Donepezil Rescues Spatial Learning and Memory Deficits following Traumatic Brain Injury Independent of Its Effects on Neurogenesis

Traumatic brain injury (TBI) is ubiquitous and effective treatments for it remain supportive largely due to uncertainty over how endogenous repair occurs. Recently, we demonstrated that hippocampal injury-induced neurogenesis is one mechanism underlying endogenous repair following TBI. Donepezil is associated with increased hippocampal neurogenesis and has long been known to improve certain aspects of cognition following many types of brain injury through unknown mechanisms. By coupling donepezil therapy with temporally regulated ablation of injury-induced neurogenesis using nestin-HSV transgenic mice, we investigated whether the pro-cognitive effects of donepezil following injury might occur through increasing neurogenesis. We demonstrate that donepezil itself enhances neurogenesis and improves cognitive function following TBI, even when injury-induced neurogenesis was inhibited. This suggests that the therapeutic effects of donepezil in TBI occur separately from its effects on neurogenesis.     

Proliferation, neurogenesis and regeneration in the non-mammalian vertebrate brain

Post-embryonic neurogenesis is a fundamental feature of the vertebrate brain. However, the level of adult neurogenesis decreases significantly with phylogeny. In the first part of this review, a comparative analysis of adult neurogenesis and its putative roles in vertebrates are discussed. Adult neurogenesis in mammals is restricted to two telencephalic constitutively active zones. On the contrary, non-mammalian vertebrates display a considerable amount of adult neurogenesis in many brain regions. The phylogenetic differences in adult neurogenesis are poorly understood. However, a common feature of vertebrates (fish, amphibians and reptiles) that display a widespread adult neurogenesis is the substantial post-embryonic brain growth in contrast to birds and mammals. It is probable that the adult neurogenesis in fish, frogs and reptiles is related to the coordinated growth of sensory systems and corresponding sensory brain regions. Likewise, neurons are substantially added to the olfactory bulb in smell-oriented mammals in contrast to more visually oriented primates and songbirds, where much fewer neurons are added to the olfactory bulb. The second part of this review focuses on the differences in brain plasticity and regeneration in vertebrates. Interestingly, several recent studies show that neurogenesis is suppressed in the adult mammalian brain. In mammals, neurogenesis can be induced in the constitutively neurogenic brain regions as well as ectopically in response to injury, disease or experimental manipulations. Furthermore, multipotent progenitor cells can be isolated and differentiated in vitro from several otherwise silent regions of the mammalian brain. This indicates that the potential to recruit or generate neurons in non-neurogenic brain areas is not completely lost in mammals. The level of adult neurogenesis in vertebrates correlates with the capacity to regenerate injury, for example fish and amphibians exhibit the most widespread adult neurogenesis and also the greatest capacity to regenerate central nervous system injuries. Studying these phenomena in non-mammalian vertebrates may greatly increase our understanding of the mechanisms underlying regeneration and adult neurogenesis. Understanding mechanisms that regulate endogenous proliferation and neurogenic permissiveness in the adult brain is of great significance in therapeutical approaches for brain injury and disease.     

Adult Neurogenesis in the Olfactory System: Improving Performance for Difficult Discrimination Tasks?

What is the function of new neurons entering the olfactory bulb? Many insights regarding the molecular control of adult neurogenesis have been uncovered, but the purpose of new neurons entering the olfactory bulb has been difficult to ascertain. Here, studies investigating the role of adult neurogenesis in olfactory discrimination in mice are reviewed. Studies in which adult neurogenesis is affected are highlighted, with a focus on the role of environment enrichment and what happens during ageing. There is evidence for a role of adult neurogenesis in fine discrimination tasks, as underscored by studies that enhance adult neurogenesis. This is also observed in ageing studies, where older mice with reduced levels of adult neurogenesis perform poorly in olfactory discrimination. Differences in methodology that could account for alternative conclusions, and the importance of specificity in methods being used to investigate the effect of adult neurogenesis in olfactory performance are emphasized.     

Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?

It is now clear that neurogenesis occurs in the brain of adult mammals. Many studies have attempted to establish relationships among neurogenesis, depression and the mechanism of action of antidepressant drugs. Therapeutic effects of antidepressants appear to be linked to increased neurogenesis in the hippocampus. Cdk inhibitors are expressed in multiple brain regions, presumably maintaining quiescence in differentiated neurons. Recently, the abundant expression of p21Cip1 was found in neuroblasts and in newly developing neurons in the subgranular zone of the hippocampus, a region where adult neurogenesis occurs. Chronic treatment with the tricyclic antidepressant imipramine markedly decreased p21Cip1 mRNA and protein levels and stimulated neurogenesis in this region. These results suggest that p21Cip1 restrains neurogenesis in the hippocampus, and antidepressant-induced stimulation of neurogenesis might be a consequence of decreased p21Cip1 expression, with the subsequent release of neuronal progenitor cells from the blockade of proliferation. These findings suggest the potential for new therapeutic strategies for the treatment of depression that target cell cycle proteins. However, there is a possibility that long-term stimulation of neurogenesis might exhaust the proliferation potentials of neuronal progenitors.     

Genetic influences on exercise-induced adult hippocampal neurogenesis across 12 divergent mouse strains

New neurons are continuously born in the hippocampus of several mammalian species throughout adulthood. Adult neurogenesis represents a natural model for understanding how to grow and incorporate new nerve cells into preexisting circuits in the brain. Finding molecules or biological pathways that increase neurogenesis has broad potential for regenerative medicine. One strategy is to identify mouse strains that display large vs. small increases in neurogenesis in response to wheel running so that the strains can be contrasted to find common genes or biological pathways associated with enhanced neuron formation. Therefore, mice from 12 different isogenic strains were housed with or without running wheels for 43 days to measure the genetic regulation of exercise-induced neurogenesis. During the first 10 days mice received daily injections of 5-bromo-2'-deoxyuridine (BrdU) to label dividing cells. Neurogenesis was measured as the total number of BrdU cells co-expressing NeuN mature neuronal marker in the hippocampal granule cell layer by immunohistochemistry. Exercise increased neurogenesis in all strains, but the magnitude significantly depended on genotype. Strain means for distance run on wheels, but not distance traveled in cages without wheels, were significantly correlated with strain mean level of neurogenesis. Furthermore, certain strains displayed greater neurogenesis than others for a fixed level of running. Strain means for neurogenesis under sedentary conditions were not correlated with neurogenesis under runner conditions suggesting that different genes influence baseline vs. exercise-induced neurogenesis. Genetic contributions to exercise-induced hippocampal neurogenesis suggest that it may be possible to identify genes and pathways associated with enhanced neuroplastic responses to exercise.     

Jagged1 is necessary for postnatal and adult neurogenesis in the dentate gyrus

Understanding the mechanisms that control the maintenance of neural stem cells is crucial for the study of neurogenesis. In the brain, granule cell neurogenesis occurs during development and adulthood, and the generation of new neurons in the adult subgranular zone of the dentate gyrus contributes to learning. Notch signaling plays an important role during postnatal and adult subgranular zone neurogenesis, and it has been suggested as a potential candidate to couple cell proliferation with stem cell maintenance. Here we show that conditional inactivation of Jagged1 affects neural stem cell maintenance and proliferation during postnatal and adult neurogenesis of the subgranular zone. As a result, granule cell production is severely impaired. Our results provide additional support to the proposal that Notch/Jagged1 activity is required for neural stem cell maintenance during granule cell neurogenesis and suggest a link between maintenance and proliferation of these cells during the early stages of neurogenesis.     

Opposing effects of bone morphogenetic proteins on neuron production and survival in the olfactory receptor neuron lineage

In olfactory epithelium (OE) cultures, bone morphogenetic proteins (BMPs) can strongly inhibit neurogenesis. Here we provide evidence that BMPs also promote, and indeed are required, for OE neurogenesis. Addition of the BMP antagonist noggin inhibited neurogenesis in OE-stromal cell co-cultures. Bmp2, Bmp4 and Bmp7 were expressed by OE stroma, and low concentrations of BMP4 (below the threshold for inhibition of neurogenesis) stimulated neurogenesis; BMP7 did not exhibit a stimulatory effect at any concentration tested. Stromal cell conditioned medium also stimulated neurogenesis; part of this effect was due to the presence within it of a noggin-binding factor or factors. Studies of the pro-neurogenic effect of BMP4 indicated that it did not increase progenitor cell proliferation, but rather promoted survival of newly generated olfactory receptor neurons. These findings indicate that BMPs exert both positive and negative effects on neurogenesis, depending on ligand identity, ligand concentration and the particular cell in the lineage that is responding. In addition, they reveal the presence of a factor or factors, produced by OE stroma, that can synergize with BMP4 to stimulate OE neurogenesis.     

Adult neurogenesis in natural populations

The dogma that the adult brain produces no new neurons has been overturned, but the critics are still asking, so what? Is adult neurogenesis a biologically relevant phenomenon, or is it perhaps harmful because it disrupts the existing neuronal circuitry? Considering that the phenomenon is evolutionarily conserved in all mammalian species examined to date and that its relevance has been well documented in non-mammalian species, it seems self-evident that neurogenesis in adult mammals must have a role. In birds, it has been established that neurogenesis varies dramatically with seasonal changes in song production. In chickadees, the learning behaviour related to finding stored food is also correlated with seasonal adult neurogenesis. Such studies are still nonexistent in mammals, but the related evidence suggests that neurogenesis does vary seasonally in hamsters and shows sexual differences in meadow voles. To promote studies on natural populations asking fundamental questions of the purpose and function of neurogenesis, we organized a Workshop on "Hippocampal Neurogenesis in Natural Populations" in Toronto in May 2000. The Workshop highlighted recent discoveries in neurogenesis from the lab, and focused on its functional consequences. The consensus at the Workshop was that demonstration of a role for neurogenesis in natural behaviours will ultimately be essential if we are to understand the purpose and function of neurogenesis in humans.     

Electroconvulsive Therapy Induces Neurogenesis in Frontal Rat Brain Areas

Electroconvulsive therapy (ECT) is an effective therapy for several psychiatric disorders, including severe major depression, mania and certain forms of schizophrenia. It had been proposed that ECT acts by modulating local plasticity via the stimulation of neurogenesis. In fact, among antidepressant therapies, ECT is the most robust enhancer of neurogenesis in the hippocampus of rodents and non-human primates. The existence of ECT-triggered neurogenesis in other brain areas, particularly in those adjacent to the other main locus of neurogenesis, the subventricular zone (SVZ), had so far remained unknown. Here we show that ECT also strongly enhances neurogenesis in frontal brain areas, especially in the rostro-medial striatum, generating specific, small-size calretinin-positive interneurons. We provide here the first evidence that ECT stimulates neurogenesis in areas outside the hippocampus. Our data may open research possibilities that focus on the plastic changes induced by ECT in frontal limbic circuitry.     

Relationship of Adult Neurogenesis with Tau Phosphorylation and GSK-3β Activity in Subventricular Zone

Altered neurogenesis has been reported in Alzheimer disease (AD), the most common neurodegenerative disorder characterized with hyperphosphorylated tau and accumulation of β-amyloid (Aβ). Recent studies suggest that tau phosphorylation is essential for hippocampal neurogenesis, however, it is not known whether tau phosphorylation also play a role in neurogenesis of subventricular zone (SVZ), another main progenitor niche in the brain. Here, we examined the expression of phosphorylated tau (p-tau) in SVZ and analyzed the role of p-tau in adult SVZ neurogenesis. We found that the expression of p-tau increased during postnatal development and remains at a high level until adulthood, and the p-tau was colocalized with some SVZ neural precursors. However, up-regulating glycogen synthase kinase-3 (GSK-3), a crucial tau kinase, had no effect on SVZ neurogenesis in adult rat brain. The SVZ neurogenesis was also unaffected in tau knockout and human tau transgenic mice. These results suggest that tau phosphorylation and GSK-3 activation may not be essential for adult SVZ neurogenesis.     

Necessity of hippocampal neurogenesis for the therapeutic action of antidepressants in adult nonhuman primates

Background

Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs.

Materials/Methodology

Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.

Results

Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.

Conclusion

We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.     

BMP Signaling Mediates Effects of Exercise on Hippocampal Neurogenesis and Cognition in Mice

Exposure to exercise or to environmental enrichment increases the generation of new neurons in the adult hippocampus and promotes certain kinds of learning and memory. While the precise role of neurogenesis in cognition has been debated intensely, comparatively few studies have addressed the mechanisms linking environmental exposures to cellular and behavioral outcomes. Here we show that bone morphogenetic protein (BMP) signaling mediates the effects of exercise on neurogenesis and cognition in the adult hippocampus. Elective exercise reduces levels of hippocampal BMP signaling before and during its promotion of neurogenesis and learning. Transgenic mice with decreased BMP signaling or wild type mice infused with a BMP inhibitor both exhibit remarkable gains in hippocampal cognitive performance and neurogenesis, mirroring the effects of exercise. Conversely, transgenic mice with increased BMP signaling have diminished hippocampal neurogenesis and impaired cognition. Exercise exposure does not rescue these deficits, suggesting that reduced BMP signaling is required for environmental effects on neurogenesis and learning. Together, these observations show that BMP signaling is a fundamental mechanism linking environmental exposure with changes in cognitive function and cellular properties in the hippocampus.     

Staggered cell-intrinsic timing of ath5 expression underlies the wave of ganglion cell neurogenesis in the zebrafish retina

In the developing nervous system, progenitor cells must decide when to withdraw from the cell cycle and commence differentiation. There is considerable debate whether cell-extrinsic or cell-intrinsic factors are most important for triggering this switch. In the vertebrate retina, initiation of neurogenesis has recently been explained by a 'sequential-induction' model--signals from newly differentiated neurons are thought to trigger neurogenesis in adjacent progenitors, creating a wave of neurogenesis that spreads across the retina in a stereotypical manner. We show here, however, that the wave of neurogenesis in the zebrafish retina can emerge through the independent action of progenitor cells--progenitors in different parts of the retina appear pre-specified to initiate neurogenesis at different times. We provide evidence that midline Sonic hedgehog signals, acting before the onset of neurogenesis, are part of the mechanism that sets the neurogenic timer in these cells. Our results highlight the importance of intrinsic factors for triggering neurogenesis, but they also suggest that early signals can modulate these intrinsic factors to influence the timing of neurogenesis many cell cycles later, thereby potentially coordinating axial patterning with control of neuron number and cell fate.     

Irradiation induces neural precursor-cell dysfunction

In both pediatric and adult patients, cranial radiation therapy causes a debilitating cognitive decline that is poorly understood and currently untreatable. This decline is characterized by hippocampal dysfunction, and seems to involve a radiation-induced decrease in postnatal hippocampal neurogenesis. Here we show that the deficit in neurogenesis reflects alterations in the microenvironment that regulates progenitor-cell fate, as well as a defect in the proliferative capacity of the neural progenitor-cell population. Not only is hippocampal neurogenesis ablated, but the remaining neural precursors adopt glial fates and transplants of non-irradiated neural precursor cells fail to differentiate into neurons in the irradiated hippocampus. The inhibition of neurogenesis is accompanied by marked alterations in the neurogenic microenvironment, including disruption of the microvascular angiogenesis associated with adult neurogenesis and a marked increase in the number and activation status of microglia within the neurogenic zone. These findings provide clear targets for future therapeutic interventions.     

Adult Neurogenesis: Basic Concepts of Signaling

Findings over the past decades demonstrating persistent neurogenesis in the adult brain havechallenged the view of a fixed circuitry in normally functioning brain and raised hopes for self-renewalfollowing brain injury. In addition to providing insights for repair, studying adult neurogenesis mayimprove our understanding of embryonic development assuming that fundamental mechanisms aresimilar. It is argued here, using examples of cell:cell communication, that parallels can be drawnbetween adult and embryonic neurogenesis. Paradoxically, cell:cell communication in neurogenicregions resembles that in a mature neuroglial network. This suggests that differences in the integrativeproperties of cells and the extracellular matrix molecules may constitute a neurogenic environment or“niche”. While reasons for persistent adult neurogenesis in humans remains obscure, recent findingsregarding the environmental and activity-driven control of neurogenesis reinforce the original conceptof a role for neurogenesis in motor memory formation and refinement of information processing.     

The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis

The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell division, migration, growth, and differentiation. Although there are several examples of MT‐stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of MT‐destabilizing proteins. Stathmin is such a MT‐destabilizing protein largely restricted to the CNS, and in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone of the mouse hippocampus. After carefully mapping stathmin expression in the adult dentate gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki‐67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA‐NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore, our data suggest that migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early postmitotic neurons. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 74: 1226–1242, 2014     

Comparative aspects of adult neural stem cell activity in vertebrates

At birth or after hatching from the egg, vertebrate brains still contain neural stem cells which reside in specialized niches. In some cases, these stem cells are deployed for further postnatal development of parts of the brain until the final structure is reached. In other cases, postnatal neurogenesis continues as constitutive neurogenesis into adulthood leading to a net increase of the number of neurons with age. Yet, in other cases, stem cells fuel neuronal turnover. An example is protracted development of the cerebellar granular layer in mammals and birds, where neurogenesis continues for a few weeks postnatally until the granular layer has reached its definitive size and stem cells are used up. Cerebellar growth also provides an example of continued neurogenesis during adulthood in teleosts. Again, it is the granular layer that grows as neurogenesis continues and no definite adult cerebellar size is reached. Neuronal turnover is most clearly seen in the telencephalon of male canaries, where projection neurons are replaced in nucleus high vocal centre each year before the start of a new mating season—circuitry reconstruction to achieve changes of the song repertoire in these birds? In this review, we describe these and other examples of adult neurogenesis in different vertebrate taxa. We also compare the structure of the stem cell niches to find common themes in their organization despite different functions adult neurogenesis serves in different species. Finally, we report on regeneration of the zebrafish telencephalon after injury to highlight similarities and differences of constitutive neurogenesis and neuronal regeneration.     

In vivo optical imaging of neurogenesis: watching new neurons in the intact brain

Adult neurogenesis is a highly dynamic process modulated by several pathologic and environmental factors, as well as by various compounds. So far, available techniques to study neurogenesis are lengthy and personnel and cost intensive. We developed a new tool based on the doublecortin promoter driving the expression of the luciferase reporter gene (DCX-promo-luciferase) in transgenic mice to perform in vivo imaging of neurogenesis. Indeed, the DCX-promo-luciferase mice allowed optical in vivo imaging of the onset of and increase in neurogenesis in developing fetal brains, as well as imaging of neurogenesis in the intact adult mouse central nervous system. Moreover, the capacity to specifically detect a small number of migrating neuronal precursors in vivo after transplantation is for the first time feasible using this DCX-promo-luciferase transgenic tool. The present imaging approach offers several crucial advantages over methods currently available, such as bromodeoxyuridine incorporation or labeling using iron oxide nanoparticles. Hence, it allows longitudinal study of neurogenesis in intact animals without the requirement of cellular prelabeling. Moreover, it guarantees that detection is specific for neuronal precursors and restricted to viable cells. Hence, our DCX-promo-luciferase transgenic model constitutes an effective tool that answers the pressing need for rapid investigation of the impact on neurogenesis of a large number of candidate compounds waiting to be tested.     

Hippocampal learning,memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults

This article is part of a Special Issue “Estradiol and Cognition”.There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment, and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus.