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Anatomy of hippocampal circuit into which new neurons integrate. Neurogenesis is localized to the dentate gyrus (DG) region, where only excitatory granule cells are continually produced throughout life. The DG has a complex local circuitry, with both inhibitory interneurons and excitatory feedback neurons (mossy cells) participating in the network's behavior. Granule cells in the DG project to the CA3 region, which in addition to a robust recurrent connection then projects to the CA1 region. The CA1 then projects back to the entorhinal cortex and subiculum regions, closing the "hippocampal loop."
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Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesi...
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... perisomatic GABAergic inhibitory currents are recorded in neurons later than functional glutamatergic inputs. Adult-born neurons receive local inhibitory inputs from all three subregions of DG: molecular layers, GCLs, and hilus (193) (FIGURE 2). With maturation, inhibitory inputs to adult-born neurons gradually increase. ...
Similar publications
Serotonin (5-HT) plays an important role in regulating adult hippocampal neurogenesis. Chronic administration of selective 5-HT reuptake inhibitors (SSRIs), which up-regulates extracellular 5-HT concentration, accelerates the maturation of adult-born hippocampal neurons. It is unknown, however, about effects of central 5-HT-deficiency on the dendri...
Citations
... Adult neurogenesis involves an initial period of neural proliferation, followed by a period of survival, selection and maturation over the course of several weeks 26,27 . This dynamic and finely-regulated process is highly dependent on the activity of neural networks and subject to modulation by various physiological and environmental stimuli 28 . The impact of spaceflight on adult neurogenesis has been little explored. ...
Cognitive impairments have been reported in astronauts during spaceflights and documented in ground-based models of simulated microgravity (SMG) in animals. However, the neuronal causes of these behavioral effects remain largely unknown. We explored whether adult neurogenesis, known to be a crucial plasticity mechanism supporting memory processes, is altered by SMG. Adult male Long-Evans rats were submitted to the hindlimb unloading model of SMG. We studied the proliferation, survival and maturation of newborn cells in the following neurogenic niches: the subventricular zone (SVZ)/olfactory bulb (OB) and the dentate gyrus (DG) of the hippocampus, at different delays following various periods of SMG. SMG exposure for 7 days, but not shorter periods of 6 or 24 h, resulted in a decrease of newborn cell proliferation restricted to the DG. SMG also induced a decrease in short-term (7 days), but not long-term (21 days), survival of newborn cells in the SVZ/OB and DG. Physical exercise, used as a countermeasure, was able to reverse the decrease in newborn cell survival observed in the SVZ and DG. In addition, depending on the duration of SMG periods, transcriptomic analysis revealed modifications in gene expression involved in neurogenesis. These findings highlight the sensitivity of adult neurogenesis to gravitational environmental factors during a transient period, suggesting that there is a period of adaptation of physiological systems to this new environment.
... This process is tightly regulated by cell-intrinsic elements (Bonaguidi et al., 2011;Bonzano et al., 2018;Encinas et al., 2011) and influenced by multiple environmental or physio-pathological factors that can increase (e.g., enriched environment or voluntary exercise) or decrease (e.g., aging, stress, and neurodegenerative diseases) the production and integration of adult-born neurons (Aimone et al., 2014;Beccari et al., 2017;Dranovsky et al., 2011;Sierra et al., 2015;Steiner et al., 2004Steiner et al., , 2008. Such factors can also enhance astrogliogenesis, often displaying opposite effects compared to neurogenesis. ...
Tamoxifen-inducible systems are widely used in research to control Cre-mediated gene deletion in genetically modified animals. Beyond Cre activation, tamoxifen also exerts off-target effects, whose consequences are still poorly addressed. Here, we investigated the impact of tamoxifen on lipopolysaccharide (LPS)-induced neuroinflammatory responses, focusing on the neurogenic activity in the adult mouse dentate gyrus. We demonstrated that a four-day LPS treatment led to an increase in microglia, astrocytes and radial glial cells with concomitant reduction of newborn neurons. These effects were counteracted by a two-day tamoxifen pre-treatment. Through selective microglia depletion, we elucidated that both LPS and tamoxifen influenced astrogliogenesis via microglia mediated mechanisms, while the effects on neurogenesis persisted even in a microglia-depleted environment. Notably, changes in radial glial cells resulted from a combination of microglia-dependent and-independent mechanisms. Overall, our data reveal that tamoxifen treatment per se does not alter the balance between adult neurogenesis and astrogliogenesis but does modulate cellular responses to inflammatory stimuli exerting a protective role within the adult hippocampal neurogenic niche. K E Y W O R D S
... We also identified genes with Cn SNPs that are important for later events in neurogenesis, such as migration, dendritogenesis, and maturation, according to the MANGO database. Additionally, we found enriched GO terms potentially involved in neuronal integration, including synaptic transmission and plasticity, as well as terms associated with neural processes that can be modulated by hippocampal adult neurogenesis, such as learning, memory, and behavior 12,44,45 . The genes with Cn SNPs were also found to be expressed in mature granule cells (GC) according to Hipposeq platform, suggesting their potential relevance for GC functionality. ...
Individuals with autism spectrum disorder (ASD) often exhibit atypical hippocampal anatomy and connectivity throughout their lifespan, potentially linked to alterations in the neurogenic process within the hippocampus. In this study, we performed an in-silico analysis to identify single-nucleotide polymorphisms (SNPs) in genes relevant to adult neurogenesis in the C58/J model of idiopathic autism. We found coding non-synonymous (Cn) SNPs in 33 genes involved in the adult neurogenic process, as well as in 142 genes associated with the signature genetic profile of neural stem cells (NSC) and neural progenitors. Based on the potential alterations in adult neurogenesis predicted by the in-silico analysis, we evaluated the number and distribution of newborn neurons in the dentate gyrus (DG) of young adult C58/J mice. We found a reduced number of newborn cells in the whole DG, a higher proportion of early neuroblasts in the subgranular layer (SGZ), and a lower proportion of neuroblasts with morphological maturation signs in the granule cell layer (GCL) of the DG compared to C57BL/6J mice. The observed changes may be associated with a delay in the maturation trajectory of newborn neurons in the C58/J strain, linked to the Cn SNPs in genes involved in adult hippocampal neurogenesis.
... These circuits involve precisely controlled steps, ranging from neurogenesis to cell migration, differentiation, neuritogenesis, target identification, and synapse formation, elimination, and stabilization. Over time, these connections may be strengthened or weakened, leading to the formation of a highly efficient neural network that is essential for proper brain function [1][2][3]. ...
... The most appealing phenomenon of neuroplasticity appears to be adult neurogenesis, a process defined as the birth of new neurons in the adult brain. Neurogenesis comprises a series of steps that can be examined separately: proliferation, differentiation, migration, and cell survival [1,2,10,11]. There is ongoing investigation into neurogenesis in various brain regions, including the striatum, cerebral cortex, amygdala, hypothalamus, hippocampus, and the lateral ventricles [12][13][14][15]. ...
... There is ongoing investigation into neurogenesis in various brain regions, including the striatum, cerebral cortex, amygdala, hypothalamus, hippocampus, and the lateral ventricles [12][13][14][15]. However, two well-researched areas where neurogenesis takes place are the subventricular zone (SVZ) along the lateral ventricle and the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus [1,2,16]. ...
Neuroplasticity refers to the nervous system’s ability to adapt and reorganize its cell structures and neuronal networks in response to internal and external stimuli. In adults, this process involves neurogenesis, synaptogenesis, and synaptic and neurochemical plasticity. Several studies have reported the significant impact of the purinergic system on neuroplasticity modulation. And, there is considerable evidence supporting the role of purine nucleosides, such as adenosine, inosine, and guanosine, in this process. This review presents extensive research on how these nucleosides enhance the neuroplasticity of the adult central nervous system, particularly in response to damage. The mechanisms through which these nucleosides exert their effects involve complex interactions with various receptors and signaling pathways. Adenosine’s influence on neurogenesis involves interactions with adenosine receptors, specifically A1R and A2AR. A1R activation appears to inhibit neuronal differentiation and promote astrogliogenesis, while A2AR activation supports neurogenesis, neuritogenesis, and synaptic plasticity. Inosine and guanosine positively impact cell proliferation, neurogenesis, and neuritogenesis. Inosine seems to modulate extracellular adenosine levels, and guanosine might act through interactions between purinergic and glutamatergic systems. Additionally, the review discusses the potential therapeutic implications of purinergic signaling in neurodegenerative and neuropsychiatric diseases, emphasizing the importance of these nucleosides in the neuroplasticity of brain function and recovery.
... Neuronal revival predominantly relied on the migration and differentiation of neuroblasts from the subventricular zone (SVZ). Nonetheless, temporal constraints on neuroblast proliferation within the SVZ and the spatial gap between the SVZ and the stroke lesion limited the effectiveness of this approach (9). Consequently, the demand for novel multifunctional materials becomes evident as a means to achieve more efficacious clinical treatments (10). ...
Stroke poses a critical global health challenge, leading to substantial morbidity and mortality. Existing treatments often miss vital timeframes and encounter limitations due to adverse effects, prompting the pursuit of innovative approaches to restore compromised brain function. This review explores the potential of filamentous phages in enhancing stroke recovery. Initially antimicrobial-centric, bacteriophage therapy has evolved into a regenerative solution. We explore the diverse role of filamentous phages in post-stroke neurological restoration, emphasizing their ability to integrate peptides into phage coat proteins, thereby facilitating recovery. Experimental evidence supports their efficacy in alleviating post-stroke complications, immune modulation, and tissue regeneration. However, rigorous clinical validation is essential to address challenges like dosing and administration routes. Additionally, genetic modification enhances their potential as injectable biomaterials for complex brain tissue issues. This review emphasizes innovative strategies and the capacity of filamentous phages to contribute to enhanced stroke recovery, as opposed to serving as standalone treatment, particularly in addressing stroke-induced brain tissue damage.
... There are several mechanisms by which cognitive function can be enhanced, and two of the most well-known ones are through protective effects by antioxidants (30) and neurogenesis (31) . ...
Brain aging, the primary risk factor for cognitive impairment, occurs because of the accumulation of age-related neuropathologies. Identifying effective nutrients that increase cognitive function may help maintain brain health. Tomatoes and lemons have various bioactive functions and exert protective effects against oxidative stress, aging, and cancer. Moreover, they have been shown to enhance cognitive function. In the present study, we aimed to investigate the effects of tomato and lemon ethanolic extracts (TEE and LEE, respectively) and their possible synergistic effects on the enhancement of cognitive function and neurogenesis in aged mice. The molecular mechanisms underlying the synergistic effect of TEE and LEE were investigated. For the in vivo experiment, TEE, LEE, or their mixture was orally administered to 12-month-old mice for 9 weeks. A single administration of either TEE or LEE improved cognitive function and neurogenesis in aged mice to some extent, as determined using the novel object recognition test and doublecortin immunohistochemical staining, respectively. However, a significant enhancement of cognitive function and neurogenesis in aged mice was observed after the administration of the TEE+LEE mixture, which had a synergistic effect. N -methyl- d -aspartate receptor 2B postsynaptic density protein 95, and brain-derived neurotrophic factor (BDNF) levels, and TrkB/extracellular signal-regulated kinase (ERK) phosphorylation also synergistically increased after the administration of the mixture compared with those in the individual treatments. In conclusion, compared to their separate treatments, treatment with the TEE+LEE mixture synergistically improved the cognitive function, neurogenesis, and synaptic plasticity in aged mice via the BDNF/TrkB/ERK signaling pathway.
... SSRIs exert their therapeutic effects by inhibiting the reuptake of 5-HT via SERT 5-HT transporters, to sustain concentrations of extracellular 5-HT 22,23 . 5-HT also plays an important role in adult neurogenesis by promoting the self-renewal of neural stem cells in the hippocampus 24 . Moreover, maternal 5-HT synthesized in the placenta of pregnant mice has been found to transiently localize in the forebrain of early-stage embryos 25 , raising the possibility that placenta-derived 5-HT regulates early brain development [26][27][28] . ...
... In adult neurogenesis of both rodents and humans, SSRIs are known to promote the proliferation of neural stem cells 24,50 . Therefore, we examined the proliferation of neural stem/progenitor cells in the optic tectum using anti-phospho-histone H3 (pH3) antibody 31 . ...
... Our results suggest that paroxetine expands the number of neural stem/progenitor cells in the zebra sh embryonic brain. This is consistent with the effect of SSRI that increases the number of neural stem/progenitor cells in the dentate gyrus of the adult mammalian hippocampus through the increased concentration of 5-HT 24,49,50 . These results also suggest that, while SSRI use during pregnancy can have therapeutic effects on the human maternal brain, it is likely to have adverse effects on the embryonic brain. ...
Autism spectrum disorder (ASD) is a neurodevelopmental condition caused by various genetic and environmental factors. This disorder has the cardinal symptoms including impaired social behavior involving the amygdala. Antidepressants such as paroxetine in early pregnancy increase the risk of ASD in offspring. However, a comprehensive picture of the underlying pathogenic mechanisms remains elusive. Here, we demonstrate that early exposure of zebrafish embryos to paroxetine suppresses neurogenesis in the optic tectum and the dorsal telencephalon which corresponds to the human amygdala. Paroxetine-treated embryos exhibit impaired growth, with small heads and short body lengths resulting from transient apoptosis. This is reminiscent of the early-onset fetal growth restriction (FGR) associated with ASD. Interestingly, the suppressed neurogenesis in the small heads was found to be restored after the cessation of paroxetine. This was accompanied by extended retinotectal projections, suggesting brain-preferential remodeling. Finally, the paroxetine-treated fish exhibited impaired social behavior, further supporting the correspondence with ASD. Our findings offer new insights into the early neurodevelopmental etiology of ASD.
... Neuronal plasticity is recognized as a crucial mechanism through which the central nervous system (CNS) learns from experience, forms memories, modifies the structure of neural networks over time, recovers after lesion or disease, and in some cases, regenerates lost nerve cells (Martino et al. 2011;Aimone et al. 2014;Bao and Song 2018;Obernier and Alvarez-Buylla 2019;Kempermann 2019;Bonfanti and Charvet 2021;La Rosa and Bonfanti 2021). Structural changes can impact the anatomy of the nervous system, from a subcellular to a neural circuit level. ...
... This form of plasticity is expected to take place in nearly all parts of the grey matter in the central nervous system (CNS) and is likely well-conserved among mammals, reflected, in part, by the low interspecies variation of synaptic density and structure (apart from some differences probably linked to evolutionary adaptations of neural circuits to particular functions; Sherwood et al. 2020;De Felipe et al. 2002;Alonso-Nanclares et al. 2022). The most striking form of plasticity is adult neurogenesis, namely the formation of new neurons in specific neurogenic regions, as the result of neural stem cell activity (Aimone et al. 2014;Lim and Alvarez-Buylla 2016;Bao and Song 2018;Obernier and Alvarez-Buylla 2019;Fig. 1B). ...
... 2). Accordingly, fish neurogenic processes can provide substantial possibilities for brain repair and regeneration after lesion (Lindsey et al. 2018;Lange and Brand 2020), whereas in mammals most regenerative capacity has been lost (Weil et al. 2008;Bonfanti 2011), the new neurons mainly playing a role in the postnatal maturation of specific neural circuits by sculpting their capability to learn from experience (Aimone et al. 2014;Semënov 2019;Kempermann 2019;Cushman et al. 2021;La Rosa and Bonfanti 2021;Fig. 2). ...
Neuronal plasticity can vary remarkably in its form and degree across animal species. Adult neurogenesis, namely the capacity to produce new neurons from neural stem cells through adulthood, appears widespread in non-mammalian vertebrates, whereas it is reduced in mammals. A growing body of comparative studies also report variation in the occurrence and activity of neural stem cell niches between mammals, with a general trend of reduction from small-brained to large-brained species. Conversely, recent studies have shown that large-brained mammals host large amounts of neurons expressing typical markers of neurogenesis in the absence of cell division. In layer II of the cerebral cortex, populations of prenatally generated, non-dividing neurons continue to express molecules indicative of immaturity throughout life (cortical immature neurons; cINs). After remaining in a dormant state for a very long time, these cINs retain the potential of differentiating into mature neurons that integrate within the preexisting neural circuits. They are restricted to the paleocortex in small-brained rodents, while extending into the widely expanded neocortex of highly gyrencephalic, large-brained species. The current hypothesis is that these populations of non-newly generated “immature” neurons might represent a reservoir of developmentally plastic cells for mammalian species that are characterized by reduced stem cell-driven adult neurogenesis. This indicates that there may be a trade-off between various forms of plasticity that coexist during brain evolution. This balance may be necessary to maintain a “reservoir of plasticity” in brain regions that have distinct roles in species-specific socioecological adaptations, such as the neocortex and olfactory structures.
... Adult hippocampal neurogenesis persists in the rodent brain, from neural stem/progenitor cells (NSPC) residing in the subgranular zone (SGZ). They divide frequently and differentiate into glial or neuronal precursors (1). More than 50% of the newborn cells undergo apoptosis shortly after exiting the cell cycle, and a subset of the neuronal progenitors survives and gives rise to new granule neurons (1)(2)(3). ...
... They divide frequently and differentiate into glial or neuronal precursors (1). More than 50% of the newborn cells undergo apoptosis shortly after exiting the cell cycle, and a subset of the neuronal progenitors survives and gives rise to new granule neurons (1)(2)(3). Newborn neuronal progenitors acquire distinct developmental morphologies during the process of maturation (4) and transiently express the microtubule-associated protein doublecortin (DCX) along their immature stages, often referred to as young or immature neurons (5,6). Within the first two weeks after birth, newborn granule neurons acquire a morphology resembling the mature neurons, characterized by a radial projection of the dendritic processes towards the molecular layer and axons extending to the cornu ammonis 3 region (CA3) (7). ...
... Within the first two weeks after birth, newborn granule neurons acquire a morphology resembling the mature neurons, characterized by a radial projection of the dendritic processes towards the molecular layer and axons extending to the cornu ammonis 3 region (CA3) (7). They become fully mature within 4-6 weeks after birth (1,8). In rodents, newborn granule neurons have been shown to contribute to certain cognitive tasks such as pattern separation and maintenance of memory functions (1,9,10). ...
Introduction
Cranial irradiation (IR) negatively regulates hippocampal neurogenesis and causes cognitive dysfunctions in cancer survivors, especially in pediatric patients. IR decreases proliferation of neural stem/progenitor cells (NSPC) and consequently diminishes production of new hippocampal neurons. Memantine, an NMDA receptor antagonist, used clinically to improve cognition in patients suffering from Alzheimer’s disease and dementia. In animal models, memantine acts as a potent enhancer of hippocampal neurogenesis. Memantine was recently proposed as an intervention to improve cognitive impairments occurring after radiotherapy and is currently under investigation in a number of clinical trials, including pediatric patients. To date, preclinical studies investigating the mechanisms underpinning how memantine improves cognition after IR remain limited, especially in the young, developing brain. Here, we investigated whether memantine could restore proliferation in the subgranular zone (SGZ) or rescue the reduction in the number of hippocampal young neurons after IR in the juvenile mouse brain.
Methods
Mice were whole-brain irradiated with 6 Gy on postnatal day 20 (P20) and subjected to acute or long-term treatment with memantine. Proliferation in the SGZ and the number of young neurons were further evaluated after the treatment. We also measured the levels of neurotrophins associated with memantine improved neural plasticity, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).
Results
We show that acute intraperitoneal treatment with a high, non-clinically used, dose of memantine (50 mg/kg) increased the number of proliferating cells in the intact brain by 72% and prevented 23% of IR-induced decrease in proliferation. Long-term treatment with 10 mg/kg/day of memantine, equivalent to the clinically used dose, did not impact proliferation, neither in the intact brain, nor after IR, but significantly increased the number of young neurons (doublecortin expressing cells) with radial dendrites (29% in sham controls and 156% after IR) and enhanced their dendritic arborization. Finally, we found that long-term treatment with 10 mg/kg/day memantine did not affect the levels of BDNF, but significantly reduced the levels of NGF by 40%.
Conclusion
These data suggest that the enhanced dendritic complexity of the hippocampal young neurons after treatment with memantine may contribute to the observed improved cognition in patients treated with cranial radiotherapy.
... Subsequently, evidence mounted for newborn neurons transitorily exhibiting distinct ephys features before becoming indistinguishable from fully mature granule cells Aimone et al, 2014). Specifically, four-to-six weeks after birth, newborn neurons were shown to develop elaborate dendritic arbors coated with spines and exhibit increased synaptic plasticity and hyperexcitability compared to the mature granule neurons (Snyder et al, 2001;Schmidt-Hieber et al, 2004;Esp osito et al, 2005;Gu et al, 2012). ...
For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental mechanisms underlying cognition. Long recognized as the brain's seat for learning and memory, a wealth of knowledge has been accumulated on how the hippocampus processes sensory input, builds complex associations between objects, events, and space, and stores this information in the form of memories to be retrieved later in life. However, despite major efforts, our understanding of hippocampal cognitive function remains fragmentary, and models trying to explain it are continually revisited. Here, we review the literature across all above‐mentioned domains and offer a new perspective by bringing attention to the most distinctive, and generally neglected, feature of the mammalian hippocampal formation, namely, the structural separability of the two blades of the dentate gyrus into “supra‐pyramidal” and “infra‐pyramidal”. Next, we discuss recent reports supporting differential effects of adult neurogenesis in the regulation of mature granule cell activity in these two blades. We propose a model for how differences in connectivity and adult neurogenesis in the two blades can potentially provide a substrate for subtly different cognitive functions.
