demonstrated in postmortem human brain from schizophrenic patients . stem cells can be characterized by two fundamental qualities : first , they have the capacity for unlimited selfrenewal , and second , they can produce at least one type of highly differentiated descendants . this particular cell division is termed  asymmetrical  : in general , each stem cell division gives rise to one stem and one committed somatic daughter cell . stem cells are single cells that , once developed , self -renew for the lifetime of the organism . these stem cells should be distinguished from transient progenitor cells , which have a limited self - renewal lifespan . some steps earlier during the embryonic period , cells become gradually restricted to distinct pathways of differentiation . this process includes modification of their developmental potential ; they become pluripotent (  many , several  ) . the major difference between totipotency and pluripotency is that an embryonic stem cell ( es cell ) which is by definition pluripotent ,  can only form cells which constitute the embryo itself but not the placenta . early es cells can be taken from the embryo and grown in vitro . when retransferred into the embryo es cells also play a central role in the generation of transgenic animals such as knockout mice . multipotent stem cells in the brain ultimately give rise to all different types of neuronal and non - neuronal cells in the central nervous system . because they are capable of generating the entire progeny of a given tissue , some investigators have termed these multipotent stem cells moreover , there is controversy as to whether neural stem cells can actually remain viable during the entire lifespan . adult forebrain neural stem cells were discovered in 1992 in the adult remnant of the embryonic brain germinal zone surrounding the lateral ventricle . evidence for their participation in repopulating the adult lateral ventricular subependyma following irradiation led to the hypothesis that neural stem cells also exist after the embryonic and fetal period , similarly to hematopoietic stem cells . hematopoietic stem cells in adult animals can restore different blood cell types . for a long time it has been thought that once a cell had been programmed to produce a particular tissue , its fate was sealed and it could not reprogram itself to form another tissue . conirarily to this view , reactivation of dormant genetic programs appears to work under certain circumstances . intriguingly , stem cells from brains of adult mice have been shown to possess the potential to become functional blood cells . similar results for the inverse case were reported , ie , multipotential mesenchymal cells transformed into neural cells - astrocytes in this case . 
  according to fred h. gage , the term  neural stem cell  should therefore be used with caution to describe cells that a ) generate neural tissue , b ) are capable of selfrenewal , and c ) give rise to cells other than themselves through asymmetric cell division .  in fact , when the issue of lineage specificity of adult neural stem and progenitor cells is considered , there is abundant reason for caution regarding the term neural stem cell . the ability of bone marrow stem cells to generate astrocytes , the finding that astrocyte - like cells in the subependyma are neural stem cells , and that oligodendrocyte - precursors contribute neural stem cell - like cells - all these findings soften the theoretical distinction between stem and progenitor cells . all this makes it really difficult to decide which type of stem cells one should use for transplantation . even during the process of grafting stem cells they can still start to differentiate and become more restricted progenitors due to cell - cell contacts or influence of adhesion inside the syringe . further , neural stem cell research suffers dearly from the lack of an antibody specifically identifying neural stem cells . putative stem cells need to differentiate into their derivative neural cell subpopulations before one can positively identify them as regular neural stem cells . in the past there are certain advantages of adult over embryonic stem cells in that the former may be easier to manage . for example , when injected subcutaneously into immunocompromised mice they grow into teratomas , tumors consisting of numerous cell types ranging from gut to skin . before applying these cells in humans , generation of the desired cell types should therefore be ensured without undesired side effects or unwanted cell populations , respectively . here , it seems that adult stem cells are better behaved , since they do not differentiate spontaneously . instead this can be induced by applying appropriate growth factors . however , adult stem cells have a different drawback , in that they seem to lose their ability to divide and differentiate after some time in culture . maybe in the end ethical considerations will also convince the scientific community to follow the adult stem cell rather than the es cell track . compared with embryonic or fetal stem cells , adult stem cells pose fewer ethical problems because they can be obtained from sources other than embryos or aborted fetuses . even postmortem human tissue can yield neural stem cells . in consensus with frank e. young the public , as well as governmental authorities , should enter the process of unbiased dialogue , in order to establish the principles according to which research needs to be conducted . as of now , we should consider the human species an appropriate source for scbi . having said this , we should take into account possible chimerae of animals with human cells in their brains , and above all with possible human behavior . another issue to be ruled out is to prevent striking behavioral traits after scbi . in parkinson 's disease patients it has been shown that after l - dopa treatment some patients responded with pathological gambling , since dopamine sustains the reward system . one could easily imagine a scenario like this in a patient after scbi . in this case , it might not be as easy to lower the dopamine production as it is with cessation of the medication . as mentioned above , grafting hematopoietic stem cells has already become a conventional clinical tool in the treatment of certain types of leukemia . currently it can only be hypothesized that transplantation of neural stem cells has potential for treating brain disease . although all these obstacles do exist , the main target for the research on neural stem cells must be to restore regular neural function in areas where cells have died or lost their physiologic behavior . clinicians are eager , for example , to transplant nscs into patients suffering from parkinson 's disease , multiple sclerosis , or spinal cord injuries , although it is not clear so far which is the appropriate cell to transplant - the cns neural stem cells , the actual neurons , or intermediate progenitors between the two . thus , in neurodegenerative diseases it is important to first determine the rules of transplantation of stem , progenitor , and mature cells , as well as to determine the sites into which the transplants must be located . in parkinson 's disease we do not know whether cells should be placed into the substantia nigra , or striatum , or both . so we continue wondering which particular region of the abovementioned brain areas should be chosen - eg , the ventral part or the dorsal putamen in only one hemisphere or both . the variability in surgical methods between centers which perform stem cell transplantation makes it very difficult to assess the results of this procedure . still , if we get to the point where all these issues are resolved , we will have to find better ways to secure the long - term survival of the grafted cells . so far , the de novo generated dopaminergic neurons have only a limited lifespan in animal studies . finally , the source of the cells should be clarified , since we need huge amounts of human fetal tissue for transplantation . although there has been much progress achieved over the last few years , especially in long - term proliferation and dopaminergic differentiation of progenitor cells , we still have to invest much effort in finding alternative methods , such as in vivo mobilization of dormant neural stem cells , which seems to be a more useful concept . in the light of recent findings such as loss of total cell volume in certain brain areas observed in depressed patients ( see below ) , we can heretically define depression as a  neurodegenerative  disease . as we will discuss , this particular illness does not necessarily require stem cell transplantation . instead , it may be possible to replenish missing neurons by regulating the microenvironment surrounding the putative sites of neural stem cells where neurogenesis takes place . lessons from recent findings in pathophysiology might open up a broad research avenue with the ultimate goal of treating depression . in a who survey , depression and manic - depressive illness will still rank among the top 10 causes for death in the year 2010 . certainly not all forms of depression eventually lead to death by suicide , but even milder courses of this illness may lead to severe incapacitation of millions of people worldwide . in particular , it impairs reintegration into their familiar social environment and into the working process . accumulating evidence from neurobiology suggests that distinct biochemical processes are derailed in a large number of depressed subjects . cellular and molecular adjustments following stress seem to play - key roles in onset and propagation of mood disorders . to most of us , stress is a beneficial response of our neuronal systems to acute challenges of the exterior world . to put it simply , it is more beneficial for a rabbit to become stressed and flee when it sees a fox approaching . however , severe or repeated stress can lead to detrimental effects on regular neural function . neural plasticity is a term which involves interneuronal communication and adaptation in order to give the appropriate responses to stress or aversive stimuli . one example of such a response could be changes in neurogenesis - the generation of new neurons . dysfunction of adequate regulatory processing due to severe or chronic stress is capable of disturbing neural plasticity . medical treatment with antidepressant agents may bring back regular function of neural systems by influencing neural plasticity : antidepressants require long - term administration , while blockade of the reuptake of serotonin ( 5-ht ) and/or norepinephrine as their most common and initial mode of action is fairly rapid . there is a process whereby neurons can adapt to and regain plasticity while the local biochemical environment is changing due to the application of antidepressants . thus , the long - term mode of action of antidepressant medication seems much more dynamic and complex than just up- or downregulation of synaptic levels of monoamines . g golgi stained hippocampal neurons with his novel silver impregnation technique , which became known as the golgi procedure . since then a great number of neuropsychiatrie phenomena have been studied in the hippocampal formation . the relatively- simple organization - pyramidal neurons in the hippocampus proper and the granule cells of the dentate gyrus are arranged in single , densely packed cell layers - is one of the major reasons why the hippocampus has frequently been used as a cytoarchitectural model of the cortex . recent findings in volumetric neuroimaging studies make a strong case that biochemical changes in the brain carry morphological sequels . so far we have learned that gray matter volumes are diminished in depressed patients and in post - traumatic stress disorder patients in the medial and orbital prefrontal cortex , the mesiotemporal cortex , and the ventral striatum , and are accompanied by an enlargement of the third and the lateral ventricles . significant reduction in numbers of nonpyramidal neurons in the ca2 area of hippocampus was reported in postmortem studies of bipolar disorder . also in regions other than hippocampus , there may be a decline in brain region volume and total cell number . elevation of cortisol levels in the elderly correlates with reduced hippocampal volume , and is associated with memory deficits . patients with depression have a functional deficit of the hypothalamic - pituitary - adrenal ( fifa ) axis . hippocampal neurons are reported to be damaged by exposure to stress or activation of the iipa axis and elevation of glucocorticoids . taken together , this overview of morphologic evidence strongly supports a functional link between changes at the molecular levels and morphology . the task of future research could be to develop strategies allowing the diseased hippocampus or other affected brain structures to regain regular morphology and function . focusing on neurogenesis - which is defined as a series of events including proliferation of a neural precursor or stem cell that results in appearance of a new neuron - may be a systematic as well as pragmatic way to proceed . localization of pluripotent progenitor cells and thus neurogenesis appears to be restricted to certain brain regions , in particular , the subventricular zone ( svz ) and the subgranular layer of the dentate gyrus of the hippocampus . neurogenesis in the adult mammalian brain is regulated by genetic and environmental factors - all leading to the exciting possibility of pharmacological regulation of neurogenesis in the adult brain , and eventually of the disease - related pathophysiological changes . one of the mainstay therapies in the treatment of recurrent mood disorders , lithium , ranks among such pharmacologic candidates . we now know that besides its role in cell cycle control , bcl-2 functions as a neurotrophic factor , since bcl-2 promotes axon regeneration as well as neurite and axonal outgrowth . in general , neurotrophic factor signaling is mediated both by the phosphatidyl - inositol-3-kinase pathway and activation of the map ( mitogen - activated kinase ) cascade . this is very likely to involve the camp responsive element binding protein ( creb ) . creb is attractive to many researchers because it appears in some way required for long - term memory . creb may increase the integrity and functional plasticity of granule cell neurons assuming that creb is a critical determinant of neural plasticity as well as cell survival . one putative gene target of creb - and thus of chronic antidepressant treatment - is brain - derived neurotrophic factor ( bdnf ) . there is a functional camp responsive element in the exon iii promoter of the bdnf gene . in the light of this , it is not surprising that local infusion of bdnf in the hippocampus produces an antidepressant effect . 
  in vitro , activation of the camp system upregulates bdnf expression in hippocampal cells . additionally , bdnf expression effects neuronal depolarization and activation of voltage -dependent calcium channels . these alterations at the synaptic level underlie the influence of bdnf on long - term potentiation . this underscores the central role of bdnf in neurogenesis considering the pivotal role attributed to bdnf in lineage differentiation of neural stem cells . another key player in the pathophysiology and treatment of depression , the biogenic amine 5-ht , should not be neglected , since 5-ht is one of the most extensively studied neurotransmitters of the central nervous system . moreover , novel findings indicate that 5 - 1 it is particularly relevant to neurogenesis in the hippocampus ( figure 1 ) , because in adult rats it has been shown that decreased 5-ht lowers the rate of neurogenesis in the dentate gyrus of hippocampus . historically , 5-ht was first described as a serum component augmenting smooth muscle contraction . in such non - neural systems all serotonergic fibers originate in the brain stem raphe nuclei . by way of extensive synaptic connections of the serotonergic fibers , 5-ht contributes to many physiologic functions such as endocrine and circadian rhythms , food intake , sleep , reproductive activity , and motor function , as well as cognition , mood , and anxiety . in the brain we currently know of 16 different cloned receptor types and subtypes , but it can be expected that their number will grow even further in the near future . in contrast to the multitude of 5 - 1 it receptors , there is only a single 5-ht transporter ( 5-htt ) responsible for the reuptake of 5-ht into serotonergic neurons after its release into the synaptic cleft . as our own studies have shown , 5 -i itt does not have a large impact on neurogenesis . 
  a possible role for 5-ht as direct mediator of granule cell generation is currently discussed , since elevated 5-ht levels in the hippocampus increase the rate of proliferation of granule cell precursors . epidermal growth factor ( egf ) is believed to exert an essential function on the generation and maintenance of neural stem cells . it is therefore not surprising that in non - neural systems , egf and 5-ht can augment the rate of cell proliferation in a synergistic manner . thus , chronic administration of 5-iit - selective reuptake inhibitors , clinically used as antidepressants , leads to upregulation of bdnf nirna . as already mentioned above , 5-ht exerts its action through a large family of receptors in the periphery and throughout the cns . a possible role for the 5-iit1a receptor in the modulation of anxiety and depression , as well as in the mode of action of anxiolytic and antidepressant drugs , has been suspected for many years . research regarding 5-ht1a receptor has shown that the effect of antidepressants upregulating extracellular serotonin levels worked via the 5-ht1a receptor subtype , thus opening a link between our in vitro system , neurogenesis , and clinical relevance in terms of affective disorders . althogh the serotonin hypothesis of depression is very attractive in this regard , it should not be omitted here that there are additional compelling findings dealing with other neurotransmitting systems , eg , supporting cholinergic mechanisms . riederer et al came to the conclusion that a brain area - specific imbalance of neurotransmitters leads to the clinically different manifestations of depression . the loss of regional interneuronal homeostasis must not necessarily affect huge brain areas ; it might be only limited to certain small and circumscripted regions in the brain . as a consequence , clinicians should be able to choose the pharmacologically appropriate medication for the affected brain region . stem - cell maintenance and generation take place in a distinct microenvironment where appropriate external signals can best exert their regulatory function on these cells . since components of regular stem - cell maintenance like bdnf are also implicated in mechanistic models characteristic of mood disorders , they thus offer new targets for pharmacologic intervention in neuropsychiatrie disease . more thorough knowledge about this complex connection mayhelp us render antidepressant treatment more efficient and reduce the undesirable side effects that impair patient compliance . so far there is no stem - cell - based approach really on the horizon for treating depression or any other psychosis .
exploring stem ceils is a fascinating task , especially in a discipline where the use of stem cells seems far - fetched at first glance , as is the case in psychiatry . in this article 
 we would like to provide a brief overview of the current situation in relation to the treatment of mental diseases . for reasons that we will explain , 
 this review will focus on affective disorders . 
 the following section will give a more detailed account of stem - cell biology , including current basic science approaches presenting in - vivo andin - vitro techniques . 
 the final part will then look into future perspectives of using these stem cells to cure mental illnesses , and discuss the related challenges and opportunities .