Do new neurons have a functional role in the adult hippocampus?

Although the existence of adult neurogenesis in the dentate gyrus is now almost universally accepted, it is not widely established that the new neurons perform any necessary function. However, evidence indicates that the number of new neurons that are generated and form functional synapses is clearly large enough to impact the circuitry of the hippocampus. Additionally, several treatments show parallel effects on neurogenesis and hippocampus-dependent behaviors, suggesting a possible causal relationship between new neurons and hippocampal function. Most importantly, several recent studies have found that killing or inhibiting proliferation of granule cell precursors impairs performance on several hippocampus-dependent tasks. Control experiments showing no impairment on slightly different behavioral tests suggest that the deficits are highly specific and unlikely to result from side effects of the neurogenesis-inhibiting treatments. In summary, the evidence to date strongly suggests that adult neurogenesis in the dentate gyrus plays a vital role in hippocampal function.     

Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus

Throughout the adult life of most mammals, new neurons are continuously generated in the dentate gyrus of the hippocampal formation. Recent work has documented specific cognitive deficits after elimination of adult hippocampal neurogenesis in rodents, suggesting that these neurons may contribute to information processing in hippocampal circuits. Young adult-born neurons exhibit enhanced excitability and have altered capacity for synaptic plasticity in hippocampal slice preparations in vitro. Still, little is known about the effect of adult-born granule cells on hippocampal activity in vivo. To assess the impact of these new neurons on neural circuits in the dentate, we recorded perforant-path evoked responses and spontaneous network activity from the dentate gyrus of urethane-anesthetized mice whose hippocampus had been focally X-irradiated to eliminate the population of young adult-born granule cells. After X-irradiation, perforant-path responses were reduced in magnitude. In contrast, there was a marked increase in the amplitude of spontaneous γ-frequency bursts in the dentate gyrus and hilus, as well as increased synchronization of dentate neuron firing to these bursts. A similar increase in gamma burst amplitude was also found in animals in which adult neurogenesis was eliminated using the GFAP:TK pharmacogenetic ablation technique. These data suggest that young neurons may inhibit or destabilize recurrent network activity in the dentate and hilus. This unexpected result yields a new perspective on how a modest number of young adult-generated granule cells may modulate activity in the larger population of mature granule cells, rather than acting solely as independent encoding units.     

Is there a role for young hippocampal neurons in adaptation to stress?

The hippocampus has been implicated in many cognitive and emotional behaviors and in the physiology of the stress response. Within the hippocampus, the dentate gyrus has been implicated in the detection of novelty. The dentate is also a major target for stress hormones and modulates the hypothalamic-pituitary-adrenal (HPA) axis response to stress. Whether these functions of the dentate integrate or segregate remains unknown, as most investigations of its role in stress and learning are separate.Since the exciting discovery of adult neurogenesis in the dentate gyrus, adult-born neurons have been implicated in both novelty detection and the stress response. In this perspective we will discuss the literature that implicates the hippocampus, and potentially, adult-born neurons in these two functions. We will attempt to reconcile the seemingly contradictory behavioral results for the function of adult-born neurons. Finally, we will speculate that a key function of adult-born neurons within hippocampal function may be to modulate the stress response and perhaps assign stress salience to the sensory context.     

Time-dependent involvement of adult-born dentate granule cells in behavior

Adult-born neurons are continuously generated and incorporated into the circuitry of the hippocampus throughout life in mammals. Cumulative evidence supports a physiological role for adult-born neurons, yet it not clear whether this subset of dentate granule cells makes a unique contribution to hippocampal function. Perturbation or ablation of adult hippocampal neurogenesis leads to deficits in the acquisition of learned associations or memory recall, whereas an increase in adult hippocampal neurogenesis enhances some forms of learning and memory. The observed effects thus far appear to be task-dependent, species-specific, and sensitive to the timing of manipulations. Here, we review the recent evidence correlating adult-born dentate granule cells (DGCs) with hippocampal-dependent behavior and focus on the dynamic properties of this neuronal population that may underlie its function. We further discuss a framework for future investigations of how newly integrated neurons may contribute to hippocampal processing using advanced genetic techniques with enhanced temporal resolution.     

Synapse formation on adult-born hippocampal neurons

It is now widely accepted that adult neurogenesis plays a fundamental role in hippocampal function. Neurons born in the adult dentate gyrus of the hippocampus undergo a series of events before they fully integrate in the network and eventually become undistinguishable from neurons born during embryogenesis. Adult hippocampal neurogenesis is strongly regulated by neuronal activity and neurotransmitters, and the synaptic integration of adult-born neurons occurs in discrete steps, some of which are very different from perinatal synaptogenesis. Here, we review the current knowledge on the development of the synaptic input and output of neurons born in the adult hippocampus, from the stem/progenitor cell to the fully mature neuron. We also provide insight on the regulation of adult neurogenesis by some neurotransmitters and discuss some specificities of the integration of new neurons in an adult environment. The understanding of the mechanisms regulating the synaptic integration of adult-born neurons is not only crucial for our understanding of brain plasticity, but also provides a framework for the manipulation and monitoring of endogenous adult neurogenesis as well as grafted cells, for potential therapeutic applications.     

Enriched Environment Promotes Adult Hippocampal Neurogenesis through FGFRs

The addition of new neurons to existing neural circuits in the adult brain remains of great interest to neurobiology because of its therapeutic implications. The premier model for studying this process has been the hippocampal dentate gyrus in mice, where new neurons are added to mature circuits during adulthood. Notably, external factors such as an enriched environment (EE) and exercise markedly increase hippocampal neurogenesis. Here, we demonstrate that EE acts by increasing fibroblast growth factor receptor (FGFR) function autonomously within neurogenic cells to expand their numbers in adult male and female mice. FGFRs activated by EE signal through their mediators, FGFR substrate (FRS), to induce stem cell proliferation, and through FRS and phospholipase Cγ to increase the number of adult-born neurons, providing a mechanism for how EE promotes adult neurogenesis.SIGNIFICANCE STATEMENT How the environment we live in affects cognition remains poorly understood. In the current study, we explore the mechanism underlying the effects of an enriched environment on the production of new neurons in the adult hippocampal dentate gyrus, a brain area integral in forming new memories. A mechanism is provided for how neural precursor cells in the adult mammalian dentate gyrus respond to an enriched environment to increase their neurogenic output. Namely, an enriched environment acts on stem and progenitor cells by activating fibroblast growth factor receptor signaling through phospholipase Cγ and FGF receptor substrate proteins to expand the pool of precursor cells.     

When is adult hippocampal neurogenesis necessary for learning? evidence from animal research

The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning.     

Forebrain neurogenesis after focal Ischemic and traumatic brain injury

Neural stem cells persist in the adult mammalian forebrain and are a potential source of neurons for repair after brain injury. The two main areas of persistent neurogenesis, the subventricular zone (SVZ)-olfactory bulb pathway and hippocampal dentate gyrus, are stimulated by brain insults such as stroke or trauma. Here we focus on the effects of focal cerebral ischemia on SVZ neural progenitor cells in experimental stroke, and the influence of mechanical injury on adult hippocampal neurogenesis in models of traumatic brain injury (TBI). Stroke potently stimulates forebrain SVZ cell proliferation and neurogenesis. SVZ neuroblasts are induced to migrate to the injured striatum, and to a lesser extent to the peri-infarct cortex. Controversy exists as to the types of neurons that are generated in the injured striatum, and whether adult-born neurons contribute to functional restoration remains uncertain. Advances in understanding the regulation of SVZ neurogenesis in general, and stroke-induced neurogenesis in particular, may lead to improved integration and survival of adult-born neurons at sites of injury. Dentate gyrus cell proliferation and neurogenesis similarly increase after experimental TBI. However, pre-existing neuroblasts in the dentate gyrus are vulnerable to traumatic insults, which appear to stimulate neural stem cells in the SGZ to proliferate and replace them, leading to increased numbers of new granule cells. Interventions that stimulate hippocampal neurogenesis appear to improve cognitive recovery after experimental TBI. Transgenic methods to conditionally label or ablate neural stem cells are beginning to further address critical questions regarding underlying mechanisms and functional significance of neurogenesis after stroke or TBI. Future therapies should be aimed at directing appropriate neuronal replacement after ischemic or traumatic injury while suppressing aberrant integration that may contribute to co-morbidities such as epilepsy or cognitive impairment.     

Mechanisms and functional significance of aberrant seizure-induced hippocampal neurogenesis

Studies of experimental mesial temporal lobe epilepsy (mTLE) indicate that prolonged seizures in the adult not only damage the hippocampal formation but also dramatically stimulate neurogenesis. Endogenous neural progenitor cells (NPCs) located in the adult rodent dentate gyrus and striatal subventricular zone are stimulated by experimental status epilepticus (SE) to generate increased numbers of dentate granule cells (DGCs) and olfactory interneurons, respectively ( Bengzon et al., 1997 ; Parent et al., 1997, 2002 ; Scott et al., 1998 ). In this review, we discuss current knowledge regarding the consequences of seizure activity on NPC proliferation, focusing on the hippocampus, and on the migration and integration of adult-born hippocampal neurons. We also describe the effects of seizure-induced neurogenesis on hippocampal network function and the potential relevance of aberrant neurogenesis to human mTLE.     

Functional dissociation of adult‐born neurons along the dorsoventral axis of the dentate gyrus

Adult‐born granule cells in the mammalian dentate gyrus have long been implicated in hippocampal dependent spatial learning and behavioral effects of chronic antidepressant treatment. Although recent anatomical and functional evidence indicates a dissociation of the dorsal and ventral regions of the hippocampus, it is not known if adult neurogenesis within each region specifically contributes to distinct functions or whether adult‐born cells along the entire dorsoventral axis are required for these behaviors. We examined the role of distinct subpopulations of adult‐born hippocampal granule cells in learning‐ and anxiety‐related behaviors using low‐dose focal x‐irradiation directed specifically to the dorsal or ventral dentate gyrus. Our findings indicate a functional dissociation between adult‐born neurons along the longitudinal axis of the dentate gyrus wherein new neurons in the dorsal dentate gyrus are required for timely acquisition of contextual discrimination while immature neurons in the ventral dentate gyrus are necessary for anxiolytic/antidepressant‐related effects of fluoxetine. Interestingly, when contexts are presented with altered temporal cues, or fluoxetine is administered alongside chronic glucocorticoid treatment, this dissociation is abrogated such that adult‐born neurons across the entire dorsoventral extent of the dentate gyrus appear to contribute to these behaviors. Our results suggest that individual subpopulations of adult‐born hippocampal neurons may be sufficient to mediate distinct behaviors in certain conditions, but are required to act in concert in more challenging situations. © 2014 Wiley Periodicals, Inc.     

New neurons in the adult brain: the role of sleep and consequences of sleep loss

Research over the last few decades has firmly established that new neurons are generated in selected areas of the adult mammalian brain, particularly the dentate gyrus of the hippocampal formation and the subventricular zone of the lateral ventricles. The function of adult-born neurons is still a matter of debate. In the case of the hippocampus, integration of new cells in to the existing neuronal circuitry may be involved in memory processes and the regulation of emotionality. In recent years, various studies have examined how the production of new cells and their development into neurons is affected by sleep and sleep loss. While disruption of sleep for a period shorter than one day appears to have little effect on the basal rate of cell proliferation, prolonged restriction or disruption of sleep may have cumulative effects leading to a major decrease in hippocampal cell proliferation, cell survival and neurogenesis. Importantly, while short sleep deprivation may not affect the basal rate of cell proliferation, one study in rats shows that even mild sleep restriction may interfere with the increase in neurogenesis that normally occurs with hippocampus-dependent learning. Since sleep deprivation also disturbs memory formation, these data suggest that promoting survival, maturation and integration of new cells may be an unexplored mechanism by which sleep supports learning and memory processes. Most methods of sleep deprivation that have been employed affect both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Available data favor the hypothesis that decreases in cell proliferation are related to a reduction in REM sleep, whereas decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep. The mechanisms by which sleep loss affects different aspects of adult neurogenesis are unknown. It has been proposed that adverse effects of sleep disruption may be mediated by stress and glucocorticoids. However, a number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones. In conclusion, while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis. These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.     

NADPH oxidase mediates β-amyloid peptide-induced activation of ERK in hippocampal organotypic cultures

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.     

Adult-born neurons are necessary for extended contextual discrimination

New neurons are continuously produced in the adult dentate gyrus of the hippocampus. It has been shown that one of the functions of adult neurogenesis is to support spatial pattern separation, a process that transforms similar memories into nonoverlapping representations. This prompted us to investigate whether adult-born neurons are required for discriminating two contexts, i.e., for identifying a familiar environment and detect any changes introduced in it. We show that depleting adult-born neurons impairs the animal's ability to disambiguate two contexts after extensive training. These data suggest that the continuous production of new dentate neurons plays a crucial role in extracting and separating efficiently contextual representation in order to discriminate features within events.     

Stress in early life inhibits neurogenesis in adulthood

Both structure and function of the hippocampus are altered by stress: by increasing levels of corticosteroids, stress causes atrophy of CA3 pyramidal cell dendrites, inhibits adult neurogenesis in the dentate gyrus, and impairs hippocampus-dependent learning. A recent study shows that adverse experience limited to early life, specifically removal of rat pups from their mother for three hours each day, decreases production of new granule neurons in adulthood through a corticosteroid-dependent mechanism. This finding suggests that stress in early life could permanently impair hippocampus-dependent learning and memory and increase susceptibility to depression by inhibiting adult neurogenesis in the hippocampus.     

Gonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents

Gonadal hormones modulate neurogenesis in the dentate gyrus differentially in male and female adult rodents. Neurogenesis is comprised of at least two components: cell proliferation (the production of new cells) and cell survival (the number of new neurons that survive to maturity). Previous studies have found sex differences in the level of cell proliferation in the dentate gyrus only when comparing females in a high estrogen state to males. This review focuses on the effects of acute and chronic levels of estrogens or androgens on hippocampal neurogenesis in the adult male and female rodent. Evidence is also reviewed for the co-localization of androgen receptors and estrogen receptors (ER) with markers for cell proliferation or immature new cell survival. Briefly, evidence suggests that acute estradiol initially enhances and subsequently suppresses cell proliferation in the dentate gyrus of adult female rodents but may have limited effects in male rodents. Both the two known ER subtypes, ER and β upregulate hippocampal neurogenesis via cell proliferation. Intriguingly, repeated exposure to estradiol modulates hippocampal neurogenesis and cell death in adult female, but not male, rodents. However short-term estradiol treatment (5 days) in male meadow voles enhances new cell survival in the dentate gyrus but only when administered during the ‘axon extension’ phase. Furthermore, evidence is also reviewed showing a difference in response to acute and chronic estradiol treatment in older female rats compared to younger female rats. Recent findings from our laboratory indicate that testosterone and dihydrotestosterone upregulate hippocampal neurogenesis (via cell survival), but not cell proliferation, in adult male rodents. Effects of endogenous fluctuations in gonadal hormones on adult neurogenesis are observed across the seasons in meadow voles and during pregnancy and lactation in the rat dam. Pregnancy and motherhood differentially regulate adult hippocampal neurogenesis in the adult female rodent, with primiparous rats displaying lower levels of hippocampal cell proliferation and survival after parturition. Few studies have compared males and females but existing research suggests a sex difference in the hormonal regulation of hippocampal neurogenesis in the adult. Clearly more work is needed to elucidate the effects of gonadal hormones on neurogenesis in the dentate gyrus of both male and female rodents across the lifespan, especially if we are to use our knowledge of how adult neurogenesis is regulated to develop strategies to repair neuron loss in neurodegenerative diseases.     

Sexual experience restores age‐related decline in adult neurogenesis and hippocampal function

Aging is associated with compromised hippocampal function and reduced adult neurogenesis in the dentate gyrus. As new neurons have been linked to hippocampal functions, such as cognition, age‐related decline in new neuron formation may contribute to impaired hippocampal function. We investigated whether a rewarding experience known to stimulate neurogenesis in young adult rats, namely sexual experience, would restore new neuron production and hippocampal function in middle‐aged rats. Sexual experience enhanced the number of newly generated neurons in the dentate gyrus with both single and repeated exposures in middle‐aged rats. Following continuous long‐term exposure to sexual experience, cognitive function was improved. However, when a prolonged withdrawal period was introduced between the final mating experience and behavioral testing, the improvements in cognitive function were lost despite the presence of more new neurons. Taken together, these results suggest that repeated sexual experience can stimulate adult neurogenesis and restore cognitive function in the middle‐aged rat as long as the experience persists throughout the testing period. The extent to which changes in adult neurogenesis underlie those in cognition remain unknown. © 2013 Wiley Periodicals, Inc.     

Impact of pediatric traumatic brain injury on hippocampal neurogenesis

Traumatic brain injury(TBI) is a major cause of mortality and morbidity in the pediatric population. With advances in medical care, the mortality rate of pediatric TBI has declined. However, more children and adolescents are living with TBI-related cognitive and emotional impairments, which negatively affects the quality of their life. Adult hippocampal neurogenesis plays an important role in cognition and mood regulation. Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases, including TBI. Promoting endogenous hippocampal neurogenesis after TBI merits significant attention. However, TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus, which results in aberrant migration and impaired dendrite development of adult-born neurons. Therefore, a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains. Secondary injuries, such as neuroinflammation and oxidative stress, exert a significant impact on hippocampal neurogenesis. Currently, a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries. In this review, we discuss the uniqueness of pediatric TBI, adult hippocampal neurogenesis after pediatric TBI, and current efforts that promote neuroprotection to the developing brains, which can be leveraged to facilitate neuroregeneration.     

Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis

Exposure to an enriched environment and physical activity, such as voluntary running, increases neurogenesis of granule cells in the dentate gyrus of adult mice. These stimuli are also known to improve performance in hippocampus-dependent learning tasks, but it is unclear whether their effects on neurogenesis are exclusive to the hippocampal formation. In this study, we housed adult mice under three conditions (enriched environment, voluntary wheel running and standard housing), and analysed proliferation in the lateral ventricle wall and granule cell neurogenesis in the olfactory bulb in comparison to the dentate gyrus. Using bromodeoxyuridine to label dividing cells, we could not detect any difference in the number of newly generated cells in the ventricle wall. When giving the new cells time to migrate and differentiate in the olfactory bulb, we observed no changes in the number of adult-generated olfactory granule cells; however, voluntary running and enrichment produced a doubling in the amount of new hippocampal granule cells. The discrepancy between the olfactory bulb and the dentate gyrus suggests that these living conditions trigger locally through an as yet unidentified mechanism specific to neurogenic signals in the dentate gyrus.     

Hippocampal neurogenesis and pattern separation: A meta‐analysis of behavioral data

The generation of new neurons in the hippocampus of adult mammals has become a widely accepted phenomenon, but the functional significance of the adult neurogenesis in the hippocampus is not fully understood. One of the main hypotheses currently investigated suggests that neurogenesis contributes to pattern separation in the dentate gyrus. Many behavioral studies were conducted aiming to test this hypothesis using rodents as animal model. In those studies, researches ablated neurogenesis in the animals and subsequently evaluate them in tests of behavioral pattern separation, that is, behaviors that are thought to rely on the computational process of pattern separation. The results of these studies are varied, with most supporting a role for neurogenesis in pattern separation, but some others not. To address this controversy we performed a systematic review and meta‐analysis of studies evaluating the effect of neurogenesis ablation on behavioral pattern separation. Analysis results indicated that most of the literature in the topic is surprisingly consistent and, although there are two studies with divergent results, the bulk of the literature supports an effect of hippocampal neurogenesis on behavioral pattern separation. We discuss those findings in light of other behavioral effects of hippocampal neurogenesis ablation, limitations of behavioral data and other lines of evidence about the effect of hippocampal neurogenesis in the dentate gyrus.     

Rit GTPase signaling promotes immature hippocampal neuronal survival

The molecular mechanisms governing the spontaneous recovery seen following brain injury remain elusive, but recent studies indicate that injury-induced stimulation of hippocampal neurogenesis contributes to the repair process. The therapeutic potential of endogenous neurogenesis is tempered by the demonstration that traumatic brain injury (TBI) results in the selective death of adult-born immature neurons, compromising the cell population poised to compensate for trauma-induced neuronal loss. Here, we identify the Ras-related GTPase, Rit, as a critical player in the survival of immature hippocampal neurons following brain injury. While Rit knock-out (Rit(-/-)) did not alter hippocampal development, hippocampal neural cultures derived from Rit(-/-) mice display increased cell death and blunted MAPK cascade activation in response to oxidative stress, without affecting BDNF-dependent signaling. When compared with wild-type hippocampal cultures, Rit loss rendered immature (Dcx(+)) neurons susceptible to oxidative damage, without altering the survival of neural progenitor (Nestin(+)) cells. Oxidative stress is a major contributor to neuronal cell death following brain injury. Consistent with the enhanced vulnerability of cultured Rit(-/-) immature neurons, Rit(-/-) mice exhibited a significantly greater loss of adult-born immature neurons within the dentate gyrus after TBI. In addition, post-TBI neuronal remodeling was blunted. Together, these data identify a new and unexpected role for Rit in injury-induced neurogenesis, functioning as a selective survival mechanism for immature hippocampal neurons within the subgranular zone of the dentate gyrus following TBI.