neurogenesis , the generation of new neuronal cells , occurs in the adult brain of mammals ( gage , 2000 ; gross , 2000 ) , including human ( eriksson et al .
neurogenesis occurs primarily in two regions of the adult brain : the dg and the subventricular zone ( svz ) ( taupin and gage , 2001 ) .
newly generated neuronal cells establish synaptic and functional connections with nerve cells of the pre - existing network ( stanfield and trice , 1988 ; markakis and gage , 1999 ; van praag et al . 2002 ) .
it is hypothesized that newborn neuronal cells arise from stem cells in the adult brain .
nscs are the self - renewing multipotent cells that generate the main phenotypes of the nervous system , neurons , astrocytes and oligodendrocytes ; as such they hold the potential to treat a broad range of cns diseases and injuries ( mckay , 1997 ) .
neural progenitor and stem cells have been isolated and characterized in vitro from the adult brain , further supporting the existence of nscs in the adult cns ( reynolds and weiss , 1992 ; gage et al .
the existence of nscs in the adult brain has tremendous consequences for cellular therapy in the cns , but also for our understanding of developmental biology ( taupin , 2006a ) .
depression is a major public health problem that affects 1217% of the population ( kessler et al .
various classes of drugs are currently prescribed for the treatment of depression ( wong and licinio , 2001 ; brunello et al .
2002 ) . among them selective serotonin reuptake inhibitors ( ssris ) , like fluoxetine , monoamine oxidase inhibitors ( maois ) , like tranylcypromine , specific norepinephrine reuptake inhibitors ( snris ) , like reboxetine and phosphodiesterase - iv inhibitors , like rolipram , alleviate symptoms of depression .
it is hypothesized that an imbalance in serotonin ( 5-hydroxytryptamine or 5-ht ) and noradrenaline ( na ) pathways may underlie the pathogenesis of depressive disorders ( hindmarch , 2001 ; owens , 2004 ) .
ssris , like fluoxetine , may produce their therapeutic effects by increasing brain levels of 5-ht , a neurotransmitter implicated in the modulation of mood and anxiety - related disorders ( whittington et al .
the 5-ht1a receptor has been prominently implicated in the modulation of mood and anxiety - related disorders ( gross et al .
there are increasing evidences that the hippocampus , a structure classically involved in leaning and memory , is involved in the modulation of emotional responses , particularly depression .
clinical magnetic resonance imaging and post - mortem studies in depression patients , as well as in animal studies , reveal that chronic stress and depression result in loss of nerve cells and atrophy in the hippocampus , and that these effects can be reversed by antidepressants ( watanabe et al .
1996 ; czeh et al . 2001 ; campbell et al . 2004 ; videbech and ravnkilde , 2004 ; colla et al .
this suggests that neurogenesis may be an underlying factor in the contribution of the hippocampus to depression . in support of this contention , glucocorticoids , stress - related hormones ,
induce brain atrophy ( sapolsky , 2000 ; mcewen , 2001 ) and decrease neurogenesis ( gould et al .
1991 ; cameron and gould , 1994 ) , whereas antidepressants , like fluoxetine , promote neurogenesis ( malberg et al .
investigators have aimed at confirming and unraveling the mechanism underlying the involvement of adult neurogenesis to the etiology of depression .
the effect of antidepressants , like fluoxetine , tranylcypromine , reboxetine and rolipram , on adult neurogenesis was assessed by means of bromodeoxyuridine ( brdu ) labeling , immunohistochemistry for neuronal specific markers and confocal microscopy ( malberg et al .
brdu is a thymidine analog that incorporates into the dna of dividing cells and is used for birthdating cells and monitoring cell proliferation ( miller and nowakowski , 1988 ; kuhn et al .
chronic administration of these antidepressants increases neurogenesis in the dg , but not the svz in adult rats , suggesting that hippocampal neurogenesis contributes to the therapeutic effects of antidepressants ( malberg et al . 2000 , 2004 ) . to study the functional implication of such observations , santarelli et al .
( 2003 ) aimed at characterizing whether an increase in neurogenesis is required for the effect of antidepressants .
x - ray irradiation of the hippocampal area in adult rats causes long - term reductions in cell proliferation in the dg ( tada et al .
hippocampal x - ray irradiation , but not irradiation of other brain areas , like the svz or the cerebellar region , prevented the neurogenic effect of antidepressants , like fluoxetine , in adult mice ( santarelli et al .
the behavioral effect of the antidepressants on the novelty - suppressed feeding ( nsf ) test was also abolished after hippocampal irradiation .
the nsf test , in which animals are food deprived , then placed into a novel environment containing food , and assessed for the latency to begin eating , is devised to assess chronic antidepressant efficacy in rodents ( bodnoff et al .
further , 5-ht1a receptor null mice were insensitive to the neurogenic and behavioral effects of fluoxetine . in all , these data show that ssris , like fluoxetine , increase hippocampal neurogenesis , which contributes to their behavioral effects ( santarelli et al .
stress , an environmental factor , is an important causal factor in precipitating episodes of depression in human , and potently suppresses hippocampal neurogenesis in adult monkey ( gould et al .
1998 ; malberg and duman , 2003 ) , probably due to increased glucocorticoid release ( gould et al . 1991
neurogenesis plays an important role in biology of depression ; particularly the stimulation of neurogenesis by antidepressants contributes to their behavioral effects ( malberg et al .
it is proposed that stress - induced decrease of neurogenesis in the dg is an important causal factor in precipitating episodes of depression .
the waning and waxing of neurogenesis in the hippocampal formation are therefore important causal factors , respectively , in the precipitation of , and recovery from , episodes of clinical depression , probably mediated through the increase in brain serotonin levels ( jacobs et al .
studies reveal that the 5-ht , particularly 5-ht1a , receptor subtypes mediate the involvement of adult neurogenesis in depression ( banasr et al .
2004 ) , and that fluoxetine targets a population of early progenitor cells in the dg , rather than stem - like cells in the dg ( encinas et al . 2006 ) .
the effect of antidepressants on neurogenesis may be mediated by trophic factors , like brain - derived neurotrophic factor ( bdnf ) . on the one hand ,
antidepressant treatments increase the level of expression of bdnf in the patents brain , and bdnf has an antidepressant effect ( siuciak et al .
2003 ) . on the other hand , administration of bdnf increases adult neurogenesis in the hippocampus ( scharfman et al .
this suggests that the effect of antidepressants on neurogenesis may be mediated by bdnf , through its signaling pathway , particularly the mitogen - activated protein ( map ) kinase pathway ( duman et al .
the map kinase pathway is a bdnf signaling cascade mediated by the activation of map kinase ( mapk ) that phosphorylates and activates the extracellular signal - regulated kinase ( erk ) pathway ( huang and reichardt , 2003 ) .
a hypothesis supported by recent findings showing that exercise promotes hippocampal neurogenesis , bdnf expression , and has an antidepressant effect ( van praag et al .
1999 ; eadie et al . 2005 ; russo - neustadt and chen , 2005 ; bjornebekk et al .
2005 ; ernst et al . 2006 ) . though these studies provide compelling evidences of the role of bdnf in depression and neurogenesis , it remains to link the activity of bdnf on the increase of neurogenesis mediated by antidepressants .
there are however controversies and debates over the involvement of the hippocampus and adult neurogenesis in the etiology of depression . among them , i ) a link between neurogenesis , loss of nerve cells , atrophy and decrease of hippocampal volume in depression subjects is yet to be demonstrated , ii ) studies show that hippocampal volume remains unchanged in depressive patients ( axelson et al .
2005 ) , iii ) the hippocampal formation may not be primarily involved in depressive episodes , as other areas of the brain may play a critical role in depression ( nestler et al .
2006 ) , iv ) there are questions over validity of animal models of depression as representative of the human disorder , and v ) neurogenesis may be more a contributing factor of cns plasticity , rather than to specific physiological or pathological processes ( taupin , 2006c ) .
in all these data involved the hippocampus , a structure classically involved in leaning and memory , and adult neurogenesis in depression and anxiety disorders ( thomas and peterson , 2003 ) .
however , the neurogenic theory of depression remains the source of debates and controversies , and to be further confirmed ( feldmann et al .
2006 ) . more data and evidences are needed to confirm the involvement of adult neurogenesis in depression .
these studies show that antidepressants increase hippocampal neurogenesis , and establish a causal relation between the stimulation of neurogenesis and the effect of antidepressants .
new neuronal cells that survived and integrate the pre - existing network survive for long period , over two years in human ( eriksson et al . 1998 ) .
therefore , antidepressants may have long - term consequence on the architecture , and functioning of the cns .
the function of newly generated neuronal cells in the adult brain remains the source of intense research and debates .
though the hippocampus and neurogenesis play an important role in depression , these data remain the source of controversies and debates , and the involvement of adult neurogenesis in the etiology of depression to be further characterized .
nonetheless , the evidence that stimulation of neurogenesis contributes to the effects of antidepressants may hold the key for the understanding of the long - term consequences of the effects of antidepressants of the physiopathology of the cns , and lead to new drugs design , and new strategies to treat depressive disorders . to this aim ,
determining the cellular and molecular mechanisms of action of antidepressants on neurogenesis will be a determining factor .
 the recent evidence that neurogenesis occurs throughout adulthood and neural stem cells ( nscs ) reside in the adult central nervous system ( cns ) suggests that the cns has the potential for self - repair . beside this potential , 
 the function of newly generated neuronal cells in the adult brain remains the focus of intense research . 
 the hippocampus of patients with depression show signs of atrophy and neuronal loss . 
 this suggests that adult neurogenesis may contribute to the biology of depression . 
 the observations that antidepressants , like fluoxetine , increase neurogenesis in the dentate gyrus ( dg ) and neurogenesis is required for the behavioral effect of antidepressants , lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression . 
 however , the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates . 
Introduction
Neurogenesis Contributes to the Therapeutic Effects of Antidepressants
A Neurogenic Theory of Depression
Conclusion