Requirement of adult-born neurons for hippocampus-dependent learning

A fundamental question in the field of adult neurogenesis relies in addressing whether neurons generated in the adult dentate gyrus are needed for hippocampal function. Increasing evidence is accumulating in support of the notion that hippocampus-dependent behaviors activate new neurons and that those neurons are highly relevant for information processing. More specifically, immature new neurons under development that have unique functional characteristics begin to emerge as a highly relevant population in the dentate gyrus network. This review focuses on how hippocampus-dependent behaviors activate adult-born neurons and how modulation and ablation of adult hippocampal neurogenesis alter spatial and associative memory. While several contradictory findings emerge when analyzing the literature, evidence in favor of a relevant role of adult-born neurons in hippocampal function is compelling.     

Hippocampal neurogenesis and neural stem cells in temporal lobe epilepsy

Virtually all mammals, including humans, exhibit neurogenesis throughout life in the hippocampus, a learning and memory center in the brain. Numerous studies in animal models imply that hippocampal neurogenesis is important for functions such as learning, memory, and mood. Interestingly, hippocampal neurogenesis is very sensitive to physiological and pathological stimuli. Certain pathological stimuli such as seizures alter both the amount and the pattern of neurogenesis, though the overall effect depends on the type of seizures. Acute seizures are classically associated with augmentation of neurogenesis and migration of newly born neurons into ectopic regions such as the hilus and the molecular layer of the dentate gyrus. Additional studies suggest that abnormally migrated newly born neurons play a role in the occurrence of epileptogenic hippocampal circuitry characteristically seen after acute seizures, status epilepticus, or head injury. Recurrent spontaneous seizures such as those typically observed in chronic temporal lobe epilepsy are associated with substantially reduced neurogenesis, which, interestingly, coexists with learning and memory impairments and depression. In this review, we discuss both the extent and the potential implications of abnormal hippocampal neurogenesis induced by acute seizures as well as recurrent spontaneous seizures. We also discuss the consequences of chronic spontaneous seizures on differentiation of neural stem cell progeny in the hippocampus and strategies that are potentially useful for normalizing neurogenesis in chronic temporal lobe epilepsy.     

Could hippocampal neurogenesis be a future drug target for treating temporal lobe epilepsy?

The dentate gyrus, a region of the hippocampal formation, displays the highest level of plasticity in the brain and exhibits neurogenesis all through life. Dentate neurogenesis, believed to be essential for learning and memory function, responds to physiological stimuli as well as pathological situations. The role of dentate neurogenesis in the pathophysiology of temporal lobe epilepsy (TLE) has received increased attention lately because of its disparate response in the early and chronic stages of the disease. Acute seizures or status epilepticus immensely enhance dentate neurogenesis and lead to an aberrant migration of newly born neurons into the dentate hilus and the formation of epileptogenic circuitry in the injured hippocampus. Conversely, spontaneous recurrent seizures that arise during chronic TLE are associated with dramatically reduced dentate neurogenesis. In this review, we discuss the potential significance of enhanced but abnormal neurogenesis taking place shortly after brain injury or the status epilepticus towards the development of chronic epilepsy, and prospective implications of dramatically waned dentate neurogenesis occurring during chronic epilepsy for learning and memory function and depression in TLE. Furthermore, we confer whether hippocampal neurogenesis is a possible drug target for preventing TLE after brain injury or the status epilepticus, and for easing learning and memory impairments during chronic epileptic conditions. Additionally, we discuss some possible drugs and approaches that need to be evaluated in future in animal models of TLE to further understand the role of neurogenesis in the pathogenesis of TLE and whether modulation of neurogenesis is useful for treating TLE.     

Implications of decreased hippocampal neurogenesis in chronic temporal lobe epilepsy

Temporal lobe epilepsy (TLE), characterized by spontaneous recurrent motor seizures (SRMS), learning and memory impairments, and depression, is associated with neurodegeneration, abnormal reorganization of the circuitry, and loss of functional inhibition in the hippocampal and extrahippocampal regions. Over the last decade, abnormal neurogenesis in the dentate gyrus (DG) has emerged as another hallmark of TLE. Increased DG neurogenesis and recruitment of newly born neurons into the epileptogenic hippocampal circuitry is a characteristic phenomenon occurring during the early phase after the initial precipitating injury such as status epilepticus. However, the chronic phase of the disease displays substantially declined DG neurogenesis, which is associated with SRMS, learning and memory impairments, and depression. This review focuses on DG neurogenesis in the chronic phase of TLE and first confers the extent and mechanisms of declined DG neurogenesis in chronic TLE. The available data on production, survival and neuronal fate choice decision of newly born cells, stability of hippocampal stem cell numbers, and changes in the hippocampal microenvironment in chronic TLE are considered. The next section discusses the possible contribution of declined DG neurogenesis to the pathophysiology of chronic TLE, which includes its potential effects on spontaneous recurrent seizures, cognitive dysfunction, and depression. The subsequent section considers strategies that may be useful for augmenting DG neurogenesis in chronic TLE, which encompass stem cell grafting, administration of distinct neurotrophic factors, physical exercise, exposure to enriched environment, and antidepressant therapy. The final section suggests possible ramifications of increasing the DG neurogenesis in chronic epilepsy.     

Is exposure to enriched environment beneficial for functional post-lesional recovery in temporal lobe epilepsy?

Exposure to enriched environment has been shown to induce robust neuronal plasticity in both intact and injured adult central nervous system, including up-regulation of multiple neurotrophic factors, enhanced neurogenesis in the dentate gyrus of the hippocampus, and improved spatial learning and memory function. Neuronal plasticity, though mostly adaptive and abnormal, also occurs during certain neurodegenerative conditions such as the temporal lobe epilepsy (TLE). The TLE is characterized by hippocampal neurodegeneration, aberrant mossy fiber sprouting, spontaneous recurrent motor seizures, cognitive deficits, and abnormally enhanced neurogenesis during the early phase and dramatically declined neurogenesis during the chronic phase of the disease. As environmental enrichment has been found to be beneficial for treating animal models of Alzheimer's, Parkinson's, and Huntington's diseases, there is considerable interest in determining the efficacy of this strategy for preventing or treating chronic TLE after the initial precipitating brain injury. This review first discusses the proof of principle behind the potential application of the environmental enrichment strategy for preventing or treating TLE after brain injury. The subsequent chapters confer the portrayed beneficial effects of enrichment for functional post-lesional recovery in TLE and the possible complications which may arise from housing epilepsy-prone or epileptic rats in enriched environmental conditions. The final segment discusses studies that are essential for further understanding the efficacy of this approach for preventing or treating TLE.     

Adulte Stammzellen in Patienten mit Temporallappenepilepsie

Adult stem cells persist in the subventricular zone and hippocampus (dentate gyrus) of the human brain. Surgical specimens obtained from patients with drug-resistant temporal lobe epilepsy (TLE) represent an important tool to study mechanisms of adult stem cells. The following issues are currently intensively discussed: (1) establishment of standardized in vitro protocols for the recruitment, proliferation, and differentiation of adult stem cells from human tissue obtained during surgery from TLE patients. (2) Can adult stem cells be used in the future for the targeted therapy of pharmacy-resistant focal epilepsy? (3) Which functions do adult stem cells or the newly formed nerve cells (neurogenesis) have in the human hippocampus? Since recent data from animal experiments support the notion that hippocampal neurogenesis is relevant in memory function, this knowledge may also offer intriguing insights into the memory deficits that commonly affect TLE patients.     

Experimental epilepsy affects Notch1 signalling and the stem cell pool in the dentate gyrus

Temporal lobe epilepsy (TLE) is the most frequent form of epilepsy in adults. In addition to recurrent focal seizures, patients suffer from memory loss and depression. The factors contributing to these symptoms are unknown. In recent years, adult hippocampal neurogenesis has been implicated in certain aspects of learning and memory, as well as in depression and anhedonia. Here we investigated whether the adult hippocampal stem cell niche is affected by status epilepticus in a mouse model of TLE using unilateral intrahippocampal kainic acid injection. Eight days after status epilepticus, we found a strong diminution in Notch signalling, a key pathway involved in stem cell maintenance, as assayed by hes5 reporter gene activity. In particular, hes5–GFP expression in the subgranular zone of the dentate gyrus was diminished. Furthermore, Sox2‐positive cells as well as stem cell proliferation were reduced, thus pointing to a disruption of the stem cell niche in epilepsy under the present experimental conditions.     

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.     

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.     

Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus

While it is clear that acute hippocampal injury or status epilepticus increases the production of new neurons in the adult dentate gyrus (DG), the effects of chronic epilepsy on dentate neurogenesis are unknown. We hypothesize that epileptogenic changes and spontaneous recurrent motor seizures (SRMS) that ensue after hippocampal injury or status epilepticus considerably decrease dentate neurogenesis. We addressed this issue by quantifying the number of cells that are positive for doublecortin (DCX, a marker of new neurons) in the DG of adult F344 rats at 16 days and 5 months after an intracerebroventricular kainic acid (ICV KA) administration or after graded intraperitoneal KA (IP KA) injections, models of temporal lobe epilepsy (TLE). At early post-KA administration, the injured hippocampus exhibited increased dentate neurogenesis in both models. Conversely, at 5 months post-KA administration, the chronically epileptic hippocampus demonstrated severely declined neurogenesis, which was associated with considerable SRMS in both KA models. Additionally, stem/progenitor cell proliferation factors, FGF-2 and IGF-1, were decreased in the chronically epileptic hippocampus. Interestingly, the overall decrease in neurogenesis and the extent of SRMS were greater in rats receiving IP KA than rats receiving ICV KA, suggesting that the extent of neurogenesis during chronic TLE exhibits an inverse relationship with SRMS. These results provide novel evidence that chronic TLE is associated with extremely declined dentate neurogenesis. As fraction of newly born neurons become GABA-ergic interneurons, declined neurogenesis may contribute to the increased seizure-susceptibility of the DG in chronic TLE. Likewise, the hippocampal-dependent learning and memory deficits observed in chronic TLE could be linked at least partially to the declined neurogenesis.     

Hippocampal neuronal density in temporal lobe epilepsy with and without gliomas

Summary The majority of patients with temporal lobe epilepsy show hippocampal sclerosis, which pathologically represents neuronal loss and gliosis. We studied volumetric neuronal density on a representative mid to mid-posterior level slice of hippocampi surgically removed from intractable temporal lobe epilepsy cases, and compared the results between 25 non-tumor epilepsy (NTE) cases and 5 tumor-associated epilepsy (TAE) cases. Eleven age-matched non-epileptic autopsy cases were studied as controls. Cells were counted in the CA1 through CA4 fields and the stratum granulosum of the dentate fascia. In NTE every hippocampal field showed statistically significant loss of neurons, the neuronal density in each field ranging from 35% to 50% of that of control. The mean neuronal density between the TAE and NTE groups also showed statistically significant differences in all hippocampal fields. The neuronal density of hippocampal fields of NTE ranged from 43% to 58% of that of TAE. Tumor-associated epilepsy cases, however, failed to show any statistically significant deviation from the control in their neuronal density. The etiology of the difference in neuronal density between the TAE and NTE groups is discussed.Supported by NIH grant NS06208     

Targeting hippocampal adult neurogenesis using transcription factors to reduce Alzheimer's disease‐associated memory impairments

Hippocampal adult neurogenesis results in the persisting formation of new neurons that contribute to hippocampal‐dependent learning and memory. This has led to the hypothesis that memory impairments associated with neurodegenerative diseases such as Alzheimer's disease may involve abnormal neurogenesis. Supporting this idea, evidence for decreased adult neurogenesis has been reported in the brain of Alzheimer's disease patients and in several mouse models of the disease. Thus, the development of strategies designed to stimulate the production of new neurons in the diseased brain has raised growing interest. In this review, we discuss putative strategies and present recent studies showing that it is now possible to instruct hippocampal endogenous neural progenitors to adopt an exclusive neuronal fate. We further report how such strategies lead to the rescue of cognitive functions in mouse models of Alzheimer's disease. Altogether, these findings provide the proof‐of‐concept that neurogenesis can be stimulated in the adult brain in vivo, and consequently overcomes pathological memory deficits.     

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.     

Inhibition of adult neurogenesis by inducible and targeted deletion of ERK5 mitogen-activated protein kinase specifically in adult neurogenic regions impairs contextual fear extinction and remote fear memory

Although there is evidence suggesting that adult neurogenesis may contribute to hippocampus-dependent memory, signaling mechanisms responsible for adult hippocampal neurogenesis are not well characterized. Here we report that ERK5 mitogen-activated protein kinase is specifically expressed in the neurogenic regions of the adult mouse brain. The inducible and conditional knock-out (icKO) of erk5 specifically in neural progenitors of the adult mouse brain attenuated adult hippocampal neurogenesis. It also caused deficits in several forms of hippocampus-dependent memory, including contextual fear conditioning generated by a weak footshock. The ERK5 icKO mice were also deficient in contextual fear extinction and reversal of Morris water maze spatial learning and memory, suggesting that adult neurogenesis plays an important role in hippocampus-dependent learning flexibility. Furthermore, our data suggest a critical role for ERK5-mediated adult neurogenesis in pattern separation, a form of dentate gyrus-dependent spatial learning and memory. Moreover, ERK5 icKO mice have no memory 21 d after training in the passive avoidance test, suggesting a pivotal role for adult hippocampal neurogenesis in the expression of remote memory. Together, our results implicate ERK5 as a novel signaling molecule regulating adult neurogenesis and provide strong evidence that adult neurogenesis is critical for several forms of hippocampus-dependent memory formation, including fear extinction, and for the expression of remote memory.     

Adult neurogenesis. From circuits to models

Our understanding of the hippocampus as a memory-encoding device is greatly helped by our knowledge of neuronal circuits and their plasticity. The trisynaptic hippocampal circuit carrying afferent input from the entorhinal cortex, controlled by a network of inhibitory interneurons and supplemented by modulatory subcortical inputs forms a platform for multiple forms of synaptic plastic mechanisms. Long-term potentiation of synaptic transmission in its various forms is an outstanding example of hippocampal ability to adapt to past neuronal activity. Adult neurogenesis is a profound plastic mechanism incorporating structural and functional changes that were previously thought to be present only in developing neural systems. These powerful forms of plasticity can mask experimental results by compensating for experimentally induced changes in the neurons or circuits. Circuit lesions have been one of the most common techniques in scientific investigations of the hippocampus. Although the effects of such lesions can be quite revealing and ground-breaking, in many cases the results are masked by compensatory mechanisms producing misleading results. This review will highlight such mechanisms and argue that the experimental results, in spite of their shortcomings, can be better understood when viewed in light of our knowledge of the neuronal circuitry, and with guidance by conceptual and computational models. Studies demonstrating a role of neurogenesis in pattern separation and memory interference are a good example of fruitful interaction between modeling and experimental approaches.     

Adult newborn neurons are involved in learning acquisition and long‐term memory formation: The distinct demands on temporal neurogenesis of different cognitive tasks

There is evidence that adult hippocampal neurogenesis influences hippocampal function, although the role these neurons fulfill in learning and consolidation processes remains unclear. Using a novel fast X‐ray ablation protocol to deplete neurogenic cells, we demonstrate that immature adult hippocampal neurons are required for hippocampal learning and long‐term memory formation. Moreover, we found that long‐term memory formation in the object recognition and passive avoidance tests, two paradigms that involve circuits with distinct emotional components, had different temporal demands on hippocampal neurogenesis. These results reveal new and unexpected aspects of neurogenesis in cognitive processes. © 2014 Wiley Periodicals, Inc.     

Environmental enrichment enhances neurogenesis and improves functional outcome after cranial irradiation

Radiation therapy is a widely used treatment for brain tumors but it can cause delayed progressive cognitive decline and memory deficits. Previous studies suggested that this neurocognitive dysfunction might be linked to the impairment of hippocampal neurogenesis. However, little is known regarding how to reduce the cognitive impairment caused by radiation therapy. To investigate whether environmental enrichment (EE) promotes neurogenesis and cognitive function after irradiation, irradiated gerbils were housed in EE for 2 months and evaluated by neurobehavioral testing for learning and memory function, and immunohistochemical analysis for neurogenesis. Our results demonstrated that even relatively low doses (5-10 Gy) of irradiation could acutely abolish precursor cell proliferation in the dentate gyrus by more than 90%. This reduction in precursor proliferation was persistent and led to a significant decline in the granule cell population 9 months later. EE housing enhanced the number of newborn neurons and increased residual neurogenesis. EE also significantly increased the total number of immature neurons in the dentate gyrus. Furthermore, irradiated animals after EE housing showed a significant improvement in spatial learning and memory during the water-maze test and in rotorod motor learning over a 5-day training paradigm. In conclusion, EE has a positive impact on hippocampal neurogenesis and functional recovery in irradiated adult gerbils. Our data suggest that there is still a considerable amount of plasticity remaining in the hippocampal progenitor cells in adult animals after radiation injury, which can become a target of therapeutic intervention for radiation-induced cognitive dysfunction.     

Fibroblast growth factor receptor-1 is required for long-term potentiation, memory consolidation, and neurogenesis.

BACKGROUND: Although substantial evidence supports the view that adult neurogenesis is involved in learning and memory, how newly generated neurons contribute to the cognitive process remains unknown. Fibroblast growth factor 2 (FGF-2) is known to stimulate the proliferation of neuronal progenitor cells (NPCs) in adult brain. Using conditional knockout mice that lack brain expression of FGFR1, a major receptor for FGF-2, we have investigated the role of adult neurogenesis in hippocampal synaptic plasticity and learning and memory. METHODS: The Fgfr1 conditional knockout mice were generated by crossing the Fgfr1-null line, the Fgfr1-flox line, and the Nestin-Cre transgenic mice. Bromodeoxyuridine (BrdU) labeling, slice electrophysiology, and Morris Water Maze experiments were performed with the Fgfr1 conditional mutant mice. RESULTS: Bromodeoxyuridine labeling experiments demonstrate that FGFR1 is required for the proliferation of NPCs as well as generation of new neurons in the adult dentate gyrus (DG). Moreover, deficits in neurogenesis in Fgfr1 mutant mice are accompanied by a severe impairment of long-term potentiation (LTP) at the medial perforant path (MPP)-granule neuron synapses in the hippocampal dentate. Moreover, the Fgfr1 mutant mice exhibit significant deficits in memory consolidation but not spatial learning. CONCLUSIONS: Our study suggests a critical role of FGFR1 in adult neurogenesis in vivo, provides a potential link between proliferative neurogenesis and dentate LTP, and raises the possibility that adult neurogenesis might contribute to memory consolidation.     

Neurogenesis within the adult hippocampus under physiological conditions and in depression

Adult neurogenesis can only be observed in some specific brain regions. One of these areas is the dentate gyrus of the hippocampal formation. The progenitor cells located in the subgranular layer of the dentate gyrus proliferate, differentiate, and give rise to young neurons that can become integrated into existing neuronal circuits. Under physiological conditions, hippocampal neurogenesis is linked to hippocampal-dependent learning, whereas deficits in adult hippocampal neurogenesis have been shown to correlate with disturbances in spatial learning and memory. This review summarizes the phenomenon of adult hippocampal neurogenesis and the use of suitable markers for the investigation of adult hippocampal neurogenesis. In addition, we focused on the disturbances in neurogenesis that can be seen in depression. Interestingly, several antidepressants have been found to be capable of increasing the rate of hippocampal neurogenesis. Based on that, it can be speculated that factors, which directly or indirectly increase the rate of hippocampal neurogenesis, may be helpful in the treatment of depression.     

Hippocampal injury-induced cognitive and mood dysfunction,altered neurogenesis,and epilepsy: Can early neural stem cell grafting intervention provide protection?

Damage to the hippocampus can occur through many causes including head trauma, ischemia, stroke, status epilepticus, and Alzheimer's disease. Certain changes such as increased levels of neurogenesis and elevated concentrations of multiple neurotrophic factors that ensue in the acute phase after injury seem beneficial for restraining hippocampal dysfunction. However, many alterations that arise in the intermediate to chronic phase after injury such as abnormal migration of newly born neurons, aberrant synaptic reorganization, progressive loss of inhibitory gamma-amino butyric acid positive interneurons including those expressing reelin, greatly declined neurogenesis, and sustained inflammation are detrimental. Consequently, the net effect of postinjury plasticity in the hippocampus remains inadequate for promoting significant functional recovery. Hence, ideal therapeutic interventions ought to be efficient for restraining these detrimental changes in order to block the propensity of most hippocampal injuries to evolve into learning deficits, memory dysfunction, depression, and temporal lobe epilepsy. Neural stem cell (NSC) grafting into the hippocampus early after injury appears alluring from this perspective because several recent studies have demonstrated the therapeutic value of this intervention, especially for preventing/easing memory dysfunction, depression, and temporal lobe epilepsy development in the chronic phase after injury. These beneficial effects of NSC grafting appeared to be mediated through considerable modulation of aberrant hippocampal postinjury plasticity with additions of new inhibitory gamma-amino butyric acid positive interneurons and astrocytes secreting a variety of neurotrophic factors and anticonvulsant proteins. This review presents advancements made in NSC grafting therapy for treating hippocampal injury in animal models of excitotoxic injury, traumatic brain injury, Alzheimer's disease, and status epilepticus; potential mechanisms of functional recovery mediated by NSC grafts placed early after hippocampal injury; and issues that need to be resolved prior to considering clinical application of NSC grafting for hippocampal injury.This article is part of a Special Issue entitled “NEWroscience 2013”.