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. 2022 Jul 16;7:16. doi: 10.1038/s41539-022-00133-y

Dissecting the role of adult hippocampal neurogenesis towards resilience versus susceptibility to stress-related mood disorders

Katherine L Jones 1, Mei Zhou 1,2, Dhanisha J Jhaveri 1,2,✉
PMCID: PMC9288448  PMID: 35842419

Abstract

Adult hippocampal neurogenesis in the developmental process of generating and integrating new neurons in the hippocampus during adulthood and is a unique form of structural plasticity with enormous potential to modulate neural circuit function and behaviour. Dysregulation of this process is strongly linked to stress-related neuropsychiatric conditions such as anxiety and depression, and efforts have focused on unravelling the contribution of adult-born neurons in regulating stress response and recovery. Chronic stress has been shown to impair this process, whereas treatment with clinical antidepressants was found to enhance the production of new neurons in the hippocampus. However, the precise role of adult hippocampal neurogenesis in mediating the behavioural response to chronic stress is not clear and whether these adult-born neurons buffer or increase susceptibility to stress-induced mood-related maladaptation remains one of the controversial issues. In this review, we appraise evidence probing the causal role of adult hippocampal neurogenesis in the regulation of emotional behaviour in rodents. We find that the relationship between adult-born hippocampal neurons and stress-related mood disorders is not linear, and that simple subtraction or addition of these neurons alone is not sufficient to lead to anxiety/depression or have antidepressant-like effects. We propose that future studies examining how stress affects unique properties of adult-born neurons, such as the excitability and the pattern of connectivity during their critical period of maturation will provide a deeper understanding of the mechanisms by which these neurons contribute to functional outcomes in stress-related mood disorders.

Subject terms: Adult neurogenesis, Cellular neuroscience

Introduction

The discovery of adult neurogenesis, i.e. the birth of new neurons in the adult brain, transformed our understanding of the extent of structural plasticity in the adult nervous system and heralded a new era in regenerative medicine by highlighting potential brain repair strategies for the treatment of neurodegenerative and neuropsychiatric conditions. The long-held dogma of a hard-wired, immutable brain was initially challenged by Joseph Altman and colleagues in the 1960s and pioneering studies by his group provided the first evidence supporting the generation of new neurons in the adult rodent brain1,2. However, these findings were largely dismissed due to the dominant views at the time and failed attempts by others to replicate their findings3–5. The field then remained dormant for the next two decades before its resurgence in the 1990s, when advances in immunolabelling and microscopy, as well as cell culture, approaches firmly established the production and integration of new neurons in the rodent brain (reviewed in detail in refs. 6,7). The multi-stage process of adult neurogenesis was shown to encompass the proliferation of endogenous populations of neural precursor cells, their differentiation into neurons and their migration and integration into existing neural circuitry7,8. This was found to occur primarily in two regions of the adult brain—the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus in most mammals9. Subsequently, several other regions, including the basolateral amygdala10,11 and hypothalamus12,13, were also shown to harbour this neurogenic capacity, albeit to a limited extent.

The hippocampus is an important brain region involved in the regulation of cognitive processes such as learning and memory as well as mood14. Studies in animal models have provided overwhelming support for the role of adult hippocampal neurogenesis in spatial and contextual learning, memory and forgetting (for details, see reviews15–17). However, its role in mood regulation is not fully understood. Given that deficits in learning and memory are common to neuropsychiatric disorders, it has been suggested that adult-born neurons could contribute to the pathophysiology of these disorders indirectly via the regulation of cognitive functions18,19. Thus, the potential of these adult-born neurons to impact fundamental brain functions spurred immense interest in establishing the occurrence and extent of neurogenesis in the adult human hippocampus. An initial birth-dating study using BrdU (5-Bromo-2′-deoxyuridine) to label dividing cells20, and a subsequent 14 C dating study21 provided tantalising evidence supporting the generation of new neurons in the adult human hippocampus. Although there are no approaches to directly and reliably measure levels of adult hippocampal neurogenesis in the live human brain, these findings have been corroborated by immunohistological studies that examined and quantified neural precursor cells and immature neurons based on marker gene expression in post-mortem human hippocampal tissue22–25. However, despite accumulating evidence supporting the presence of a sizeable population of immature neurons throughout adult life22,24,25, the origin of these neurons and the extent of neurogenesis in the adult human hippocampus continues to be debated26–29.

As true for many ground-breaking biomedical discoveries, the field of adult neurogenesis has also oscillated from discovery to initial scepticism, and from convincing evidence in animals to deliberation around its occurrence and significance in the human brain. However, a feature of adult hippocampal neurogenesis that has intrigued several neuroscientists is the unique physiology of adult-born neurons. These neurons exhibit heightened intrinsic excitability and a lower activation threshold30–32, particularly during their immature phase, which is believed to confer a high degree of plasticity and modulate excitation/inhibition balance with the hippocampal circuitry. Therefore, it is not surprising that considerable efforts have been devoted to answering two major questions. (i) how is adult hippocampal neurogenesis regulated? and (ii) what is its functional role?—with a view to harnessing this form of neural plasticity for promoting emotional and cognitive functions in various neurological conditions.

The mammalian hippocampus is densely packed with stress hormone receptors and is the key brain region involved in both sensing and regulating the response to stress33. Chronic and uncontrollable stress is a major risk factor for a wide range of neuropsychiatric disorders, including anxiety and depression34. In this review, we focus on the significance of adult hippocampal neurogenesis in mood regulation, evaluating the role of adult-born hippocampal neurons in mediating stress response and recovery. Although strong links exist between exposure to chronic stress, impairment in adult hippocampal neurogenesis and anxiety- and depression-like behaviour35, the nature of the relationship between this form of cellular plasticity and mood-related disorders requires further clarification. Here, we appraise studies that have directly examined the causal role of adult-born hippocampal neurons in altering mood-related behaviour in rodent models. These include both loss-of-function studies that have used ablation approaches and gain-of-function studies that have adopted genetic strategies to probe the function of these cells under baseline conditions as well as following stress and antidepressant treatment. We consider the strengths and limitations of these approaches in resolving the debate around whether adult-born neurons in the hippocampus confer resilience or promote susceptibility to stress-induced mood dysfunction. Lastly, we propose a unifying framework that may help to unravel the mechanisms that link stress-induced changes in adult hippocampal neurogenesis to affective behaviour, thereby paving the way for the development of novel antidepressant and/or resilience-promoting therapeutics.

Regulation of adult hippocampal neurogenesis by stress and antidepressants

Stress and clinical antidepressants have been identified as major regulators of adult hippocampal neurogenesis, with stress generally decreasing and antidepressants increasing the number of newborn neurons. Landmark studies in the 1990s by Gould and colleagues revealed that exposure to stressors decreases cell proliferation in the adult hippocampus36,37, an effect that was postulated to be driven by increases in the release of the stress hormone, glucocorticoid. In support of this notion, adrenalectomised animals showed an increase in cell proliferation38,39, whereas treatment with corticosterone (the major glucocorticoid in rodents) decreased cell proliferation38 in the hippocampus. Since these initial findings, numerous studies have reported a decline in adult hippocampal neurogenesis following exposure to various stressors during the prenatal or early postnatal periods, as well as in adult life (reviewed in ref. 40). A decrease in hippocampal neurogenesis has commonly been observed across multiple stress paradigms including chronic unpredictable mild stress41,42, social defeat stress43, and restraint stress41,44 as well as following chronic administration of corticosterone45,46. Besides affecting cell proliferation, chronic stress has been shown to impair neuronal differentiation and decrease the survival of newborn neurons43,47. However, there have also been studies that show no effects of stress on hippocampal cell proliferation48–51, with some even reporting an increase in hippocampal neurogenesis following stress52–54. Overall, stress-induced impairments in adult hippocampal neurogenesis appear to be influenced by multiple factors such as the nature and duration (acute versus chronic) of the stressors, and species, sex and strain of the animal.

The results demonstrating the deleterious effects of stress on adult hippocampal neurogenesis raised the question of whether antidepressant treatment could reverse or ameliorate these effects55. The first evidence appeared in 2000 from the Duman laboratory56, who demonstrated that the administration of different classes of antidepressants such as a monoamine oxidase inhibitor (tranylcypromine), a selective serotonin reuptake inhibitor (fluoxetine), and a selective norepinephrine reuptake inhibitor (reboxetine), as well as electroconvulsive therapy, led to an increase in cell proliferation and enhancement of adult hippocampal neurogenesis. These findings were replicated in several subsequent studies which highlighted the requirement of chronic but not acute administration of these clinical antidepressants to produce the neurogenic effect56–59. More recently, the fast-acting antidepressant ketamine has also been shown to enhance hippocampal neurogenesis by accelerating the maturation of adult-born neurons60. Similar to the effects of stress, these antidepressants have been shown to regulate different stages of adult neurogenesis, from stimulating the proliferation of neural precursor cells61, to promoting the survival and accelerating the maturation of the newborn neurons60,62–64. The neurogenesis-enhancing effects of antidepressants have also been found to be evolutionarily conserved, with post-mortem studies showing increases in cell proliferation in the hippocampi of depressed patients treated with antidepressants65. Interestingly, as opposed to the neurogenesis-promoting effects of antidepressants, chronic administration of diazepam, a commonly prescribed anxiolytic, has been shown to have no effects on the levels of adult hippocampal neurogenesis66,67.

Evidence for a causal link between adult hippocampal neurogenesis and mood regulation

Evidence showing that chronic stress exerts an inhibitory effect on adult neurogenesis36,38 and is a major risk factor for the development of mood disorders68 together with data showing neurogenesis-enhancing actions of antidepressants56 led to the neurogenic theory of anxiety/depression69, which posits that stress-induced impairment in neurogenesis is an important causal factor in the aetiology of anxiety/depression and that restoration of neurogenesis is necessary for the therapeutic effects of antidepressants.

To test this theory, various approaches including chemical70–72, X-ray irradiation45,73, and genetic strategies41,74,75 were developed to ablate adult neurogenesis in rodents (summarised in Table 1). In naïve non-stressed animals, most studies using methylazoxymethanol acetate (MAM), a mitotic blocker, or focal X-irradiation, which efficiently ablates adult neurogenesis reported no changes in anxiety/depression-related behaviours (see Box 1). However, findings from studies using transgenic rodent models in which adult neurogenesis was abrogated by expressing ‘toxic’ genes under neural precursor cell promoters such as the glial fibrillary acidic protein (GFAP) or Nestin have proven more variable. For example, in mice expressing a viral form of the enzyme thymidine kinase (TK) under the control of GFAP, ganciclovir treatment led to a near-complete abrogation of adult hippocampal neurogenesis41. An increase in anxiety-like behaviour in the forced swim test but not in the elevated plus maze, open field test or light/dark test was noted in these neurogenesis-ablated mice. On the other hand, expression of the proapoptotic protein Bax in Nestin-Bax mice led to increased anxiety-like behaviour in the elevated plus maze and light/dark test but not in the novelty-suppressed feeding test74, whereas inducible expression of the Diptheria toxin A chain (DTA) in an inducible Nestin-Cre mice resulted in increased latency to eat in the novelty-suppressed feeding test but not in the light/dark test75. The emergence of anxiety-like behaviour in naïve, non-stressed mice was therefore evident in select behavioural tests and was specific to genetic models used for ablating adult neurogenesis. In contrast, a study using inducible deletion of Tbr2, a T-box transcription factor highly expressed in neural precursor cells to block adult neurogenesis reported a reduction in anxiety-like behaviour in neurogenesis-ablated compared to control mice, but only when these tests were conducted during the dark cycle76.

Table 1.

Effects of ablating adult neurogenesis on mood-related behaviours in naïve, non-stressed animals.

Ablation approach Species Hippocampus-specific ablation? Behavioural tests Increased depressive/anxious behaviours? Reference
MAM Rats No Novelty-suppressed feeding Yes Bessa et al., 200970
Sucrose preference test No Bessa et al., 200970
Sucrose consumption No Jayatissa et al., 201071
Forced swim test No Bessa et al., 200970
Elevated plus maze No Shors et al., 200272
X-irradiation Mice Yes Novelty-suppressed feeding No David et al., 200945; Santarelli et al., 200373; Wang et al., 200864
Yes Sucrose consumption No Noonan et al., 2010106
Yes Forced swim test No Holick et al., 2008107; David et al., 200945
Yes Elevated plus maze No Saxe et al., 2006108
Yes Social interaction/avoidance Yes Lagace et al., 201052
Yes Open field test No Saxe et al., 2006108; David et al., 200945; Fuss et al., 2010109
Yes Light/Dark test No Saxe et al., 2006108
Yes Fuss et al., 2010109
Rats Yes Novelty-suppressed feeding No Zhu et al., 201084
Yes Sucrose consumption No Noonan et al., 2010106
Forced swim test No Airan et al., 2007110; Zhu et al., 201084
GFAP-TK Mice No Forced swim test Yes Snyder et al., 201141
Sucrose preference test Yes Snyder et al., 201141
Elevated plus maze No Snyder et al., 201141
No Open field test No Schloesser et al., 201043
Light/Dark test No Schloesser et al., 201043
GFAP-TK Rats No Novelty-suppressed feeding No Snyder et al., 201641
Sucrose preference test Yes Snyder et al., 201641
Open field test No Snyder et al., 201641
Nestin-Bax Mice No Novelty-suppressed Feeding No Revest et al., 200974
Forced swim test No Revest et al., 200974
Elevated plus maze Yes Revest et al., 200974
Light/Dark test Yes Revest et al., 200974
Nestin-TK Mice No Tail suspension test No Singer et al., 2009111
Nestin-CreERT2/floxed DTA Mice No Novelty induced hypophagia Yes Yun et al., 201675
Open field test No Yun et al., 201675
Tail suspension test Yes Yun et al., 201675
Light/Dark test No Yun et al., 201675
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Taken together, the role of adult-born hippocampal neurons in the regulation of baseline anxiety- or depression-related behaviour remains equivocal. Future studies using more specific strategies that selectively target adult-born neurons in the hippocampus while sparing those in other neurogenic niches in the brain are therefore needed. A recent study employing optogenetic activation of adult-born hippocampal neurons reported no changes in baseline anxiety-like behaviour77.

Compared to studies which investigated whether the loss of adult-born neurons is sufficient to induce anxiety- and depression-like behaviour, the findings from those which examined whether adult hippocampal neurogenesis is required for antidepressant efficacy have been more consistent. Using head-focused X-rays, Hen and colleagues were the first to show that the ablation of adult hippocampal neurogenesis blocked some of the beneficial effects of antidepressants fluoxetine and imipramine, in particular, their anxiolytic effects which were evaluated using the novelty-suppressed feeding test73. These findings were replicated by several other studies which used different approaches to ablate adult neurogenesis45,64,78,79. Recently, Tunc-Ozcan et al.80 used a chemogenetic approach to selectively modulate the activity of adult-born neurons and found that silencing their activity using Gi-coupled DREADDs (designer receptors exclusively activated by designer drugs) blocked the efficacy of fluoxetine in the tail suspension and open field tests. However, it is also worthwhile noting that the actions of antidepressants have been shown to be mediated via both neurogenesis-dependent and -independent mechanisms45,78,81–83.

Box 1 Behavioural tests assessing anxiety- and depression-like behaviour in rodents.

Assessing externally measurable anxiety- and depression-related phenotypes in rodents remains a major challenge, with widely used behavioural tasks recapitulating only aspects of these conditions. Various strategies exhibiting face, predictive and construct validity have now been developed112. For rodents, environments such as bright-lit, open exposed spaces where they are more visible to predators, are innately recognised as harbouring threats and avoided. These environmental features (open field) have therefore been used in the laboratory setting to elicit avoidance behaviour as a proxy for anxiety state. Approach–avoidance tasks exploiting conflicting motivational states such as measuring the rodent’s exploratory drive against the innate drive to avoid danger113 have been developed to assess levels of anxiety. Such features are present in tasks such as the novelty-suppressed feeding, elevated plus maze, and light/dark box test. A major advantage of these tasks is that they require no prior training, thereby assessing animals’ innate valence without the confounding effects of extensive learning. Similarly, measuring symptoms associated with depression, which is a complex, multifactorial, and heterogenous clinical syndrome in rodents has been difficult. However, some of the symptoms commonly observed in human patients are measured as depression-like behaviour in rodents. These include social avoidance which is measured following a chronic social defeat stress paradigm which induces avoidance behaviour in susceptible animals, anhedonia which is measured using a sucrose preference test, and learned helplessness and passive coping which are measured using a forced swim test and tail suspension test.

Do adult-born hippocampal neurons buffer or increase susceptibility to stress-induced mood disorders?

To fully realise the potential of adult hippocampal neurogenesis as a therapeutic strategy for stress-induced mood disorders, several studies have explored whether and how adult-born neurons in the hippocampus mediate the behavioural and endocrine response to chronic stressors (summarised in Table 2). Most studies using nonspecific ablation strategies such as cranial X-irradiation or cytostatic agents have reported no changes in the susceptibility to stress-induced anxiety- or depression-related behaviours43,45,78,84–86. One exception was the study by Bessa and colleagues which showed that treatment with the cytostatic agent MAM during the last two weeks of a 6-week chronic mild stress paradigm exacerbated stress-induced anxiety-like behaviour in the novelty-suppressed feeding test70, suggesting the stress-buffering actions of adult hippocampal neurogenesis. However, adult neurogenesis has also been implicated in promoting susceptibility to stress-induced mood dysfunction52,87. Using cranial X-irradiation ref. 52 found that ablation of adult neurogenesis prevented social defeat stress-induced social avoidance behaviour in mice. In another study, fluoxetine-induced enhancement of hippocampal neurogenesis was found to increase behavioural vulnerability, and blockade of neurogenesis using MAM was shown to protect against maladaptive behavioural changes induced by stress re-exposure87.

Table 2.

Effects of ablating adult neurogenesis on mood-related behaviours in stressed animals.

Ablation methods Start of ablation Stress model Behavioural Test Effects of ablation on stress-induced changes in behaviour Reference
X-irradiation The 22nd day of stress 5 weeks of UCMS Coat score No effects Zhu et al., 201084
Novelty-suppressed feeding No effects
5 weeks before stress 5 weeks of UCMS Splash test No effects Surget et al., 200878
Novelty-suppressed feeding No effects
5 weeks before stress 10 days of social defeat stress Social interaction test Blocked stress-induced social avoidance Lagace et al., 201052
1 week before stress 4 weeks chronic low CORT Open field test No effects David et al., 200945
Novelty-suppressed feeding No effects
Forced swim test No effects
MAM The 4th week of chronic stress 6 weeks of UCMS Forced swim test No effects Bessa et al., 200970
Sucrose preference test No effects
Novelty-suppressed feeding Aggravated stress-induced anxiety-like behaviour
GFAP-TK animal models Before stress 14 days of social defeat stress Sucrose preference test No effects Schloesser et al., 201043
Light-dark box No effects
Social interaction test No effects
The start of stress 4 weeks of unpredictable restraint stress Novelty-suppressed feeding A trend of decreased anxiety-like behaviour in stressed mice Schoenfeld et al., 201789
Sucrose Preference Test No effects
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On the other hand, studies using genetic strategies have reported that adult hippocampal neurogenesis buffers the stress response such that blocking neurogenesis leads to an enhanced glucocorticoid response and an increase in anxiety- and depressive-like behaviour41,82. Corroborating these results, a recent study found that chemogenetic silencing of adult-born neurons specifically in the ventral dentate gyrus increased the susceptibility to social defeat stress, resulting in avoidance of a novel mouse in a social interaction test88. However, as opposed to these findings supporting the stress-buffering actions of adult-born hippocampal neurons, a decrease in stress-induced anxiety-like behaviour has also been reported following blockade of adult neurogenesis in GFAP-TK rats89.

Based on these conflicting findings, the question of whether adult-born neurons in the hippocampus buffer or exacerbate the behavioural and endocrine effects of stress remains unresolved. Several factors may contribute to these discrepant results, including the ablation strategy and its efficacy and selectivity, the type of stressor and the timing and duration of both the stressor and ablation. For example, X-irradiation which robustly ablates hippocampal neurogenesis has also been shown to induce inflammation and morphological and synaptic alterations that take a long time to fully recover52,70,78,90. Moreover, it has been also shown to impact oligodendrocyte progenitor cells in the brain—a cell population that regulates anxiety and depressive-like behaviours in rodents91,92. While transgenic rodent models (GFAP-TK or Nestin-TK) have provided a more controlled approach to ablate adult neurogenesis, they also require prolonged ganciclovir treatment lasting up to several weeks to achieve good ablation efficiency43. In addition to ablating neural precursor cells, the addition of new glial cells is also impaired in these models93 which may further confound interpretations given the important roles of these cells in the pathophysiology of major depression94–96. Another important confound is that global manipulations of neurogenesis affect other neurogenic areas such as the subventricular zone which in turn likely impair olfactory functions which are known to influence emotional states97,98. These limitations highlight the need to use specific approaches with spatial and temporal control to either deplete or regulate the activity of adult-born neurons in the hippocampus in order to define their role in mediating the stress response and/or recovery.

Is enhancement of adult hippocampal neurogenesis sufficient to improve mood-related behaviour?

Compared to loss-of-function studies, very few investigations have examined whether selectively increasing adult hippocampal neurogenesis is sufficient to improve mood-related behaviour. A gain-of-function approach involving neural precursor cell-selective deletion of the proto-oncogene Bax was developed to genetically expand the population of adult-born neurons99. Although no baseline improvement in mood was found, enhancing the level of neurogenesis using this approach was shown to promote behavioural resilience to chronic corticosterone administration46 and chronic social defeat stress88. However, these results need to be considered carefully given that Bax has a non-apoptotic role in the regulation of synaptic plasticity100. Interestingly, a recent study showed that chemogenetic stimulation of adult-born neurons alleviates depressive-like behaviour following uncontrolled chronic mild stress in mice80, indicating that the activity of these neurons is sufficient to promote stress resilience.

Concluding remarks and outlook

The connection between stress, adult hippocampal neurogenesis and neuropsychiatric disorders has been a subject of intense investigation over the past two decades. However, so far, the neurogenic theory of mood disorders has fallen short in providing a unified mechanism that links stress to affective behaviour, as simple subtraction or addition of adult-born neurons alone is not sufficient to lead to anxiety/depression or have antidepressant-like effects, respectively. Moreover, the jury is still out regarding whether and how adult-born neurons in the hippocampus contribute towards promoting resilience or susceptibility to stress-related mood disorders.

Several important considerations have emerged from these studies. First, a change in the absolute number of adult-born hippocampal neurons alone is unlikely to be the key factor linking stress to altered behaviour. Instead, the activity of these neurons could be a major determinant in unravelling their role in the regulation of stress-induced changes in mood-related behaviour. Second, off-target effects of ablation approach used in the majority of studies, including the chronic nature of manipulations which likely lead to compensatory mechanisms as well as brain-wide ablation, as in the case of genetic strategies, preclude determining the precise role of adult-born hippocampal neurons. A third important consideration is the nature and duration of the stressors modelled in these studies, which are likely to influence the hypothalamic-pituitary-adrenal axis differently, resulting in stressor-specific alterations in the neurotransmitter and neuropeptide signalling in the brain. These may differentially impact various stages of adult hippocampal neurogenesis. Fourth, the timing of ablation is also a critical variable, with most studies examining the effects of stress on mood-related behaviour in neurogenesis-null animals. Characterising stress-induced changes in the properties of adult-born neurons and evaluating their causal role during different phases (acute, sub-chronic, chronic) of stress is likely to provide significant insights into the role of these neurons in mediating stress susceptibility versus resilience. Finally, not all mood-related behaviours are equally impacted following manipulation of adult hippocampal neurogenesis in rodents, with greater effects seen on anxiety-like (such as approach–avoidance) behaviour compared to depression-related (such as passive coping, anhedonia). Even amongst approach–avoidance type behaviour which is evaluated using the elevated plus maze, novelty-suppressed feeding or social avoidance tasks, differential effects of adult neurogenesis manipulations have been reported. It is likely that these may be driven by differences in exploration, motivation and reward contingencies associated with these tasks, which have distinct underlying neural circuits. Therefore, unravelling specific neural circuits that are modulated by adult hippocampal neurogenesis is an important direction for future studies. As stress-associated neuropsychiatric disorders are complex and heterogeneous in symptom criteria, defining the role of adult-born hippocampal neurons in the regulation of specific behaviour may therefore aid in stratifying patients who are likely to benefit from neurogenesis-based therapeutic strategies. Moreover, changes in cognitive processes such as spatial and contextual learning and memory that are modulated by adult-born neurons are not usually examined in these models but are likely to contribute towards differences in susceptibility versus resilience to stress-related mood disorders15,19.

Another key consideration which has largely been overlooked in previous studies is the relative contribution of adult-born neurons at immature versus mature stages of their development in both encoding and mediating the response to stressors101. The connectivity of adult-born neurons within the dentate gyrus—CA3 circuit at different stages of their morphological and functional maturation is complex but is beginning to be unravelled102,103. In particular, adult-born neurons exhibit a critical period of heightened intrinsic excitability and synaptic plasticity during their immature phase (approximately 4–6-week-old neurons) with the capacity to profoundly influence the activity of mature neurons within the dentate gyrus, thereby influencing the local circuit to control behaviour88. Therefore, unravelling how stress modifies intrinsic excitability as well as the presynaptic and postsynaptic connectome of adult-born neurons would shed further light on their contribution to the hippocampal circuit regulation and the control of behaviour.

Based on collective findings from previous studies, our working hypothesis is that the unique properties of adult-born hippocampal neurons during their critical period of maturation are functionally important and causally link chronic stress to altered mood-related behaviour. We posit therefore that (i) chronic stress exposure alters the cellular and physiological properties of these neurons, and their pattern of connectivity, resulting in a dysfunctional hippocampal circuit and that (ii) antidepressants exert their beneficial effects, in part, by modulating distinct cellular and functional properties of immature adult-born hippocampal neurons.

Thus, future studies should move beyond altering the overall levels of adult hippocampal neurogenesis and instead focus on monitoring and manipulating stress-induced changes in the molecular, cellular, and physiological properties of adult-born neurons as well as mapping their connectome. Also, given the functional dichotomy between dorsal and ventral hippocampal functions104 with the ventral hippocampus preferentially involved in mood regulation, future research should consider conducting region-specific manipulation of adult hippocampal neurogenesis to better define their role in regulating specific aspects of mood-related behaviour. This coupled with approaches that allow spatial and temporal control to both visualise and modulate the activity of newborn neurons at various stages of their maturation during a behavioural task, would help reveal their contribution to the stress response, recovery, and mood regulation. Whilst historically male rodents have been used in most studies, given the higher incidence of stress-related mood disorders in women than men, future studies should investigate the role of adult-born hippocampal neurons in both sexes. Recently, there have been some efforts towards developing new chronic stress paradigms that are effective in both adult male and female rodents in inducing mood-related behavioural changes105.

Collectively, the findings from this integrated approach are likely to provide important new perspectives on the physiological and functional significance of adult-born hippocampal neurons in mediating the stress response. This would bring us closer to developing treatments for stress-related mood disorders that are founded on a deeper molecular and cellular understanding of a defined neural subtype and circuit.

Reporting summary

Further information on research design is available in the Nature Research Reporting Summary linked to this article.

Supplementary information

Reporting Summary (908.1KB, pdf)

Acknowledgements

The writing of this review was supported by Mater Foundation Fellowship and the National Health and Medical Research Project grant (GNT1165060) to D.J.J. We are grateful to Rowan Tweedale for editorial assistance.

Author contributions

D.J.J. conceived the review; K.L.J. and D.J.J. prepared the original draft; M.Z. prepared the tables; D.J.J. reviewed and edited the manuscript, provided supervision and obtained funding.

Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

The online version contains supplementary material available at 10.1038/s41539-022-00133-y.

References

  • 1.Altman J. Are new neurons formed in the brains of adult mammals? Science. 1962;135:1127–1128. doi: 10.1126/science.135.3509.1127. [DOI] [PubMed] [Google Scholar]
  • 2.Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J. Comp. Neurol. 1965;124:319–335. doi: 10.1002/cne.901240303. [DOI] [PubMed] [Google Scholar]
  • 3.Gross CG. Three before their time: neuroscientists whose ideas were ignored by their contemporaries. Exp. Brain Res. 2009;192:321–334. doi: 10.1007/s00221-008-1481-y. [DOI] [PubMed] [Google Scholar]
  • 4.Rakic P. Limits of neurogenesis in primates. Science. 1985;227:1054–1056. doi: 10.1126/science.3975601. [DOI] [PubMed] [Google Scholar]
  • 5.Rakic P. Adult neurogenesis in mammals: an identity crisis. J. Neurosci. 2002;22:614–618. doi: 10.1523/JNEUROSCI.22-03-00614.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Ming G-l, Song H. Adult neurogenesis in the mammalian central nervous system. Annu. Rev. Neurosci. 2005;28:223–250. doi: 10.1146/annurev.neuro.28.051804.101459. [DOI] [PubMed] [Google Scholar]
  • 7.Ming GL, Song H. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011;70:687–702. doi: 10.1016/j.neuron.2011.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Jhaveri DJ, Taylor CJ, Bartlett PF. Activation of different neural precursor populations in the adult hippocampus: does this lead to new neurons with discrete functions? Dev. Neurobiol. 2012;72:1044–1058. doi: 10.1002/dneu.22027. [DOI] [PubMed] [Google Scholar]
  • 9.Ma DK, Kim WR, Ming GL, Song H. Activity-dependent extrinsic regulation of adult olfactory bulb and hippocampal neurogenesis. Ann. N. Y Acad. Sci. 2009;1170:664–673. doi: 10.1111/j.1749-6632.2009.04373.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Bernier PJ, Bedard A, Vinet J, Levesque M, Parent A. Newly generated neurons in the amygdala and adjoining cortex of adult primates. Proc. Natl Acad. Sci. USA. 2002;99:11464–11469. doi: 10.1073/pnas.172403999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Jhaveri DJ, et al. Evidence for newly generated interneurons in the basolateral amygdala of adult mice. Mol. Psychiatry. 2018;23:521–532. doi: 10.1038/mp.2017.134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Kokoeva MV, Yin H, Flier JS. Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science. 2005;310:679–683. doi: 10.1126/science.1115360. [DOI] [PubMed] [Google Scholar]
  • 13.Lee DA, et al. Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat. Neurosci. 2012;15:700–702. doi: 10.1038/nn.3079. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Jonas P, Lisman J. Structure, function, and plasticity of hippocampal dentate gyrus microcircuits. Front. Neural Circuits. 2014;8:107. doi: 10.3389/fncir.2014.00107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Christian KM, Ming GL, Song H. Adult neurogenesis and the dentate gyrus: Predicting function from form. Behav. Brain Res. 2020;379:112346. doi: 10.1016/j.bbr.2019.112346. [DOI] [PubMed] [Google Scholar]
  • 16.Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? Nat. Rev. Neurosci. 2010;11:339–350. doi: 10.1038/nrn2822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Toda T, Parylak SL, Linker SB, Gage FH. The role of adult hippocampal neurogenesis in brain health and disease. Mol. Psychiatry. 2019;24:67–87. doi: 10.1038/s41380-018-0036-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Anacker C, Hen R. Adult hippocampal neurogenesis and cognitive flexibility - linking memory and mood. Nat. Rev. Neurosci. 2017;18:335–346. doi: 10.1038/nrn.2017.45. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Yun S, Reynolds RP, Masiulis I, Eisch AJ. Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis. Nat. Med. 2016;22:1239–1247. doi: 10.1038/nm.4218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Eriksson PS, et al. Neurogenesis in the adult human hippocampus. Nat. Med. 1998;4:1313–1317. doi: 10.1038/3305. [DOI] [PubMed] [Google Scholar]
  • 21.Spalding KL, et al. Dynamics of hippocampal neurogenesis in adult humans. Cell. 2013;153:1219–1227. doi: 10.1016/j.cell.2013.05.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Boldrini M, et al. Human hippocampal neurogenesis persists throughout aging. Cell Stem Cell. 2018;22:589–599 e585. doi: 10.1016/j.stem.2018.03.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Knoth R, et al. Murine features of neurogenesis in the human hippocampus across the lifespan from 0 to 100 years. PLoS ONE. 2010;5:e8809. doi: 10.1371/journal.pone.0008809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Moreno-Jimenez EP, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat. Med. 2019;25:554–560. doi: 10.1038/s41591-019-0375-9. [DOI] [PubMed] [Google Scholar]
  • 25.Tobin MK, et al. Human hippocampal neurogenesis persists in aged adults and Alzheimer’s disease patients. Cell Stem Cell. 2019;24:974–982 e973. doi: 10.1016/j.stem.2019.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Franjic D, et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron. 2022;110:452–469.e414. doi: 10.1016/j.neuron.2021.10.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Kempermann G, et al. Human adult neurogenesis: evidence and remaining questions. Cell Stem Cell. 2018;23:25–30. doi: 10.1016/j.stem.2018.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Snyder JS. Recalibrating the relevance of adult neurogenesis. Trends Neurosci. 2019;42:164–178. doi: 10.1016/j.tins.2018.12.001. [DOI] [PubMed] [Google Scholar]
  • 29.Sorrells SF, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018;555:377–381. doi: 10.1038/nature25975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Christian KM, Song H, Ming GL. Functions and dysfunctions of adult hippocampal neurogenesis. Annu. Rev. Neurosci. 2014;37:243–262. doi: 10.1146/annurev-neuro-071013-014134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Dieni CV, Nietz AK, Panichi R, Wadiche JI, Overstreet-Wadiche L. Distinct determinants of sparse activation during granule cell maturation. J. Neurosci. 2013;33:19131–19142. doi: 10.1523/JNEUROSCI.2289-13.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Temprana SG, et al. Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells. Neuron. 2015;85:116–130. doi: 10.1016/j.neuron.2014.11.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.McEwen BS. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 1999;22:105–122. doi: 10.1146/annurev.neuro.22.1.105. [DOI] [PubMed] [Google Scholar]
  • 34.Nestler EJ, et al. Neurobiology of depression. Neuron. 2002;34:13–25. doi: 10.1016/S0896-6273(02)00653-0. [DOI] [PubMed] [Google Scholar]
  • 35.Miller BR, Hen R. The current state of the neurogenic theory of depression and anxiety. Curr. Opin. Neurobiol. 2015;30:51–58. doi: 10.1016/j.conb.2014.08.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Gould E, McEwen BS, Tanapat P, Galea LAM, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J. Neurosci. 1997;17:2492. doi: 10.1523/JNEUROSCI.17-07-02492.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Gould E, Tanapat P, McEwen BS, Flügge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc. Natl Acad. Sci. USA. 1998;95:3168–3171. doi: 10.1073/pnas.95.6.3168. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Cameron HA, Gould E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience. 1994;61:203–209. doi: 10.1016/0306-4522(94)90224-0. [DOI] [PubMed] [Google Scholar]
  • 39.Cameron HA, McKay RD. Restoring production of hippocampal neurons in old age. Nat. Neurosci. 1999;2:894–897. doi: 10.1038/13197. [DOI] [PubMed] [Google Scholar]
  • 40.Levone BR, Cryan JF, O’Leary OF. Role of adult hippocampal neurogenesis in stress resilience. Neurobiol. Stress. 2015;1:147–155. doi: 10.1016/j.ynstr.2014.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011;476:458–461. doi: 10.1038/nature10287. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Jayatissa MN, Bisgaard C, Tingström A, Papp M, Wiborg O. Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology. 2006;31:2395–2404. doi: 10.1038/sj.npp.1301041. [DOI] [PubMed] [Google Scholar]
  • 43.Schloesser RJ, Lehmann M, Martinowich K, Manji HK, Herkenham M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol. Psychiatry. 2010;15:1152–1163. doi: 10.1038/mp.2010.34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Rosenbrock H, Koros E, Bloching A, Podhorna J, Borsini F. Effect of chronic intermittent restraint stress on hippocampal expression of marker proteins for synaptic plasticity and progenitor cell proliferation in rats. Brain Res. 2005;1040:55–63. doi: 10.1016/j.brainres.2005.01.065. [DOI] [PubMed] [Google Scholar]
  • 45.David DJ, et al. Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 2009;62:479–493. doi: 10.1016/j.neuron.2009.04.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Hill AS, Sahay A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to reduce anxiety and depression-like behaviors. Neuropsychopharmacology. 2015;40:2368–2378. doi: 10.1038/npp.2015.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Mineur YS, Belzung C, Crusio WE. Functional implications of decreases in neurogenesis following chronic mild stress in mice. Neuroscience. 2007;150:251–259. doi: 10.1016/j.neuroscience.2007.09.045. [DOI] [PubMed] [Google Scholar]
  • 48.Dagyte G, et al. Chronic but not acute foot-shock stress leads to temporary suppression of cell proliferation in rat hippocampus. Neuroscience. 2009;162:904–913. doi: 10.1016/j.neuroscience.2009.05.053. [DOI] [PubMed] [Google Scholar]
  • 49.Hanson ND, Owens MJ, Boss-Williams KA, Weiss JM, Nemeroff CB. Several stressors fail to reduce adult hippocampal neurogenesis. Psychoneuroendocrinology. 2011;36:1520–1529. doi: 10.1016/j.psyneuen.2011.04.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Thomas RM, Urban JH, Peterson DA. Acute exposure to predator odor elicits a robust increase in corticosterone and a decrease in activity without altering proliferation in the adult rat hippocampus. Exp. Neurol. 2006;201:308–315. doi: 10.1016/j.expneurol.2006.04.010. [DOI] [PubMed] [Google Scholar]
  • 51.Thomas RM, Hotsenpiller G, Peterson DA. Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation. J. Neurosci. 2007;27:2734–2743. doi: 10.1523/JNEUROSCI.3849-06.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Lagace DC, et al. Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance. Proc. Natl Acad. Sci. USA. 2010;107:4436. doi: 10.1073/pnas.0910072107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Lyons DM, et al. Stress coping stimulates hippocampal neurogenesis in adult monkeys. Proc. Natl Acad. Sci. USA. 2010;107:14823–14827. doi: 10.1073/pnas.0914568107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Parihar VK, Hattiangady B, Kuruba R, Shuai B, Shetty AK. Predictable chronic mild stress improves mood, hippocampal neurogenesis and memory. Mol. Psychiatry. 2011;16:171–183. doi: 10.1038/mp.2009.130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Duman RS, Malberg J, Thome J. Neural plasticity to stress and antidepressant treatment. Biol. Psychiatry. 1999;46:1181–1191. doi: 10.1016/S0006-3223(99)00177-8. [DOI] [PubMed] [Google Scholar]
  • 56.Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 2000;20:9104–9110. doi: 10.1523/JNEUROSCI.20-24-09104.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Madsen TM, et al. Increased neurogenesis in a model of electroconvulsive therapy. Biol. Psychiatry. 2000;47:1043–1049. doi: 10.1016/S0006-3223(00)00228-6. [DOI] [PubMed] [Google Scholar]
  • 58.Scott BW, Wojtowicz JM, Burnham WM. Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures. Exp. Neurol. 2000;165:231–236. doi: 10.1006/exnr.2000.7458. [DOI] [PubMed] [Google Scholar]
  • 59.Tanti A, Belzung C. Hippocampal neurogenesis: a biomarker for depression or antidepressant effects? Methodological considerations and perspectives for future research. Cell Tissue Res. 2013;354:203–219. doi: 10.1007/s00441-013-1612-z. [DOI] [PubMed] [Google Scholar]
  • 60.Ma Z, et al. TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response. Nat. Commun. 2017;8:1668. doi: 10.1038/s41467-017-01709-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Jhaveri DJ, et al. Norepinephrine directly activates adult hippocampal precursors via β3-adrenergic receptors. J. Neurosci. 2010;30:2795–2806. doi: 10.1523/JNEUROSCI.3780-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.David DJ, et al. Implications of the functional integration of adult-born hippocampal neurons in anxiety-depression disorders. Neuroscientist. 2010;16:578–591. doi: 10.1177/1073858409360281. [DOI] [PubMed] [Google Scholar]
  • 63.Kodama M, Fujioka T, Duman RS. Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol. Psychiatry. 2004;56:570–580. doi: 10.1016/j.biopsych.2004.07.008. [DOI] [PubMed] [Google Scholar]
  • 64.Wang JW, David DJ, Monckton JE, Battaglia F, Hen R. Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J. Neurosci. 2008;28:1374–1384. doi: 10.1523/JNEUROSCI.3632-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Boldrini M, et al. Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol. Psychiatry. 2012;72:562–571. doi: 10.1016/j.biopsych.2012.04.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Furukawa T, et al. Impaired cognitive function and hippocampal changes following chronic diazepam treatment in middle-aged mice. Front. Aging Neurosci. 2021;13:777404. doi: 10.3389/fnagi.2021.777404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Wu X, Castrén E. Co-treatment with diazepam prevents the effects of fluoxetine on the proliferation and survival of hippocampal dentate granule cells. Biol. Psychiatry. 2009;66:5–8. doi: 10.1016/j.biopsych.2009.01.023. [DOI] [PubMed] [Google Scholar]
  • 68.Kendler KS, Karkowski LM, Prescott CA. Causal relationship between stressful life events and the onset of major depression. Am. J. Psychiatry. 1999;156:837–841. doi: 10.1176/ajp.156.6.837. [DOI] [PubMed] [Google Scholar]
  • 69.Jacobs BL, van Praag H, Gage FH. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol. Psychiatry. 2000;5:262–269. doi: 10.1038/sj.mp.4000712. [DOI] [PubMed] [Google Scholar]
  • 70.Bessa JM, et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol. Psychiatry. 2009;14:764–773. doi: 10.1038/mp.2008.119. [DOI] [PubMed] [Google Scholar]
  • 71.Jayatissa MN, Henningsen K, Nikolajsen G, West MJ, Wiborg O. A reduced number of hippocampal granule cells does not associate with an anhedonia-like phenotype in a rat chronic mild stress model of depression. Stress. 2010;13:95–105. doi: 10.3109/10253890902951786. [DOI] [PubMed] [Google Scholar]
  • 72.Shors TJ, Townsend DA, Zhao M, Kozorovitskiy Y, Gould E. Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus. 2002;12:578–584. doi: 10.1002/hipo.10103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Santarelli L, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–809. doi: 10.1126/science.1083328. [DOI] [PubMed] [Google Scholar]
  • 74.Revest JM, et al. Adult hippocampal neurogenesis is involved in anxiety-related behaviors. Mol. Psychiatry. 2009;14:959–967. doi: 10.1038/mp.2009.15. [DOI] [PubMed] [Google Scholar]
  • 75.Yun S, et al. Stress-induced anxiety- and depressive-like phenotype associated with transient reduction in neurogenesis in adult nestin-CreERT2/diphtheria toxin fragment A transgenic mice. PLoS ONE. 2016;11:e0147256. doi: 10.1371/journal.pone.0147256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Tsai CY, Tsai CY, Arnold SJ, Huang GJ. Ablation of hippocampal neurogenesis in mice impairs the response to stress during the dark cycle. Nat. Commun. 2015;6:8373. doi: 10.1038/ncomms9373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Danielson NB, et al. Distinct contribution of adult-born hippocampal granule cells to context encoding. Neuron. 2016;90:101–112. doi: 10.1016/j.neuron.2016.02.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Surget A, et al. Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal. Biol. Psychiatry. 2008;64:293–301. doi: 10.1016/j.biopsych.2008.02.022. [DOI] [PubMed] [Google Scholar]
  • 79.Li Y, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron. 2008;59:399–412. doi: 10.1016/j.neuron.2008.06.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Tunc-Ozcan E, et al. Activating newborn neurons suppresses depression and anxiety-like behaviors. Nat. Commun. 2019;10:3768. doi: 10.1038/s41467-019-11641-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Mendez-David I, et al. Rapid anxiolytic effects of a 5-HT4 receptor agonist are mediated by a neurogenesis-independent mechanism. Neuropsychopharmacology. 2014;39:1366–1378. doi: 10.1038/npp.2013.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Mateus-Pinheiro A, et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl. Psychiatry. 2013;3:e210–e210. doi: 10.1038/tp.2012.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Soumier, A., Carter, R. M., Schoenfeld, T. J. & Cameron, H. A. New hippocampal neurons mature rapidly in response to ketamine but are not required for its acute antidepressant effects on neophagia in rats. eNeuro3, ENEURO.0116-15.2016 (2016). [DOI] [PMC free article] [PubMed]
  • 84.Zhu XH, et al. Intermittent hypoxia promotes hippocampal neurogenesis and produces antidepressant-like effects in adult rats. J. Neurosci. 2010;30:12653–12663. doi: 10.1523/JNEUROSCI.6414-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Surget A, et al. Antidepressants recruit new neurons to improve stress response regulation. Mol. Psychiatry. 2011;16:1177–1188. doi: 10.1038/mp.2011.48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Lehmann ML, Brachman RA, Martinowich K, Schloesser RJ, Herkenham M. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis. J. Neurosci. 2013;33:2961–2972. doi: 10.1523/JNEUROSCI.3878-12.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.Alves ND, et al. Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression. Transl. Psychiatry. 2017;7:e1058. doi: 10.1038/tp.2017.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Anacker C, et al. Hippocampal neurogenesis confers stress resilience by inhibiting the ventral dentate gyrus. Nature. 2018;559:98–102. doi: 10.1038/s41586-018-0262-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Schoenfeld TJ, McCausland HC, Morris HD, Padmanaban V, Cameron HA. Stress and loss of adult neurogenesis differentially reduce hippocampal volume. Biol. Psychiatry. 2017;82:914–923. doi: 10.1016/j.biopsych.2017.05.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Puspitasari A, et al. X irradiation induces acute cognitive decline via transient synaptic dysfunction. Radiat. Res. 2016;185:423–430. doi: 10.1667/RR14236.1. [DOI] [PubMed] [Google Scholar]
  • 91.Irvine KA, Blakemore WF. A different regional response by mouse oligodendrocyte progenitor cells (OPCs) to high-dose X-irradiation has consequences for repopulating OPC-depleted normal tissue. Eur. J. Neurosci. 2007;25:417–424. doi: 10.1111/j.1460-9568.2007.05313.x. [DOI] [PubMed] [Google Scholar]
  • 92.Pepper RE, Pitman KA, Cullen CL, Young KM. How do cells of the oligodendrocyte lineage affect neuronal circuits to influence motor function, memory and mood? Front. Cell. Neurosci. 2018;12:399. doi: 10.3389/fncel.2018.00399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.von Bohlen und Halbach O. Immunohistological markers for proliferative events, gliogenesis, and neurogenesis within the adult hippocampus. Cell Tissue Res. 2011;345:1–19. doi: 10.1007/s00441-011-1196-4. [DOI] [PubMed] [Google Scholar]
  • 94.Czéh B, Di Benedetto B. Antidepressants act directly on astrocytes: evidences and functional consequences. Eur. Neuropsychopharmacol. 2013;23:171–185. doi: 10.1016/j.euroneuro.2012.04.017. [DOI] [PubMed] [Google Scholar]
  • 95.Rajkowska G, Miguel-Hidalgo JJ. Gliogenesis and glial pathology in depression. CNS Neurol. Disord. Drug Targets. 2007;6:219–233. doi: 10.2174/187152707780619326. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Wennström M, Hellsten J, Ekstrand J, Lindgren H, Tingström A. Corticosterone-induced inhibition of gliogenesis in rat hippocampus is counteracted by electroconvulsive seizures. Biol. Psychiatry. 2006;59:178–186. doi: 10.1016/j.biopsych.2005.08.032. [DOI] [PubMed] [Google Scholar]
  • 97.Kontaris I, East BS, Wilson DA. Behavioral and neurobiological convergence of odor, mood and emotion: a review. Front. Behav. Neurosci. 2020;14:35. doi: 10.3389/fnbeh.2020.00035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Sakamoto M, et al. Continuous neurogenesis in the adult forebrain is required for innate olfactory responses. Proc. Natl Acad. Sci. USA. 2011;108:8479–8484. doi: 10.1073/pnas.1018782108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Sahay A, et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011;472:466–470. doi: 10.1038/nature09817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Adlaf EW, et al. Adult-born neurons modify excitatory synaptic transmission to existing neurons. Elife. 2017;6:e19886. doi: 10.7554/eLife.19886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Kim WR, Christian K, Ming G-L, Song H. Time-dependent involvement of adult-born dentate granule cells in behavior. Behav. Brain Res. 2012;227:470–479. doi: 10.1016/j.bbr.2011.07.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Miller SM, Sahay A. Functions of adult-born neurons in hippocampal memory interference and indexing. Nat. Neurosci. 2019;22:1565–1575. doi: 10.1038/s41593-019-0484-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Trinchero MF, Giacomini D, Schinder AF. Dynamic interplay between GABAergic networks and developing neurons in the adult hippocampus. Curr. Opin. Neurobiol. 2021;69:124–130. doi: 10.1016/j.conb.2021.03.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65:7–19. doi: 10.1016/j.neuron.2009.11.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Yohn CN, et al. Social instability is an effective chronic stress paradigm for both male and female mice. Neuropharmacology. 2019;160:107780. doi: 10.1016/j.neuropharm.2019.107780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.Noonan MA, Bulin SE, Fuller DC, Eisch AJ. Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction. J. Neurosci. 2010;30:304–315. doi: 10.1523/JNEUROSCI.4256-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Holick KA, Lee DC, Hen R, Dulawa SC. Behavioral effects of chronic fluoxetine in BALB/cJ mice do not require adult hippocampal neurogenesis or the serotonin 1A receptor. Neuropsychopharmacology. 2008;33:406–417. doi: 10.1038/sj.npp.1301399. [DOI] [PubMed] [Google Scholar]
  • 108.Saxe MD, et al. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc. Natl Acad. Sci. USA. 2006;103:17501–17506. doi: 10.1073/pnas.0607207103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109.Fuss J, et al. Deletion of running-induced hippocampal neurogenesis by irradiation prevents development of an anxious phenotype in mice. PLoS ONE. 2010;5:e12769. doi: 10.1371/journal.pone.0012769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Airan RD, et al. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science. 2007;317:819–823. doi: 10.1126/science.1144400. [DOI] [PubMed] [Google Scholar]
  • 111.Singer BH, et al. Conditional ablation and recovery of forebrain neurogenesis in the mouse. J. Comp. Neurol. 2009;514:567–582. doi: 10.1002/cne.22052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112.Anderson DJ, Adolphs R. A framework for studying emotions across species. Cell. 2014;157:187–200. doi: 10.1016/j.cell.2014.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Calhoon GG, Tye KM. Resolving the neural circuits of anxiety. Nat. Neurosci. 2015;18:1394–1404. doi: 10.1038/nn.4101. [DOI] [PMC free article] [PubMed] [Google Scholar]

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