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Newly generated granule cells in adult hippocampus are defined by high input resistance, PSA-NCAM immunoreactivity and immature dendritic morphology.a, c, Biocytin-filled mature (a) and young (c) granule cell. b, d, Confocal images of PSA-NCAM immunoreactivity (red) and biocytin staining (green) of the cells in a and c, respectively. Note the high PSA-NCAM expression of the immature cell (red dendrite and yellow rim at the soma). e, Distribution of input resistance of cells in the inner (grey bars) and outer part of the granule cell layer (open bars). Continuous curves represent the sum of two gaussian functions fitted to the histogram. f, Summary graph of PSA-NCAM immunoreactivity and total dendritic length.
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Neural stem cells in various regions of the vertebrate brain continuously generate neurons throughout life. In the mammalian hippocampus, a region important for spatial and episodic memory, thousands of new granule cells are produced per day, with the exact number depending on environmental conditions and physical exercise. The survival of these ne...
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Citations
... Alterations in the structure of hippocampal neurons are crucial in the onset and progression of cognitive decline [18]. Adult neurogenetic dysfunction in the hippocampus is thought to be the cause of spatial learning and memory dysfunction [19]. ...
Consuming a high-fat diet (HFD) is widely recognized to cause obesity and result in chronic brain inflammation that impairs cognitive function. Repetitive transcranial magnetic stimulation (rTMS) has shown effectiveness in both weight loss and cognitive improvement, although the exact mechanism is still unknown. Our study examined the effects of rTMS on the brain and intestinal microecological dysfunction. rTMS successfully reduced cognitive decline caused by an HFD in behavioral assessments involving the Y maze and novel object recognition. This was accompanied by an increase in the number of new neurons and the transcription level of genes related to synaptic plasticity (spindlin 1, synaptophysin, and postsynaptic protein-95) in the hippocampus. It was reached that rTMS decreased the release of high mobility group box 1, activation of microglia, and inflammation in the brains of HFD rats. rTMS also reduced hypothalamic hypocretin levels and improved peripheral blood lipid metabolism. In addition, rTMS recovered the HFD-induced gut microbiome imbalances, metabolic disorders, and, in particular, reduced levels of the microvirus. Our research emphasized that rTMS enhanced cognitive abilities, resulting in positive impacts on brain inflammation, neurodegeneration, and the microbiota in the gut, indicating the potential connection between the brain and gut, proposing that rTMS could be a new approach to addressing cognitive deficits linked to obesity.
... This atrophy is mirrored at the cellular level, where reductions in mature granule cells and the granular layer's volume have been observed in MDD patients [13]. The dentate gyrus (DG), central to neurogenesis, is crucial for integrating new neurons into existing circuits, supporting cognitive functions and stress resilience -a process compromised in depression, potentially exacerbating the disorder [14][15][16][17][18][19][20][21][22]. Notably, the ventral DG's response to emotional stimuli and its role in stress modulation highlight the therapeutic potential of targeting neurogenesis. ...
... Behavioral and neurochemical assessments were conducted on separate sets of animals 3 weeks after the peptide administration. This timeline aligns with findings from Decressac's study on the neurogenic effects of NPY1R [69], along with other research, demonstrating that newborn neurons can start to functionally contribute to hippocampal activity in rats within 2-3 weeks [15,17,18]. ...
Background:
Major Depressive Disorder (MDD) is a prevalent and debilitating condition, necessitating novel therapeutic strategies due to the limited efficacy and adverse effects of current treatments. We explored how galanin receptor 2 (GALR2) and Neuropeptide Y1 Receptor (NPYY1R) agonists, working together, can boost brain cell growth and increase antidepressant-like effects in rats. This suggests new ways to treat Major Depressive Disorder (MDD).
Research design and methods:
In a controlled laboratory setting, adult naive Sprague-Dawley rats were administered directly into the brain's ventricles, a method known as intracerebroventricular (ICV) administration, with GALR2 agonist (M1145), NPYY1R agonist, both, or in combination with a GALR2 antagonist (M871). Main outcome measures included long-term neuronal survival, differentiation, and behavioral.
Results:
Co-administration of M1145 and NPYY1R agonist significantly enhanced neuronal survival and maturation in the ventral dentate gyrus, with a notable increase in Brain-Derived Neurotrophic Factor (BDNF) expression. This neurogenic effect was associated with an antidepressant-like effect, an outcome partially reversed by M871.
Conclusions:
GALR2 and NPYY1R agonists jointly promote hippocampal neurogenesis and exert antidepressant-like effects in rats without adverse outcomes, highlighting their therapeutic potential for MDD. The study's reliance on an animal model and intracerebroventricular delivery warrants further clinical exploration to confirm these promising results.
... Functional studies on new neurons have proposed they exhibit distinct physiological responses that confer them enhanced excitability and increased plasticity compared to mature GCs (Snyder et al., 2001;Schmidt-Hieber et al., 2004;Espósito et al., 2005;Ge et al., 2006Ge et al., , 2007Overstreet-Wadiche et al., 2006;Piatti et al., 2006;Zhao et al., 2006;Marín-Burgin et al., 2012). Some studies have described physiological and functional critical windows in new neurons 1-3 weeks of age (Shors et al., 2001(Shors et al., , 2002Snyder et al., 2001Snyder et al., , 2005Jessberger and Kempermann, 2003;Madsen et al., 2003;Bruel-Jungerman et al., 2006;Tashiro et al., 2007;Deng et al., 2009;Trouche et al., 2009;Aasebø et al., 2011), although as described above, 1-3-week-old new neurons have not established enough afferent or efferent connections (van Praag et al., 2002;Zhao et al., 2006;Toni et al., 2007;Farioli-Vecchioli et al., 2008;Faulkner et al., 2008;Deshpande et al., 2013) to produce meaningful information processing in the hippocampal circuit. ...
Contrary to humans, adult neurogenesis in rodents is not controversial. And in the last three decades, multiple studies in rodents have deemed adult neurogenesis essential for most hippocampal functions. The functional relevance of new neurons relies on their distinct physiological properties during their maturation before they become indistinguishable from mature granule cells. Most functional studies have used very young animals with robust neurogenesis. However, this trait declines dramatically with age, questioning its functional relevance in aging animals, a caveat that has been mentioned repeatedly, but rarely analyzed quantitatively. In this meta-analysis, we use data from published studies to determine the critical functional window of new neurons and to model their numbers across age in both mice and rats. Our model shows that new neurons with distinct functional profile represent about 3% of the total granule cells in young adult 3-month-old rodents, and their number decline following a power function to reach less than 1% in middle aged animals and less than 0.5% in old mice and rats. These low ratios pose an important logical and computational caveat to the proposed essential role of new neurons in the dentate gyrus, particularly in middle aged and old animals, a factor that needs to be adequately addressed when defining the relevance of adult neurogenesis in hippocampal function.
... We combined this with BrdU labeling and subsequently studied the phenotype of the newly generated cells in the dentate gyrus 3 weeks following the treatment. This period was chosen based on prior research that indicates new granule neurons can contribute functionally and behaviorally to hippocampal function as early as 2-3 weeks of age [41,42]. However, other studies suggest that these new neurons might not substantially contribute to behavior until they reach about 6-8 weeks of age [43,44]. ...
Background
Spatial memory deficits and reduced neuronal survival contribute to cognitive decline seen in the aging process. Current treatments are limited, emphasizing the need for innovative therapeutic strategies. This research explored the combined effects of intranasally co-administered galanin receptor 2 (GALR2) and neuropeptide Y1 receptor (NPY1R) agonists, recognized for their neural benefits, on spatial memory, neuronal survival, and differentiation in adult rats.
After intranasal co-delivery of the GALR2 agonist M1145 and a NPY1R agonist to adult rats, spatial memory was tested with the object-in-place task 3 weeks later. We examined neuronal survival and differentiation by assessing BrdU-IR profiles and doublecortin (DCX) labeled cells, respectively. We also used the GALR2 antagonist M871 to confirm GALR2's crucial role in promoting cell growth.
Results
Co-administration improved spatial memory and increased the survival rate of mature neurons. The positive effect of GALR2 in cell proliferation was confirmed by the nullifying effects of its antagonist. The treatment boosted DCX-labeled newborn neurons and altered dendritic morphology, increasing cells with mature dendrites.
Conclusions
Our results show that intranasal co-delivery of GALR2 and NPY1R agonists improves spatial memory, boosts neuronal survival, and influences neuronal differentiation in adult rats. The significant role of GALR2 is emphasized, suggesting new potential therapeutic strategies for cognitive decline.
... The authors report a slower neural maturation rate in nonhuman primates than in rodents. This property has far-reaching consequences since only the maturing neurons carry unique features by displaying higher excitability and stronger synaptic plasticity [15]. In other words, because the temporal window, in which new neurons are particularly functional, is longer in nonhuman primates than in other species, the functional impact of hippocampal neurogenesis in primates has been so far undervalued. ...
In most mammals, new neurons are not only produced during embryogenesis but also after birth. Soon after adult neurogenesis was discovered, the influence of recruiting new neurons on cognitive functions, especially on memory, was documented. Likewise, the late process of neuronal production also contributes to affective functions, but this outcome was recognized with more difficulty. This review covers hypes and hopes of discovering the influence of newly-generated neurons on brain circuits devoted to affective functions. If the possibility of integrating new neurons into the adult brain is a commonly accepted faculty in the realm of mammals, the reluctance is strong when it comes to translating this concept to humans. Compiling data suggest now that new neurons are derived not only from stem cells, but also from a population of neuroblasts displaying a protracted maturation and ready to be engaged in adult brain circuits, under specific signals. Here, we discuss the significance of recruiting new neurons in the adult brain circuits, specifically in the context of affective outcomes. We also discuss the fact that adult neurogenesis could be the ultimate cellular process that integrates elements from both the internal and external environment to adjust brain functions. While we must be critical and beware of the unreal promises that Science could generate sometimes, it is important to continue exploring the potential of neural recruitment in adult primates. Reporting adult neurogenesis in humankind contributes to a new vision of humans as mammals whose brain continues to develop throughout life. This peculiar faculty could one day become the target of treatment for mental health, cognitive disorders, and elderly-associated diseases. The vision of an adult brain which never stops integrating new neurons is a real game changer for designing new therapeutic interventions to treat mental disorders associated with substantial morbidity, mortality, and social costs.
... The present research seeks to study the influence of NPY and GAL on the dorsal hippocampus 3 weeks following treatment. The chosen timeline is founded on previous research that suggests new granular neurons can functionally contribute to hippocampal function within 2−3 weeks (Schmidt-Hieber et al., 2004;Bruel-Jungerman et al., 2005;Snyder et al., 2009). Our methodological approach includes an examination of hippocampal cell proliferation effects mediated by NPY1R and GALR2 agonists through the use of proliferating cell nuclear antigen (PCNA). ...
Introduction
This study may unveil novel insights into the interactions between neuropeptide Y receptor 1 (NPY1R) and galanin receptor 2 (GALR2), in the dentate gyrus of the dorsal hippocampus, shedding light on their role in neurogenesis and cognitive functions. Existing literature highlights the potential of these interactions in enhancing learning and memory, yet detailed mechanisms remain underexplored.
Methods
Utilizing intracerebroventricular injections of GALR2 and NPY1R agonists in Sprague-Dawley male rats, we examined neurogenesis via markers PCNA and DCX, and memory consolidation through the object-in-place task over a three-week period.
Results
Significant increases in NPY1R-GALR2 co-localization and neuroblast proliferation were observed, alongside enhanced memory consolidation. These findings suggest a synergistic effect of NPY1R and GALR2 activation on cognitive functions.
Discussion
Our findings may foster the development of novel heterobivalent or multitargeting drugs, affecting NPY1R-GALR2 interaction, and suggest a future pharmacogical strategy for improving learning and memory found in many brain diseases. Further research is encouraged to explore these mechanisms in pathological models.
... Potent suppression of entorhinal inputs 60 by increased HIPP cell output may explain the reduced activity of GCs during exploration of novel environments 10 (Supplementary Fig. 7a). This increased dendritic inhibition may furthermore limit synaptic plasticity at entorhinal cortex inputs 8,96 in new environments and thereby protect highly stable GC place fields gradually formed through repeated exposure 10 from being 'overwritten' 97,98 (see also ref. 96). Whether adult-born GCs at~4-7 postnatal weeks of maturation, which receive the least lateral inhibition compared to older GCs 99 and show enhanced activity in response to novelty 100 , may be particularly involved in the initial representation of novel environments, will require further investigations in future. ...
The hippocampus is the brain’s center for episodic memories. Its subregions, the dentate gyrus and CA1-3, are differentially involved in memory encoding and recall. Hippocampal principal cells represent episodic features like movement, space, and context, but less is known about GABAergic interneurons. Here, we performed two-photon calcium imaging of parvalbumin- and somatostatin-expressing interneurons in the dentate gyrus and CA1-3 of male mice exploring virtual environments. Parvalbumin-interneurons increased activity with running-speed and reduced it in novel environments. Somatostatin-interneurons in CA1-3 behaved similar to parvalbumin-expressing cells, but their dentate gyrus counterparts increased activity during rest and in novel environments. Congruently, chemogenetic silencing of dentate parvalbumin-interneurons had prominent effects in familiar contexts, while silencing somatostatin-expressing cells increased similarity of granule cell representations between novel and familiar environments. Our data indicate unique roles for parvalbumin- and somatostatin-positive interneurons in the dentate gyrus that are distinct from those in CA1-3 and may support routing of novel information.
... The previously mentioned increase in glutamatergic drive to the granule cells, as well as the decreased GABAergic inhibition, may also explain the increased postsynaptic activation upon stimulating the presynaptic components. Altered intrinsic excitability could also contribute to this finding as adult-born granule cells are hyperexcitable compared to neonatally born granule cells in IHKA animals [41,42]. This is further supported by the trend-significantly increased granule cell output (PS) for a similar synaptic input (fPSP slope) and by the spatially expanded granule cell output in IHKA versus control mice. ...
The intrahippocampal kainic acid (IHKA) mouse model is an extensively used in vivo model to investigate the pathophysiology of mesial temporal lobe epilepsy (mTLE) and to develop novel therapies for drug-resistant epilepsy. It is characterized by profound hippocampal sclerosis and spontaneously occurring seizures with a major role for the injected damaged hippocampus, but little is known about the excitability of specific subregions. The purpose of this study was to electrophysiologically characterize the excitability of hippocampal subregions in the chronic phase of the induced epilepsy in the IHKA mouse model. We recorded field postsynaptic potentials (fPSPs) after electrical stimulation in the CA1 region and in the dentate gyrus (DG) of hippocampal slices of IHKA and healthy mice using a multielectrode array (MEA). In the DG, a significantly steeper fPSP slope was found, reflecting higher synaptic strength. Population spikes were more prevalent with a larger spatial distribution in the IHKA group, reflecting a higher degree of granule cell output. Only minor differences were found in the CA1 region. These results point to increased neuronal excitability in the DG but not in the CA1 region of the hippocampus of IHKA mice. This method, in which the excitability of hippocampal slices from IHKA mice is investigated using a MEA, can now be further explored as a potential new model to screen for new interventions that can restore DG function and potentially lead to novel therapies for mTLE.
... The adult brain undergoes continuous neurogenesis, generating new functional neurons in the dentate gyrus (DG) region of the hippocampus [18]. In terms of physiological properties, immature neurons are inactivated, which have better plasticity, higher excitability, and lower inhibition [19][20][21]. Moreover, the number and survival of newborn neurons in the DG of the dHip has been suggested to be involved in the acquisition of new learning and memory processes, and neurogenesis in the DG of the vHip effectively ameliorates emotional impairment [22][23][24][25][26]. Shh is a typical morphogen that controls hippocampal neurogenesis and induces the formation of newborn neurons [27,28], raising the possibility that the process linking Shh activity with cognitive and emotional processes may involve immature neurons. ...
Specific memory processes and emotional aberrations in depression can be attributed to the different dorsal–ventral regions of the hippocampus. However, the molecular mechanisms underlying the differential functions of the dorsal hippocampus (dHip) and ventral hippocampus (vHip) remain unclear. As Sonic Hedgehog (Shh) is involved in the dorsal–ventral patterning of the neural tube and its signaling is dysregulated by chronic unpredictable mild stress (CUMS), we investigated its role in influencing the differential functions of the dHip and vHip. Here, CUMS downregulated the expression of Shh signaling markers, including Shh and its downstream effectors GLI family zinc finger 12 (Gli1/2), Patched (Ptch), and smoothened (Smo), in both the dHip and vHip of rats, though more so in the vHip. Additionally, Shh knockdown in the dorsal or ventral dentate gyrus (DG) resulted in restrained neurogenic activity in newborn neurons, especially in immature neurons through decreased expression of Shh signaling markers. Furthermore, Shh knockdown in the DG of the dHip led to memory impairment by inhibiting experience-dependent activation of immature neurons, whereas its knockdown in the DG of the vHip led to an emotional handicap by delaying the maturation of immature neurons. Finally, Shh knockdown in either the dDG or vDG of hippocampus abolished the corresponding cognitive enhancement and emotional recovery of fluoxetine. In conclusion, Shh is essential to maintain the functional heterogeneity of dHip and vHip in depressed rat, which was mainly mediating by local changes of dependent activation and maturity of immature neurons, respectively.
... It is currently understood that the adult mammalian brain has two major reservoirs of neural stem cells (NSCs), called "neurogenic niches" in the SVZ of the lateral wall of the lateral ventricle and the subgranular zone (SGZ) of the DG of the hippocampus (20). Under resting conditions, neurogenesis is restricted in the above two neurogenic niches, while under pathological conditions, neural precursor cells generated in the SGZ and SVZ need to migrate to the olfactory bulb and the subgranular zone of the DG of the hippocampus to compensate for neuronal loss in the brain to maintain hippocampal structural and functional plasticity (21). Although the process of neurogenesis is sophisticated, it can be summarized in four phases: In the first stage, NSCs divide and proliferate to form a pool of NSCs, which can differentiate to produce neuroblasts and further differentiate into immature neurons. ...
Adult hippocampal neurogenesis generates functional neurons from neural progenitor cells in the hippocampal dentate gyrus (DG) to complement and repair neurons and neural circuits, thus benefiting the treatment of depression. Increasing evidence has shown that aberrant microglial activity can disrupt the appropriate formation and development of functional properties of neurogenesis, which will play a crucial role in the occurrence and development of depression. However, the mechanisms of the crosstalk between microglia and adult hippocampal neurogenesis in depression are not yet fully understood. Therefore, in this review, we first introduce recent discoveries regarding the roles of microglia and adult hippocampal neurogenesis in the etiology of depression. Then, we systematically discuss the possible mechanisms of how microglia regulate adult hippocampal neurogenesis in depression according to recent studies, which involve toll-like receptors, microglial polarization, fractalkine-C-X3-C motif chemokine receptor 1, hypothalamic-pituitary-adrenal axis, cytokines, brain-derived neurotrophic factor, and the microbiota-gut-brain axis, etc. In addition, we summarize the promising drugs that could improve the adult hippocampal neurogenesis by regulating the microglia. These findings will help us understand the complicated pathological mechanisms of depression and shed light on the development of new treatment strategies for this disease.
