Elsevier

Behavioural Brain Research

Volume 227, Issue 2, 14 February 2012, Pages 440-449
Behavioural Brain Research

Review
Role of vascular endothelial growth factor in adult hippocampal neurogenesis: Implications for the pathophysiology and treatment of depression

https://doi.org/10.1016/j.bbr.2011.04.022Get rights and content

Abstract

It is now well established that the adult brain has the capacity to generate new neurons throughout life. Although the functional significance of adult neurogenesis still remains to be established, increasing evidence has implicated compromised hippocampal neurogenesis as a possible contributor in the development of major depressive disorder. Antidepressants increase hippocampal neurogenesis and there is evidence in rodent models that the therapeutic efficacy of these agents is attributable, in part, to this neurogenic effect. As such, considerable interest has been directed at identifying molecular signals, including neurotrophic factors and related signaling pathways that are associated with antidepressant action and could operate as key modulators in the regulation of neurogenesis in the adult hippocampus. One interesting candidate is vascular endothelial growth factor (VEGF), which is known to possess strong neurogenic effects. In this review, we will discuss the involvement of VEGF signaling in the etiology and treatment of depression.

Highlights

► Stress decreases and antidepressant treatment increases VEGF levels in limbic structures of the brain, most notably hippocampus. ► VEGF is necessary and sufficient for the neurogenic and behavioral actions of antidepressant treatments. ► Rapid and robust induction of VEGF expression can increase the proliferation of quiescent neural progenitor cells, and lead to a robust increase in neurogenesis.

Introduction

Major depressive disorder (MDD) is a highly debilitating and pervasive illness affecting as many as one in five Americans [1]. Given that MDD is a leading cause of disability worldwide [2], a high priority of current research is to understand the cellular and molecular mechanisms underlying depression, including both its pathogenesis and recovery. Despite the difficulty in elucidating the neural substrates of MDD [3], a growing body of evidence has suggested that dysfunction of the hippocampus may underlie, at least in part, the etiology and treatment of this disorder [4], [5]. Recent neuroimaging and histopathological studies of postmortem tissue have confirmed this view and provide some interesting clues about the nature of the cellular changes in the hippocampus of depressed patients [6]. Along these lines, one of the most consistent findings reported in the literature is decreased hippocampal volume and altered cell morphology in patients with MDD, especially those with a long history of pharmacoresistant depression [7], [8], [9], [10], [11]. In addition, preclinical studies have also demonstrated that exposure to high levels of glucocorticoids or chronic stress can result in neuronal atrophy and cell loss in this region [12], [13]. Although several different mechanisms could contribute to the structural alterations and neuronal loss in the hippocampus, one of the most intriguing findings to emerge from this research is the possible involvement of neurogenesis in the etiology and treatment of stress-related illnesses, notably MDD.

Previously, it was believed that neurogenesis was restricted mainly to prenatal or early postnatal periods. However, over the last two decades, it has been shown that new neurons are continuously generated in discrete regions of the brain throughout life leading to wide acceptance that neurogenesis occurs in the adult brain. The two major germinal sites, the anterior portion of the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus, serve as the main regions of neurogenesis in the mature brain. Adult hippocampal neurogenesis in particular has received extensive study mainly due to its phylogenetic conservation across multiple species, including non-human primates and humans [14], [15], [16], and its possible relevance in various neuropsychiatric and neurological conditions, as well as playing a role in cognitive processes such as learning and memory. In the context of MDD, preclinical studies have found that stress and chronic antidepressant treatment exert opposing effects on hippocampal neurogenesis. That is, stress generally results in a reduction in hippocampal neurogenesis and chronic antidepressant treatments increase neurogenesis [17], [18] suggesting that adult hippocampal neurogenesis may be an important component in the therapeutic action of antidepressants.

Significant progress has been made at uncovering the molecular signals that regulate the division of neuronal progenitors in the adult hippocampus and could serve as potential candidates in the treatment of MDD. In this review, we will discuss one such target, vascular endothelial growth factor (VEGF), and the role of this multifunctional growth factor in both the pathophysiology and treatment of depression. We will first provide an overview of the neurogenic/neurotrophic hypothesis of depression and the role of VEGF signaling in adult neurogenesis. Finally, we will present the current state of knowledge of VEGF in animal models of stress and in the behavioral action of antidepressants.

Section snippets

The neurogenic/neurotrophic hypothesis of depression

The birth of new cells in the adult hippocampus of rodents can be detected by the presence of cells labeled by an injection with the DNA synthesis marker bromodeoxyuridine (BrdU) or by examining the expression of endogenous cell cycle marker proteins (e.g., PCNA, Ki67, phosphohistone H3). In the adult rat hippocampus, it has been estimated that over 9000 new cells are born each day [19]. Of the dividing cells that survive (∼50%) [20], the vast majority express markers of neuronal lineage (e.g.,

Neurotrophic factors regulating neurogenesis

The mechanism(s) through which antidepressants increase hippocampal neurogenesis has been the subject of intense experimental investigation. Although early theories of antidepressant action focused mainly on the ability of these compounds to reverse imbalances in monoamine neurotransmitters, such as dopamine, noradrenalin, and serotonin, it has become increasingly clear that elevations in intrasynaptic levels of biogenic amines alone cannot account for the therapeutic efficacy of

VEGF and depression: blood, sweat, and tears

Recently, there has been intense effort made to examine the role of vascular dysfunction in the development of MDD. It has been known that cerebrovascular diseases, including stroke, are associated with a high incidence of MDD [111]. Decreased cerebral blood flow and metabolism in the hippocampus and prefrontal cortices are frequently found in patients with treatment resistant depression [112], [113]. In this context, it is worth mentioning that endothelial cell dysfunction, decreased

Future directions and conclusions

The prevalence of MDD is on the rise, resulting in an enormous health care burden that not only affects the individual but permeates throughout all avenues of social, work, and family life. Progress has been made in revealing candidate molecular pathways and neural substrates that could serve as important targets for pharmacological intervention. Strategies targeting adult hippocampal neurogenesis have received considerable attention in the possible treatment of MDD. However, several key

Acknowledgements

This work is supported by USPHS grants MH45481 (RSD), 2 P01 MH25642 (RSD), the Connecticut Mental Health Center (RSD), and a postdoctoral fellowship award from the Natural Sciences and Engineering Council of Canada (NMF).

References (158)

  • H.A. Cameron et al.

    Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus

    Neuroscience

    (1994)
  • Y.S. Mineur et al.

    Functional implications of decreases in neurogenesis following chronic mild stress in mice

    Neuroscience

    (2007)
  • C.L. Coe et al.

    Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys

    Biol Psychiatry

    (2003)
  • E.Y. Sterner et al.

    Behavioral and neurobiological consequences of prolonged glucocorticoid exposure in rats: relevance to depression

    Prog Neuropsychopharmacol Biol Psychiatry

    (2010)
  • R.S. Duman et al.

    Neuronal plasticity and survival in mood disorders

    Biol Psychiatry

    (2000)
  • H. Manev et al.

    Antidepressants alter cell proliferation in the adult brain in vivo and in neural cultures in vitro

    Eur J Pharmacol

    (2001)
  • G. Grassi Zucconi et al.

    ‘One night’ sleep deprivation stimulates hippocampal neurogenesis

    Brain Res Bull

    (2006)
  • T.M. Madsen et al.

    Increased neurogenesis in a model of electroconvulsive therapy

    Biol Psychiatry

    (2000)
  • B.W. Scott et al.

    Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures

    Exp Neurol

    (2000)
  • M. Kodama et al.

    Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat

    Biol Psychiatry

    (2004)
  • B. Vollmayr et al.

    Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness

    Biol Psychiatry

    (2003)
  • M.N. Jayatissa et al.

    Decreased cell proliferation in the dentate gyrus does not associate with development of anhedonic-like symptoms in rats

    Brain Res

    (2009)
  • A. Surget et al.

    Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal

    Biol Psychiatry

    (2008)
  • D.J. David et al.

    Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression

    Neuron

    (2009)
  • M.A. Riva et al.

    Emerging role of the FGF system in psychiatric disorders

    Trends Pharmacol Sci

    (2005)
  • H. Thoenen

    Neurotrophins and activity-dependent plasticity

    Prog Brain Res

    (2000)
  • E.A. Stone et al.

    A final common pathway for depression? Progress toward a general conceptual framework

    Neurosci Biobehav Rev

    (2008)
  • R.S. Duman et al.

    A neurotrophic model for stress-related mood disorders

    Biol Psychiatry

    (2006)
  • J.E. Malberg et al.

    Antidepressant action: to the nucleus and beyond

    Trends Pharmacol Sci

    (2005)
  • W.Y. Wang et al.

    Vascular endothelial growth factor and its receptor Flk-1 are expressed in the hippocampus following entorhinal deafferentation

    Neuroscience

    (2005)
  • M.R. Pitzer et al.

    Angiogenic and neurotrophic effects of vascular endothelial growth factor (VEGF165): studies of grafted and cultured embryonic ventral mesencephalic cells

    Exp Neurol

    (2003)
  • A.A. Khaibullina et al.

    Vascular endothelial growth factor promotes neurite maturation in primary CNS neuronal cultures

    Brain Res Dev Brain Res

    (2004)
  • J.M. Rosenstein et al.

    New roles for VEGF in nervous tissue—beyond blood vessels

    Exp Neurol

    (2004)
  • H.F. Dvorak

    VPF/VEGF and the angiogenic response

    Semin Perinatol

    (2000)
  • D.G. Blazer et al.

    The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey

    Am J Psychiatry

    (1994)
  • P.E. Greenberg et al.

    Depression: a neglected major illness

    J Clin Psychiatry

    (1993)
  • 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)
  • G.M. MacQueen et al.

    Course of illness, hippocampal function, and hippocampal volume in major depression

    Proc Natl Acad Sci USA

    (2003)
  • J.D. Bremner et al.

    Hippocampal volume reduction in major depression

    Am J Psychiatry

    (2000)
  • B.S. McEwen

    Plasticity of the hippocampus: adaptation to chronic stress and allostatic load

    Ann N Y Acad Sci

    (2001)
  • R.M. Sapolsky

    Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders

    Arch Gen Psychiatry

    (2000)
  • D.R. Kornack et al.

    Continuation of neurogenesis in the hippocampus of the adult macaque monkey

    Proc Natl Acad Sci USA

    (1999)
  • P.S. Eriksson et al.

    Neurogenesis in the adult human hippocampus

    Nat Med

    (1998)
  • E. Gould et al.

    Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation

    J Neurosci

    (1997)
  • C. Mirescu et al.

    Stress and adult neurogenesis

    Hippocampus

    (2006)
  • J.E. Malberg et al.

    Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus

    J Neurosci

    (2000)
  • H.A. Cameron et al.

    Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus

    J Comp Neurol

    (2001)
  • A.G. Dayer et al.

    Short-term and long-term survival of new neurons in the rat dentate gyrus

    J Comp Neurol

    (2003)
  • W. Deng et al.

    New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?

    Nat Rev Neurosci

    (2010)
  • E. Gould et al.

    Adult-generated hippocampal and neocortical neurons in macaques have a transient existence

    Proc Natl Acad Sci USA

    (2001)
  • Cited by (125)

    View all citing articles on Scopus
    View full text