Elsevier

Neuropharmacology

Volume 58, Issue 6, May 2010, Pages 884-893
Neuropharmacology

Invited review
Hippocampal neurogenesis as a target for the treatment of mental illness: A critical evaluation

https://doi.org/10.1016/j.neuropharm.2009.12.013Get rights and content

Abstract

Over one-quarter of adult Americans are diagnosed with a mental illness like Major Depressive Disorder (MDD), Post-Traumatic Stress Disorder (PTSD), schizophrenia, and Alzheimer's Disease. In addition to the exceptional personal burden these disorders exert on patients and their families, they also have enormous cost to society. Although existing pharmacological and psychosocial treatments alleviate symptoms in many patients, the comorbidity, severity, and intractable nature of mental disorders strongly underscore the need for novel strategies. As the hippocampus is a site of structural and functional pathology in most mental illnesses, a hippocampal-based treatment approach has been proposed to counteract the cognitive deficits and mood dysregulation that are hallmarks of psychiatric disorders. In particular, preclinical and clinical research suggests that hippocampal neurogenesis, the generation of new neurons in the adult dentate gyrus, may be harnessed to treat mental illness. There are obvious applications and allures of this approach; for example, perhaps stimulating hippocampal neurogenesis would reverse the overt and noncontroversial hippocampal atrophy and functional deficits observed in Alzheimer's Disease and schizophrenia, or the more controversial hippocampal deficits seen in MDD and PTSD. However, critical examination suggests that neurogenesis may only correlate with mental illness and treatment, suggesting targeting neurogenesis alone is not a sufficient treatment strategy. Here we review the classic and causative links between adult hippocampal neurogenesis and mental disorders, and provide a critical evaluation of how (and if) our basic knowledge of new neurons in the adult hippocampus might eventually help combat or even prevent mental illness.

Introduction

Each year over 25% of adult Americans carry the diagnosis of at least one mental disorder (Kessler et al., 2005a, Kessler et al., 2005b). By far, the greatest percentage of the adult US population – 18.7% – is diagnosed with an anxiety disorder like Post-Traumatic Stress Disorder (PTSD, 3.5%), but notable percentages of the population are also diagnosed with mood disorders (9.5%) like Major Depressive Disorder (MDD, 6.7%), or with Alzheimer's Disease (∼2%) and schizophrenia (1.1%) (Kessler et al., 2005a, Kessler et al., 2005b). Combined with psychosocial support, pharmacological interventions like anxiolytic, antidepressive, and antipsychotic drugs alleviate many symptoms associated anxiety disorders, MDD, and schizophrenia, respectively. However, the persistence and severity of symptoms of these individual disorders, the high proportion of individuals with comorbid psychiatric disorders, like addiction, or other severe health challenges, like obesity or cardiovascular disease, results in enormous personal and societal cost. Therefore, there is extraordinary interest in identifying and pursuing novel strategies for the treatment and even prevention of mental illness.

While mental disorders are exceptionally diverse and likely have discrete and complex neurobiological underpinnings, one particular brain region has long been studied for its potential involvement in mental illness in general: the hippocampus (Fig. 1) (Bloom, 1975, Bloom, 1984, Frith and Done, 1988, Holsboer, 1988, Kling et al., 1987, McEwen et al., 1992, Meaney et al., 1988). Primarily known for its role in learning and memory, the hippocampus also has an important role in general cognition, mood regulation, response to stress, and even in encoding predictions for future events (Bast, 2007, Eichenbaum and Fortin, 2009, Fuchs and Flugge, 1998, Price and Drevets, 2009, Squire, 2004). A large body of literature shows that, in general, mental illness is marked by diminished hippocampal structure and function. For example, MDD, PTSD, schizophrenia, Alzheimer's disease and even stress – a precipitating factor in many mental disorders – are marked by decreased hippocampal volume, learning and memory deficits, and mood dysregulation (e.g. Bremner, 1999, Campbell and Macqueen, 2004, Geuze et al., 2005, Goldman and Mitchell, 2004, Liberzon and Sripada, 2008, Lupien et al., 2007b, Pfefferbaum and Marsh, 1995, Sala et al., 2004, Sapolsky, 2000b, Savitz and Drevets, 2009, Villarreal and King, 2001). Intriguingly, successful improvement of the behavioral and cognitive symptoms of these disorders is often linked to attenuation or reversal of these changes in hippocampal structure and function. Such work has encouraged consideration of whether hippocampal atrophy is a useful target for the treatment of mental illness (Dhikav and Anand, 2007, Sala et al., 2004, Sapolsky, 2000a).

The hippocampus is one of most “responsive” brain structures in that it demonstrates rapid plasticity at the molecular, cellular, structural, and functional levels after specific stimuli. Thus, it has been challenging for scientists to narrow which aspect of hippocampal plasticity might be best targeted to counteract the symptoms of such diverse disorders. One particular aspect of hippocampal plasticity that has received significant attention is adult hippocampal neurogenesis, or the ability of the hippocampus to generate new neurons throughout life. First discovered by Joseph Altman more than forty-five years ago (Altman, 1963), it is now accepted that stem-like and progenitor cells residing in the aptly-named subgranular zone (SGZ; Fig. 1) give rise to dentate gyrus granule neurons that integrate into circuitry and contribute to discrete aspects of hippocampal functions (Balu and Lucki, 2009, Pathania et al., this issue). As reviewed in detail elsewhere (Abrous et al., 2005, Kempermann et al., 2008) and briefly here (Table 1), there is an enormous amount of correlative evidence linking hippocampal neurogenesis with mental disorders. More recent work has provided striking causative connections as well (e.g. Li et al., 2008b, Revest et al., 2009, Santarelli et al., 2003). The surge of primary and review papers on this topic urge revisiting the question, “Is manipulation of hippocampal neurogenesis a promising target for the treatment of mental disorders?”

A number of excellent reviews have recently tackled questions including “What is neurogenesis good for?” and “Is targeting hippocampal atrophy useful for mental illness?” (e.g. Aimone et al., 2006, Becker and Wojtowicz, 2007, Bruel-Jungerman et al., 2007, Drew and Hen, 2007, Eisch et al., 2008, Elder et al., 2006, Gould et al., 1999, Kempermann et al., 2008, Kempermann and Kronenberg, 2003, Ming and Song, 2005, Morgan, 2007, Perera et al., 2008, Sahay and Hen, 2007, Thomas and Peterson, 2008, Thompson et al., 2008, Vaidya et al., 2007). Therefore, the goal for this brief review is to critically evaluate hippocampal neurogenesis as a viable treatment aim and to provide an “update” to previous reviews that have been more narrowly focused on individual psychiatric disorders, such as depression (e.g. Drew and Hen, 2007, Feldmann et al., 2007 #10060) or schizophrenia/DISC1 (e.g. Dranovsky and Hen, 2007). While the preponderance of literature to date has provided insight into psychiatric illnesses through rodent models, there is surprisingly little known about normal and pathological neurogenesis in humans. Much recent work in human neurogenesis focuses on seizure activity and epilepsy, known to robustly increase neurogenesis in both rodents and humans. However, the lack of data on other human psychiatric illnesses has not been emphasized elsewhere. We critically evaluate the hopes in targeting adult hippocampal neurogenesis for treating mental disorders, then highlight major obstacles to overcome before translational applications of adult hippocampal neurogenesis can be realized. We particularly hope this review will engage those readers outside the fields of adult neurogenesis and mental illness research, because stimulating interdisciplinary research is likely critical to future integration of our basic knowledge of new cells in the adult brain with clinical need.

Section snippets

Adult hippocampal neurogenesis in a nutshell

The hippocampus is one of two well-accepted regions of the adult brain in which new neurons are added through mammalian life. While the human and rodent hippocampi have anatomical similarities (Fig. 1A–C), the process of neurogenesis has been best characterized within the rodent dentate gyrus and has been the subject of many extensive reviews. However, we would be remiss if we did not provide essential information regarding basic progression of neurogenic stages. The reader is strongly

Hippocampal dysfunction in mental illness: the case for targeting neurogenesis

Adult hippocampal neurogenesis has been suggested as a target for the amelioration or prevention of mental illness (Balu and Lucki, 2009, Kaneko and Sawamoto, 2009). Each of the psychiatric disorders discussed here – MDD, PTSD, Alzheimer's Disease, and schizophrenia – is linked to decreased hippocampal volume and function. As summarized in Table 1, an enormous amount of evidence connects animal models of mental illness with altered hippocampal neurogenesis. Here we provide a selective review of

Hippocampal dysfunction in mental illness: the case against targeting neurogenesis

While Table 1 and the review above support the breadth and depth of neurogenesis as target for the treatment of mental illness, there are problems with hippocampal neurogenesis as a clinically-viable treatment. First, none of these psychiatric disorders is marked by overt loss of dentate gyrus granule neurons as a primary pathology. While both Alzheimer's Disease and schizophrenia are incontrovertibly accompanied by hippocampal atrophy, decreased hippocampal volume may be correlative, and this

Harnessing hippocampal neurogenesis: obstacles to overcome

Many obstacles stand in the way of fully harnessing hippocampal neurogenesis for the treatment of mental illness and other brain disorders. One of the most glaring knowledge gaps is the lack of understanding about differences between rodent and human neurogenesis. More specifically, almost nothing is known about human neurogenesis except that it persists into adulthood (Eriksson et al., 1998, Manganas et al., 2007). More information is needed on the extent of neurogenesis, the function of

Present and future approaches to the promote hippocampal neurogenesis

Even if adult hippocampal neurogenesis is not an immediate target for the amelioration of the symptoms and trajectory of mental disorders, it does makes sense both to study it and harness it where feasible and practical, and to in general promote hippocampal health. Indeed, driving hippocampal neurogenesis is tightly correlated with other things presumed to be good for the hippocampus, such as angiogenesis, blood flow, and growth factor production and cytokine reduction (e.g. Pereira et al.,

Conclusion

Because the primary pathology in MDD, PTSD, schizophrenia and Alzheimer's Disease is not an early and overt loss of dentate gyrus granule cells, it is obvious that dentate gyrus granule cell replacement strategies via stimulation of adult hippocampal neurogenesis alone will not be sufficient for treatment of these disorders. However, the general consensus among researchers and physicians is that activities that promote overall health and wellness, such as physical and mental exercises, are

Acknowledgements

The authors thank Jessica Ables for excellent help with figures and schematics. We gratefully acknowledge funding from NIH and NIDA to AJE: DA023555; DA023701; DA016765 and to NAD from NINDS F31-NS064632 and NIDA T32-DA7290. We also gratefully acknowledge support from NASA.

References (156)

  • L.A. Galea

    Gonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents

    Brain Res. Rev.

    (2008)
  • E. Gould et al.

    Neurogenesis in adulthood: a possible role in learning

    Trends Cogn. Sci.

    (1999)
  • K. Jin et al.

    Alzheimer's disease drugs promote neurogenesis

    Brain Res.

    (2006)
  • N. Kaneko et al.

    Adult neurogenesis and its alteration under pathological conditions

    Neurosci. Res.

    (2009)
  • G. Kempermann et al.

    Depressed new neurons – adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression

    Biol. Psychiatry

    (2003)
  • J.Y. Kim et al.

    DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212

    Neuron

    (2009)
  • M.A. Kling et al.

    Neuroendocrine effects of limbic activation by electrical, spontaneous, and pharmacological modes: relevance to the pathophysiology of affective dysregulation in psychiatric disorders

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1987)
  • S. Kotani et al.

    Donepezil, an acetylcholinesterase inhibitor, enhances adult hippocampal neurogenesis

    Chem. Biol. Interact

    (2008)
  • V. Krishnan et al.

    Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions

    Cell

    (2007)
  • E.D. Lephart et al.

    Neurobehavioral effects of dietary soy phytoestrogens

    Neurotoxicol. Teratol.

    (2002)
  • Y. Li et al.

    TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment

    Neuron

    (2008)
  • S.J. Lupien et al.

    Hippocampal volume is as variable in young as in older adults: implications for the notion of hippocampal atrophy in humans

    Neuroimage

    (2007)
  • S.J. Lupien et al.

    The effects of stress and stress hormones on human cognition: implications for the field of brain and cognition

    Brain Cogn.

    (2007)
  • K. Maeda et al.

    Clozapine prevents a decrease in neurogenesis in mice repeatedly treated with phencyclidine

    J. Pharmacol. Sci.

    (2007)
  • M. Maekawa et al.

    NMDA receptor antagonist memantine promotes cell proliferation and production of mature granule neurons in the adult hippocampus

    Neurosci. Res.

    (2009)
  • S.S. Magavi et al.

    Induction of neuronal type-specific neurogenesis in the cerebral cortex of adult mice: manipulation of neural precursors in situ

    Brain Res. Dev. Brain Res.

    (2002)
  • Y. Mao et al.

    Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling

    Cell

    (2009)
  • P. Meerlo et al.

    New neurons in the adult brain: the role of sleep and consequences of sleep loss

    Sleep Med. Rev.

    (2009)
  • D.N. Abrous et al.

    Adult neurogenesis: from precursors to network and physiology

    Physiol. Rev.

    (2005)
  • J.B. Aimone et al.

    Potential role for adult neurogenesis in the encoding of time in new memories

    Nat. Neurosci.

    (2006)
  • R.D. Airan et al.

    High-speed imaging reveals neurophysiological links to behavior in an animal model of depression

    Science

    (2007)
  • J. Altman

    Autoradiographic investigation of cell proliferation in the brains of rats and cats

    Anat. Rec.

    (1963)
  • C. Andrade et al.

    The prevention and treatment of cognitive decline and dementia: an overview of recent research on experimental treatments

    Indian J. Psychiatry

    (2009)
  • C. Arango et al.

    At issue: stress, hippocampal neuronal turnover, and neuropsychiatric disorders

    Schizophr. Bull.

    (2001)
  • M. Banasr et al.

    Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment

    CNS Neurol. Disord. Drug Targets

    (2007)
  • T. Bast

    Toward an integrative perspective on hippocampal function: from the rapid encoding of experience to adaptive behavior

    Rev. Neurosci.

    (2007)
  • F.E. Bloom

    Modern concepts in electrophysiology for psychiatry

    Psychopharmacol. Commun.

    (1975)
  • F.E. Bloom

    Endorphins and psychiatry: pre-clinical perspectives

    Psychiatr. Dev.

    (1984)
  • M. Boldrini et al.

    Antidepressants increase neural progenitor cells in the human hippocampus

    Neuropsychopharmacology

    (2009)
  • J.D. Bremner

    Alterations in brain structure and function associated with post-traumatic stress disorder

    Semin. Clin. Neuropsychiatry

    (1999)
  • J.D. Bremner

    Traumatic stress: effects on the brain

    Dialogues Clin. Neurosci.

    (2006)
  • J.J. Breunig et al.

    Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus

    Proc. Natl. Acad. Sci. U.S.A.

    (2007)
  • B.D. Brown et al.

    Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications

    Nat. Rev. Genet.

    (2009)
  • E. Bruel-Jungerman et al.

    Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses

    Rev. Neurosci.

    (2007)
  • A.R. Brunoni et al.

    A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression

    Int. J. Neuropsychopharmacol.

    (2008)
  • S. Campbell et al.

    The role of the hippocampus in the pathophysiology of major depression

    J. Psychiatry Neurosci.

    (2004)
  • B. Czeh et al.

    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.

    (2001)
  • B. Czeh et al.

    What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated?

    Eur. Arch. Psychiatry Clin. Neurosci.

    (2007)
  • M.H. Donovan et al.

    Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease

    J. Comp. Neurol.

    (2006)
  • M.R. Drew et al.

    Adult hippocampal neurogenesis as target for the treatment of depression

    CNS Neurol. Disord. Drug Targets

    (2007)
  • Cited by (0)

    View full text