Elsevier

Progress in Brain Research

Volume 163, 2007, Pages 697-722, 822
Progress in Brain Research

Dentate gyrus neurogenesis and depression

https://doi.org/10.1016/S0079-6123(07)63038-6Get rights and content

Abstract

Major depressive disorder (MDD) is a debilitating and complex psychiatric disorder that involves multiple neural circuits and genetic and non-genetic risk factors. In the quest for elucidating the neurobiological basis of MDD, hippocampal neurogenesis has emerged as a candidate substrate, both for the etiology as well as treatment of MDD. This chapter critiques the advances made in the study of hippocampal neurogenesis as they relate to the neurogenic hypothesis of MDD. While an involvement of neurogenesis in the etiology of depression remains highly speculative, preclinical studies have revealed a novel and previously unrecognized role for hippocampal neurogenesis in mediating some of the behavioral effects of antidepressants. The implications of these findings are discussed to reevaluate the role of hippocampal neurogenesis in MDD.

Introduction

Understanding the neurobiological basis of major depressive disorder (MDD) is one of the most pressing challenges for today's society. Severe forms of depression affect 2–5% of the U.S. population, and mood disorders impact 7% of the world's population and rank among the top ten causes of disability (Murray and Lopez, 1996). The diagnosis of MDD based on the criteria established by the Diagnostics and Statistical Manual of Mental Disorders (American Psychological Association, 2000) includes the persistence of depressed mood, low self esteem, feelings of hopelessness, decreased ability to concentrate, diminished interest in pleasurable activities, daily insomnia or hypersomnia, weight loss or gain, and recurrent suicidal ideation. The diagnostic criteria for MDD convey the complexity of the disease and suggest that multiple neural circuits subserving distinct cognitive and affective processes are likely to be involved.

Our comprehension of the mechanisms underlying the pathogenesis of MDD has evolved considerably since the formulation of the monoamine hypothesis (Bunney and Davis, 1965; Schildkraut, 1965; Nestler et al., 2002). The recent emphasis on neural circuits as opposed to a chemical imbalance catalyzed a fundamental shift in our conceptualization of MDD and psychiatric disorders. It provided a framework to understand how genes, through their effects on neural circuits, influence our ability to encode experience and adapt to environmental stimuli and stressors. Implicit in this idea is that genes moderate vulnerability to the effects of environmental stress during particularly sensitive or critical periods in brain development by determining the optimal range of neuronal circuit function for the organism. Indeed, the neurotrophic, neuroplasticity and network hypotheses of MDD all reflect the biology of gene products in the context of synaptic and structural plasticity of neural circuitry (Duman et al., 1997; Duman, 2002; Nestler et al., 2002; Castren, 2005).

Dentate gyrus neurogenesis has gained considerable attention as both a form of structural plasticity and as a neural substrate for the pathophysiology of MDD. The neurogenic hypothesis posits that a decrease in the production of newborn dentate granule cells in the hippocampus causally relates to the pathogenesis and pathophysiology of MDD and that enhanced neurogenesis is necessary for treatment of depression (Duman et al., 2000; Jacobs et al., 2000). The hypothesis, when first proposed, was predicated on the following observations, which are reviewed in greater detail in subsequent sections. First, stress, which is widely recognized as a major causal factor in MDD, is known to suppress neurogenesis. Second, most antidepressant (AD) treatments increase hippocampal neurogenesis. Third, imbalance in the serotonin system influences hippocampal neurogenesis. Fourth, the induction of neurogenesis is contingent upon chronic but not subchronic (acute) selective serotonin reuptake inhibitor (SSRI) treatment, paralleling the time course for therapeutic actions of ADs. Finally, the therapeutic lag in the response to SSRIs in patients with MDD mirrors the timeline of maturation and integration of newborn dentate granule cells. Consequently, the dentate gyrus and neurogenesis therein are potential substrates for the AD response.

Central to the neurogenic hypothesis is the assumption that the dentate gyrus plays an important role in mediating cognitive and affective processes. Moreover, since levels of neurogenesis change during the lifetime of the organism, changes in dentate neurogenesis may contribute to dentate gyrus function in different ways. Another assumption is that neurogenesis represents a potentially adaptive mechanism or form of plasticity. Deficits in neurogenesis during critical periods in brain development could, therefore, be pathogenic in that they profoundly impact the trajectory of emotional development. Deficits in adult hippocampal neurogenesis could compromise hippocampal-dependent functions and contribute to the pathophysiology of MDD.

In this chapter, we focus on hippocampal neurogenesis as it relates to MDD. Our aim is to distill the observations made in the rapidly growing field of hippocampal neurogenesis and to critically assess the putative role of neurogenesis in the etiology and treatment of MDD. We begin by defining a framework for the reader to understand how neurogenesis can contribute to dentate gyrus function. Within this framework, we will first evaluate evidence for deficits in hippocampal neurogenesis in patients with MDD. We will then examine the role of the serotonergic system in hippocampal neurogenesis because the best characterized genetic risk alleles for MDD encode components of this system. Because susceptibility to MDD conferred by genes is likely to be revealed by environmental risk factors such as stress, we will discuss the relationship between stress and neurogenesis. We then review the considerable evidence linking the effects of ADs with increased hippocampal neurogenesis. Finally, we will turn to evidence provided by studies using preclinical models that attempt to establish a causal link between hippocampal neurogenesis and the etiology, and pathophysiology of MDD and the requirement for neurogenesis in mediating the behavioral effects of ADs.

Section snippets

A general framework for neurogenesis and dentate gyrus function

Since the seminal findings of Altman and Das in 1965, it is now well accepted that the adult hippocampus is host to the birth and integration of newborn dentate granule cells in the dentate gyrus (Altman and Das, 1965). In the rat, the species for which the best data are available, it is estimated that 9000 new cells are born each day in the DG, and, of these, approximately 50% go on to express neuron-specific markers. At this rate, the number of new granule neurons born each month is equal to

Genes, environment and MDD

Depression is a complex and multifactorial illness with genetic and non-genetic underpinnings. The heritability of MDD is likely to be in the range of 40–50% and there is substantial evidence to suggest that the phenotypic expression of MDD is contingent upon interactions between the genetic make-up of the individual and environmental factors, an interaction that has a dramatic effect on the formation and functioning of neural circuitry (Sullivan et al., 2000; Kendler et al., 2001; Caspi and

Neurogenesis and antidepressants

It is well recognized that all of the major classes of ADs are associated with a several week delay in onset. This delay is likely to reflect changes in structural and synaptic plasticity in the brain mediated by multiple mechanisms involving monoaminergic signaling and neurotrophins. PET imaging studies on MDD patients treated with SSRIs such as paroxetine and fluoxetine have helped define a neuroanatomical basis comprising corticolimbic circuits (Seminowicz et al., 2004). Structures that

Preclinical studies: in the search for causality

Ultimately, whether neurogenesis is causally related to the etiology or treatment of depression requires the use of animal models in which neurogenesis and emotional state can be experimentally manipulated. If reduced neurogenesis contributes to depression, it should be possible to produce a depressive phenotype by experimentally reducing neurogenesis. Conversely, behavioral manipulations that produce a depressive phenotype should reduce neurogenesis and do so before the behavioral

General insights: is neurogenesis a missing link or is the link still missing?

Research on MDD in the last decade has led to considerable maturation of our understanding of how different neural circuits function in a normal brain and in the context of pathology. Several notable findings have emerged from studies in humans with MDD and preclinical models of MDD. First, the AD response and the pathogenesis of MDD may have different neural substrates. Second, the pathogenic mechanisms may differ from those that underlie the pathophysiology of MDD. Third, any model explaining

Acknowledgments

The authors would like to thank members of the Hen laboratory for helpful discussions. Funding support was provided by NARSAD (A.S, M.R.D and R.H) and by Charles H. Revson Foundation Senior Fellowship in Biomedical Science (M.R.D).

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