Kellen Gandy
Sohye Kim
Carla Sharp4
Mirjana Maletic-Savatic- 1Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States
- 2Department of Obstetrics and Gynecology, Baylor College of Medicine and Center for Reproductive Psychiatry, Pavilion for Women, Texas Children's Hospital, Houston, TX, United States
- 3Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, United States
- 4Department of Psychology, University of Houston, Houston, TX, United States
- 5Dan and Jan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, United States
Adult neurogenesis involves the generation of new neurons, particularly in the dentate gyrus of the hippocampus. Decreased hippocampal neurogenesis has been implicated in both animal models of depression and in patients with major depressive disorder (MDD), despite some inconsistency in the literature. Here, we build upon current models to generate a new testable hypothesis, linking impaired neurogenesis to downstream psychological outcomes commonly observed in MDD. We contend that disruption in adult neurogenesis impairs pattern separation, a hippocampus-dependent function requiring the careful discrimination and storage of highly similar, but not identical, sensory inputs. This, in turn, can affect downstream processing and response selection, of relevance to emotional wellbeing. Specifically, disrupted pattern separation leads to misperceived stimuli (i.e., stimulus confusion), triggering the selection and deployment of established responses inappropriate for the actual stimuli. We speculate that this may be akin to activation of automatic thoughts, described in the Cognitive Behavior Theory of MDD. Similarly, this impaired ability to discriminate information at a fundamental sensory processing level (e.g., impaired pattern separation) could underlie impaired psychological flexibility, a core component of Acceptance and Commitment Therapy of MDD. We propose that research is needed to test this model by examining the relationship between cognitive functioning (e.g., pattern separation ability), psychological processes (e.g., perseveration and psychological inflexibility), and neurogenesis, taking advantage of emerging magnetic resonance spectroscopy-based imaging that measures neurogenesis in-vivo.
Introduction
Major depressive disorder (MDD) is characterized by a triad of mood, neuro-vegetative, and cognitive symptoms (American Psychiatric Association, 2013). MDD is most prevalent among young adults (18–25 years old), particularly women, and is the second leading cause of disability worldwide (National Survey on Drug Use Health, 2015). Despite significant progress over the last few decades, treatment efficacy remains sub-optimal for the majority of patients with MDD (National Institute of Mental Health, 2015). Moreover, research has yet to fully elucidate the underlying pathophysiology. This may not be surprising, given the complexity and clinical heterogeneity of MDD.
In this paper, we build upon current models (Hanson et al., 2011; Shelton and Kirwan, 2013; Hill et al., 2015; Lucassen et al., 2015; Miller and Hen, 2015; Yun et al., 2016) to propose that reduced adult neurogenesis in the dentate gyrus of the hippocampus causes deficits in pattern separation and downstream impairment in information processing. This, in turn, contributes to MDD presentation, at least in a subgroup of patients. We begin by reviewing the nascent literature on hippocampal neurogenesis in MDD. We then link neurogenesis and pattern separation in the context of MDD, and complete the review with a speculation regarding the potential downstream impairment in information processing contributing to cognitive patterns characteristic of patients with MDD.
Hippocampal Neurogenesis and MDD
Neurogenesis involves generating new, functional neurons. As such, it has traditionally been thought to occur only during embryogenesis and the perinatal stages of the mammalian nervous system development. However, over the past two decades, research has firmly established that newborn neurons are generated in two germinal zones of the postnatal and adult brain of rodents as well as primates, including humans: the subgranular zone of the dentate gyrus of the hippocampus (Altman, 1962; Palmer et al., 1997; Eriksson et al., 1998; Knoth et al., 2010; Miller et al., 2013) and the subventricular zone of the lateral ventricles (Morshead et al., 1994; Doetsch et al., 1997; Quinones-Hinojosa et al., 2006; Bergmann et al., 2012; Curtis et al., 2012). Adult-generated neurons form synaptic connections and integrate into the local circuitry. In the dentate gyrus, it is estimated that about 9,000 newborn neurons are generated daily in the adult rat, replacing about 40% of the structure over the life-span (Snyder and Cameron, 2012). In humans, carbon-dating estimated that about 700 newborn neurons are added to the hippocampal adult circuitry daily, replacing about 30% of the structure over the life-span (Spalding et al., 2013). These data indicate that the number of new neurons incorporated into the hippocampal circuitry in the adult brain is likely to be large enough to affect hippocampal function both in rodents and in humans. Importantly, based on animal studies, these new neurons participate in the modulation and refinement of established neuronal circuitry, affecting both regional physiology and the functional connectivity of more distant brain regions, such as the prefrontal cortex, amygdala, and other structures within the limbic system (van Praag et al., 2002; Ramirez-Amaya et al., 2006; Toni et al., 2007, 2008; Vivar et al., 2012; Vivar and van Praag, 2013). The integration of these new neurons into the hippocampal circuitry suggests an important role for adult neurogenesis in hippocampus-dependent functions. For instance, newly-generated neurons in the murine dentate gyrus contribute to the encoding of new memories (Farioli-Vecchioli et al., 2008; Jessberger et al., 2009), spatial learning (Snyder et al., 2005; Dupret et al., 2008; Clelland et al., 2009), pattern separation (Sahay et al., 2011a,b), affect regulation (Ibi et al., 2008), and cognitive flexibility (Burghardt et al., 2012), which, coincidentally, can all be affected in individuals diagnosed with MDD (Bremner et al., 2004; Deveney and Deldin, 2006; Gould et al., 2007; Joormann and Gotlib, 2010; Shelton and Kirwan, 2013).
Dysregulated neurogenesis may contribute to MDD, anxiety and other neuropsychiatric disorders (Lucassen et al., 2015). Due to the lack of precise animal models of MDD, studies utilize different stressors to induce depressive-like states. In rodents, both acute psychosocial stress (e.g., exposure to a social dominance paradigm, social instability or social isolation), as well as chronic stress reduce hippocampal neurogenesis (Thomas et al., 2007; Brummelte and Galea, 2010; Castilla-Ortega et al., 2011; McCormick et al., 2012). Similarly, social isolation-stress in primates decreases hippocampal neurogenesis and concurrently induces depressive and anxiety-like phenotypes, including anhedonia and self-defeating behavior (Perera et al., 2011). Moreover, the lasting effects of chronic stress during early life include the inhibition of adult neurogenesis (Karten et al., 2005; Korosi et al., 2012), and potentiation of anxiety-like behaviors (de Andrade et al., 2013). However, stress-related effects are dose-dependent, and a “short” exposure to “weaker” stressors may not affect hippocampal neurogenesis (Kempermann, 2002).
While the debate on the association of MDD and hippocampal adult neurogenesis continues (Boldrini et al., 2009, 2013; Hayes et al., 2013; Huang et al., 2013; Wu et al., 2014; Miller and Hen, 2015), the most convincing data on this association comes from studies examining the impact of interventions with anti-depressant potential on neurogenesis. In fact, therapeutic interventions that promote mental well-being stimulate hippocampal neurogenesis. For instance, routine aerobic exercise reduces learned helplessness and depressive-like behaviors (i.e., sucrose preference, forced swim test, etc.) in animals (Binder et al., 2004; Yau et al., 2011; Liu et al., 2013), endogenous corticosterone (Starzec et al., 1983), stress-mediated responses from the hypothalamic-pituitary-adrenal (HPA) axis (Luger et al., 1987; Campeau et al., 2010), and also promotes neurogenesis in the dentate gyrus (van Praag et al., 1999; Bjornebekk et al., 2005; Kronenberg et al., 2006; Marlatt et al., 2012; Dery et al., 2013). Similarly, environmental enrichment enhances the proliferation of neural stem cells in the dentate gyrus of mice, while concurrently improving depressive-like behaviors (Kempermann, 2002; Veena et al., 2009a,b; Jha et al., 2011). Finally, antidepressant treatments, such as SSRIs and electroconvulsive shock (equivalent to human electroconvulsive therapy, ECT) increase neurogenesis specifically in the hippocampus and not in other neurogenic regions (Santarelli et al., 2003; Kodama et al., 2004; David et al., 2009; Klomp et al., 2014). In fact, animal research indicates that electroconvulsive shock is one of the strongest stimuli for hippocampal adult neurogenesis (Madsen et al., 2005; Warner-Schmidt et al., 2008; Chen et al., 2009). In rats, even a single electroconvulsive shock can increase neurogenesis by 67–197% (Segi-Nishida et al., 2008; Chen et al., 2009). In clinical practice, ECT is administered as a series of treatments over a number of weeks. The closest analog to this paradigm examined the effect of electroconvulsive stimulations in adult monkeys and found a 4-fold increase in dentate subgranular zone cell proliferation (Santarelli et al., 2003; Perera et al., 2007). Notably, the maturation period of newly-generated neurons in the dentate gyrus appears consistent with the delay for the full therapeutic effects of antidepressants to become manifest (Esposito et al., 2005; Ngwenya et al., 2006). In sum, these preclinical findings suggest that adult neurogenesis may be modulated by factors associated with MDD, including chronic stress (Cohen et al., 2007), and activation of the HPA axis (Pariante and Lightman, 2008).
While pre-clinical findings do not always translate to humans, research has also found evidence potentially implicating impaired hippocampal neurogenesis in MDD. First, MDD has long been associated with abnormalities in the limbic system, including the hippocampus (MacQueen et al., 2003; Whittle et al., 2014). This has been highlighted in a recent meta-analysis reporting that smaller hippocampal volumes are the most consistent sub-cortical abnormality in patients with MDD, particularly adolescents and emerging adults (i.e., <21 years old), as well as in those with recurrent MDD (Schmaal et al., 2016). More specifically, high-resolution volumetric magnetic resonance imaging (MRI) and postmortem studies have found decreased dentate gyrus size in unmedicated patients with MDD (Boldrini et al., 2009, 2013; Huang et al., 2013). In fact, the number of granule cells, derived from neural progenitor cells, was smaller in the anterior and mid regions of the dentate gyrus of untreated MDD patients (Boldrini et al., 2013). Interestingly, for untreated MDD, younger age of MDD onset correlated with fewer granule cells in the anterior dentate gyrus. Moreover, untreated patients with MDD appear to have a smaller number of dividing cells in the dentate gyrus compared to healthy controls (Boldrini et al., 2009). Of note, while this finding was not significant likely due to lack of statistical power (n = 5 for unmedicated MDD, n = 7 for healthy controls), the group differences were quite large (Cohen's d effect size ≥ 1.2). Although the exact mechanism is not yet known, these findings suggest that cell division and granule cell survival in the dentate gyrus are reduced in unmedicated MDD patients. Nonetheless, the number of cells generated by adult neurogenesis and their corresponding volume cannot entirely account for the observed change in hippocampal volume in patients with MDD. In fact, hippocampal volume in patients with MDD is likely the result of various factors, including reduced neuronal number and size, synaptic density, dendritic complexity, axonal hypotrophy and glial cell density (Stockmeier et al., 2004; Duman et al., 2016). Rather, associated changes in local brain circuitry and glial cells, including secondary apoptosis, could follow impaired neurogenesis in MDD, resulting in the volumetric differences (Wiskott et al., 2006; Kubera et al., 2011; Lee et al., 2012). Of course, additional research is needed to more convincingly determine whether and to which extent neurogenesis is impaired in MDD and how this contributes to the observed volumetric and functional brain changes.
While the evidence reviewed above suggests the presence of a link between reduced hippocampal adult neurogenesis and MDD, preclinical and clinical studies have also reported findings that are inconsistent with this hypothesis (Miller and Hen, 2015). For instance, exposure to several stress models failed to reduce hippocampal neurogenesis in rodents (Hanson et al., 2011). Moreover, depressive-like symptoms in rodents can improve without change in hippocampal neurogenesis (Meshi et al., 2006; Bessa et al., 2009). Similarly, depressive-like behaviors in rodents improve following antidepressant treatment, despite ablated hippocampal neurogenesis (Cowen et al., 2008; Holick et al., 2008; Huang et al., 2008; David et al., 2009). Finally, not all postmortem studies found reduced neurogenesis in patients with MDD (Reif et al., 2006). However, these seemingly contradictory findings may rather reflect differences in the genetic strains of the rodents studied (Semerci and Maletic-Savatic, 2016), the paradigms used to induce depressive-like behaviors in the lab (e.g., unpredictable mild stress, cortisol-induced depression), or the behaviors used as markers of depressive-like states in animals (e.g., sucrose preference test, learned helplessness, and forced swim test) (Santarelli et al., 2003; Bjornebekk et al., 2005; Meshi et al., 2006; Bessa et al., 2009; Yau et al., 2014). In human studies, mixed results could also reflect methodological differences given that different biomarkers of adult neurogenesis exist, with varying sensitivity (Reif et al., 2006; Boldrini et al., 2009). Additionally, the presence of inconsistent findings could also reflect the fact that neurogenesis may be sufficient but not necessary for the development of depression or for antidepressants to be efficacious. Moreover, decreased neurogenesis may be associated with only certain characteristics of MDD or with a subgroup of patients with MDD, given the multifactorial nature of this disorder. For example, while in preclinical research, hippocampal adult neurogenesis could be virtually completely aborted experimentally, it can be affected to varying degrees in patients with MDD, depending on etiology, severity, subtype, and comorbidity. Finally, it is also important to keep in mind that evolutionary pressures may have led to very different roles played by hippocampal adult neurogenesis in the human brain compared to that of a rodent.
Pattern Separation as a Cognitive Marker of Adult Neurogenesis
The ability to discriminate and store similar, but not identical, inputs of sensory information into distinct representations (e.g., form distinct memories) is referred to as “pattern separation.” This function is notable for its dependence on hippocampal adult neurogenesis (Aimone et al., 2011). In fact, rodents with ablated neurogenesis in the dentate gyrus display impairments in pattern separation ability (Clelland et al., 2009). In contrast, increasing hippocampal neurogenesis leads to enhanced pattern separation ability in animals (Sahay et al., 2011a). Hippocampal neurogenesis is also implicated in a variety of additional processes, including cognitive flexibility (Burghardt et al., 2012), hippocampus-dependent memory functions (Winocur et al., 2006), spatial memory (Snyder et al., 2005; Dupret et al., 2008; Clelland et al., 2009), memory encoding (Epp et al., 2016), and executive function (Saxe et al., 2007). However, whether its role is required for these functions remains to be determined (Cushman et al., 2012; Groves et al., 2013; Swan et al., 2014; Park et al., 2015; Svensson et al., 2016). A significant challenge in this research is determining the magnitude of pattern separation demanded by each of these cognitive task. It is those tasks that manipulate the level of sensory discrimination by altering the degree of similarity among study items that appear to most strongly correlate with neurogenesis in the dentate gyrus (Hvoslef-Eide and Oomen, 2016).
In humans, experimental tasks which place a high demand on sensory discrimination have been correlated with dentate gyrus activity in healthy controls. Kirwan and Stark (2007) developed a mnemonic similarity task that involves discriminating the visual similarities of two different, but similar, images. Increased performance on pattern separation while completing this task was associated with increased blood oxygen level-dependent (BOLD) signal in the dentate gyrus and CA3 region of the hippocampus (Kirwan and Stark, 2007; Yassa and Stark, 2011). Additionally, changes in dentate gyrus activity correlate with the degree of mnemonic discrimination, with highly similar lures resulting in increased BOLD signaling (Bakker et al., 2008; Lacy et al., 2011). Moreover, Déry et al. found that aerobic exercise, which is known to promote adult neurogenesis, was prospectively associated with improved performance on the mnemonic similarity task (Dery et al., 2013). In addition, they observed a concurrent decline in depressive symptoms (Dery et al., 2013). This is consistent with findings from a study in college students, whereby performance on the same task was inversely correlated with depression severity, as captured by the Beck Depression Inventory (Shelton and Kirwan, 2013). This should not be surprising in light of evidence showing poor performance on hippocampus-dependent tasks in MDD (MacQueen et al., 2003).
Additionally, MDD patients consistently display impairments in long-term memory (Burt et al., 1995; Soderlund et al., 2014), working memory (Rose and Ebmeier, 2006), negative emotional bias (Gotlib and Joormann, 2010) and executive function, including problem solving, attentional control, planning, and cognitive inhibition (Frodl et al., 2006; Letkiewicz et al., 2014). These deficits in executive functioning are positively associated with depression severity (Snyder, 2013) and are typically accompanied by structural and functional brain abnormalities in the prefrontal cortex, ventromedial basal ganglia, amygdala, and hippocampus (Frodl et al., 2006; Drevets et al., 2008). Thus, while to our knowledge tasks that specifically activate the dentate gyrus have not been directly examined in MDD, the available evidence suggests performance would be suboptimal. To what extent such impairment is specific to MDD would require further investigation given that disrupted pattern separation ability has been observed in schizophrenia (Das et al., 2014), mild cognitive impairment (Stark et al., 2013), and amnesia (Kirwan et al., 2012). Of note, these studies relied exclusively on behavioral data without a neuroimaging component, making it difficult to establish in humans the direct involvement of the hippocampus in general, or the dentate gyrus in particular, in pattern separation.
Deficit in Information Processing as a Sequelae of Pattern Separation Impairment in MDD
As previously noted, adult neurogenesis in the dentate gyrus is necessary for the discrimination of new sensory information (e.g., pattern separation). Thus, impaired pattern separation may hamper one's ability to process new information. We speculate that this may explain some of the phenomena observed in patients with MDD. For instance, individuals with impaired pattern separation ability could mistake comparable stimuli as being identical which, in turn, may lead to these distinct stimuli triggering the same response (e.g., responding with sadness to both negative and ambiguous events). In fact, individuals diagnosed with or at-risk for depression and anxiety disorders tend to interpret ambiguous stimuli as threatening or negative, further supporting the hypothesis that pattern separation may be deficient in MDD (Leppanen et al., 2004; Mogg et al., 2006; Dearing and Gotlib, 2009). We contend that an impaired ability to discriminate information at the fundamental sensory processing level, in conjunction with a tendency to over-generalize information, could underlie ruminative thinking, perseverative or inflexible behavior, and cognitive rigidity; all of which are common in MDD (Watkins and Teasdale, 2001; Marazziti et al., 2010). As such, it could explain the mechanism underlying the activation of “automatic thoughts” or “schemas,” described in the Cognitive Behavioral Therapy model of MDD (Beck, 1979). For instance, the inability to identify discrepancies between stimuli may lead to stimulus “confusion,” triggering “responses” rehearsed and reinforced in overlapping but not identical situations. When these reflexive “responses” are cognitive, they are akin to automatic thoughts. Such stereotypic responses to situations could also disrupt psychological flexibility, highlighted in Acceptance and Commitment Therapy as a core process (Hayes et al., 2013). It refers to one's propensity to willingly select behavioral responses based on his/her chosen values, rather than reflexively reverting to familiar actions (e.g., maladaptive habits), that may provide short-term relief without regard to the long-term ramifications. In fact, inflexibility related to impaired pattern separation may also extend to social interactions and relationships where the inability to take the perspective of others and adequately reflect on one's own motives, thoughts, desires and feelings are described as mentalizing deficits (Fonagy, 2003; Fischer-Kern et al., 2013). In this sense, neurogenesis, via pattern separation, may be critical for the development of metacognitive function, with clear implications for psychological well-being.
Finally, hippocampal neurogenesis also appears to contribute to emotional regulation (Femenia et al., 2012). The psychological regulation of emotions is a complex process, dependent on widespread neural networks, involving the limbic system, prefrontal cortex, amygdala and hippocampus (Davidson and Irwin, 1999; Lane et al., 2000; Phan et al., 2002). The ability to regulate one's emotions has been repeatedly found to be impaired in MDD (Gotlib and Joormann, 2010). This, again, highlights the potential functional impact of hippocampal adult neurogenesis in modulating local and more distant brain circuitry, including that involved in emotion regulation.
In sum, we speculate that impaired neurogenesis in MDD disrupts performance in pattern separation. This, in turn, affects higher-level processes resulting in cognitive and behavioral rigidity thought to manifest in ruminative thinking, activation of automatic thoughts and schemas, psychological inflexibility, and deficient mentalizing. Future studies in MDD should, therefore, aim not only to examine the association between adult neurogenesis and behavioral performance on pattern separation tasks, but also strive to investigate its association with the functioning of higher-order psychological processes implicated in MDD (e.g., psychological inflexibility, ruminative thinking, and mentalizing). As such, a multi-level assessment could be undertaken with different units of analysis (Table 1), similar to what has been proposed in the Research Domain Criteria matrix (Cuthbert and Insel, 2013).
Table 1. Proposed units of analysis to examine the role of pattern separation in depressive and anxiety disorders, presented in a Research Domain Criteria (RDoC) matrix format (Cuthbert and Insel, 2013).
Conclusion
This review proposes that reduced adult neurogenesis in the dentate gyrus causes deficits in pattern separation and downstream impairment in intra- and interpersonal information processing, thus forming one of the mechanisms underlying MDD and perhaps antidepressant efficacy. As such, future studies should build on available findings from non-clinical samples linking performance on pattern separation tasks to depression severity in order to determine its association with psychological functioning implicated in depressive and anxiety disorders, such as catastrophizing, impaired psychological flexibility, and mentalizing deficit (Beck et al., 1961; Young, 1994; Fonagy, 2003; Hayes et al., 2013). This could be combined with emerging state-of-the-art technology to assess neurogenesis in-vivo in humans. In fact, magnetic resonance spectroscopy (MRS)-based imaging is making progress toward this goal, measuring mono-unsaturated fatty acids highly enriched in neuroprogenitor cells that resonate at 1.28 ppm in the NMR spectrum (Ma et al., 2011; Choi et al., 2017). While providing only an indirect measure of neurogenesis, this state-of-the-art MRS-based technique will be a valuable tool to supplement other advances recently made in in-vivo imaging of hippocampal adult neurogenesis in humans (Sierra et al., 2011; Ho et al., 2013; Tamura and Kataoka, 2017; Van de Bittner et al., 2017). Ultimately, any measure of hippocampal neurogenesis would need to be combined with measures of functional brain activity in order to provide further validation of the model we propose.
Author Contributions
KG, MM, and CC conceptualized this work and prepared the first draft. SK, CS, and LD provided revisions for important intellectual content. All authors gave final approval of the manuscript to be published and have agreed to be held accountable for the accuracy and integrity of this manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Aimone, J. B., Deng, W., and Gage, F. H. (2011). Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589–596. doi: 10.1016/j.neuron.2011.05.010
Altman, J. (1962). Are new neurons formed in the brains of adult mammals? Science 135, 1127–1128. doi: 10.1126/science.135.3509.1127
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). Arlington, VA.
Bakker, A., Kirwan, C. B., Miller, M., and Stark, C. E. (2008). Pattern separation in the human hippocampal CA3 and dentate gyrus. Science 319, 1640–1642. doi: 10.1126/science.1152882
Beck, A. T., Ward, C. H., Mendelson, M., Mock, J., and Erbaugh, J. (1961). An inventory for measuring depression. Arch. Gen. Psychiatry 4, 561–571. doi: 10.1001/archpsyc.1961.01710120031004
Bergmann, O., Liebl, J., Bernard, S., Alkass, K., Yeung, M. S., Steier, P., et al. (2012). The age of olfactory bulb neurons in humans. Neuron 74, 634–639. doi: 10.1016/j.neuron.2012.03.030
Bessa, J. M., Ferreira, D., Melo, I., Marques, F., Cerqueira, J. J., Palha, J. A., et al. (2009). The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol. Psychiatry 14, 764–773, 739. doi: 10.1038/mp.2008.119
Binder, E., Droste, S. K., Ohl, F., and Reul, J. M. (2004). Regular voluntary exercise reduces anxiety-related behaviour and impulsiveness in mice. Behav. Brain Res. 155, 197–206. doi: 10.1016/j.bbr.2004.04.017
Bjornebekk, A., Mathe, A. A., and Brene, S. (2005). The antidepressant effect of running is associated with increased hippocampal cell proliferation. Int. J. Neuropsychopharmacol. 8, 357–368. doi: 10.1017/S1461145705005122
Boldrini, M., Santiago, A. N., Hen, R., Dwork, A. J., Rosoklija, G. B., Tamir, H., et al. (2013). Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression. Neuropsychopharmacology 38, 1068–1077. doi: 10.1038/npp.2013.5
Boldrini, M., Underwood, M. D., Hen, R., Rosoklija, G. B., Dwork, A. J., John Mann, J., et al. (2009). Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34, 2376–2389. doi: 10.1038/npp.2009.75
Bremner, J. D., Vythilingam, M., Vermetten, E., Vaccarino, V., and Charney, D. S. (2004). Deficits in hippocampal and anterior cingulate functioning during verbal declarative memory encoding in midlife major depression. Am. J. Psychiatry 161, 637–645. doi: 10.1176/appi.ajp.161.4.637
Brummelte, S., and Galea, L. A. (2010). Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats. Neuroscience 168, 680–690. doi: 10.1016/j.neuroscience.2010.04.023
Burghardt, N. S., Park, E. H., Hen, R., and Fenton, A. A. (2012). Adult-born hippocampal neurons promote cognitive flexibility in mice. Hippocampus 22, 1795–1808. doi: 10.1002/hipo.22013
Burt, D. B., Zembar, M. J., and Niederehe, G. (1995). Depression and memory impairment: a meta-analysis of the association, its pattern, and specificity. Psychol. Bull. 117, 285–305. doi: 10.1037/0033-2909.117.2.285
Campeau, S., Nyhuis, T. J., Sasse, S. K., Kryskow, E. M., Herlihy, L., Masini, C. V., et al. (2010). Hypothalamic pituitary adrenal axis responses to low-intensity stressors are reduced after voluntary wheel running in rats. J. Neuroendocrinol. 22, 872–888. doi: 10.1111/j.1365-2826.2010.02007.x
Castilla-Ortega, E., Pedraza, C., Estivill-Torrus, G., and Santin, L. J. (2011). When is adult hippocampal neurogenesis necessary for learning? Evidence from animal research. Rev. Neurosci. 22, 267–283. doi: 10.1515/rns.2011.027
Chen, F., Madsen, T. M., Wegener, G., and Nyengaard, J. R. (2009). Repeated electroconvulsive seizures increase the total number of synapses in adult male rat hippocampus. Eur. Neuropsychopharmacol. 19, 329–338. doi: 10.1016/j.euroneuro.2008.12.007
Choi, W. M. L., Thakkar, A., Gopakumar, S., MacKenzie, K., and Maletic-Savatic, M. (2017). “Lipid biomarker of neural stem and progenitor cells affects Nr2e1 (Tlx) transcriptional activity,” in Keystone Symposium on Adult Neurogenesis, (Stockholm).
Clelland, C. D., Choi, M., Romberg, C., Clemenson, G. D. Jr., Fragniere, A., Tyers, P., et al. (2009). A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325, 210–213. doi: 10.1126/science.1173215
Cohen, S., Janicki-Deverts, D., and Miller, G. E. (2007). Psychological stress and disease. JAMA 298, 1685–1687. doi: 10.1001/jama.298.14.1685
Cowen, D. S., Takase, L. F., Fornal, C. A., and Jacobs, B. L. (2008). Age-dependent decline in hippocampal neurogenesis is not altered by chronic treatment with fluoxetine. Brain Res. 1228, 14–19. doi: 10.1016/j.brainres.2008.06.059
Curtis, M. A., Low, V. F., and Faull, R. L. (2012). Neurogenesis and progenitor cells in the adult human brain: a comparison between hippocampal and subventricular progenitor proliferation. Dev. Neurobiol. 72, 990–1005. doi: 10.1002/dneu.22028
Cushman, J. D., Maldonado, J., Kwon, E. E., Garcia, A. D., Fan, G., Imura, T., et al. (2012). Juvenile neurogenesis makes essential contributions to adult brain structure and plays a sex-dependent role in fear memories. Front. Behav. Neurosci. 6:3. doi: 10.3389/fnbeh.2012.00003
Cuthbert, B. N., and Insel, T. R. (2013). Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med. 11:126. doi: 10.1186/1741-7015-11-126
Das, T., Ivleva, E. I., Wagner, A. D., Stark, C. E., and Tamminga, C. A. (2014). Loss of pattern separation performance in schizophrenia suggests dentate gyrus dysfunction. Schizophr. Res. 159, 193–197. doi: 10.1016/j.schres.2014.05.006
David, D. J., Samuels, B. A., Rainer, Q., Wang, J. W., Marsteller, D., Mendez, I., et al. (2009). Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron 62, 479–493. doi: 10.1016/j.neuron.2009.04.017
Davidson, R. J., and Irwin, W. (1999). The functional neuroanatomy of emotion and affective style. Trends Cogn. Sci. 3, 11–21. doi: 10.1016/S1364-6613(98)01265-0
de Andrade, J. S., Cespedes, I. C., Abrao, R. O., Dos Santos, T. B., Diniz, L., Britto, L. R., et al. (2013). Chronic unpredictable mild stress alters an anxiety-related defensive response, Fos immunoreactivity and hippocampal adult neurogenesis. Behav. Brain Res. 250, 81–90. doi: 10.1016/j.bbr.2013.04.031
Dearing, K. F., and Gotlib, I. H. (2009). Interpretation of ambiguous information in girls at risk for depression. J. Abnorm. Child Psychol. 37, 79–91. doi: 10.1007/s10802-008-9259-z
Dery, N., Pilgrim, M., Gibala, M., Gillen, J., Wojtowicz, J. M., Macqueen, G., et al. (2013). Adult hippocampal neurogenesis reduces memory interference in humans: opposing effects of aerobic exercise and depression. Front. Neurosci. 7:66. doi: 10.3389/fnins.2013.00066
Deveney, C. M., and Deldin, P. J. (2006). A preliminary investigation of cognitive flexibility for emotional information in major depressive disorder and non-psychiatric controls. Emotion 6, 429–437. doi: 10.1037/1528-3542.6.3.429
Doetsch, F., Garcia-Verdugo, J. M., and Alvarez-Buylla, A. (1997). Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J. Neurosci. 17, 5046–5061.
Drevets, W. C., Price, J. L., and Furey, M. L. (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct. Funct. 213, 93–118. doi: 10.1007/s00429-008-0189-x
Duman, R. S., Aghajanian, G. K., Sanacora, G., and Krystal, J. H. (2016). Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat. Med. 22, 238–249. doi: 10.1038/nm.4050
Dupret, D., Revest, J. M., Koehl, M., Ichas, F., De Giorgi, F., Costet, P., et al. (2008). Spatial relational memory requires hippocampal adult neurogenesis. PLoS ONE 3:e1959. doi: 10.1371/journal.pone.0001959
Epp, J. R., Silva Mera, R., Kohler, S., Josselyn, S. A., and Frankland, P. W. (2016). Neurogenesis-mediated forgetting minimizes proactive interference. Nat. Commun. 7:10838. doi: 10.1038/ncomms10838
Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A. M., Nordborg, C., Peterson, D. A., et al. (1998). Neurogenesis in the adult human hippocampus. Nat. Med. 4, 1313–1317. doi: 10.1038/3305
Esposito, M. S., Piatti, V. C., Laplagne, D. A., Morgenstern, N. A., Ferrari, C. C., Pitossi, F. J., et al. (2005). Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086. doi: 10.1523/JNEUROSCI.3114-05.2005
Farioli-Vecchioli, S., Saraulli, D., Costanzi, M., Pacioni, S., Cina, I., Aceti, M., et al. (2008). The timing of differentiation of adult hippocampal neurons is crucial for spatial memory. PLoS Biol. 6:e246. doi: 10.1371/journal.pbio.0060246
Femenia, T., Gomez-Galan, M., Lindskog, M., and Magara, S. (2012). Dysfunctional hippocampal activity affects emotion and cognition in mood disorders. Brain Res. 1476, 58–70. doi: 10.1016/j.brainres.2012.03.053
Fischer-Kern, M., Fonagy, P., Kapusta, N. D., Luyten, P., Boss, S., Naderer, A., et al. (2013). Mentalizing in female inpatients with major depressive disorder. J. Nerv. Ment. Dis. 201, 202–207. doi: 10.1097/NMD.0b013e3182845c0a
Fonagy, P. (2003). Clinical implications of attachment and mentalization: efforts to preserve the mind in contemporary treatment. Epilogue. Bull. Menninger Clin. 67, 271–280. doi: 10.1521/bumc.67.3.271.23438
Frodl, T., Schaub, A., Banac, S., Charypar, M., Jager, M., Kummler, P., et al. (2006). Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J. Psychiatry Neurosci. 31, 316–323.
Gotlib, I. H., and Joormann, J. (2010). Cognition and depression: current status and future directions. Annu. Rev. Clin. Psychol. 6, 285–312. doi: 10.1146/annurev.clinpsy.121208.131305
Gould, N. F., Holmes, M. K., Fantie, B. D., Luckenbaugh, D. A., Pine, D. S., Gould, T. D., et al. (2007). Performance on a virtual reality spatial memory navigation task in depressed patients. Am. J. Psychiatry 164, 516–519. doi: 10.1176/ajp.2007.164.3.516
Groves, J. O., Leslie, I., Huang, G. J., McHugh, S. B., Taylor, A., Mott, R., et al. (2013). Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic model. PLoS Genet. 9:e1003718. doi: 10.1371/journal.pgen.1003718
Hanson, N. D., Owens, M. J., Boss-Williams, K. A., Weiss, J. M., and Nemeroff, C. B. (2011). Several stressors fail to reduce adult hippocampal neurogenesis. Psychoneuroendocrinology 36, 1520–1529. doi: 10.1016/j.psyneuen.2011.04.006
Hayes, S. C., Levin, M. E., Plumb-Vilardaga, J., Villatte, J. L., and Pistorello, J. (2013). Acceptance and commitment therapy and contextual behavioral science: examining the progress of a distinctive model of behavioral and cognitive therapy. Behav. Ther. 44, 180–198. doi: 10.1016/j.beth.2009.08.002
Hill, A. S., Sahay, A., and Hen, R. (2015). Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology 40, 2368–2378. doi: 10.1038/npp.2015.85
Ho, N. F., Hooker, J. M., Sahay, A., Holt, D. J., and Roffman, J. L. (2013). In vivo imaging of adult human hippocampal neurogenesis: progress, pitfalls and promise. Mol. Psychiatry 18, 404–416. doi: 10.1038/mp.2013.8
Holick, K. A., Lee, D. C., Hen, R., and Dulawa, S. C. (2008). Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology 33, 406–417. doi: 10.1038/sj.npp.1301399
Huang, G. J., Bannerman, D., and Flint, J. (2008). Chronic fluoxetine treatment alters behavior, but not adult hippocampal neurogenesis, in BALB/cJ mice. Mol. Psychiatry 13, 119–121. doi: 10.1038/sj.mp.4002104
Huang, Y., Coupland, N. J., Lebel, R. M., Carter, R., Seres, P., Wilman, A. H., et al. (2013). Structural changes in hippocampal subfields in major depressive disorder: a high-field magnetic resonance imaging study. Biol. Psychiatry 74, 62–68. doi: 10.1016/j.biopsych.2013.01.005
Hvoslef-Eide, M., and Oomen, C. A. (2016). Adult neurogenesis and pattern separation in rodents: a critical evaluation of data, tasks and interpretation. Front. Biol. 11, 168–181. doi: 10.1007/s11515-016-1406-2
Ibi, D., Takuma, K., Koike, H., Mizoguchi, H., Tsuritani, K., Kuwahara, Y., et al. (2008). Social isolation rearing-induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion-related behaviors in juvenile mice. J. Neurochem. 105, 921–932. doi: 10.1111/j.1471-4159.2007.05207.x
Jessberger, S., Clark, R. E., Broadbent, N. J., Clemenson, G. D. Jr., Consiglio, A., Lie, D. C., et al. (2009). Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn. Mem. 16, 147–154. doi: 10.1101/lm.1172609
Jha, S., Dong, B., and Sakata, K. (2011). Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV. Transl. Psychiatry 1:e40. doi: 10.1038/tp.2011.33
Joormann, J., and Gotlib, I. H. (2010). Emotion regulation in depression: relation to cognitive inhibition. Cogn. Emot. 24, 281–298. doi: 10.1080/02699930903407948
Karten, Y. J., Olariu, A., and Cameron, H. A. (2005). Stress in early life inhibits neurogenesis in adulthood. Trends Neurosci. 28, 171–172. doi: 10.1016/j.tins.2005.01.009
Kempermann, G. (2002). Regulation of adult hippocampal neurogenesis-implications for novel theories of major depression. Bipolar Disord. 4, 17–33. doi: 10.1034/j.1399-5618.2002.40101.x
Kirwan, C. B., Hartshorn, A., Stark, S. M., Goodrich-Hunsaker, N. J., Hopkins, R. O., and Stark, C. E. (2012). Pattern separation deficits following damage to the hippocampus. Neuropsychologia 50, 2408–2414. doi: 10.1016/j.neuropsychologia.2012.06.011
Kirwan, C. B., and Stark, C. E. (2007). Overcoming interference: an fMRI investigation of pattern separation in the medial temporal lobe. Learn. Mem. 14, 625–633. doi: 10.1101/lm.663507
Klomp, A., Vaclavu, L., Meerhoff, G. F., Reneman, L., and Lucassen, P. J. (2014). Effects of chronic fluoxetine treatment on neurogenesis and tryptophan hydroxylase expression in adolescent and adult rats. PLoS ONE 9:e97603. doi: 10.1371/journal.pone.0097603
Knoth, R., Singec, I., Ditter, M., Pantazis, G., Capetian, P., Meyer, R. P., et al. (2010). Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE 5:e8809. doi: 10.1371/journal.pone.0008809
Kodama, M., Fujioka, T., and Duman, R. S. (2004). Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol. Psychiatry 56, 570–580. doi: 10.1016/j.biopsych.2004.07.008
Korosi, A., Naninck, E. F., Oomen, C. A., Schouten, M., Krugers, H., Fitzsimons, C., et al. (2012). Early-life stress mediated modulation of adult neurogenesis and behavior. Behav. Brain Res. 227, 400–409. doi: 10.1016/j.bbr.2011.07.037
Kronenberg, G., Bick-Sander, A., Bunk, E., Wolf, C., Ehninger, D., and Kempermann, G. (2006). Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus. Neurobiol. Aging 27, 1505–1513. doi: 10.1016/j.neurobiolaging.2005.09.016
Kubera, M., Obuchowicz, E., Goehler, L., Brzeszcz, J., and Maes, M. (2011). In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 744–759. doi: 10.1016/j.pnpbp.2010.08.026
Lacy, J. W., Yassa, M. A., Stark, S. M., Muftuler, L. T., and Stark, C. E. (2011). Distinct pattern separation related transfer functions in human CA3/dentate and CA1 revealed using high-resolution fMRI and variable mnemonic similarity. Learn. Mem. 18, 15–18. doi: 10.1101/lm.1971111
Lane, R. D., Nadel, L., Allen, J. J., and Kaszniak, A. W. (2000). “The study of emotion from the perspective of cognitive neuroscience,” in Cognitive Neuroscience of Emotion, eds R. D. Lane and L. Nadel (New York, NY: Oxford University Press, Inc.), 3–11.
Lee, R. S., Hermens, D. F., Porter, M. A., and Redoblado-Hodge, M. A. (2012). A meta-analysis of cognitive deficits in first-episode major depressive disorder. J. Affect. Disord. 140, 113–124. doi: 10.1016/j.jad.2011.10.023
Leppanen, J. M., Milders, M., Bell, J. S., Terriere, E., and Hietanen, J. K. (2004). Depression biases the recognition of emotionally neutral faces. Psychiatry Res. 128, 123–133. doi: 10.1016/j.psychres.2004.05.020
Letkiewicz, A. M., Miller, G. A., Crocker, L. D., Warren, S. L., Infantolino, Z. P., Mimnaugh, K. J., et al. (2014). Executive function deficits in daily life prospectively predict increases in depressive symptoms. Cognit. Ther. Res. 38, 612–620. doi: 10.1007/s10608-014-9629-5
Liu, W., Sheng, H., Xu, Y., Liu, Y., Lu, J., and Ni, X. (2013). Swimming exercise ameliorates depression-like behavior in chronically stressed rats: relevant to proinflammatory cytokines and IDO activation. Behav. Brain Res. 242, 110–116. doi: 10.1016/j.bbr.2012.12.041
Lucassen, P. J., Oomen, C. A., Naninck, E. F., Fitzsimons, C. P., van Dam, A. M., Czeh, B., et al. (2015). Regulation of adult neurogenesis and plasticity by (Early) stress, glucocorticoids, and inflammation. Cold Spring Harb. Perspect. Biol. 7:a021303. doi: 10.1101/cshperspect.a021303
Luger, A., Deuster, P. A., Kyle, S. B., Gallucci, W. T., Montgomery, L. C., Gold, P. W., et al. (1987). Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. Physiologic adaptations to physical training. N. Engl. J. Med. 316, 1309–1315. doi: 10.1056/NEJM198705213162105
Ma, L. H., Li, Y., Djuric, P. M., and Maletic-Savatic, M. (2011). Systems biology approach to imaging of neural stem cells. Methods Mol. Biol. 711, 421–434. doi: 10.1007/978-1-61737-992-5_21
MacQueen, G. M., Campbell, S., McEwen, B. S., Macdonald, K., Amano, S., Joffe, R. T., et al. (2003). Course of illness, hippocampal function, and hippocampal volume in major depression. Proc. Natl. Acad. Sci. U.S.A. 100, 1387–1392. doi: 10.1073/pnas.0337481100
Madsen, T. M., Yeh, D. D., Valentine, G. W., and Duman, R. S. (2005). Electroconvulsive seizure treatment increases cell proliferation in rat frontal cortex. Neuropsychopharmacology 30, 27–34. doi: 10.1038/sj.npp.1300565
Marazziti, D., Consoli, G., Picchetti, M., Carlini, M., and Faravelli, L. (2010). Cognitive impairment in major depression. Eur. J. Pharmacol. 626, 83–86. doi: 10.1016/j.ejphar.2009.08.046
Marlatt, M. W., Potter, M. C., Lucassen, P. J., and van Praag, H. (2012). Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice. Dev. Neurobiol. 72, 943–952. doi: 10.1002/dneu.22009
McCormick, C. M., Thomas, C. M., Sheridan, C. S., Nixon, F., Flynn, J. A., and Mathews, I. Z. (2012). Social instability stress in adolescent male rats alters hippocampal neurogenesis and produces deficits in spatial location memory in adulthood. Hippocampus 22, 1300–1312. doi: 10.1002/hipo.20966
Meshi, D., Drew, M. R., Saxe, M., Ansorge, M. S., David, D., Santarelli, L., et al. (2006). Hippocampal neurogenesis is not required for behavioral effects of environmental enrichment. Nat. Neurosci. 9, 729–731. doi: 10.1038/nn1696
Miller, B. R., and Hen, R. (2015). The current state of the neurogenic theory of depression and anxiety. Curr. Opin. Neurobiol. 30, 51–58. doi: 10.1016/j.conb.2014.08.012
Miller, J. A., Nathanson, J., Franjic, D., Shim, S., Dalley, R. A., Shapouri, S., et al. (2013). Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. Development 140, 4633–4644. doi: 10.1242/dev.097212
Mogg, K., Bradbury, K. E., and Bradley, B. P. (2006). Interpretation of ambiguous information in clinical depression. Behav. Res. Ther. 44, 1411–1419. doi: 10.1016/j.brat.2005.10.008
Morshead, C. M., Reynolds, B. A., Craig, C. G., McBurney, M. W., Staines, W. A., Morassutti, D., et al. (1994). Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13, 1071–1082. doi: 10.1016/0896-6273(94)90046-9
Ngwenya, L. B., Peters, A., and Rosene, D. L. (2006). Maturational sequence of newly generated neurons in the dentate gyrus of the young adult rhesus monkey. J. Comp. Neurol. 498, 204–216. doi: 10.1002/cne.21045
National Institute of Mental Health (2015). U.S. Department of Health and Human Services N.I.o.H. Depression. Bethesda, MD: U.S.G.P. Office. NIH Publication No. 15–3561.
National Survey on Drug Use and Health (2015). Substance Abuse and Mental Health Services Administration, Results from the: National Findings. O.o.A. Studied, Rockville, MD: NSDUH Series H-50, SAMHSA.
Palmer, T. D., Takahashi, J., and Gage, F. H. (1997). The adult rat hippocampus contains primordial neural stem cells. Mol. Cell. Neurosci. 8, 389–404. doi: 10.1006/mcne.1996.0595
Pariante, C. M., and Lightman, S. L. (2008). The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 31, 464–468. doi: 10.1016/j.tins.2008.06.006
Park, H., Yang, J., Kim, R., Li, Y., Lee, Y., Lee, C., et al. (2015). Mice lacking the PSD-95-interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning. Sci. Rep. 5:16410. doi: 10.1038/srep16410
Perera, T. D., Coplan, J. D., Lisanby, S. H., Lipira, C. M., Arif, M., Carpio, C., et al. (2007). Antidepressant-induced neurogenesis in the hippocampus of adult nonhuman primates. J. Neurosci. 27, 4894–4901. doi: 10.1523/JNEUROSCI.0237-07.2007
Perera, T. D., Dwork, A. J., Keegan, K. A., Thirumangalakudi, L., Lipira, C. M., Joyce, N., et al. (2011). Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates. PLoS ONE 6:e17600. doi: 10.1371/journal.pone.0017600
Phan, K. L., Wager, T., Taylor, S. F., and Liberzon, I. (2002). Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 16, 331–348. doi: 10.1006/nimg.2002.1087
Quinones-Hinojosa, A., Sanai, N., Soriano-Navarro, M., Gonzalez-Perez, O., Mirzadeh, Z., Gil-Perotin, S., et al. (2006). Cellular composition and cytoarchitecture of the adult human subventricular zone: a niche of neural stem cells. J. Comp. Neurol. 494, 415–434. doi: 10.1002/cne.20798
Ramirez-Amaya, V., Marrone, D. F., Gage, F. H., Worley, P. F., and Barnes, C. A. (2006). Integration of new neurons into functional neural networks. J. Neurosci. 26, 12237–12241. doi: 10.1523/JNEUROSCI.2195-06.2006
Reif, A., Fritzen, S., Finger, M., Strobel, A., Lauer, M., Schmitt, A., et al. (2006). Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol. Psychiatry 11, 514–522. doi: 10.1038/sj.mp.4001791
Rose, E. J., and Ebmeier, K. P. (2006). Pattern of impaired working memory during major depression. J. Affect. Disord. 90, 149–161. doi: 10.1016/j.jad.2005.11.003
Sahay, A., Scobie, K. N., Hill, A. S., O'Carroll, C. M., Kheirbek, M. A., Burghardt, N. S., et al. (2011a). Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 472, 466–470. doi: 10.1038/nature09817
Sahay, A., Wilson, D. A., and Hen, R. (2011b). Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582–588. doi: 10.1016/j.neuron.2011.05.012
Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., et al. (2003). Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809. doi: 10.1126/science.1083328
Saxe, M. D., Malleret, G., Vronskaya, S., Mendez, I., Garcia, A. D., Sofroniew, M. V., et al. (2007). Paradoxical influence of hippocampal neurogenesis on working memory. Proc. Natl. Acad. Sci. U.S.A. 104, 4642–4646. doi: 10.1073/pnas.0611718104
Schmaal, L., Veltman, D. J., van Erp, T. G., Samann, P. G., Frodl, T., Jahanshad, N., et al. (2016). Subcortical brain alterations in major depressive disorder: findings from the ENIGMA major depressive disorder working group. Mol. Psychiatry 21, 806–812. doi: 10.1038/mp.2015.69
Segi-Nishida, E., Warner-Schmidt, J. L., and Duman, R. S. (2008). Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus. Proc. Natl. Acad. Sci. U.S.A. 105, 11352–11357. doi: 10.1073/pnas.0710858105
Semerci, F., and Maletic-Savatic, M. (2016). Transgenic mouse models for studying adult neurogenesis. Front. Biol. 11, 151–167. doi: 10.1007/s11515-016-1405-3
Shelton, D. J., and Kirwan, C. B. (2013). A possible negative influence of depression on the ability to overcome memory interference. Behav. Brain Res. 256, 20–26. doi: 10.1016/j.bbr.2013.08.016
Sierra, A., Encinas, J. M., and Maletic-Savatic, M. (2011). Adult human neurogenesis: from microscopy to magnetic resonance imaging. Front. Neurosci. 5:47. doi: 10.3389/fnins.2011.00047
Snyder, H. R. (2013). Major depressive disorder is associated with broad impairments on neuropsychological measures of executive function: a meta-analysis and review. Psychol. Bull. 139, 81–132. doi: 10.1037/a0028727
Snyder, J. S., and Cameron, H. A. (2012). Could adult hippocampal neurogenesis be relevant for human behavior? Behav. Brain Res. 227, 384–390. doi: 10.1016/j.bbr.2011.06.024
Snyder, J. S., Hong, N. S., McDonald, R. J., and Wojtowicz, J. M. (2005). A role for adult neurogenesis in spatial long-term memory. Neuroscience 130, 843–852. doi: 10.1016/j.neuroscience.2004.10.009
Soderlund, H., Moscovitch, M., Kumar, N., Daskalakis, Z. J., Flint, A., Herrmann, N., et al. (2014). Autobiographical episodic memory in major depressive disorder. J. Abnorm. Psychol. 123, 51–60. doi: 10.1037/a0035610
Spalding, K. L., Bergmann, O., Alkass, K., Bernard, S., Salehpour, M., Huttner, H. B., et al. (2013). Dynamics of hippocampal neurogenesis in adult humans. Cell 153, 1219–1227. doi: 10.1016/j.cell.2013.05.002
Stark, S. M., Yassa, M. A., Lacy, J. W., and Stark, C. E. (2013). A task to assess behavioral pattern separation (BPS) in humans: data from healthy aging and mild cognitive impairment. Neuropsychologia 51, 2442–2449. doi: 10.1016/j.neuropsychologia.2012.12.014
Starzec, J. J., Berger, D. F., and Hesse, R. (1983). Effects of stress and exercise on plasma corticosterone, plasma cholesterol, and aortic cholesterol levels in rats. Psychosom. Med. 45, 219–226. doi: 10.1097/00006842-198306000-00004
Stockmeier, C. A., Mahajan, G. J., Konick, L. C., Overholser, J. C., Jurjus, G. J., Meltzer, H. Y., et al. (2004). Cellular changes in the postmortem hippocampus in major depression. Biol. Psychiatry 56, 640–650. doi: 10.1016/j.biopsych.2004.08.022
Svensson, M., Grahm, M., Ekstrand, J., Hoglund, P., Johansson, M., and Tingstrom, A. (2016). Effect of electroconvulsive seizures on cognitive flexibility. Hippocampus 26, 899–910. doi: 10.1002/hipo.22573
Swan, A. A., Clutton, J. E., Chary, P. K., Cook, S. G., Liu, G. G., and Drew, M. R. (2014). Characterization of the role of adult neurogenesis in touch-screen discrimination learning. Hippocampus 24, 1581–1591. doi: 10.1002/hipo.22337
Tamura, Y., and Kataoka, Y. (2017). PET imaging of neurogenic activity in the adult brain: toward in vivo imaging of human neurogenesis. Neurogenesis 4:e1281861. doi: 10.1080/23262133.2017.1281861
Thomas, R. M., Hotsenpiller, G., and Peterson, D. A. (2007). Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J. Neurosci. 27, 2734–2743. doi: 10.1523/JNEUROSCI.3849-06.2007
Toni, N., Laplagne, D. A., Zhao, C., Lombardi, G., Ribak, C. E., Gage, F. H., et al. (2008). Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat. Neurosci. 11, 901–907. doi: 10.1038/nn.2156
Toni, N., Teng, E. M., Bushong, E. A., Aimone, J. B., Zhao, C., Consiglio, A., et al. (2007). Synapse formation on neurons born in the adult hippocampus. Nat. Neurosci. 10, 727–734. doi: 10.1038/nn.1908
Van de Bittner, G. C., Riley, M. M., Cao, L., Ehses, J., Herrick, S. P., Ricq, E. L., et al. (2017). Nasal neuron PET imaging quantifies neuron generation and degeneration. J. Clin. Invest. 127, 681–694. doi: 10.1172/JCI89162
van Praag, H., Kempermann, G., and Gage, F. H. (1999). Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270. doi: 10.1038/6368
van Praag, H., Schinder, A. F., Christie, B. R., Toni, N., Palmer, T. D., and Gage, F. H. (2002). Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034. doi: 10.1038/4151030a
Veena, J., Srikumar, B. N., Mahati, K., Bhagya, V., Raju, T. R., and Shankaranarayana Rao, B. S. (2009a). Enriched environment restores hippocampal cell proliferation and ameliorates cognitive deficits in chronically stressed rats. J. Neurosci. Res. 87, 831–843. doi: 10.1002/jnr.21907
Veena, J., Srikumar, B. N., Raju, T. R., and Shankaranarayana Rao, B. S. (2009b). Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats. Neurosci. Lett. 455, 178–182. doi: 10.1016/j.neulet.2009.03.059
Vivar, C., Potter, M. C., Choi, J., Lee, J. Y., Stringer, T. P., Callaway, E. M., et al. (2012). Monosynaptic inputs to new neurons in the dentate gyrus. Nat. Commun. 3:1107. doi: 10.1038/ncomms2101
Vivar, C., and van Praag, H. (2013). Functional circuits of new neurons in the dentate gyrus. Front. Neural Circuits 7:15. doi: 10.3389/fncir.2013.00015
Warner-Schmidt, J. L., Madsen, T. M., and Duman, R. S. (2008). Electroconvulsive seizure restores neurogenesis and hippocampus-dependent fear memory after disruption by irradiation. Eur. J. Neurosci. 27, 1485–1493. doi: 10.1111/j.1460-9568.2008.06118.x
Watkins, E., and Teasdale, J. D. (2001). Rumination and overgeneral memory in depression: effects of self-focus and analytic thinking. J. Abnorm. Psychol. 110, 353–357. doi: 10.1037/0021-843X.110.2.333
Whittle, S., Lichter, R., Dennison, M., Vijayakumar, N., Schwartz, O., Byrne, M. L., et al. (2014). Structural brain development and depression onset during adolescence: a prospective longitudinal study. Am. J. Psychiatry 171, 564–571. doi: 10.1176/appi.ajp.2013.13070920
Winocur, G., Wojtowicz, J. M., Sekeres, M., Snyder, J. S., and Wang, S. (2006). Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus 16, 296–304. doi: 10.1002/hipo.20163
Wiskott, L., Rasch, M. J., and Kempermann, G. (2006). A functional hypothesis for adult hippocampal neurogenesis: avoidance of catastrophic interference in the dentate gyrus. Hippocampus 16, 329–343. doi: 10.1002/hipo.20167
Wu, M. V., Shamy, J. L., Bedi, G., Choi, C. W., Wall, M. M., Arango, V., et al. (2014). Impact of social status and antidepressant treatment on neurogenesis in the baboon hippocampus. Neuropsychopharmacology 39, 1861–1871. doi: 10.1038/npp.2014.33
Yassa, M. A., and Stark, C. E. (2011). Pattern separation in the hippocampus. Trends Neurosci. 34, 515–525. doi: 10.1016/j.tins.2011.06.006
Yau, S. Y., Lau, B. W., Tong, J. B., Wong, R., Ching, Y. P., Qiu, G., et al. (2011). Hippocampal neurogenesis and dendritic plasticity support running-improved spatial learning and depression-like behaviour in stressed rats. PLoS ONE 6:e24263. doi: 10.1371/journal.pone.0024263
Yau, S. Y., Li, A., Hoo, R. L., Ching, Y. P., Christie, B. R., Lee, T. M., et al. (2014). Physical exercise-induced hippocampal neurogenesis and antidepressant effects are mediated by the adipocyte hormone adiponectin. Proc. Natl. Acad. Sci. U.S.A. 111, 15810–15815. doi: 10.1073/pnas.1415219111
Young, J. E. (1994). Cognitive Therapy for Personality Disorders: A Schema-Focused Approach. Sarasota, FL: Professional Resource Press/Professional Resource Exchange.
Keywords: neurogenesis, pattern separation, major depressive disorder, dentate gyrus, RDoC matrix, psychological inflexibility, emotional dysfunction
Citation: Gandy K, Kim S, Sharp C, Dindo L, Maletic-Savatic M and Calarge C (2017) Pattern Separation: A Potential Marker of Impaired Hippocampal Adult Neurogenesis in Major Depressive Disorder. Front. Neurosci. 11:571. doi: 10.3389/fnins.2017.00571
Received: 17 July 2017; Accepted: 29 September 2017;
Published: 26 October 2017.
Edited by:
João O. Malva, University of Coimbra, PortugalReviewed by:
Muriel Koehl, Institut National de la Santé et de la Recherche Médicale, FranceJosé Luis Trejo, Consejo Superior de Investigaciones Científicas (CSIC), Spain
Copyright © 2017 Gandy, Kim, Sharp, Dindo, Maletic-Savatic and Calarge. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mirjana Maletic-Savatic, maletics@bcm.edu
Chadi Calarge, chadi.calarge@bcm.edu