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Neurogenesis and Depression: still an open debate

Posted by jrbecker on July 21, 2004, at 15:06:35

the latest volume of the journal of Biological Psychiatry is dedicated to the ongoing debate of whether neurogenesis is the major causal factor in depression...

IS IMPAIRED NEUROGENESIS RELEVANT TO THE AFFECTIVE SYMPTOMS OF DEPRESSION?
Robert M. Sapolsky

Biological Psychiatry
Volume 56, Issue 3 , 1 August 2004, Pages 137-139


doi:10.1016/j.biopsych.2004.04.012
Copyright © 2004 Society of Biological Psychiatry. Published by Elsevier Inc.

Gilbert Laboratory,Department of Biological Sciences,Room MC5020, Stanford, CA, 94305-5020, USA

Available online 19 June 2004.

Article Outline
• Does the time course of neurogenesis help to explain the time-course paradox of antidepressant action?
• Does the idea that impaired hippocampal neurogenesis gives rise to the affective symptoms of depression "make sense"?
• Do stress and/or glucocorticoids inhibit adult neurogenesis in the hippocampus? what are the morphometric consequences of this?
• Can depression occur without impaired hippocampal neurogenesis? can impaired hippocampal neurogenesis occur without depression?
• Do all antidepressant drugs or therapies stimulate hippocampal neurogenesis?
• If you block the ability of an antidepressant to stimulate neurogenesis, is it no longer capable of relieving depressive symptoms?
• Conclusions
• References


Readers of this journal are likely to agree with three statements. First, it is impossible to think effectively about depression outside the context of biology. Second, it is impossible to think effectively about depression as only being a matter of biology (see Caspi et al 2003 for a brilliant demonstration of this). Finally, despite the vast quantities of excellent research on which those two conclusions rest, we remain woefully inadequate at effectively treating depression in vast numbers of its sufferers.

Because of this, a new, exciting hypothesis that promises to transform how we think about the causes and treatment of depression is obviously welcome. The notion that depression can arise from impaired hippocampal neurogenesis and that an array of antidepressants ultimately work by stimulating such neurogenesis is one such exciting hypothesis (with both parts of that idea henceforth collectively referred to as the "neurogenesis" hypothesis).

Does the bulk of evidence support or go against this hypothesis? As seen in the two preceding reviews by leaders in this field, the answer to this question is not at all clear, because the relevant literature is sparse and subject to some markedly differing interpretations. Thus, it seems useful to summarize what is known at this point, what are the key assumptions and criticisms surrounding the interpretations of each set of findings, and what new experiments are most needed. I begin with three of the more peripheral or distal questions that arise from this hypothesis.

Does the time course of neurogenesis help to explain the time-course paradox of antidepressant action?
The seemingly clear mechanisms of action of selective serotonin reuptake inhibitors (SSRIs), tricyclics, and monoamine oxidase (MAO) inhibitors are greatly complicated by the fact that although the drugs have relatively rapid effects upon monoamine signaling, the latency until they are clinically efficacious is far longer. This has prompted models focusing on the more prolonged consequences of their direct monoamine effects (e.g., receptor downregulation and interactions with presynaptic autoreceptors).

Although these models are perfectly plausible, they are complex and rely on many assumptions. Thus, the possibility that these antidepressants are effective, instead, by stimulating neurogenesis, immediately begs the question of whether the time course of such neurogenesis fits with the delayed time course of clinical efficacy.

At present, an array of studies suggests this to be the case (although these studies have not always demonstrated that these new neurons have formed functional synapses during that time). Were this not so, this would be strong evidence against the neurogenesis hypothesis of depression. Instead, the clear and well-replicated finding that the time course does fit constitutes indirect, correlative support.

Does the idea that impaired hippocampal neurogenesis gives rise to the affective symptoms of depression "make sense"?
Major depression is often accompanied by problems with declarative learning and memory (Austin et al 2001), a province of the hippocampus, and virtually all participants in this debate agree that impaired hippocampal neurogenesis during depression could help explain the cognitive deficits of the disease. This consensus would be somewhat controversial in some quarters. This is because the adult neurogenesis field is wrestling with the issues of whether new hippocampal neurons actually function and, if so, what those functions are; whether new neurons support even the "traditional" hippocampal roles in declarative memory is a highly contentious topic ( Rakic, 2002 and Shors et al., 2001). But the neurogenesis hypothesis is more expansive, in that is posits that hippocampal neurogenesis is also relevant to the defining affective symptoms of the disease. How plausible is this?

Advocates of this position have constructed some scenarios built around 1) the fact that the hippocampus communicates with many of the neuroanatomical "hot spots" of depression (the prefrontal and cingulated cortices and the amygdala); and 2) a sequence that can be summarized as follows: declarative memory deficits make it more difficult to accurately perceive cause and effect; such inaccuracies make it difficult to detect control and agency; this increases the likelihood of a globalized sense of helplessness, which is the cognitive foundation of depression.

There will obviously be considerable differences as to how much of a stretch this seems to those assessing the hypothesis. Is there a pattern as to who finds this plausible? There is the frequent phenomenon that neuroscientists who study brain region X tend toward the view that region X is the center of the neurobiological universe; however, in this case, in surveying opinions regarding this matter, I think I detect the opposite pattern, namely that the more expertise someone has about the hippocampus and its role in cognition, the less plausible they find this novel role for the hippocampus; I believe I fall into this camp. At present, teleology does not strike me as providing particularly strong support for the hypothesis.

Do stress and/or glucocorticoids inhibit adult neurogenesis in the hippocampus? what are the morphometric consequences of this?
In many ways, the biology and psychology of depression intersect with stress (to briefly summarize: major stressors precede many depressions; pathologic or pharmacologic excesses of glucocorticoids can cause depression; approximately half of depressives have some version of glucocorticoid excess; glucocorticoids and stress have many neurochemical and neuroanatomical effects that are commensurate with the biology of depression; and antiglucocorticoids can act as antidepressants [reviewed at length in Sapolsky, 2000 and Wolkowitz et al., 1999]). Thus, a key issue is whether stress and/or glucocorticoids inhibit neurogenesis.

This is one of the best-replicated findings in the field. Stress and glucocorticoids are among the strongest, if not the strongest, inhibitors of hippocampal neurogenesis; both parties in the preceding debate are in agreement about this. Were this not to be the case, this would weigh strongly against the neurogenesis hypothesis. Instead, the solid evidence of such inhibition constitutes indirect, correlative support for the hypothesis. As pointed out by the authors, it is critical that the difficult studies be carried out to determine whether human depression is associated with decreased rates of neurogenesis.

This segues to a related issue, namely whether stress- or glucocorticoid-induced inhibition of neurogenesis can ever be of sufficient magnitude to cause an overall decrease in hippocampal volume. This question is prompted by the now well-replicated finding that prolonged major depression can be associated with a selective loss of hippocampal volume (reviewed in Sapolsky 2000). This finding is weakened somewhat by the fact that it has not yet been shown that volume loss only occurs in hypercortisolemic depressives (amid indirect evidence for this [ Sheline et al 1996]). Nonetheless, such volume loss is commensurate with a huge preclinical literature showing how stress and glucocorticoids can preferentially damage the hippocampus. A number of investigators in the adult neurogenesis field have generated estimates regarding the rate of neurogenesis, suggesting that a substantial percentage of the dentate gyrus (the site of hippocampal neurogenesis in the adult) might be replaced with new neurons over the course of the lifetime ( Gould and Gross 2002). The following should be considered, however: 1) these are thought to be fairly soft estimates by many in the field ( Rakic 2002); 2) it is not yet known whether the hippocampal volume loss in human depression is preferentially centered in the dentate (which would support the neurogenesis hypothesis); 3) it is not known whether the volume loss involves a paucity of neurons (which would also support the neurogenesis hypothesis) or an atrophy of neuronal processes (which can be a consequence of stress or glucocorticoid exposure); and 4) if there is indeed a depletion of neurons, it is not known whether it is due to the failure of new neurons to be born (supporting the neurogenesis hypothesis) or due to the death of preexisting neurons (for which there is some precedent).

Thus, although it is well established that stress and glucocorticoids inhibit hippocampal neurogenesis in nonhuman species, it is not yet known whether the same occurs in human depression or whether any such inhibition could give rise to the hippocampal volume loss in many cases of depression. It should be noted, however, that the hypothesis does not require that neurogenesis be relevant to total hippocampal volume, just that it be relevant to the affective symptoms of depression.

To summarize this section, the ability of stress to inhibit neurogenesis and the time course of antidepressant-induced neurogenesis offer indirect support for the hypothesis, although the notion of hippocampal neurogenesis being relevant to the affective symptoms of depression seems like a stretch to many. We now turn to what strike me as more central, proximal questions related to the neurogenesis hypothesis. As can be seen, studies addressing these questions have generated some very clear data with some very conflicting interpretations. The first question is a dual one and is related to the first half of the neurogenesis hypothesis (i.e., the role of impaired neurogenesis in the emergence of depression).

Can depression occur without impaired hippocampal neurogenesis? can impaired hippocampal neurogenesis occur without depression?
In considering the first question, Henn, Vollmayr, and colleagues showed that bromodeoxyuridine labeling in the hippocampus did not differ between rats who were learned helpless and those who were resistant to such helplessness (Vollmayr et al 2003).

Data regarding the second issue has come from Duman, Henn, and Vollmayr and, pleasingly, there seems to be consensus on this issue. In three studies, hippocampal neurogenesis was decreased substantially (40%–90%) and, importantly, by three different means (restraint stress, an active avoidance task, and selective irradiation of the hippocampus). In all three studies, this did not produce "depression" in the models used (Malberg and Duman, 2003; Santarelli et al., 2003 and Vollmayr et al., 2003). In the case of the irradiation study, Duman (one of the co-authors) suggests that a longer duration of impaired neurogenesis is needed to produce depression.

As is obligatory in this business, one must immediately question whether the behavioral consequences of stress in a rodent can ever be synonymous with human depression and whether the tests used are appropriate for assessing such putative rodent "depression." Two of the studies used variants on the learned helplessness tests that are arguably the gold standard for rodent models of depression, whereas one used a rather different test (which will be discussed below).

Amid the differing tests and the questions that can be raised about them, the consensus in the findings is impressive. At this point, it seems as if an acute impairment of neurogenesis is neither necessary nor sufficient to generate rodent models of depression.

We now turn to two critical questions related to the second half of the neurogenesis hypothesis, namely whether antidepressants are effective only insofar as they stimulate neurogenesis.

Do all antidepressant drugs or therapies stimulate hippocampal neurogenesis?
It is clear that the neurogenesis hypothesis would be gravely weakened if it turned out that some effective antidepressant therapy failed to stimulate adult neurogenesis. At present, there have been an impressive number of studies showing such stimulation in preclinical models. Antidepressant drugs that have this effect include SSRIs, tricyclics, MAO inhibitors, and tianeptine (the final drug is controversial, insofar as it is in use in Europe but not in the United States and because its mechanism of action seems to be virtually opposite to that of SSRIs). Moreover, neurogenesis is stimulated by lithium (which, despite the uneducated assumption of this nonpsychiatrist that it only works against the manic phase of bipolar disorder, can stabilize depression and potentiate the effects of other antidepressants [Bauer et al., 2003 and Fawcett, 2003]) and by electroconvulsive therapy.

Thus, an impressively large and varied array of antidepressants has been shown to stimulate neurogenesis in clear and replicated studies; however, the hypothesis requires that there be no exceptions to this pattern, and a potentially key exception comes with two reports (in rats and monkeys) that transcranial magnetic stimulation (TMS) fails to stimulate hippocampal neurogenesis (though still having salutary effects commensurate with antidepressant action).

This should seem a fatal blow for the neurogenesis hypothesis, particularly given the demonstration in two species, including one phylogenetically close to humans (Czeh et al 2001; Scalia et al, unpublished data). The responses to this by advocates of the hypothesis are twofold: first, TMS is one of the newest of mainstream antidepressant therapies and thus is not enthusiastically accepted in many circles (i.e., many have argued that it is not sufficiently effective). Second, TMS is typically applied to the frontal cortex in humans, and even if it is a highly effective therapy, it is intrinsically problematic to study TMS in rats, because rats have little frontal cortex; countering this, of course, is the study using Old World primates, who are considerably more frontally well-endowed (Scalia et al, unpublished data).

Amid the impressive array of antidepressants that stimulate neurogenesis, TMS could represent a fatal blow to the hypothesis. It does not yet, and intensive research regarding TMS and neurogenesis is needed, dovetailing on the broader body of research needed regarding the antidepressant efficacy of TMS.

If you block the ability of an antidepressant to stimulate neurogenesis, is it no longer capable of relieving depressive symptoms?
A demonstration that antidepressant efficacy requires enhanced neurogenesis would be the strongest possible support for the hypothesis, and such support seemingly comes with the well-publicized Science article discussed at length in both the preceding reviews (Santarelli et al 2003). To reiterate, the authors established a rodent model of depression, one whose behavioral symptoms were relieved by antidepressant treatment. The authors then inhibited hippocampal neurogenesis with localized irradiation of the structure and showed that the antidepressants were no longer effective at correcting the rodent depression. This was a well-controlled study, in that the authors showed 1) that the irradiation did not alter neurogenesis in the subventricular zone (the other brain region in which adult neurogenesis occurs); 2) irradiation of other parts of the brain did not alter hippocampal neurogenesis or block antidepressant efficacy; and 3) that a number of standard electrophysiologic measures of hippocampal function were unchanged by the irradiation.

This seems like immensely strong, even irrefutable support for the neurogenesis hypothesis. Naturally, criticisms have been voiced. They have taken two forms. First, demonstrating that electrophysiologic parameters were spared by the irradiation is important but is insufficient to conclude that a change in neurogenesis rates is the only thing changed by the irradiation regime. A priori, it has struck many that it would be surprising if the effects of irradiation were so focal. The second concern, voiced by many in the field, is that the test purported by the investigators to be one of depression was, in fact, a test of anxiety (the willingness of a hungry rodent to overcome its aversion to bright light and enter a brightly lit room for food). This concern was raised by Henn and Vollmayr and seems quite legitimate. Addressing this issue, Duman offers something that is a bit of a tautology, namely that a behavior in a rodent qualifies as a depression if it is normalized by antidepressants. The wide range of clinical uses of SSRIs seems to counter this argument.

Thus, this difficult study has generated some of the strongest support for the neurogenesis hypothesis; however, it seems clear that more support in this realm is needed along the lines of 1) replication; 2) use of more traditional rodent tests of depression; 3) testing with a broader range of antidepressant drugs and treatments; and 4) broader documentation of what is preserved in the hippocampi of these animals, despite the radiation.

Conclusions
As stated, the neurogenesis hypothesis has two components. The first is that impaired neurogenesis plays a role in causing depression. Although there is only a small relevant body of literature examining the issue at this point, it seems fairly clear that this is not tenable. Insofar as rodents can be valid subjects in modeling depression, decreased neurogenesis and depression can be dissociated.

The second component of the hypothesis is that antidepressants work by normalizing the (putative) neurogenesis defect. Here the evidence is markedly conflicting. The demonstration in two reports that TMS does not stimulate neurogenesis should put that part of the hypothesis to rest; however, as seen, some question whether TMS is enough of an antidepressant therapy to merit such veto power. Conversely, the demonstration that selective hippocampal irradiation blocks antidepressant efficacy should establish that part of the hypothesis on very strong footing; however, as seen, numerous caveats have been raised regarding that single study.

It is obligatory at this point to say that more research is needed, and that is indeed the case. The relevance of various animal models to human depression must be tested further. The arduous studies must be carried out examining the cellular basis of the hippocampal volume loss in human depressives. And further tests of this hypothesis must tackle the separate components of the neurogenesis phenomenon, namely the birth, differentiation and survival of new cells.

If the neurogenesis hypothesis withers for lack of any further supporting evidence, it will still have served a useful role. This is because of the status of adult neurogenesis as, arguably, the hottest topic in neuroscience. As a result of the spotlight being cast on neurogenesis, some light of attention will also be shone on the desperate need to develop new classes of antidepressants.

References
Austin, M., Mitchell, P. and Goodwin, G., 2001. Cognitive deficits in depression. Br J Psychiatry 178, pp. 200–211.

Bauer, M., Forsthoff, A., Baethge, C., Adli, M., Berghofer, A. and Dopfmer, S., 2003. Lithium augmentation therapy in refractory depression—update 2002. Eur Arch Psychiatry Clin Neurosci 253, pp. 132–139. Abstract-MEDLINE | Abstract-PsycINFO | Abstract-EMBASE | Full Text via CrossRef

Caspi, A., Sugden, K., Moffitt, T., Taylor, A., Craig, I., Harrington, H. et al., 2003. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 301, pp. 386–390.

Czeh, B., Michaelis, T., Watanabe, T., Frahm, J., de Biurrun, G., van Kampen, M. et al., 2001. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A 98, pp. 12796–12801. Abstract-MEDLINE | Full Text via CrossRef

Fawcett, J., 2003. Lithium combinations in acute and maintenance treatment of unipolar and bipolar depression. J Clin Psychiatry 64, pp. 32–37. Abstract-MEDLINE | Abstract-EMBASE | Abstract-PsycINFO

Gould, E. and Gross, C., 2002. Neurogenesis in adult mammals: Some progress and problems. J Neurosci 22, pp. 619–623. Abstract-MEDLINE | Abstract-Elsevier BIOBASE | Abstract-PsycINFO | Abstract-EMBASE

Malberg, J. and Duman, R., 2003. Cell proliferation in adult hippocampus is decreased by inescapable stress: Reversal by fluoxetine treatment. Neuropsychopharm 28, pp. 1562–1571. Abstract-MEDLINE | Abstract-PsycINFO | Full Text via CrossRef

Rakic, P., 2002. Neurogenesis in adult primate neocortex: An evaluation of the evidence. Nat Rev Neurosci 3, pp. 65–71. Abstract-MEDLINE | Full Text via CrossRef

Santarelli, L., Saxe, M., Gross, C., Surget, A., Basttaglia, F., Dulawa, S. et al., 2003. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, pp. 805–809. Abstract-PsycINFO | Abstract-Elsevier BIOBASE | Abstract-EMBASE | Abstract-Compendex | Abstract-MEDLINE | Abstract-GEOBASE | Full Text via CrossRef

Sapolsky, R., 2000. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 57, pp. 925–934.

Sheline, Y., Wany, P., Gado, M., Csernansky, J. and Vannier, M., 1996. Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 93, pp. 3908–3913. Abstract-MEDLINE | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Full Text via CrossRef

Shors, T., Miesegaes, G., Beylin, A., Zhao, M., Rydel, T. and Gould, E., 2001. Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, pp. 372–376. Abstract-PsycINFO | Abstract-EMBASE | Abstract-Elsevier BIOBASE | Abstract-MEDLINE | Full Text via CrossRef

Vollmayr, B., Simonis, C., Weber, S., Gass, P. and Henn, F., 2003. Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness. Biol Psychiatry 54, pp. 1035–1040. SummaryPlus | Full Text + Links | PDF (172 K)

Wolkowitz, O., Reus, V., Chan, T., Manfredi, F., Raum, W., Johnson, R. and Canick, J., 1999. Antiglucocorticoid treatment of depression: Double-blind ketoconazole. Biol Psychiatry 45, pp.

DEPRESSION: A CASE OF NEURONAL LIFE AND DEATH?
Ronald S. Duman,

Biological Psychiatry
Volume 56, Issue 3 , 1 August 2004, Pages 140-145
doi:10.1016/j.biopsych.2004.02.033
Copyright © 2004 Society of Biological Psychiatry. Published by Elsevier Inc.
Debates in neuroscience

a Division of Molecular Psychiatry, Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA

Available online 10 May 2004.


Abstract
Preclinical and clinical studies have demonstrated that stress or depression can lead to atrophy and cell loss in limbic brain structures that are critically involved in depression, including the hippocampus. Studies in experimental animals demonstrate that decreased birth of new neurons in adult hippocampus could contribute to this atrophy. In contrast, antidepressant treatment increases neurogenesis in the hippocampus of adult animals and blocks the effects of stress. Moreover, blockade of hippocampal neurogenesis blocks the actions of antidepressants in behavioral models of depression, demonstrating a direct link between behavior and new cell birth. This perspective reviews the literature in support of the hypothesis that altered birth of new neurons in the adult brain contributes to the etiology and treatment of depression and considers research strategies to test this hypothesis.

Article Outline
• Neurogenesis in adult brain
• Clinical evidence for atrophy of hippocampus in mood disorders
• Hippocampus and depression
• Stress decreases adult neurogenesis
• Antidepressant treatment increases adult neurogenesis
• Antidepressant treatment blocks the effects of stress on adult neurogenesis
• Neurogenesis is necessary for the action of antidepressants in behavioral models
• Consideration of time course and other behavioral models
• Testing the hypothesis: analysis of neurogenesis in the brains of depressed patients
• Conclusions
• Acknowledgements
• References


Previous hypotheses to explain the cause and treatment of depression have been based in part on the acute actions of antidepressants (i.e., blockade of serotonin and norepinephrine reuptake or breakdown); however, the time lag for a therapeutic response has led to the hypothesis that adaptations to the acute actions of antidepressants are necessary. Cellular adaptations can occur at many levels, including regulation of neurotransmitter receptors, signal transduction cascades, and gene transcription. Advances in cell biology and imaging have revealed that these neurochemical adaptations can lead to alterations in cell morphology (e.g., alterations in the length and complexity of neuronal processes) and even the birth of new neurons. Moreover, it is now clear that alterations in neuronal morphology and cell number represent fundamental mechanisms of neuronal plasticity that allow an animal to adapt to environmental, behavioral, and pharmacologic stimuli and thereby make appropriate long-term responses. These concepts and advances have been applied to studies of antidepressants and have resulted in the novel hypothesis that altered neurogenesis plays a role in the etiology and treatment of depression (Duman et al., 2001; Gage, 2000 and Kempermann and Gage, 2002). The focus of this perspective is to review the evidence in favor of this hypothesis. Avenues of research that can be developed to test this exciting hypothesis are also discussed.

Neurogenesis in adult brain
The presence of neural progenitor cells that give rise to new neurons in the adult brains of a variety of species, including humans, has been firmly established (Figure 1; Duman et al., 2001; Gage, 2000 and Gould et al., 1999). Adult neurogenesis is restricted to the subventricular zone, which gives rise to granule cells in the olfactory bulb and in the subgranular zone, which generates new granule cells in the adult hippocampus. Immature neurons in subgranular zone of the hippocampus migrate into the granule cell layer, extend processes, and mature into granule cells that have physiologic characteristics that are similar to existing granule cells ( van Praag et al 2002). In rodent brain, it is estimated that approximately 250,000 new neurons, or approximately 6% of the granule cell layer, are formed each month ( Cameron and McKay 2001). The estimates of the number of new neurons are much smaller in primates than rodents (~10%; Gould et al., 1999 and Kornack and Rakic, 2001), but even this lower rate of neurogenesis over longer periods of time may be sufficient to have functional significance.


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Figure 1. Model of neurogenesis in adult hippocampus. The upper panel demonstrates immunohistochemical analysis of neurogenesis in adult rat hippocampus. In dividing cells a thymidine analog, bromodeoxy uridine (BrdU) is incorporated into newly synthesized DNA, and an antibody against BrdU is then used to visualize newborn cells. At a short time point after proliferation (2 hours after BrdU administration), BrdU-immunopositive cells (arrowheads) are often found in clusters and are localized to the subgranular zone (SGZ) between granule cell layer (GCL) and hilus. A diagram depicting the location of neural progenitor cells and maturing neurons is shown in the bottom panel. Approximately 80% of the newborn cells differentiate into neurons and the remaining cells differentiate into glia or have an undetermined phenotype. Cells destined to become neurons migrate into the granule cell layer, mature, and take on characteristics of adult granule cells. This includes extension of dendrites into the molecular layer (ML) and axons into the CA3 pyramidal cell layer via the mossy fiber pathway (mfp). Scale bar is upper panel represents 200 m.

Clinical evidence for atrophy of hippocampus in mood disorders
Indirect evidence suggesting that altered neurogenesis could occur in mood disorders is provided by brain imaging studies of hippocampus. These studies report that hippocampus volume is decreased in patients with depression (Bremner et al., 2000; Frodl et al., 2002; MacQueen et al., 2003; Mervaala et al., 2000; Saarelainen et al., 2003; Shah et al., 1998; Sheline et al., 1996; Sheline et al., 1999; Sheline et al., 2003; Steffens et al., 2000 and Vermetten et al., 2003). Other studies have reported no reduction in hippocampal volume, although specific measurements of hippocampus were not conducted or included the amygdala ( Axelson et al., 1993 and Vakali et al., 2000; for complete references, see Posener et al 2003). One study found no change in volume but reported that the shape of the hippocampus is different in depressed patients ( Posener et al 2003). The magnitude of the reduction in volume is reported to be directly related to the length of illness ( Sheline et al 2000). Moreover, antidepressant medication reduces or even reverses hippocampal atrophy in depressed or PTSD patients ( Sheline et al., 2003 and Vermetten et al., 2003). Imaging studies of other brain regions also report altered brain morphology, including reduced volume of prefrontal cortex ( Bremner et al., 2000 and Drevets et al., 1997). In addition, postmortem studies demonstrate that there is a reduction in the size of neurons and number of glia that could underlie the reduction in cortical volume ( Cotter et al., 2001; Ongur et al., 1998 and Rajkowska et al., 1999). It is unlikely that decreased neurogenesis contributes to the atrophy of these cortical brain regions because most studies to date have not observed neurogenesis in adult cerebral cortex ( Koketsu et al., 2003 and Kornack and Rakic, 2001), although this has been a controversial subject ( Gould et al., 1999 and Gould et al., 2001).

The imaging studies provide indirect evidence for alterations in cell number or morphology in the hippocampus in mood disorders and a major goal of current research is to identify these cellular changes. One possibility is that decreased neurogenesis contributes to hippocampal atrophy and thereby underlies the pathophysiology of depression and stress-related disorders; however, it is likely that other mechanisms such as death or atrophy of existing neuronal processes or loss of glia could also contribute to the reduced volume of hippocampus (McEwen, 1999 and Sapolsky, 2002). Detailed postmortem analysis of the hippocampus of depressed patients will be necessary to address this issue.

Hippocampus and depression
The hippocampus is a brain region most often associated with control of learning and memory; however, reduced volume of this brain region in depressed patients suggests that the hippocampus could also contribute to certain symptoms of depression. Cognitive dysfunction and altered control of the hypothalmic-pituitary-adrenal (HPA) axis could be explained in part by decreased function of the hippocampus. The hippocampus has also been implicated in anxiety as local infusions of anxiolytics or lesions of hippocampus produce anxiolytic responses in behavior in models of anxiety (Deacon et al., 2002; Degroot and Treit, 2002; File et al., 2000 and Menard and Treit, 2001). In addition, the hippocampus provides inputs to other brain regions, including the prefrontal cortex, cingulate cortex, and amygdala that contributes heavily to altered mood and emotion in depression ( Drevets, 2001 and Manji et al., 2001). Based on these considerations, it is plausible to hypothesize that altered neurogenesis in hippocampus contributes directly to some, but not all aspects of depression, and could indirectly influence other symptoms of mood disorders including PTSD.

Stress decreases adult neurogenesis
A key connection between neurogenesis and depression comes from studies of stress, which can precipitate or worsen depression (Brown et al., 2003 and Gold and Chrousos, 2002) and is often used as a model in preclinical studies ( Willner 1990). Stress produces a profound effect on neurogenesis, causing rapid and robust reductions in the proliferation of newborn neurons in adult brain ( Table 1). Decreased neurogenesis has been reported with different types of stress and in different experimental animals, including intruder stress in marmosets (Gould et al 1998), subordination/psychosocial stress in tree shrews ( Czeh et al., 2001; Gould et al., 1997 and van der Hart et al., 2002) and in rodents predator odor ( Tanapat et al 2001), social defeat ( Czeh et al 2002), chronic restraint ( Pham et al 2003), footshock stress ( Malberg and Duman 2003), and chronic mild stress ( Alonso et al 2004). Prenatal stress also decreases neurogenesis in the adult hippocampus and is associated with reduced learning in rat ( Lemaire et al 2000) and emotional behavior in rhesus monkeys ( Coe et al 2003). In addition, inescapable stress leads to a reduction in neurogenesis that correlates with behavioral despair several days after exposure to stress in the learned helplessness model of depression ( Malberg and Duman 2003). This correlation between decreased neurogenesis and behavioral despair at a time point well after exposure to stress indicates that the reduction in neurogenesis is not simply due to acute stress, and suggests that there is a relationship between reduced neurogenesis and the behavioral state of the animal.

Table 1. Influence of Stress or Antidepressant Treatment on Neurogenesis in Adult Hippocampus


ECS, electroconvulsive seizures; TMS, transcranial magnetic stimulation; DHEA, dehydroepiandrosterone; NK1-R, neurokinin1-receptor; CRF-R1, corticotrophin releasing hormone receptor 1; AVP1b, arginine vasopressin receptor 1b; Inescap, inescapable footshock stress; Chr Mild, chronic mild stress; Mat Sep, maternal separation stress.


The influence of the hypothalamic-pituitary-adrenal (HPA) axis on adult neurogenesis also provides a link with mood disorders. Activation of the HPA axis is one of the primary physiologic responses that prepares an animal physically and behaviorally to respond to stressful conditions. Approximately 50% of depressed patients exhibit dysfunctional regulation of this system, resulting in sustained elevation of cortisol, and lack of response to acute challenge with a synthetic glucocorticoid (i.e., nonresponders in the dexamethasone suppression test; Brown et al., 2003 and Gold and Chrousos, 2002). Administration of adrenal-glucocorticoids to experimental animals decreases neurogenesis in the adult brain, mimicking the effects of stress ( Cameron et al., 1998 and Gould et al., 1992). The implication of these findings is that activation of the HPA axis and sustained elevation of glucocorticoids could lead to chronic inhibition of adult neurogenesis in the hippocampus. Because the hippocampus also provides negative feedback regulation of the HPA axis, it has been suggested that atrophy in depressed patients could lead to a recurrent and damaging cycle of HPA overactivation and sustained hippocampal atrophy ( McEwen, 1999 and Sapolsky, 2001).

Antidepressant treatment increases adult neurogenesis
Another important link between neurogenesis and mood disorders comes from studies of antidepressant drugs. In contrast to the effects of stress, antidepressant treatment increases neurogenesis in adult hippocampus (Table 1) ( Czeh et al., 2001; Madsen et al., 2000; Malberg et al., 2000; Manev et al., 2001 and Santarelli et al., 2003). The induction of neurogenesis by antidepressants is dependent on chronic treatment, consistent with the time course for the therapeutic action of these medications. Upregulation of neurogenesis in the adult hippocampus occurs after chronic administration of different classes of antidepressants, including 5-HT and norepinephrine selective reuptake inhibitors, monoamine oxidase inhibitors, and electroconvulsive seizures. This suggests that induction of adult neurogenesis may represent a common final target of different classes of antidepressants. Other treatments reported to have antidepressant effects and to increase neurogenesis include estrogen ( Tanapat et al 1999), dehydroepiandrosterone (DHEA; Karishma and Herbert 2002), and exercise ( van Praag et al 1999). One study has found that transcranial magnetic stimulation did not increase adult neurogenesis, although this treatment partially reversed the effects of social defeat on adult neurogenesis ( Czeh et al 2002).

Antidepressant treatment influences at least two important aspects of adult neurogenesis, proliferation and survival of newborn neurons. Proliferation refers to the number of cells that are born in a given period of time and is typically analyzed within a short period (2 hours) after BrdU administration. This short time point is the approximate length of S phase of the cell cycle. The results of a study that directly analyzes cell proliferation at this early time indicates that antidepressants increase the rate of new cell birth (Malberg et al 2000).

After cell birth approximately half of the cells undergo a process of degeneration over the course of 3–4 weeks. Administration of antidepressants during this critical period increases the number of neurons that survive when determined at a 4-week time point (Nakagawa et al 2002a). Current studies are underway to determine whether antidepressants also increase the rate of neuronal maturation, which can be determined by the rate of growth of the processes (i.e., number and length of dendrites) of newborn neurons. The putative antidepressant, rolipram, has been shown to increase neuronal maturation ( Fujioka et al 2004), as well as proliferation and survival ( Nakagawa et al., 2002a and Nakagawa et al., 2002b). All of these effects would be expected to block or reverse the effects of stress, and possibly depression, on hippocampal atrophy.

Antidepressant treatment blocks the effects of stress on adult neurogenesis
Antidepressant treatment also blocks the effects of stress, or normalizes levels of neurogenesis, in adult hippocampus. This interaction has been observed with several types of stress models and antidepressant treatments (Table 1). Chronic administration of an atypical antidepressant, tianeptine, blocks the effects of subordination stress on neurogenesis in the hippocampus of adult tree shrews ( Czeh et al 2001). A similar effect has been observed after chronic administration of a neurokinin-1 receptor antagonist, a drug that has been shown to have antidepressant efficacy in clinical trials, or a tricyclic antidepressant (clomipramine; van der Hart et al 2002). These two elegant studies also demonstrate that the volume of the hippocampus is decreased by subordination stress and that antidepressant treatment reverses this atrophy. Downregulation of neurogenesis by social defeat is partially reversed by transcranial magnetic stimulation ( Czeh et al 2002). A recent study found that chronic administration of either a corticotrophin releasing factor receptor-1 (CRF-R1) or arginine vasopressin receptor-1b (AVP1b) antagonist blocks the downregulation of neurogenesis caused by chronic mild stress ( Alonso et al 2004). The influence of maternal separation stress on neurogenesis in young rats (14–21 days) is reversed by chronic fluoxetine administration ( Lee et al 2001). We have found that the long-lasting decrease in neurogenesis that occurs after exposure to inescapable stress is reversed by antidepressant treatment, and this effect is accompanied by a reversal of the behavioral despair in the learned helplessness model of depression ( Malberg and Duman 2003). The results of these studies demonstrate that antidepressant treatment not only influences neurogenesis in normal, unchallenged animals but can also block the effects of stress on neurogenesis in the adult brain.

Neurogenesis is necessary for the action of antidepressants in behavioral models
The ability of antidepressant treatment to increase neurogenesis in adult brain and to block the effects of stress provides strong evidence that adult neurogenesis may play a role in the treatment of depression and could possibly contribute to the illness itself; however, this data is only correlative and does not provide direct evidence that neurogenesis is a necessary cellular response for the treatment of mood disorders. The function of newborn neurons in adult brain has been difficult to assess experimentally because it is difficult to specifically block cell birth without influencing mature neurons and glia in the brain as well as nonneuronal cells in other tissues.

The function of newborn cells in hippocampus has been addressed in a recent study, however, that provides direct evidence that adult neurogenesis is necessary for an antidepressant response in behavioral models (Santarelli et al 2003). In this study, cell proliferation was blocked by exposure to irradiation that is focused on the hippocampus of adult mice. Irradiation decreases basal and blocks antidepressant induction of neurogenesis in the hippocampus and results in a corresponding blockade of the response to antidepressant treatment in two behavioral paradigms, novelty suppressed feeding and chronic unpredictable stress. In the novelty suppressed feeding paradigm, irradiation blocks the effect of antidepressant treatment on the latency to approach food pellets in the middle of an open field (i.e., antidepressants decrease the latency). In the chronic unpredictable stress model, irradiation blocks the effects of antidepressant treatment on the maintenance of the coat condition and grooming, which deteriorate with long-term stress. Important controls were also conducted in this study: irradiation did not influence neurogenesis in the subventricular zone, demonstrating the specificity of the irradiation treatment, and irradiation did not influence the functional properties of hippocampal neurons, determined by analysis of long-term potentiation.

These data provide strong support for the hypothesis that neurogenesis is required for antidepressant responses; nonetheless, there are a few points to consider. First, it is possible that other effects of irradiation, not decreased neurogenesis, account for the blockade of the behavioral responses to antidepressants. Second, the results do not demonstrate that blockade of neurogenesis leads to a more depressive condition in these behavioral models. Although irradiation dramatically reduces neurogenesis by 90% relative to sham-treated controls, there was no significant difference in the baseline behavior in either novelty suppressed feeding or chronic unpredictable stress (Santarelli et al 2003). This is consistent with another report that decreased neurogenesis is not correlated with behavior in the learned helplessness model of depression ( Vollmayr et al 2003). These results indicate that neurogenesis may not be necessary for baseline responding in these behavioral models. Alternatively, mature neurons that are already present may be sufficient to support baseline behavioral responses. To test this hypothesis, the influence of more long-term blockade of neurogenesis on behavioral responding should be tested. Irradiation produces a long-lasting blockade of neurogenesis and animals could be examined at a longer time point to test this hypothesis. It is also possible that repeated or sustained downregulation of neurogenesis could contribute to recurrent depression or more severe cognitive deficits in older depressed patients, as discussed by Henn and colleagues ( Vollmayr et al 2003).

In addition to their findings on irradiation, Santarelli et al (2003) found that antidepressant regulation of neurogenesis is blocked in 5-HT1A null mutant mice and that there is a corresponding blockade of the behavioral response to a 5-HT selective reuptake inhibitor in the novelty suppressed feeding paradigm. This provides additional evidence that 5-HT1A receptors mediate responding to 5-HT selective antidepressants and provides additional correlative data for neurogenesis in the behavioral actions of antidepressants.

Consideration of time course and other behavioral models
The novelty suppressed feeding and chronic unpredictable stress models were chosen because the effect of antidepressants in these models is dependent on chronic treatment (i.e., 3 weeks), consistent with the time course for the therapeutic action of antidepressants. Although novelty suppressed feeding is usually considered a model of anxiety, the requirement for long-term antidepressant treatment validates the choice of this model. This is a critical point because it is likely that the function of newborn neurons may not be manifested for several weeks after birth, when the new neurons mature and make appropriate synaptic contacts.

The rapid response time to antidepressants is a limitation of other standard models of depression, such as forced swim and learned helplessness, that is, acute (1 day) or subchronic (~5 days) antidepressant treatments are effective in these paradigms. This raises a question regarding the validity of these paradigms to model the actions of long-term antidepressant treatment required for a therapeutic response, even though these models are widely used for drug testing and behavioral studies. Consequently, the rapid response makes it difficult to test the role of neurogenesis in the behavioral actions of antidepressants in the forced swim test and learned helplessness models. One possible explanation is that newborn neurons that have already been born before testing and are in the process of maturing are influenced by acute or subchronic antidepressant treatment (i.e., the survival or function, but not proliferation, of newborn neurons is regulated and could be involved in the antidepressant response). Yet another consideration is that the depression–antidepressant paradigms are better models of general stress effects seen in a number of illnesses, most notably posttraumatic stress disorder.

Testing the hypothesis: analysis of neurogenesis in the brains of depressed patients
The results of studies in experimental animals provides evidence that neurogenesis could contribute to the alterations in hippocampal volume identified in brain imaging studies of depressed patients; however, to test this hypothesis directly, analysis of neurogenesis and cell number in hippocampus of depressed patients, on or off antidepressant medication, are required. Analysis of postmortem tissue from depressed patients and matched control subjects can provide this type of information. Total cell counts can be obtained by stereologic counting of neurons and glia. In addition, immunohistochemical studies using antibodies against cell cycle markers or immature newborn neurons can be used as a measure of cell proliferation in postmortem tissue. This type of analysis will indicate whether neurogenesis is reduced in depressed patients and whether antidepressant treatment blocks this effect or even increases adult neurogenesis in humans. It is also possible that a ligand or marker of neurogenesis for imaging studies in living patients will eventually be developed, although the low rate of neurogenesis in human brains will require a sensitive probe with extremely low background.

Further testing of this hypothesis will be possible as new approaches are developed to manipulate neurogenesis in the adult human brain. A major focus of current research efforts in the field is to identify the neurotrophic and growth factors and signaling pathways that control adult neurogenesis (see reviews by Duman et al., 2001 and Gage, 2000). In this rapidly advancing field, it may be possible in the near future to deliver the appropriate combination of growth factors that support or promote neurogenesis in the human hippocampus. Alternatively, it may be possible to use pharmacologic approaches that target endogenous neurotransmitter signaling systems to stimulate expression of these growth factors in the hippocampus.

Conclusions
The studies cited and discussed in this review provide support for the hypothesis that regulation of neurogenesis in the adult hippocampus contributes to the treatment, and possibly the pathophysiology, of depression. Additional studies, in both experimental animals and in humans, are required to test this hypothesis. It is possible that neurogenesis in hippocampus underlies specific symptoms of depression but that alternate adaptive mechanisms in hippocampus as well as other limbic structures (i.e., amygdala and prefrontal cortex) are also required. This may include regulation of gene transcription and expression of neurotrophic factors that influence neuronal morphology in other ways (e.g., increased length and number of neuronal processes and/or synaptogenesis; Duman et al., 2000 and McEwen, 1999). In either case, it is likely that these studies of cell birth and neuronal morphology, as well as brain imaging studies, will continue to demonstrate that structural as well as neurochemical alterations play a significant role in mood disorders.

Acknowledgements
This work is supported by U.S. Public Health Service Grant Nos. MH45481 and 2 PO1 MH25642, a Veterans Administration National Center Grant for Posttraumatic Stress Disorder, and by the Connecticut Mental Health Center.

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NEUROGENESIS AND DEPRESSION: ETIOLOGY OR EPIPHENOMENON?
Fritz A. Henn, a and Barbara Vollmayra

Biological Psychiatry
Volume 56, Issue 3 , 1 August 2004, Pages 146-150

doi:10.1016/j.biopsych.2004.04.011
Copyright © 2004 Society of Biological Psychiatry. Published by Elsevier Inc.
Debates in neuroscience

a Central Institute of Mental Health, Mannheim, Germany

Received 31 October 2003; Revised 16 March 2004; accepted 25 April 2004. Available online 17 June 2004.


Abstract
The concept that decreased neurogenesis might be the cause of depression is supported by the effects of stress on neurogenesis and the demonstration that neurogenesis seems to be necessary for antidepressant action. Data from the animal models tested to date show that decreasing the rate of neurogenesis does not lead to depressive behavior. Furthermore, evidence shows that an effective treatment for depression, transcranial magnetic stimulation, does not alter rates of neurogenesis. On the basis of these findings, it is suggested that neurogenesis might play a subtle role in depression but that it is not the primary factor in the final common pathway leading to depression.

Author Keywords: Depression; neurogenesis; animal models; antidepressants; behavioral responses

Article Outline
• Regulation of neurogenesis
• Evidence supporting a role for neurogenesis in the etiology of depression
• Evidence against neurogenesis being an etiologic factor in depression
• Issues of timing
• Summary
• References


The finding that the fully developed mammalian brain has two areas containing progenitor cells that develop and differentiate into a variety of cell types, including fully functional neurons, has led to a re-examination of the possibility that neurogenesis might be a mechanism of the central nervous system to adapt to environmental influences. One suggested hypothesis, which seems to be consistent with many lines of evidence, is that a decrease in the formation of new neurons might be a final common pathway in the etiology of depression (Duman et al., 2000 and Jacobs et al., 2000). To evaluate this hypothesis, it is necessary to look at the factors that influence the rate of neurogenesis, attempt to determine the role of new neurons, and to look at the timing of their integration into neural networks.

The idea that the brain adapts or exhibits plasticity goes back to Hebb (1949), who thought that this could be accomplished by strengthening or weakening existing synapses. A clear example of this is long-term potentiation. Subsequently, changes in structure were postulated, and eventually it was shown that synaptic remodeling could be brought about by aging or experience ( Greenough et al 1978). Additionally, Altman and Das (1965) showed that new neurons are produced in the dentate gyrus of the hippocampus; this observation was subsequently confirmed with the use of better labeling methods. These cells have increasingly been implicated in central nervous system plasticity. Neurogenesis seems to occur in only two areas of the mammalian brain: the subventricular zone (SVZ), which leads to new neurons in the olfactory bulb, and the subgranular zone (SGZ), which leads to new neurons in the dentate gyrus of the hippocampus. Interestingly, stress seems to be a major regulator of the rate of new cell formation in the SGZ but does not affect the SVZ. Thus, the hippocampus seems to be the focus for hypotheses related to stress and its effects.

Regulation of neurogenesis
Factors that seem to influence the birth and survival of new cells include a variety of stressors, from tube restraint (Vollmayr et al 2003) to predator odor ( Tanapat et al 2001), probably mediated through the hypothalamic–pituitary–adrenal (HPA) axis. It has been shown that corticosterone decreases new cell formation in the hippocampus ( Cameron and Gould, 1994 and Cameron and McKay, 1999). Long-term changes in neurogenesis can also be induced by prenatal stress ( Coe et al., 2003 and Lemaire et al., 2000). Several factors also seem to increase new cell proliferation or survival, including exposure to an enriched environment ( Kempermann et al 1997), running on a running wheel ( van Praag et al 1999), or increased estrogen levels ( Tanapat et al 1999).

The most provocative and important function that has been postulated to involve newly formed neurons in the adult brain is learning. This was first proposed by Barnea and Nottebohm (1994) for song birds. In mammals, Gould and her collaborators ( Gould et al., 1999; Shors et al., 2001 and Shors et al., 2002) have provided evidence that trace conditioning leads to a greater survival rate of new neurons. The learning tasks that seem to depend on new neurons in mammalian species are limited. In a recent report, Shors et al (2002) were able to show that neither performance in the Morris water maze nor fear conditioning required newly formed neurons. These studies also indicated that it was not the increased birth of new neurons from progenitor cells but rather the continued survival of cells that were born approximately 5 days before the learning trials that was important for learning. The evidence for a specific role for neurogenesis in learning is limited to aspects of associative learning with temporal dimensions that are hippocampal dependent. Recent work by Deisseroth et al (unpublished data) suggests that newly born cells tend to reduce the expression of genes that promote glial cell formation when they detect excitation; that is, neuronal turnover seems to be regulated in an activity-dependent manner. This could explain why it is the survival of already-born cells that is critical to learning. These cells sense the activity and then are activated to integrate themselves into the neuronal network in the area. Such an interpretation emphasizes that it is not the birth of more cells but rather the activation and survival of already-born cells into neuronal networks that is important for learning. Thus, neurogenesis might clearly influence specific aspects of learning that play a role in a variety of behavioral changes, including depression.

To begin to understand the roles newly formed neurons and glia might have in the hippocampus, it is necessary to have an estimate of how quantitatively important neurogenesis is. Cameron and McKay (1999) have shown that approximately 9000 new cells are produced daily; this in a structure (the dentate gyrus) that contains between 1 and 2 million cells, suggests that the structure could completely turn over in 4–8 months. Because it seems that not all cells are turned over this rapidly in the hippocampus, it might be that new cells are specifically used in the acquisition of specific types of memories and that these are turned over relatively quickly, with the memories subsequently going to cortical sites and new cells used for the short-term acquisition of the next memory. This fits with the suggestion of McClelland et al (1995), that the initial encoding of new information takes place in the hippocampus to protect the cortex from "catastrophic interference," which occurs when new connections are continually added to a network. The mechanism described above would protect the hippocampus from a similar fate through turnover of the network elements. This is consistent with a computational model proposed by the Stanford group (Singla et al, unpublished data) and provides an explanation as to why the hippocampus is so important in short-term memory formation but seems to play no role in long-term memory retention. This model suggests that new neurons are necessary to form new memories with a limited half-life in the hippocampus and that turnover is necessary to allow the continual formation of new networks encoding new memories. Such a model for understanding the role of neurogenesis in the hippocampus would suggest a plausible role for this process in the etiology of depression. Lower levels of neuron formation as a result of stress could lead to less adaptive behavior and the acquisition of a helpless attitude and depressive affect. This is consistent with Beck's cognitive formulation of depression and offers a reasonable hypothesis for a final common neurobiological pathway.

Evidence supporting a role for neurogenesis in the etiology of depression
Evidence from clinical studies concerning neurogenesis is indirect and related to the effects of depression on the volume of the hippocampus. Many studies suggest that depression results in a decrease in hippocampal volume; however, these are by no means consistent (see Davidson et al 2002). Hippocampal changes are also seen, again with some inconsistency, in bipolar disorder and posttraumatic stress disorder. In all these cases, it has been suggested that this might well be related to HPA dysfunction and increased glucocorticoid concentrations in the hippocampus leading to neuronal degeneration (see Gold et al., 1988 and Sapolsky, 2000). Recent evidence suggests that these changes might be reversible ( Frodl et al 2002). Proponents of the neurogenesis hypothesis of depression have argued that these volume changes might be due to changes in the rate of production of new cells ( Jacobs 2002). Although these data might be suggestive, they are far from conclusive. This has led to a series of indirect animal studies aimed at assessing the effect of stress and antidepressant treatment on neurogenesis.

As reported above, several stressors have clearly been shown to decrease the rate of cell proliferation and neurogenesis. Although consistent with a role for neurogenesis in depression, this line of research imparts no specificity for depression, in that stress plays a role in a variety of psychiatric illnesses, such as posttraumatic stress disorder and bipolar disorder, which also show volume reduction in the hippocampus. This suggests that all stress-related illnesses, at least when they become chronic and show decreased hippocampal volume, might have as a component of their pathophysiology decreases in the rate of neurogenesis. In an effort to specifically test this, a variety of groups have looked at the role of antidepressants on neurogenesis.

Almost all currently clinically active antidepressants act through either the serotonin (5HT) and/or norepinephrine (NE) systems. These compounds are able to alter synaptic levels of the catecholamines relatively rapidly; however, antidepressants are known to act with a lag time of from 10 days to 3 weeks, and this lag period has been one of the central reasons that depression research has pushed beyond the monoamine receptors and transporters. An event that underscored the importance of examining the effects of alterations in the signal transduction cascade (and downstream effects) was the publication by Duman et al (1997) of a molecular and cellular theory of depression. This has helped focus depression research on the possible structural and functional alterations secondary to changes in monoamine activity and has led to an attempt to define a common final structural pathway that would have an appropriate lag period. A major requirement for such a pathway to be a candidate for the final common pathway involved in depression is that all effective clinical treatments for depression should induce similar changes in this pathway. The corollary of this is that changes opposite to those brought about by antidepressant treatment should result in depression.

The idea that changes in the rate of neurogenesis could be the final common pathway leading to depression was proposed by Jacobs et al (2000) and Duman et al (2000) and amplified by Kempermann, 2002; D'Sa and Duman, 2002 and Jacobs, 2002, and Kempermann and Kronenberg (2003). The evidence cited above plus the clear role of the 5HT system in controlling rates of neurogenesis was cited as the basis for the hypothesis. Tests of this hypothesis involved looking at the action of antidepressants on the rates of cell proliferation and neurogenesis. Malberg et al (2000) were able to show that chronic antidepressant administration increased neurogenesis in the hippocampus and that a common antipsychotic did not produce this effect. Czeh et al (2001), working with the tree shrew, were able to show that antidepressant treatment was protective when the animals were stressed and that hippocampal volume reductions were avoided and neurogenesis was stimulated by tianeptine. The most effective treatment in dealing with severe depression remains electroconvulsive therapy (ECT). Madsen et al (2000) showed that both a single ECT treatment and chronic ECT increased neurogenesis in the adult rat hippocampus. Thus, it seems that a consistent finding in animals is that antidepressant therapies seem to increase the rate of neurogenesis. There were two problems in fully accepting these data. The first involved the question of correlation or cause and posed the question: is neurogenesis necessary for antidepressant activity? The second is more subtle and involves the question of the effects of drugs on wild-type animals as opposed to animals having the pathologic condition.

The first question, whether neurogenesis is really necessary for the action of antidepressants, was addressed in part by Santarelli et al (2003). In their study, these investigators used two methods to interrupt cell proliferation. In the first case they used x-ray treatment of the hippocampus to abolish neurogenesis and showed that this disrupted the behavioral effects of two antidepressants, fluoxetine and imipramine. They used an anxiety test to assess depression, which is somewhat questionable because this test is used to screen for antianxiety agents and is very responsive to benzodiazepines, which are ineffective in treating depression. The test they chose was novelty suppressed feeding, in which an animal is placed in an open field with a brightly illuminated center; in the center is food, and the animal must overcome fear of brightly lit spaces to reach the food. The latency to begin feeding is a measure of anxiety, which in this study was taken as a measure of depression. Both imipramine and fluoxetine reduced the latency to feeding and increased the rate of neurogenesis after 28 days of treatment but not after 5 days of treatment. The authors then carefully irradiated the hippocampus of the animals and were able to show that they had reduced the rate of cell proliferation by more than 80%, as assessed by bromodeoxyuridine (BrdU) labeling on day 27. Irradiated mice did not show a significant response to the antidepressants fluoxetine or imipramine. This suggests that the drugs worked through increasing neurogenesis. The second approach was specific to the 5HT system, in that 5HT1A-knockout mice were used. It was shown that these mice were insensitive to the effects of fluoxetine on behavior or neurogenesis; however, effects on both neurogenesis and behavior were seen when antidepressants that act through NE as well as 5HT were used. It was also noted that the knockout mice had a greater latency to feed than wild-type mice but had exactly the same rate of cell proliferation. This suggests that changes in neurogenesis might not be necessary for changes in this behavior. If latency to feed can really be viewed as depressive, then the knockout mice are more depressive but have the same rate of neurogenesis. In looking at the radiation data, the same sort of paradox is seen: the irradiated animals had only a very low level of cell proliferation but showed exactly the same latency to feed as wild-type animals. Thus, decreased neurogenesis apparently does not lead to altered behavior in this model.

In a subsequent study, Malberg and Duman (2003) used a much more realistic animal model of depression to assess the role of antidepressants on neurogenesis. We believe that the use of an appropriate model is critical in these tests. The question of differences in pharmacologic effects on wild-type as opposed to pathologic tissue is almost never considered; however, in the case of depression, we have evidence that it could be critical. We use a very carefully developed version of the learned helplessness test, which shows excellent face validity to test this. Using learned helpless animals, we have shown that the NE receptor is upregulated in helplessness and downregulated by all classes of antidepressants, including selective serotonin reuptake inhibitors (Henn et al, unpublished data). Because the prevailing evidence concerning receptor downregulation was obtained on wild-type animals, the role of this receptor has fallen from consideration. Selective serotonin reuptake inhibitors clearly do not downregulate normal receptors, only those that seem to be pathologically upregulated. Although we certainly do not believe that the NE receptor is the central etiologic target in depression, these studies illustrate the possibility that wild-type tissue will react differently from pathologic tissue. This needs to be kept in mind in studies of drug action and tested in a variety of appropriate models.

Thus, the use of an inescapable stress model to test the effects of antidepressants on neurogenesis is welcome and addresses the question of whether an antidepressant acts similarly on a pathologic model. What Malberg and Duman (2003) did was to use inescapable shock to form a group of helpless animals and compare these animals with control animals that received no inescapable shock. After 9 days the control animals were split into two groups; half were analyzed for cell proliferation and half were given a shuttle box avoidance test. The group of helpless animals was also given a shuttle box avoidance test, and cell proliferation was determined after that test. The results show that the animals exposed to inescapable shock had a much longer latency to respond in the avoidance test. Interestingly, both the control and experimental animals exposed to inescapable shock had an approximately 40% reduction in cell proliferation after the avoidance task. In a second experiment, another group of helpless animals was formed; half were treated for 7 days with fluoxetine, and half were given saline. Fluoxetine reversed the increased latency in the shuttle box avoidance task. Inescapable shock had no effects on cell proliferation when measured 9 days later or on corticosterone production at 9 days. These results support the idea that fluoxetine can reverse the behavioral effects of inescapable shock and that there is a statistically significant increase in cell proliferation at day 9 due to fluoxetine treatment.

Evidence against neurogenesis being an etiologic factor in depression
In an attempt to demonstrate that decreases in neurogenesis might lead to depressive-like behavior, we further examined the learned helplessness model (Vollmayr et al 2003). We trained and tested a cohort of animals and formed two extreme groups, those showing helpless behavior and those showing no helplessness. We looked at the effect of helplessness training on cell proliferation and found a decrease in labeled cells beginning on day 3 after testing. This was not evident 24 hours after training, a point when helpless behavior was firmly established, but by 3 days both the helpless and nonhelpless animals had a significant decrease in cells labeled with BrdU. Although the helpless animals had slightly fewer cells, there was no statistical difference between the helpless and nonhelpless animals at day 3, or for that matter at any time point measured. This suggested to us that although the stress of helplessness training had an effect on the survival of new cells, this effect was identical in those animals showing behavioral changes and those showing no behavioral changes. That is, a decrease in new cells did not lead to helpless behavior. We examined this in another way by using restraint stress to decrease the rate of cell proliferation by approximately 40%; these animals were then subjected to helplessness training. The idea behind this experiment was that if a decrease in neurogenesis predisposes to depression, we would see a higher proportion of animals develop helplessness after exposure to restraint stress. To our surprise, this was not the case: there was no change in the proportion of animals that developed helplessness. One problem with these experiments was that we only measured BrdU labeling and could not be sure that this reflected changes in new neurons. In a replication, we analyzed specifically for neurons, astrocytes, and oligodendrocytes and obtained similar results. Our conclusion was that there is no evidence that a decrease in neurogenesis leads to depressive-like behavior in animals. This is consistent with the results of Santarelli et al (2003) and with the data of Malberg and Duman (2003). In their experiment, Malberg and Duman showed that aversion testing alone reduces labeling, and these animals showed no behavioral deficit. It is well known that after one exposure to aversion training, subsequent testing will lead to an even shorter latency of response, thus the decrease in cell proliferation does not result in a behavioral defect; in fact, improved performance is often seen.

Even if a decrease in neurogenesis does not lead to depressive-like behavior, perhaps increasing neurogenesis is still the mechanism by which antidepressants act. If this is the case, then all treatments that show clinical effectiveness should increase neurogenesis. Recent data suggest that this might not be the case. Czeh et al (2002) reported that transcranial magnetic stimulation was able to reverse the effects on the HPA axis produced by stress but did not stimulate cell proliferation in rats. Similar results were obtained by Scalia et al (unpublished data) in rhesus monkeys. They compared six weeks of ECT and transcranial magnetic stimulation in terms of BrdU incorporation and mossy fiber sprouting. They were able to show that, as expected, ECT increased both mossy fiber sprouting and cell proliferation, whereas magnetic stimulation showed no increased labeling with BrdU compared with sham treatment and only a moderate increase in mossy fiber sprouting in the hippocampus. The question remains, is transcranial magnetic stimulation an effective treatment for depression? A recent, carefully controlled trial with treatment-resistant patients suggests clearly that it is ( Fitzgerald et al 2003). In this study, severely ill, treatment-resistant patients received a 4-week trial of either low- or high-frequency stimulation, and both groups showed a good response compared with a matched control group. It was clear that at least 4 weeks of treatment were necessary for a response. Thus, the study by Scalia et al, which involved 6 weeks of treatment, was an ideal model of an effective antidepressant treatment. These studies suggest that it is possible to dissociate the effect of antidepressant treatment from changes in cell proliferation. Effective antidepressant treatments apparently do not require changes in cell proliferation ( Table 1).

Table 1. Comparison of Effects Seen in Depression and Seen by Decreasing Neurogenesis


HPA, hypothalamic–pituitary–adrenal axis; SSRIs, selective serotonin reuptake inhibitors; ECT, electroconvulsive therapy; TMS, transcranial magnetic stimulation.


Issues of timing
If the evidence produced by Deisseroth et al (unpublished data) can be reproduced and amplified, it would suggest that it is not the fact of cell division but rather the direction cell differentiation takes after cell division within a short time window, during which the cell's fate is not yet determined, that might be crucial in learning. The direction the cell takes seems to be a function of the activity it senses in its immediate environment. From the work of Dayer et al (2003), it seems that cells begin to die at approximately day 4 after cell division and that by 1 month more than half of the new cells have died. Those that differentiate into granule cells and survive 1 month live at least for half a year. Thus, it might be that only those cells that sense specific activity are able to differentiate, integrate into circuits, and survive. This suggests that it is not changes in the rate of cell division but rather changes in which cells survive that will mark a learning event. The experiments on trace conditioning (see Shors et al 2002) involved labeling cells 5 days before the conditioning experiment. Thus, cells at the critical developmental juncture would have been labeled. In totally ruling out an etiologic role of neurogenesis in helplessness, and by analogy depression, it would be necessary to look at the fate of cells 4–6 days old when helplessness training takes place. Such experiments are now under way and should help us determine whether there is a role for neurogenesis in affective disorders.

Another timing issue that is critical is the rate of onset of depression. In regularly treating severely depressed patients, we are impressed by how some patients can specify the hour when their depression began. It is textbook knowledge that depression has an acute onset, but the realization that it occurs so rapidly in many cases must make us consider whether such an onset is consistent with structural changes. This observation suggests a two-phase hypothesis of depression, in which acute neurochemical changes precipitate a depressive episode and slower structural changes might occur that allow the condition to persist and increase the vulnerability to subsequent episodes. We would suggest that changes in the rate of neurogenesis are totally inconsistent with the rapid onset often seen in major depression.

Summary
We have reviewed the evidence that changes in neurogenesis can lead to depressive behavior. In all the studies in which there are data on this point, including those studies that claim to support a role for neurogenesis in depression, we have found no evidence that decreased cell proliferation leads to depressive-like behavior. On the contrary, it seems clear that decreasing the rate of cell proliferation does not alter behavior in any test of anxiety or depression used to date. In looking at the mechanism of action of antidepressant treatments, it is clear that many but not all can increase cell proliferation. Thus, it does not seem that increasing neurogenesis is necessary for effective antidepressant action, although it might contribute to antidepressant activity in some cases. These findings suggest to us that at present neurogenesis must be considered more of an epiphenomenon than an etiologic variable in depression. The possibility that some learning event associated with stress might involve neurogenesis and might play a role in depression has not been totally ruled out but seems unlikely at present. Gould et al 1998

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