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No one knows the precise mecha-nism that triggers clinical depres-

sion, but people have speculated aboutit for centuries. From the time of the an-cient Greeks until well into the Renais-sance, philosophers and scientists be-lieved that bodily fluids called humorswere responsible for our moods andpersonality. Specifically, they thoughtthat one called black bile controlled de-pression. By the 17th century, dualism—the separation of mind and body—wasthe dominant dogma. Consequently, itwas believed that depression, a diseaseof the “mind,” arose from somethinggone awry in your physical or social en-vironment. But eventually, by the early20th century, even Sigmund Freud—thefather of psychoanalysis—had come tobelieve that brain dysfunction would ul-timately explain mental illness. Today,neuroscientists know that, in many cas-es, psychopathology arises because ofdysfunctions in particular brain struc-tures or particular brain chemicals. Asdescribed in this article, recent evidencesuggests that clinical depression might

arise from the brain failing to grow newneurons in a specific area.

Neurobiologists long believed thatadult brains did not make new neurons,but now we know otherwise. In the early1960s, Joseph Altman at MIT reportedthat new neurons were being producedin the brains of adult rats. Those findingswere somewhat forgotten for the next 30years. Recently, this work has been re-vived and advanced. Elizabeth Gould ofPrinceton University, one of this article’sauthors (Gage) and others have reportedthe birth of new neurons—neurogene-sis—in the hippocampus of adult rats,monkeys and humans. This region of thebrain lies beneath the cortex in the tem-poral lobe (see Figure 2)—basically thepart of your brain behind your ear—andit appears to play a crucial role in form-ing new memories. Preventing depres-sion might depend in part on propercontrol of this ongoing neurogenesis.

Currently available antipsychoticmedications usually fall short of the de-sired therapeutic efficacy and invariablyproduce unwanted side effects, such asdry mouth or sleep disturbances. Thesetreatments typically act by globally al-tering the chemical communication be-tween neurons throughout the brain.More recently, cell and molecular biolo-gy have begun to exert a strong impacton our understanding and treatment ofmental illness. By targeting specific mol-ecular sites in neurons, these techniquescan provide precise, powerful and effec-tive means of influencing brain function.One of these approaches—controllingneurogenesis in the adult brain—mighthave a significant impact on the treat-ment of mental illness.

Let us first examine the current state ofknowledge regarding adult brain neuro-genesis. Then we shall focus specifically

on the role of neurogenesis in chronicclinical depression. As we shall see, con-trolling neurogenesis might also be usedto treat or prevent a variety of otherforms of neuro- and psychopathology.

New Brain CellsAll of the cells in the body are derivedfrom stem cells—primitive cells that areformed soon after fertilization and thatcan divide indefinitely. They can sim-ply copy themselves, or they can makea variety of differentiated cells, includ-ing blood, muscle and neuron. Theycan also make progenitor cells, whichcan divide a limited number of timesand give rise to cell types such as neu-rons and glia.

Most neurons in the mammalianbrain and spinal cord are generated dur-ing the pre- and perinatal periods of de-velopment. Nevertheless, neurons con-tinue to be born throughout life in theolfactory bulb, which processes scents,and in the dentate gyrus of the hippocam-pus. (Very recent evidence indicates thatsome additional brain areas might alsoproduce new brain cells.) These newneurons are derived from progenitorcells that reside in the brain’s subventric-ular zone, which lines open spaces deepin the brain called ventricles, or in a layerof the hippocampus called the subgranu-lar zone. The existing neurons in theadult brain cannot divide. Some progen-itor cells, however, remain, and they cango through cell division to produce twodaughter neurons, or one glial cell orneuron and one progenitor cell capableof further division. Apparently, in mostparts of the adult brain, something in-hibits progenitor cells from dividing toproduce new neurons. No one knowsexactly why neurogenesis continues insome areas and not others. The olfactory

340 American Scientist, Volume 88

Depression and the Birth and Death

of Brain Cells

The turnover of neurons in the hippocampus might help to explain the onset of and recovery from clinical depression

Barry L. Jacobs, Henriette van Praag and Fred H. Gage

© 2000 Sigma Xi, The Scientific Research Society. Reproductionwith permission only. Contact perms@amsci.org.

Barry L. Jacobs is a professor and the director of theProgram in Neuroscience at Princeton University.He received his doctorate from the University ofCalifornia, Los Angeles and was a postdoctoral fel-low in the psychiatry department at the StanfordUniversity Medical School. Henriette van Praag isa research associate at the Salk Institute. She re-ceived her doctorate from Tel-Aviv University andwas a postdoctoral fellow in the Department ofNeuroscience and Cell Biology at the Robert WoodJohnson Medical School. Fred H. Gage is a profes-sor in the laboratory of genetics at the Salk Insti-tute. He received his doctorate at the Johns HopkinsUniversity and spent four years in the departmentof histology at the University of Lund. Address forJacobs: Program in Neuroscience, Green Hall,Princeton University, Princeton, NJ 08544. Inter-net for Jacobs: barryj@princeton.edu

bulb and dentate gyrus might requireconstant renewal in order to process andstore new information, whereas other re-gions might need a stable population ofneurons in order to maintain ongoingfunction. Understanding the mecha-nisms involved in this process could pro-vide the opportunity for disinhibitingprogenitor cells throughout the centralnervous system to allow them to pro-duce new neurons. This, of course, couldhave a major impact on the repair ofbrain regions where cells have been lostfor any of a variety of reasons: disease,trauma, aging and so on.

Investigators follow neurogenesis inthe laboratory by treating animals withtritiated-thymidine or bromodeoxyuri-dine. These compounds get incorporat-

ed into the DNA of cells preparing to di-vide. Once these cells begin the processof cell division, their daughter cells canbe identified by examination of post-mortem brain tissue. The compound in-corporated into cells can be visualizedunder the microscope with autoradi-ographic or immunologic techniques fortritiated-thymidine or bromodeoxyuri-dine, respectively. Investigators countthe labeled cells to quantify the numberof proliferating and newly born cells.

These techniques show that progeni-tor cells in the subgranular zone produceprogeny that migrate outward to thegranule-cell layer and differentiate intoneurons. In this way, these new granulecells join the population of existing neu-rons. These newly born cells mature in

the granule-cell layer and send their den-drites outward, whereas their cellprocesses go inward and follow paths toother structures within the hippocam-pus, such as the CA3 cell fields. Conse-quently, these new neurons get integrat-ed in the basic circuitry of the brain.

The dentate gyrus produces 1,000–3,000 new neurons per day in rats andmice. Although this might seem like asmall number, it could represent a sub-stantial proportion of the total popula-tion over an animal’s lifespan. Further-more, these recently born neuronsmight serve a more important role inprocessing new information than thosein the extant population of granulecells. So far, such data have not beencollected for primates. Some investiga-

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Figure 1. Theories of the etiology of clinical depression have vacillated thoughout history between environmental and biological models. Theauthors propose a model in which environmental influences can produce biological changes—the suppression of production of new neuronsin a portion of the hippocampus, initiating depressive episodes. This model derives from the relatively recent discovery that adult humanbeings do continue to produce some new neurons throughout their lives and that the rate of production can be influenced by both environ-mental and biochemical factors. Wilhelm Lehmbruck, who sculpted this figure, “Seated Youth,” was himself a victim of depression and tookhis own life in 1919—a time when even Sigmund Freud was coming to believe that brain dysfunction would explain mental illness.

Cor

bis

tors believe that the magnitude of neu-rogenesis is lower in higher mammals,but that has not been proved.

Stress and GlucocorticoidsMany scientists believe that stress is themost significant causal agent—with thepossible exception of genetic predispo-sition—in the etiology of depression. Inaddition, nerve cells in the hippocam-pal formation are among the most sen-sitive to the deleterious effects of stress.Consequently, a stress-induced decreasein neurogenesis in the hippocampusmight be an important factor in precipi-

tating episodes of depression. On theother hand, increasing serotonergic neu-rotransmission is the most effectivetreatment for depression, and it alsoaugments hippocampal neurogenesis.So serotonin-induced increases in neu-rogenesis might promote recovery fromdepression. Considering all of this, wesuggest that the waning and waxing ofneurogenesis in the hippocampal for-mation might trigger the precipitationof and recovery from episodes of clini-cal depression.

Gould and her colleagues examinedthe relation between stress and hip-

pocampal neurogenesis in severalspecies. First, they reported that remov-ing a rat’s adrenal glands increased neu-rogenesis in the adult dentate gyrus.Moreover, they could reverse that effectwith the glucocorticoid hormone corti-costerone, which normally comes fromthe adrenals. The circulating level of glu-cocorticoids apparently suppressed thebirth of neurons in the dentate gyrus un-der normal conditions. In an extensionof these results, Gould’s group showedthat systemic administration of corticos-terone to normal animals suppresseddentate gyrus neurogenesis.

This group also examined the effectsof naturally stressful situations. For in-stance, they exposed a rat to the odor ofone of its natural predators—a fox—andthat suppressed cell proliferation in therat’s dentate gyrus. They also demon-strated reduced dentate-gyrus cell prolif-eration in adult tree shrews after thepsychosocial stress of exposing them tosame-sex individuals. Most recently,Gould’s group reported suppressed celldivision in a marmoset monkey’s dentategyrus after putting it in a cage with an-other marmoset that had already beenliving there. In combination, these studiesshow clearly that stress suppresses therate of dentate-gyrus cell proliferation inadults of a number of species. Further-more, it probably does so through in-creases in brain glucocorticoids.

Additional, but older, literature isalso relevant here. Over the past 15years, work by Robert Sapolsky of Stan-ford University, Bruce McEwen of Rock-efeller University and others has shown,in a number of species, that stress andglucocorticoids cause widespread mor-phological changes and even cell death

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Figure 3. Dentate gyrus—a region shaped like a backward C—lies in the lower, middle area of the hippocampus (left). Neurogenesis (right)in this region begins when a progenitor cell (green and red) proliferates to produce progeny, which migrate outward and differentiate intoneurons. These newly born cells send their dendrites outward, whereas their cell processes go inward and follow paths to other structureswithin the hippocampus, such as the CA3 cell fields. Consequently, these new neurons get integrated in the basic circuitry of the brain.

Figure 2. Hippocampus (blue) lies beneath the cerebral cortex in the temporal lobe, roughlybehind your ear. Although neurobiologists long identified this area as playing a crucial role informing new memories, it might also participate in various forms of neuro- and psychopathology.

in parts of the hippocampus, such as inthe CA3 subfields. This region of thehippocampus is the main target of theoutput of neurons in the dentate gyrus.Whether this hippocampal damage is atleast in part dependent on the suppres-sion of neurogenesis in the dentategyrus is not known.

Depression and the HippocampusSeveral pieces of evidence link clinicaldepression to changes in the hippocam-pus. Nevertheless, we do not suggestthat this is the only change in the brainassociated with depression, nor do wesuggest that alterations in the hip-pocampus underlie all of the phenome-nological aspects of depression.

Utilizing the brain imaging techniqueof MRI, Yvette Shelineand her colleaguesat Washington University in St. Louis re-ported smaller hippocampal volumes ina group of older women with recurrentmajor depression. Although the subjectswere in remission, they had smaller leftand right hippocampal volumes—butcomparable total cerebral volumes—incomparison with carefully selected con-trols. Sheline’s group also found a signif-icant negative correlation between totaldays of depression and the volume of theleft hippocampal gray matter. The inves-tigators speculate that this hippocampalloss might result from glucocorticoid-in-duced neurotoxicity associated with re-current episodes of depression. In a morerecent study, this same group confirmedtheir original report and also showed thatthe decrease in hippocampal volume cor-related with total lifetime duration of de-pression and not with age. Other studiesconfirm the relationship between depres-sion and hippocampal volume. For ex-ample, Premal Shah and his colleaguesat the Royal Edinburgh Hospital also re-ported smaller hippocampal volumes inchronically depressed patients but foundno decrease in hippocampal volume inrecovered patients.

Temporal-lobe epilepsy also points toa connection between hippocampaldamage and depression. First of all, tem-poral-lobe epilepsy involves a massiveloss of cells in various structures in andaround the hippocampus. Second, de-pression is the most common psychiatriccomplication in patients with epilepsy.Moreover, patients with temporal-lobeepilepsy experience depression morethan patients with other forms of epilep-sy or than patients with comparably de-bilitating diseases. If there is a causal re-lation between temporal-lobe epilepsy

and depression, some evidence indicatesthat it might be bidirectional. Becausethe neuropathology in temporal-lobeepilepsy encompasses most of the tem-poral lobe, however, no definitive con-clusion can be drawn regarding the siteof specific damage that might underliethe psychopathology.

Stimulation from SerotoninAs mentioned above, prescriptiondrugs that increase serotonergic neuro-transmission are currently the mostcommon and most effective treatmentfor depression. Furthermore, serotonin

stimulates cell division in a variety ofperipheral tissues and triggers neuro-genesis in the central nervous systemduring development. It also plays animportant role in neuronal and synap-tic plasticity. That evidence made sero-tonin worthy of further study.

Recently, one of us (Jacobs) and hiscolleagues used adult rats to study theeffect of d,l-fenfluramine, a drug that re-leases serotonin throughout the centralnervous system. In those studies, sys-temic administration of that drug in-creased cell division two- to threefold inthe dentate gyrus. Moreover, an antago-

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Figure 5. Stress reduces cell proliferation inthe dentate gyrus of primates. When Eliz-abeth Gould of Princeton University and hercolleagues placed a marmoset monkey in acage with another marmoset that had alreadybeen living there, the intruders (right) showedfewer bromodeoxyuridine-labeled cells percubic millimeter of dentate gyrus than didcontrols (left). Presumably, such a stressfulencounter increases brain glucocorticoids,which inhibit neurogenesis. (Adapted fromGould et al. 1998.)

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Figure 4. Photomicrograph from a mouse’s brain shows the dentate gyrus, which consists pri-marily of mature neurons (green). This mouse spent 40 days running on a wheel and thenwas treated with bromodeoxyuridine, which reveals newborn cells (red). Some of the new-born cells are neurons (orange, from the combination dyes). This image also shows someglial cells (blue). The exercise stimulates neurogenesis in the dentate gyrus, and a variety ofevidence indicates that such neurogenesis could relieve or fend off depression.(Photomicrograph courtesy of the authors.)

nist for a specific serotonin receptor—called 5-HT1A (serotonin is also knownby the name 5-hydroxytryptamine, or5-HT for short)—completely blockedthis effect of d,l-fenfluramine. (Otherserotonin receptors might also be in-volved in this process.) We later showedthat much of this increase in cell divi-sion ended up making more neurons.So these studies highlight serotonin’simpact on granule-cell neurogenesis inan adult rat’s dentate gyrus.

The clinical benefit of drugs that in-crease serotonergic neurotransmissionencouraged one of the authors (Jacobs)to test fluoxetine (Prozac), which in-creases brain levels of circulating sero-tonin by inhibiting it from being takenback into neurons that release it. Wegave adult rats a three-week, systemictreatment of fluoxetine and found anapproximately 70-percent increase inthe number of cells produced in thedentate gyrus. Ronald Duman’s groupat Yale University confirmed and ex-tended that result. They found thatfluoxetine, antidepressants acting pref-erentially on norepinephrine andchronic electroconvulsive shock all in-creased cell proliferation in a rat’s den-tate gyrus.

In combination, the above studiesdemonstrate that serotonin can dramat-ically augment cell proliferation andthat it does so, at least in part, by action

at the 5-HT1A receptor. Consistent withthis, the hippocampus—especially thedentate gyrus—has an extremely denseconcentration of these receptors.

If this receptor plays a role in depres-sion, it would be useful to test 5-HT1A-agonist drugs as therapeutic agents.Unfortunately, we lack a potent andspecific 5-HT1A-receptor agonist for hu-man use. Partial agonists for the 5-HT1Areceptor, however, can reduce anxietyand provide some antidepressant effect.To better understand this possiblemechanism, we must examine 5-HT1Afunction in depressed patients. SharonCheetham and her colleagues at Uni-versity College, London did report adecreased number of 5-HT1A bindingsites in the hippocampus of depressedsuicide victims, but they did not exam-ine specific 5-HT1A binding in the hip-pocampus. More recently, Stanley Wat-son and his colleagues at the Universityof Michigan reported a decrease in theexpression of 5-HT1A mRNA in the hip-pocampus in a group of depressed sui-cide victims. These findings provideadditional support for this receptor’simportance in controlling depression.

A final feature of this hypothesis isthat it provides a conceptually simpleexplanation for the therapeutic lag, inwhich antidepressant treatments—both drugs and electroconvulsive ther-apy—typically require 3–6 weeks to

become effective. We suggest that thisis because it takes time for newly borndentate-gyrus neurons to fully mature,extend their neurites and integratewith the existing brain circuitry.

344 American Scientist, Volume 88 © 2000 Sigma Xi, The Scientific Research Society. Reproductionwith permission only. Contact perms@amsci.org.

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Figure 7. One of the authors (Jacobs) treatedrats with d,l-fenfluramine, a drug that releas-es serotonin throughout the central nervoussystem. This drug (center) produced a two- tothreefold increase in the number of bromod-eoxyuridine-labeled cells in the dentate gyrusas compared to normal (left). In addition, aproprietary drug called WAY 100, 635 (right)—an antagonist for a specific serotonin recep-tor—blocked the effect of d,l-fenfluramine.These studies and others show that the levelof neurogenesis in the dentate gyrus dependson circulating levels of serotonin.

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Figure 6. Magnetic resonance images (left) canbe used to measure the volume of a person’shippocampus (the hook-shaped structure inthe middle). Yvette Sheline and her colleaguesat Washington University used this techniqueto compare left and right hippocampal vol-umes in pairs of matched subjects (above), inwhich one suffered from clinical depression(red) and the other was a control (blue).Despite having comparable total cerebral vol-umes, the depressed subjects had smaller leftand right hippocampal volumes in nearly allcases. As a result, the average hippocampalvolumes for control subjects (blue boxes onvertical error bars) exceeded those fordepressed subjects (red dots on vertical bars)on both the left and right sides of the brain.(Image courtesy of Yvette Sheline.)

Other PossibilitiesDespite proposing that alterations inhippocampal neurogenesis play a cru-cial role in the etiology and recoveryfrom depression, we do not exclude oth-er changes as being important. For ex-ample, besides suppressing neurogene-sis, increased glucocorticoids mightmediate additional direct neuronal ef-fects in the cerebral cortex, hippocam-pus and other subcortical areas, such asthe amygdala. Similarly, changes in sero-tonin neurotransmission might also ex-ert direct effects in the brain stem, sub-cortical sites and the cortex. All of thesechanges, acting in concert, give rise tothe complex syndrome of depression.

Although this article focuses on theaugmentation of dentate-gyrus neuro-genesis by serotonin, other means of in-creasing neurogenesis might also haveclinical relevance. For example, it is wellknown that exercise, especially running,has an antidepressant action, and we re-cently found that 4–10 days of runningon a wheel induces a significant increasein cell proliferation in a mouse’s dentategyrus. After several weeks of running,neurogenesis increased as well. Also,norepinephrine appears to increase celldivision in the dentate gyrus. These fac-tors might also play roles in depression.

There are also several related theories.Pierre Blier and Claude de Montigny ofMcGill University, for example, suggestthat antidepressant therapies act in thehippocampus by increasing neurotrans-mission at the serotonin 5-HT1A recep-tor and by decreasing it at the beta-adrenergic receptor, which can beactivated by norepinephrine. Watsonand his colleagues emphasize the im-portance of glucocorticoid-induceddown regulation of the 5-HT1A receptorsin the hippocampus of experimental an-imals. In examining these and relatedtheories of depression, we find that ourtheory does not supplant or contradictthem. Rather, it complements and ex-tends these previous ideas by pointingto a particular neural event, the rise andfall of dentate-gyrus neurogenesis.

Still, one might wonder how the hip-pocampus could affect depression. His-torically, neurobiologists thought of it aspart of the brain’s cognitive circuitry andnot involved in mediating mood oremotion. Nevertheless, recent evidenceindicates that structures considered to becentral to the brain’s emotional circuitry,such as the amygdala, are strongly in-terconnected with the hippocampus.This connection would provide the

anatomical substrate for linking cogni-tive and emotional information process-ing. Consistent with our hypothesis,clinically depressed patients have a vari-ety of memory deficits, which wouldalso point to hippocampal involvement.

In addition to treating clinical de-pression, advances in controlling neu-rogenesis might also be used to treatmany other diseases where brain cellshave died. In this context, two separatestrategies are being weighed. Some in-vestigators harvest stem cells from theadult brain, expand them in tissue cul-ture, induce the cells to make specificcell lines, say neurons, and then trans-plant them to a specific brain regionwhere they could replace or augmentendogenous cells. On the other hand,cells already in the brain might be acti-vated by pharmacological or environ-mental stimulation and induced to pro-liferate and migrate to a damaged ordiseased brain region, where theywould take up residence in areas to re-place or augment lost function. Al-though progress is being made on bothof these fronts, much additional workremains to make these repair strategiesroutine. In any case, we now know thatstructural correlates of neural plasticityextend beyond synaptic reorganizationand include the addition of new neu-rons to important circuits.

AcknowledgmentsThis work was supported by PrincetonUniversity and a grant from the NationalInstitute of Mental Health. The authorswould also like to thank Steve Forbes,Lynne Moore, Bobbi Miller and LindaKitabayashi for their excellent technical as-sistance. Special thanks to Mary Lynn Gagefor crucial reading of this manuscript. Theauthors are grateful for continued supportfrom the Hollfelder Foundation, Robert J.and Claire Pasarow Foundation and a grantand contract from the National Institutesof Health.

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Eriksson, P. S., E. Perfilieva, T. Bjork-Eriksson,A. M. Alborn, C. Nordberg, D. A. Petersonand F. H. Gage. 1998. Neurogenesis in theadult human hippocampus. Nature Medicine4:1313–1317.

Gould, E., A. Beylin, P. Tanapat, A. Reeves andT. J. Shors. 1999. Learning enhances adultneurogenesis in the hippocampal formation.Nature Neuroscience 2: 260–265.

Gould, E., A. J. Reeves, M. S. A. Graziano andC. G. Gross. 1999. Neurogenesis in the neo-cortex of adult primates. Science 286:548–552.

Jacobs, B. L. 1994. Serotonin, motor activity anddepression-related disorders. American Sci-entist 82: 456–463.

Jacobs, B. L., and E. C. Azmitia. 1992. Structureand function of the brain serotonin system.Physiological Reviews 72:165–229.

2000 July–August 345© 2000 Sigma Xi, The Scientific Research Society. Reproductionwith permission only. Contact perms@amsci.org.

Figure 8. Exercise also affects neurogenesis in the dentate gyrus. The authors saw morebromodeoxyuridine-labeled cells in the dentate gyrus of a running mouse after 12 days (upperright) in comparison to a control mouse (upper left). The increased level of cell survival couldalso be seen in running mice after six weeks (lower right) in comparison with controls (lowerleft). These results might explain some of the antidepressant action of exercise.

12 days 12 days

6 weeks6 weeks