The atrophy and death of hippocampal neurons induced by stress may be compensated for during antidepressant treatment by the generation of new neurons. Clear evidence now exists that new neurons are born in the adult mammalian brain [216
]. The phenomenon of adult neurogenesis in the dentate gyrus of the human hippocampus has been further validated by the recent visualization of neural stem cells in the hippocampus of live humans [217
There is a decrease in the volume of the hippocampus in depressed patients [9
] and it is documented that there is a decrease in hippocampal proliferation rates in animal models of depression and stress [219
]. However, there is mounting evidence that changes in hippocampal neurogenesis are not actually responsible for the reduced hippocampal volume associated with depression. Ablation of neurogenesis by x-ray irradiation does not cause a reduction in the size of the hippocampus or elicit a depression-like phenotype [224
], suggesting that neurogenesis is not critical to the depression phenotype. One study shows that the development of helpless behavior does not correlate with a decrease in neurogenesis which may suggest that learned helpless behavior may be due to reduced differentiation or survival of cells [226
]. The current theory is that changes in hippocampal volume in depressed patients and animal models is likely due to changes in neuropil and glial cell number or reduced dendritic completixity [18
]. However, neurogenesis may still play a role in the pathogenesis of depression, either during development or in combination with genetic susceptibility which should be studied in future investigations [228
It is currently believed that neurogenesis, rather than being a major contributor to the development of depression, may be required for some of the behavioral effects of antidepressants [228
]. In support of this, one effect of antidepressants as well as ECT is to increase proliferation of progenitor cells within the subgranular zone (SGZ) of the dentate gyrus [222
]. Chronic fluoxetine increases the proliferation of early neuronal progenitors specifically rather than stem cells in the dentate gyrus [231
]. Indeed, most of the cells generated by antidepressant treatment which survive, differentiate into neurons [229
]. The effect of antidepressant therapy on neurogenesis has also recently been demonstrated in adult non-human primates [234
] thus indicating the generality of the phenomenon. Finally, the decrease in hippocampal volume detected in depressed patients is not apparent in PTSD patients treated with antidepressants, suggesting that antidepressants reverse the hippocampal volume reduction [235
], however more longitudinal studies are required to study this phenomenon in depression.
Importantly, it has been demonstrated that neurogenesis is actually necessary for the actions of antidepressants in a rodent model of depression using 5-HT1A
receptor knockout mice or x-ray irradiation of the hippocampus to block de novo proliferation [225
]. These findings have been confirmed by studies demonstrating that the synthetic cannabinoid HU210 has antidepressant-like effects that require neurogenesis [237
] and that neurogenesis is necessary for the behavioral effects of fluoxetine in rats in the FST [224
]. However, the requirement of adult hippocampal neurogenesis for the behavioral effects of fluoxetine is not observed in every mouse strain, including BALB/c which is a highly anxious strain of mice [238
] suggesting that there is a genetic component. The requirement of neurogenesis for antidepressant actions may be one of the reasons for the delay in the onset of clinical effects of current therapies.
Different regions of the hippocampus have different responses to antidepressants with regard to neurogenesis. For exapmple, antidepressants may exert their behavioral effects by increasing neurogenesis preferentially in the ventral hippocampus which sends projections to the prefrontal cortex, nucleus accumbens and components of the HPA axis [228
]. These regions have all been implicated in the pathogenesis of depression. The ventral hippocampus also has a higher density of serotonergic innervation than the dorsal hippocampus [239
], suggesting that the ventral region is more responsive to changes in serotonergic function. Finally, lesion studies suggest that the ventral hippocampus is more involved in anxiety and the dorsal hippocampus is responsible for spatial learning and memory [240
]. In sum, these studies implicate the ventral hippocampus as being a target of antidepressant effects.
The simultaneous increase of both CREB and neurogenesis following antidepressant treatment suggests that CREB could promote neurogenesis. Indeed, both cAMP and CREB have been implicated in the antidepressant response with respect to behavior as well as cell proliferation [241
]. Activation of cAMP-CREB cascade increases neurogenesis [232
]. In contrast, dominant-negative CREB results in decreased rates of neurogenesis [242
]. However, CREB mutant mice are still able to display the normal behavioral responses to antidepressants suggesting that there is also a CREB-independent mechanism for some of the effects of antidepressants [23
]. Surprisingly, rather than exhibiting a decrease in neurogenesis, one study reports that mice lacking CREB expression throughout the brain and development display an increase in hippocampal neurogenesis compared to wildtype mice and these mice have less depressive behavior in paradigms that respond to both acute and chronic antidepressant treatment [119
]. An explanation for these disparate findings is that the behavioral consequences of manipulation of CREB expression may depend on the specific brain region targeted and the timing of the deletion [119
]. Despite these seemingly conflicting results with regard to CREB and neurogenesis, the findings of Gur et al. [243
] do support the association of increased neurogenesis with antidepressive behavior.
BDNF which is a CREB mediated gene has been implicated in increased number of hippocampal progenitor cells. Overexpression or infusion of BDNF in the adult rat results in newly generated cells in the SGZ of the dentate gyrus and forebrain [233
]. Chronic infusion of BDNF into the dorsal hilus has widespread effects since neurogenesis was also increased by BDNF in the contralateral hippocampus [233
]. It has also been demonstrated that BDNF is required for the enhancement of hippocampal neurogenesis following environmental enrichment [246
]. Finally, BDNF is required for basal neurogenesis and mediates in part the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice [247
]. Thus BDNF, like antidepressants increase neurogenesis.
The mechanism by which antidepressants and BDNF increase the number of newly generated cells has been explored. Antidepressant treatment in mice with genetically reduced BDNF signaling results in similar proliferation rates to wild type, however long-term survival of newborn cells is reduced in the BDNF+/-mice. These findings suggest that whereas antidepressants increase turnover of hippocampal neurons, BDNF is required for the long-term survival of newborn neurons [118
]. Consistent with a role for BDNF in survival rather than proliferation, a recent study examining knock-in mice containing the Val66Met polymorphism in the prodomain of BDNF exhibit deficits in survival but not proliferation [248
]. A recently discovered role for the precursor form of BDNF (proBDNF) in promoting cell death through the p75 receptor [249
] may explain the ying/yang effects of BDNF and proBDNF on survival [250
In contrast to the studies of Sairanen et al., [118
] a recent study elegantly confirmed a critical role for TrkB signaling in proliferation and antidepressant effects. TrkB deletion specifically in progenitor cells of dentate gyrus results in impaired proliferation and neurogenesis and eliminates the behavioral response to antidepressant treatment in depression and anxiety-like paradigms. Deletion of TrkB in differentiated cells of the dentate gyrus had no effect suggesting that proliferation of progenitor cells is mediated by TrkB signaling and is crucial to the behavioral effects of antidepressants and exercise [251
]. One reason for the difference between the study by Li et al. [251
] and those of others [118
] may be the use of different promoters [252
Voluntary exercise also may have its beneficial effects on mood by affecting neurogenesis. Exercise increases proliferation of neural progenitor cells in the hippocampus, increases the number of new neurons and promotes the survival of those newly-born cells which become integrated into the hippocampus [165
]. However, the effects of exercise on anxiety-like behavior can occur independently of increased neurogenesis [256
]. Thus it is not clear if exercise and antidepressants use independent mechanisms or not. Furthermore, other than BDNF the underlying molecular mechanisms of exercise’s beneficial effects have not been explored until now.
We have demonstrated for the first time that the neuropeptide VGF which is a CREB mediated gene induced by both BDNF and exercise [162
] enhances neurogenesis of hippocampal cells indicating a possible mechanism for actions of VGF as an antidepressant-like agent. Specificially, in vitro and in vivo experiments revealed an increase in cells undergoing DNA synthesis following VGF treatment (). In addition, VGF increased the number of BrdU+ cells that expressed neuronal markers and decreased the number of cells expressing GFAP suggesting that VGF may influence the differentiation of neurons over glia. Our studies also suggest that the proliferating cells survive for at least 3 weeks. Furthermore, the co-localization of BrdU with NeuN in the dentate gyrus in vivo confirmed that the proliferating cells differentiate into neurons [133
]. Recently a shorter VGF peptide, TLQP-21, was shown to prevent cerebellar granule cell death induced by serum and potassium deprivation in a Ca2+ dependent manner and requiring Erk1/2, Akt, PKC and c-jun N-terminal kinase (JNK) activation [257
], suggesting a trophic-like activity for VGF.
Fig. 2 Intrahippocampal infusion of VGF increases BrdU+ cells in the SGZ plus GCL. (A), Saline or (B), VGF (4μg) was infused daily via a cannula into the hippocampi of adult male rats for 7 days followed by a single BrdU injection (100 mg/kg). The animals (more ...)
Our study is the first to link VGF to proliferation however other neuropeptides induced by BDNF and 5-HT also affect neurogenesis. NPY through the Y1 receptor induces neuroproliferative effects on cultured postnatal hippocampal cells [258
]. Furthermore, the Y1 receptor knockout mouse has a 40% decrease in the number of dividing cells in the SGZ of the hippocampus in vivo [259
]. Antagonists to opioid receptors inhibit the number of newly generated cells [260
]. In addition, mice mutant for ß-endorphin did not exhibit an increase in proliferation in response to voluntary wheel running compared to wild type mice. However, there was an increased survival and a decrease in cell death in knockout mice [261
]. These studies suggest that while ß-endorphin is a key factor in exercise induced cell proliferation, there is also homeostatic regulation of final cell number. Mice lacking CCK receptors, like NPY receptors, have fewer proliferating cells and neuroblasts and a reduction of interneurons in the olfactory bulb compared to wild type mice, suggesting that CCK regulates the proliferation and differentation of neurons [262
] although this study did not examine proliferation in the dentate gyrus.
It is not clear that all neuropeptide pathways enhance neurogenesis or require neurogenesis for their antidepressant-like behavioral effects. While one study shows that exposure of neurons to Substance P both in vitro and in vivo results in an increase in proliferation of neural progenitor cells in the dentate gyrus [263
], another report demonstrates that NK1 knockout mice exhibit increased neurogenesis as well as elevated BDNF levels compared to wild type mice. However the knockout mice do not exhibit increased proliferation in response to chronic antidepressant drug therapy [264
]. This study is consistent with the finding that NK1 antagonists can act as antidepressant-like agents and supports the theory that neurogenesis accompanied by increase BDNF levels, may contribute to the efficacy of antidepressant drugs, however further studies are required determine whether NK1 signaling is a positive or negative regulator of neurogenesis. Galanin may also be inhibitory to neurogenesis since antisense oligonucleotide infusion promotes viability of hippocampal interneurons and stimulates seizure-induced neurogenesis [265
]. In contrast to these neuropeptides which influence neurogenesis, vasopressin antagonists do not appear to require neurogenesis for their antidepressant-like effects as shown by blocking neurogenesis using x-ray irradiation [266
]. Therefore not all neuropeptides work via neurogenesis. There is no information to date as to the effects of other neuropeptides implicated in affective disorders such as oxytocin or OFQ on neural proliferation so that is an area of future interest.
The effects of antidepressants on proliferation may be influenced by synaptic activity. There is evidence that both excitatory and inhibitory neuronal activity affects the proliferation of neural stem cells and the integration of newly-born cells into the neuronal network [267
]. Recently, it was confirmed that neurons born in the adult dentate gyrus form functional synapses with target cells in the CA3 area and hilus [271
]. Thus synaptic activity may play a significant role in the effect of antidepressants on neurogenesis as well as the integration and function of those newly-born cells.