Invited reviewHippocampal neurogenesis as a target for the treatment of mental illness: A critical evaluation
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.
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