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Running head: NEUROGENESIS MEDIATING ANTIDEPRESSANT ACTION 1

Neurogenesis: a factor mediating the therapeutic effects of antidepressant treatments

Dima Obari

American University of Beirut

NEUROGENESIS MEDIATING ANTIDEPRESSANT ACTION 2

Abstract

Different therapeutic modalities are available for treating major depressive disorder, and

most have been shown to significantly alleviate depressive symptoms. However, their

mechanism of action remains poorly understood. In the current review, we will present

neurogenesis as a possible underlying mechanism of action, common to several treatment

modalities. For this matter, we will first present the neurogenic hypothesis of depression

along with several lines of evidence supporting it. Next we will consider several forms of

depression treatment separately, including antidepressant drugs, electroconvulsive

therapy, repeated transcranial magnetic stimulation, deep brain stimulation, vagus nerve

stimulation and exercise therapy. We will see how each of these affect the levels of

neuroegenesis, along with several of its regulatory molecular mechanisms.


Major depressive disorder (MDD) is a psychological illness affecting more than

350 million people worldwide (World Health Organization, 2012), and expected to

become the second leading cause of disability after cardiovascular disease, by year 2020

(Murray & Lopez, 1996). MDD is also characterized by high rates of disability and

morbidity, and is the most common illness among those who commit suicide

(Cavanaugh, Carson &Sharpe, 2003). Several treatment modalities exist for treating

depression, however their mechanism of action remains poorly understood, and about one

third of subjects with MDD who undergo treatment do not attain full remission, and 15%

stay significantly depressed (Gebhart et al., 2013).

Recently, several findings have pointed towards the increase in adult hippocampal

neurogenesis seen subsequent to antidepressant treatment as a potential mechanism

underlying the alleviation of depressive symptoms. Indeed, PubMed citations

comprehending the search items “neurogenesis” and “depression” have augmented 14-

fold in just three years (Eisch & Petrik, 2012).

In the current review our aim is to find molecular mechanisms that could link the

therapeutic effects of various antidepressant treatments to an increase in neurogenesis.

For this matter, we will start by summarizing current knowledge of neurogenesis, and the

rationale behind the neurogenic hypothesis of depression. Next, we will consider the

efficacy of several treatment modalities in treating depression, and their effect on

neurogenesis and molecular mechanisms thought to regulate it. Understanding these

mechanisms could shed some light on the processes by which antidepressants work, and,


ultimately, lead to the development of more rapid and efficient treatments for depression,

along with many other psychological disorders.

Neurogenesis in the adult brain

In the adult brain, “the nerve paths are something fixed, ended, immutable.

Everything may die, nothing may be regenerated” (Ramon y Cajal, 1913-14), or so was

the dogma that dominated most neurobiology research in the previous century. However,

it later became increasingly evident that even in adulthood, the brain was, in fact, capable

of generating new neurons, and by the early 1900s, neurogenesis was a widely accepted

phenomenon (Colucci-D’Amato, Bonavita & di Porzio, 2006).

Adult neurogenesis describes the process by which new neurons are generated in

the adult brain; it is believed to be primarily confined to two areas, the subgranular zone

(SGZ) in the dentate gyrus of the hippocampus, and the subventricular zone near the

lateral ventricles. Although it was recently found to occur in the neocortex under certain

conditions, it has not been determined whether the newborn cells in this areas become

functional (Dayer et al., 2005). For our purposes, we will focus on hippocampal

neurogenesis in the SGZ. Neurogenesis in that area is achieved through the differentiation

and maturation of progenitor cells located below the granule cell layer (GCL), giving rise

to an approximation of 9000 neurons per day. These will then migrate into the GCL, and

become physiologically and morphologically identical to mature neurons (van Praag &

Christie, 2002).

Neurogenic hypothesis of depression


However the causal mechanisms underlying depression remain poorly understood

to date. One suggested explanation is the adult hippocampal neurogenesis hypothesis of

MDD, which points to the decreased rate of adult-generated neurons in the hippocampus

found in patients suffering from major depression, as causal factor underlying the

expression of the disorder (Ernst et al., 2006).This hypothesis finds support in several

lines of evidence.

The hippocampus is smaller in depressed populations

First, several anomalies in limbic-related structures have been associated with

major depressive disorder, the most consistent of which concerning the hippocampus.

Indeed, numerous magnetic resonance imaging (MRI) studies have shown the

hippocampus to be reduced in size in subjects with major depressive disorder. In a meta-

analysis of 12 MRI studies, the left and right hippocampi were found to be reduced by

8% and 10%, respectively (Sheline et al.,1999). Additionally, there was a significant

correlation between the reduction of the right hippocampus volume, and the number and

duration of depressive episodes (Videbech & Ravnkilde, 2004). Furthermore, no sign of

accelerated neural degeneration in the hippocampus of patients with MDD was found to

date (Ernst et al., 2006). This suggests a causal relationship between depression and

hippocampal atrophy. Postmortem studies were also conducted using brain tissue from

depressed subjects and these revealed more peculiarities such as a decrease in the number

of neurons and glial cells, and an increase in their density by 30-35% in the dentate gyrus

of the hippocampus. Moreover, when other brain structures were analyzed for

comparison (frontal lobe, temporal love, caudate, amygdala), they showed no significant


volume reduction, relative to controls who were not depressed (Bremner et al., 2000),

thus the volume reduction is specific to the hippocampus. These findings are relevant as

the hippocampus is a major site for neurogenesis, and thus a decreased rate of

neurogenesis in this region may be partially responsible for the loss in volume.

Antidepressants increase neurogenesis

Second is the finding that neurogenesis levels, while decreased by stress and

depression, are normalized by effective antidepressant treatments (Boldrini et al., 2009).

Indeed, stress is an important risk factor for depression, as it is capable of

triggering depressive episodes or worsening them. Stress was shown to exert a potent

inhibitory effect on neurogenesis. Indeed, using the resident-intruder paradigm, Tanapat

and colleagues (1998) rat pups exposed to the odor of an adult male rat, a psychosocial

stressor. They found that a single exposure led to elevated levels of corticosterone and

diminished levels of newborn cells in hippocampus. This indicates that a higher

activation of the HPA axis could be contributing to a decrease in cell proliferation in the

dentate gyrus of depressed populations. Additionally, several studies reported

neurogenesis to be necessary for the therapeutic effect to occur. Indeed, in an animal

model of depression, Santarelli and colleagues (2003) demonstrated that ablation of

neurogenesis through irradiation of the hippocampus eliminated the antidepressant effects

of fluoxetine. This effect was replicated in a subsequent study by Perera and colleagues

(2011).

Time lapse of therapeutic effects is the same than that that for neuronal maturation


Third, the onset of therapeutic effects for several treatment modalities, notably

antidepressant drugs (Wong & Licinio, 2001) and electroconvulsive therapy (Segman et

al., 1995), is delayed by a period of 4 weeks. This suggests gradual changes in the

structure and neurochemistry of the brain. In fact, this delay closely matches the time

needed for newly generated neurons to become functionally integrated in the

hippocampus (Ernst et al., 2006).

Antidepressant drugs

Chronic antidepressant treatment increases cell proliferation and survival

Several classes of antidepressant drugs have been shown to alleviate behavioral

symptoms of depression, but to also reverse the deleterious effects on the hippocampus

volume depressed populations. Indeed, studies attesting for the serotonin reuptake

inhibitor fluoxetine’s antidepressant effects on behavior also found that it reversed the

volume loss seen in the temporal lobes of depressed populations, along with inducing a

significant increase in cell proliferation in the adult hippocampus by 60%. However, this

effect was only present after chronic administration of the drug for 11 or 28 days, as

opposed to acute administrations of 5 days which did not have any significant effects

(Santarelli et al., 2003). This suggests that a certain period is needed for antidepressants

to work; because this period corresponds to the time needed for neuronal maturation, it

may be that neurogenesis underlies antidepressant action.

Using adult male rats, Malberg and colleagues (2000) investigated the effects of

two antidepressant types in addition to fluoxetine: reboxetine (a norepinephrine slective

reuptake inhibitor) and tranylcypromine (a monoamine oxidase inhibitor). They also used


two additional groups for comparison; one was administered an antipsychotic

(haloperidol) and the other a placebo. All antidepressants resulted in a significant increase

in BrdU-labeled cells in the dentate gyrus compared to the control group, indicating an

increase in the rate of neurogenesis. Thus these antidepressants may share the

upregulation of neurogenesis as a common mechanism of action. In accordance with

Santarelli et al.’s findings, this effect was only present when the drugs were administered

for either 14 or 28 days, but not 1 or 5 days. Also, there was no difference in the rate of

neurogenesis between the rats that were treated for 14 days, and those treated for 28 days,

indicating the possibility of a plateau effect after 2 weeks of drug administration.

In contrast, administration of haloperidol had no effect on neurogenesis. Eisch and

colleagues (2002) also showed that administration of morphine has an opposite effect on

neurogenesis, as it decreases it. Thus the increase in neurogenesis is specific to certain

classes of drugs. Additionally, neurogenesis upregulation is also specific to certain brain

regions. Indeed, when the subventricular zone (SVZ) near the lateral ventricles was

examined subsequent to fluoxetine administration, no increase in BrdU-positive cells was

found compared to controls.

The increase in neurogenesis may be due to alterations in cell proliferation,

differentiation or survival of the granule cells. As the BrdU-positive cells increased just 2

hours after injection of BrdU, we already know that antidepressants increase cell

proliferation. As for the cell differentiation stage, Malberg and colleagues (2000) also

used neuronal (NeuN) and glial markers (GFAP), and found that 75% of the newborn

cells differentiated into neurons in both rats treated with antidepressants, and rats in the

control group. Thus administration of antidepressants has no significant effect on the


differentiation of granule cells in the dentate gyrus. However, antidepressants do increase

survival of the new granule cells, when administered for longer periods. Indeed, in a

separate experiment, the rats were injected with BrdU before the treatment with

fluoxetine, to see whether the labeled cells would survive longer. They found that in

comparison with the 14 days treatment, the 28 days treatment resulted in a 25% increase

in BrdU-positive cells (Malberg et al., 2004). Thus although treatment with fluoxetine for

periods longer than 14 days does not affect cell proliferation, it does seem to increase

survival. Similar findings were obtained for rolipram, a phosphodiesterase-IV inhibitor,

which, in addition to increasing cell proliferation, increased survival after 3 weeks of

administration (Nakagawa et al., 2002). Thus chronic treatment (14 days) with chemical

antidepressants increases the number of granule cells in the dentate gyrus by increasing

their proliferation, and, when administered for longer periods of time (28 days), their

survival. This effect however seems to be restricted to the hippocampus.

Antidepressant neuorgenic action is mediated by upregulation of neurotrophic factors

In Santarelli and colleagues’ experiment, fluoxetine also significantly increased

the expression of brain-derived neurotrophic factor (BDNF) in the dentate gyrus of the

hippocampus. This protein that has been strongly implicated in the regulation of

neurogenesis by numerous studies; one such study noted a superior level of BDNF in

postmortem examinations of the dentate gyrus of depressed patients who received

treatment, in comparison to those who did not and to controls who were not depressed

(Chen et al., 2001). In another study, using genetically modified mice with either lower

levels of BDNF, or altered functioning of trkb, the receptor for BDNF, had lower levels


of neurogenesis, which were, however, normalized after chronic treatment with

fluoxetine. It was concluded that BDNF may be required for survival and proliferation of

the newly generated cells, and that antidepressant drugs may exert their effect on

neurogenesis indirectly by increasing the levels of BDNF (Sairanen et al., 2005). This

hypothesis is supported by the finding that in vitro addition of BDNF to granule cells

cultured from the dentate gyrus, and direct injection of BDNF into the rat hippocampus

both increased the newly generated cells’ survival &differentiation.

Some studies also reported an increase in other growth factors. For instance, the

vascular endothelial growth factor (VEGF) is a cellular mitogen which was initially

recognized for its role in angiogenesis, but also mediates cytogenesis and therapeutic

effects of antidepressants on behavior. It is increased subsequent to administration of

chemical antidepressants, and its injection directly into the lateral ventricles is sufficient

to upregulate neurogenesis in the dentate gyrus. In contrast, blocking VEGF signaling

blocks both serotonin and norepinephrine-induced neurogenesis. Thus VEGF signaling

may be required for chemical antidepressants to increase neurogenesis. In addition,

VEGF was found to stimulate endothelial cells, therby upregulating the release of other

regulatory proteins such as BDNF. Similarly, fibroblast growth factor-2 (FGF2), is

thought to augment the number of both neurons and glial cells, and in postmortem

studies, it was found to be decreased in the hippocampus of depressed populations (Evans

et al., 2004). Insulin-like growth factor (IGF1) was also shown to contribute to the

neurogenic action of antidepressants (Warner-Schmidt & Dunman, 2007), . Therefore,

different classes of chemical antidepressants increase proliferation and survival of the

granule cells in the dentate gyrus of the hippocampus by altering the signaling of several


regulatory proteins (BDNF, VGEF, FGF2, IGF1).

Serotonin and Norepinephrine induce neurogenesis through different mechanisms

Moreover, knock-out (KO) mice in which the HT1a serotonin receptor was

selectively suppressed did not show any behavioral effect or increase in neurogenesis

subsequent to fluoxetine administration; additionally, administration of 8-OH-DPAT, a

5-HT1a-selective agonist, resulted in behavioral and neurogenic effects similar to those

associated with fluoxetine. Together these two findings point to the HT1a serotonin

receptor as site of action for fluoxetine. HT1a has indeed been previously reported to

have an important role in mood and anxiety disorders, and thus it warrants further

investigation with regards to the pharmacotherapies of depression.

However this does not hold true for other antidepressant drugs such as

imipramine, a tricyclic antidepressant (TCA) which acts upon the neurotransmitter

norepinephrine (NE). Indeed, the antidepressant effects of imipramine were not affected

by the suppression of this serotonin receptor 5-HT1a. This suggests that norepinephrine

induces neurogenesis through a mechanism which is qualitatively different from the one

used by serotonin. That said, both SSRIs and TCAs were found to induce similar

increases of neurogenesis, and in a postmortem analysis, the dentate gyrus of patients

treated with either medication was significantly larger than that in controls who did not

suffer from depression.

Neurogenesis is required for antidepressant action


Finally, a major finding in the last decade was the fact that neurogenesis not only

accompanies therapeutic effects on behavior, but may also be required for them to occur.

Santarelli and colleagues (2003) used a low dose of x-irradiation on adult rats to trigger

apoptosis in neural progenitor cells, thereby eliminating neurogenesis. Indeed, the

irradiation resulted in an 85% decrease in BrdU-labeled cells in the subgranular zone of

the hippocampus for a period of 8 weeks, without affecting other areas such as the

subventricular zone. They then treated the rats with either fluoxetine or imipramine (a

tricyclic antidepressant), and tested them on an animal model of depression, the Novelty-

suppressed feeding (NSF). Neither antidepressants altered the rats’ response on this test;

thus we conclude that ablation of neurogenesis through irradiation of the hippocampus

blocked the antidepressants’ therapeutic effects on behavior. This finding was replicated

by Perera and colleagues (2011) on nonhuman primates (NHPs), some of which had their

temporal lobes irradiated. Next, all NHPs underwent repeated social separation stress,

while being administered with fluoxetine. The antidepressant prevented depressive-like

behavioral symptoms such as anhedonia and lower hierarchy scores from appearing, only

in the NHPs whose temporal lobes were not irradiated. This demonstrates, once again,

that neurogenesis is required for antidepressant action, as neurogenesis ablation blocks

the antidepressants’ therapeutic effects.

ECT/ECS

ECS upregulates cell proliferation in the hippocampus

Certain instances of severe depression do not show improvement subsequent to

drug therapy; however, patients with treatment-resistant therapy can consider a variety of


somatic therapies. One such treatment is electroconvulsive therapy (ECT); it is the most

powerful treatment for depression, and produces the most rapid and the largest increase in

neurogenesis, compared to other forms of treatment. However, its mechanism of action

remains largely unknown to date (Malberg et al., 2000).

In the first study linking ECS, the equivalent form of ECT in animals, to

neurogenesis, Madsen and colleagues (2000) found that the increase in neurogenesis was

dose-dependent; that is, while administration of ECS in the form of a single seizure was

sufficient to increase neurogenesis, along with synaptic density in the CA1 filed of the

hippocampus and the volume of the dentate gyrus overall, this effect was even more

apparent when a series of seizures was applied. Also, the increased neurogenesis rate was

still apparent 3 months after the treatment, as the number of BrdU-positive cells did not

decline. Moreover, the new cells were fully functional, and there was no sign of increased

apoptosis (programmed cell death) during this period. Similar conclusions were reached

by Hellsten et. al (2002), who found that a 75% reduction in neurogenesis in rats induced

by chronic administration of corticosterone, was counteracted by just one

electronconvulsive shock.

ECS produces an increase in regulatory proteins

Moreover, ECS was found to increase the amount of several regulatory proteins,

notably B-cell chronic lymphocytic lymphoma 2 (BCL2), which protect newborn cells

and promote their differentiation. The BCL2 were produced by local mature cells which

were thereby enhancing the new cells’ survival (Kuhn et al., 2005).

Similarly, research has implicated the growth factor in the antidepressant effect of ECS.


Warner-Schmidt and colleagues (2008) irradiated the hippocampus of rats, thereby

decreasing neurogenesis; this procedure also reduced hippocampal levels of VEGF

mRNA and protein. VGEF levels were almost completely reversed with administration of

ECS, without affecting the subventricular zone. Effectively, the increase in cell

proliferation was detectable for months post treatment. ECS was found to affect different

types of cells in the granule cell layer (GCL), as it increased the numbers of neurons,

endothelial cells, astrocytes and ogliodendrocytes. Specifically, while irradiation

decreased the number of new neuron in the GCL by 98%, ECS restored this number to

40% of the number found in control rats. This is in line with previous findings by Madsen

and colleagues (2000). ECS also increase cell survival in the granule cell layer (GCL) in

both irradiated rats sham-treated controls. Thus ECS successfully restored some, but not

all of the neural progenitor cells’ proliferative capacity in the GCL; this increase in

VEGF could constitute one of the mechanisms by which ECS stimulates neurogenesis.

ECS was also found to cause a far greater rise in the levels of BDNF, compared to the

chemical antidepressant tranylcypromine. This is consistent with the fact that ECS also

has more powerful therapeutic effects than antidepressant drugs. Thus the sharp increase

in BDNF mRNA and protein subsequent to ECS may explain this treatment modality’s

advantage in alleviating symptoms in treatment-resistant patients (Altara et al., 2003).

ECT alleviates depressive symptoms in humans

As for the ECT’s behavioral effects in humans, patients with MDD recovered 72

days after the treatment was completed (Weeks et al, 1980), with a remission rate of 87%,

and significant decrease in expressed suicidal intent (Petrides et. al, 2001).


However, it is important to note that ECT, unlike other treatment modalities, induces

generalized seizures which affect all of the central nervous system. Furthermore, ECT,

again, in contrast to other antidepressant treatments, is also used in the treatment of

mania, psychosis and Parkinson’s disease. These two factors strongly suggest that ECT

acts by mechanisms other than the regionally selective neurogenesis, and which remain to

be explained (Ongur & Heckers, 2004).

Repetitive Transcranial Magnetic Stimulation

Repetitive transcranial magnetic simulation (rTMS) is a noninvasive therapeutic

tool which has been demonstrated to attenuate the activity of the hypothalamic-pituitary-

adrenal (HPA) axis in patients undergoing high levels of stress. Chronic psychosocial

stress, a risk factor for depression, is known to suppress neurogenesis in the dentate

gyrus. However, although clinical trials have previously found rTMS to augment the

levels of BDNF and neurogenesis in the dentate gyrus (Muller et al., 2000), a subsequent

study by Czeh and colleagues (2001) showed rTMS to attenuate the increase in stress-

induces rise in glucocorticoids, however, with very mild effects on neurogenesis.

Additionally, the rate of survival of BRdU-positive cells was even decreased by the

treatment, a finding inconsistent with previous literature on rTMS treatment.

This emphasizes the little understanding we currently have of the mechanisms underlying

the effects of rTMS, and suggests that additional cellular mechanisms should be

investigated for this treatment modality.

Deep Brain Stimulation


Deep brain stimulation (DBS) is a powerful neuromodulation therapy used for a

variety of neurological, psychiatric, and movement disorders, and successful in the

treatment of patients with TRD with large rates of remission (Anderson et al., 2012). It

consists in the application of a continuous electrical current to specific neuroanatomical

structures, and has the advantage of being a non-ablative, highly adjustable procedure

with both long-term and acute therapeutic effects, in contrast to other invasive somatic

treatments (e.g. anterior capsulotomy, limbic leucotomy). This treatment is of significant

interest to us, as its applicability to specific neural circuits can be used to elucidate

relationships between these circuits (Schlaepfer et al., 2011).

In a recent clinical study, Encinas and colleagues (2011) investigated the effect of

stimulation of the anterior thalamic nuclei (ATN) on neurognesis in the dentate gyrus,

and found that the number of BrdU-positive cells was 45% higher in mice subjected to

the high frequency-stimulation, compared to mice who were not stimulated. Specifically,

their study showed that DBS increases the amount of symmetric divisions of transient

amplifying neural progenitors, which translates into a larger number of neurons in the

GCL of the dentate gyrus. These findings draw attention to structures of the limbic

system which could, upon stimulation, cause an increased rate of neurogenesis in the

dentate gyrus, and so far have been used to treat patients with epilepsy by stimulation of

the ANS. Further studies on the limbic system’s relation to neurogenesis could help

improve treatment of depression by deep brain stimulation.

With regards to the trophic factors discussed in other treatment modalities, these

remain to be investigated as little research on the use of DBS in TRD patietns is available

at the current time.


Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) was investigated by Rush and colleagues (2005)

as an alternative to current pharmacotherapies for treating both severe depression and

treatment-resistant depression (TRD). This investigation was motivated by the need for a

more efficient treatment, with lower rates of relapse and faster onset of effects.

They tested the treatment in clinical trials on TRD patients; these showed variable

response rates for more than two months but nevertheless continued to improve in the

following year.

In another study on rats, researchers pointed to possible molecular and neurochemical

events underlying the effectiveness of VNS; they found, similarly to research on

antidepressant drugs, an increased rate in adult hippocampal neurogenesis, as well as

higher levels of BDNF and FGF levels in the hippocampus by 26.3% and 22,3%

respectively, and of higher levels norepinephrine by 70% in the prefrontal cortex.

However these effects were observed following a briefer period of time and thus VNS

offers an advantage in comparison to other treatment modalities (Follesa et al., 2007).

Recently, Gebhardt and colleagues (2013) conducted the first study that tests VNS effects

on behavior in an animal model of depression, the bilateral olfactory bulbectomy (OBX).

3 weeks after treatment with VNS, OBX rats improved significantly on the disturbed one-

way active avoidance task, which attests to the treatment’s beneficial effects.

Furthermore, these rats also showed increased BrdU labeling, and, 8 weeks later, they

demonstrated levels of neurogenesis similar to control rats. This effect was dependent on

the intensity of the stimulation, and this relationship could be described by an inverted U-


shape. They also found a region-dependent increase in growth factors, notably BDNF,

and basic epidermal growth factor (BEGF). The latter molecule stimulates neurogenesis

as it binds to its receptor.

However in this particular study, control rats didn't show an increased neurogenesis after

VNS, which is in contrast to other studies. This may be due a different length of the

stimulation period.

Exercise Therapy

In addition to the traditional antidepressant treatments, exercise therapy is also

found to significantly attenuate symptoms of depression in humans, mice and rats.

Each year, brain tissue in older adults shrinks by 1-2%. However, Erikson and

colleagues (2011) showed that exercise was a neuroprotective factor which, under certain

conditions, could increase the volume of the hippocampus by 2% in just about a year,

thereby reversing age-related volume loss by 1 to 2 years. This effect was confined to the

caudal hippocampus and did not affect the thalamus and the caudate nucleus, indicating

that exercise acts on regionally-dependent molecular pathways rather than the whole

brain.

This study also showed the temporal lobe to be significantly larger in more active

adults, which could be explained by an increase in neurogenesis, dendritic branching and

complexity, as well as vascularization in the dentate gyrus.

Due to the difficulties associated with analyzing cellular mechanisms underlying

therapeutic effects in premortem human brain tissue, many studies were also conducted

on animals using approved animal models of depression. In their study, Huang and


colleagues (2012) used three different paradigms to demonstrate the effects of exercise on

behavior. In all three models, both rats that exercised daily and rats that were chronically

treated with fluoxetine displayed less depressive-like patterns of behaviors compared to

other conditions (enriched environment) or drugs (Clozapine, Haloperidol). Similarly, the

biological effects induced by exercise in rats closely matched those induced by

fluoxetine. Indeed, both exercise and fluoxetine acted by increasing neurogenesis and

spinal density in the CA1 field of the hippocampus, a finding that was not shared by the

rats in the other groups.

Exercise was also found to increase levels of ß-endorphins, VEGF, BDNF as well

as serotonin, and ultimately, to an increase in neurogenesis. This increase in cell

proliferation may have been mediated by the increase in BDNF (Eisch, 2002). However,

another study by Bjornebekk, Mather and Brene (2005) suggested that exercise increases

cell proliferation independently of the levels of BDNF, as the latter, in contrast to cell

proliferation, did not correlate with exercise’s antidepressant effect.


Conclusion

In conclusion, different treatment modalities exist for treating major depressive

disorder, and most represent efficient ways of alleviating and even suppressing symptoms

associated with depression. Although little is known about their underlying mechanism of

action, they all seem to influence the rate of neurogenesis in the adult hippocampus, and

the delayed onset of their therapeutic effects is a close match to the time needed for

neuronal maturation (4 weeks). Additionally, reduction of symptoms is also associated

with a reversal of brain anomalies seen in patients with MDD, specifically in the

hippocampus which plays a critical role in many cognitive functions affected by

depression.

Thus neurogenesis, which occurs primarily in this region, may constitute a

mediator for antidepressant effects. Indeed, this is line with previous findings implicating

neurogenesis in hippocampal functions such as transient place recognition and trace fear

conditioning, which are associated with depression. Thus suppression of neurogenesis in

the hippocampus could be responsible for the inaccurate representations of the external

world &ultimately the cognitive distortions seen in patients with MDD (Perera et al,

2011).

Additionally, the role of neurogenesis as a mediator finds additional support in the

fact that, as shown in this review, many of the molecular mechanisms associated with

neurogenesis (BDNF, VEGF, FGF2) are also affected by antidepressant treatments.

That said, this does not eliminate the possibility that the increased neurogenesis is no

more than an epiphenomenon, unrelated to antidepressant effects. Indeed, it could be that

the cellular mechanisms discussed regulate many factors in addition to neurogenesis, and


as such, these factors would be the ones mediating the therapeutic effects of

antidepressants, and not neurogenesis. Another limitation concerns the fact that although

major depressive disorder is a human condition, it has been mostly studied in rodents, due

to the difficulty of analyzing cellular mechanisms in the human brain premortem. Finally,

other mechanisms have emerged as alternatives to neurogenesis in explaining

antidepressant effects, such as the neuronal remodeling suggested by Bessa and

colleagues (2009); however, further investigation of these will be required in attempt to

determine their validity.


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