Hippocampal Neurogenesis Research Articles

Hippocampal neurogenesis modulated by Quinic acid: A therapeutic strategy for the neurodegenerative disorders.

Neural progenitor cells (NPCs) reside in the brain and participate in the mechanism of neurogenesis that permits the brain to generate the building blocks for enhancement of cognitive abilities and acquisition of new skills. The existence of NPCs in brain has opened a novel dimension of research to explore their potential for treatment of various neurodegenerative disorders. The present study provides novel insights into the intracellular mechanisms in neuronal cells proliferation, maturation and differentiation regulated by Quinic acid (QA). Furthermore, this study might help in discovery and development of lead molecule that can overcome the challenges in the treatment of neurodegenerative diseases. The growth supporting effect of QA was studied using MTT assay. For that purpose, hippocampal cell cultures of neonatal rats were treated with different concentrations of QA and incubated for 24, 48 and 72 h. Gene and protein expressions of the selected molecular markers nestin, neuron-specific class III beta-tubulin (Tuj-1), neuronal nuclear protein (NeuN), neuronal differentiation 1 (NeuroD1), glial fibrillary acidic protein (GFAP), neuroligin (NLGN) and vimentin were analyzed. QA-induced cell proliferation and differentiation of hippocampal progenitor cells was also accompanied by significantly increased expression of progenitor and immature neuronal marker, mature neuronal marker and differentiating factor, that is, nestin, Tuj-1, NeuN and NeuroD1, respectively. On the other hand, vimentin downregulation and constant GFAP expression were observed following QA treatment. Additionally, the effects of QA on the recovery of stressed cells was studied using in vitro model of oxygen glucose deprivation (OGD). It was observed that hippocampal cells were able to recover from OGD following the treatment with QA. These findings suggest that QA treatment promotes hippocampal neurogenesis by proliferating and differentiating of NPCs and recovers neurons from stress caused by OGD. Thus, the neurogenic potential of QA can be explored for the treatment of neurodegenerative disorders.

Luteolin promotes neuronogenesis in hippocampus of chronic unpredictable mild stress rats and primary hippocampus of fetal rats.

To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action. The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo, novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro, BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis. Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons. The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.

The importance of neuroplasticity and excitability of adult-born neurons in alleviating depression and anxiety-like behaviour in mice

The increase in excitability of newborn adult neurons had been shown to have an antidepressant effect in rodents in previous studies, however whether the same result would apply to mature neurons remains unknown. This paper therefore proposes two experiments that investigate the role of neuroplasticity and mature neuron excitability in reducing depressive behaviour in rodents. Old neurons are known to have reduced neuroplasticity compared to newborn neurons, and the main factor influencing this seems to be the reduced NMDA:AMPA receptor ratio in mature neurons. By knocking out the NR1 gene that codes for the NMDA receptor in newborn neurons, experiment one investigates whether reduced neuroplasticity in the rodent hippocampus would induce anxiety-like behaviour, thus the importance of adult hippocampal neurogenesis (AHN) in maintaining neuroplasticity in the brain and normal affective behaviour. Subsequently the artificially made-mature neurons in the hM4Dq+ tamoxifen inducible Cre-recombinase transgenic mouse line are being activated through injection of tamoxifen followed by CNO, which increases neuronal excitability. This is hypothesised to reduce depressive behaviour to an extent however less effective than activating newborn neurons. These experiments can potentially be valuable in the application of relevant depression treatments in humans, alongside with the maintenance and stimulation of AHN with regards to its anti-depressive effect

Genetic determinants of coping, resilience and self-esteem in schizophrenia suggest a primary role for social factors and hippocampal neurogenesis

Schizophrenia is a severe psychiatric disorder, associated with a reduction in life expectancy of 15–20 years. Available treatments are at least partially effective in most affected individuals, and personal resources such as resilience (successful adaptation despite adversity) and coping abilities (strategies used to deal with stressful or threatening situations), are important determinants of disease outcomes and long-term sustained recovery. Published findings support the existence of a genetic background underlying resilience and coping, with variable heritability estimates. However, genome-wide analyses concerning the genetic determinants of these personal resources, especially in the context of schizophrenia, are lacking. Here, we performed a genome-wide association study coupled with accessory analyses to investigate potential genetic determinants of resilience, coping and self-esteem in 490 schizophrenia patients. Results revealed a complex genetic background partly overlapping with that of neuroticism, worry and schizophrenia itself and support the importance of social aspects in shapingthese psychological constructs. Hippocampal neurogenesis and lipid metabolism appear to be potentially relevant biological underpinnings, and specific miRNAs such as miR-124 and miR-137 may warrant further studies as potential biomarkers. In conclusion, this study represents an important first step in the identification of genetic and biological correlates shaping resilience, coping resources and self-esteem in schizophrenia.

The Derlin-1-Stat5b axis maintains homeostasis of adult hippocampal neurogenesis

Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis.

Treadmill exercise in combination with acousto-optic and olfactory stimulation improves cognitive function in APP/PS1 mice through the brain-derived neurotrophic factor- and Cygb-associated signaling pathways.

A reduction in adult neurogenesis is associated with behavioral abnormalities in patients with Alzheimer's disease. Consequently, enhancing adult neurogenesis represents a promising therapeutic approach for mitigating disease symptoms and progression. Nonetheless, non-pharmacological interventions aimed at inducing adult neurogenesis are currently limited. Although individual non-pharmacological interventions, such as aerobic exercise, acousto-optic stimulation, and olfactory stimulation, have shown limited capacity to improve neurogenesis and cognitive function in patients with Alzheimer's disease, the therapeutic effect of a strategy that combines these interventions has not been fully explored. In this study, we observed an age-dependent decrease in adult neurogenesis and a concurrent increase in amyloid-beta accumulation in the hippocampus of amyloid precursor protein/presenilin 1 mice aged 2-8 months. Amyloid deposition became evident at 4 months, while neurogenesis declined by 6 months, further deteriorating as the disease progressed. However, following a 4-week multifactor stimulation protocol, which encompassed treadmill running (46 min/d, 10 m/min, 6 days per week), 40 Hz acousto-optic stimulation (1 hour/day, 6 days/week), and olfactory stimulation (1 hour/day, 6 days/week), we found a significant increase in the number of newborn cells (5'-bromo-2'-deoxyuridine-positive cells), immature neurons (doublecortin-positive cells), newborn immature neurons (5'-bromo-2'-deoxyuridine-positive/doublecortin-positive cells), and newborn astrocytes (5'-bromo-2'-deoxyuridine-positive/ glial fibrillary acidic protein-positive cells). Additionally, the amyloid-beta load in the hippocampus decreased. These findings suggest that multifactor stimulation can enhance adult hippocampal neurogenesis and mitigate amyloid-beta neuropathology in amyloid precursor protein/presenilin 1 mice. Furthermore, cognitive abilities were improved, and depressive symptoms were alleviated in amyloid precursor protein/presenilin 1 mice following multifactor stimulation, as evidenced by Morris water maze, novel object recognition, forced swimming test, and tail suspension test results. Notably, the efficacy of multifactor stimulation in consolidating immature neurons persisted for at least 2 weeks after treatment cessation. At the molecular level, multifactor stimulation upregulated the expression of neuron-related proteins (NeuN, doublecortin, postsynaptic density protein-95, and synaptophysin), anti-apoptosis-related proteins (Bcl-2 and PARP), and an autophagy-associated protein (LC3B), while decreasing the expression of apoptosis-related proteins (BAX and caspase-9), in the hippocampus of amyloid precursor protein/presenilin 1 mice. These observations might be attributable to both the brain-derived neurotrophic factor-mediated signaling pathway and antioxidant pathways. Furthermore, serum metabolomics analysis indicated that multifactor stimulation regulated differentially expressed metabolites associated with cell apoptosis, oxidative damage, and cognition. Collectively, these findings suggest that multifactor stimulation is a novel non-invasive approach for the prevention and treatment of Alzheimer's disease.

Altering adult Hippocampal Neurogenesis in the dentate gyrus through varying glucocorticoid receptor concentrations

Adult Hippocampal Neurogenesis, short for AHN, is an essential yet foundational process of producing new nerve cells in the dentate gyrus of the hippocampus. It is a fact that increasing AHN will enhance peoples ability to learn, memorize, regulate mood, etc. Therefore, scientists strive to pursue the factors which influence AHN. Until now, research had proved that GR activity is associated with the degree of AHN. Additionally, a high GR activity will potentially reduce the level of ANH and an optimal level of GR activity will create the optimized level of AHN. Consequently, how a low level of GR activity will possibly influence AHN will be examined in this paper. For Experiment 1, the GR antagonist reduces the GR activity in 8-year-old male mice: C57BL/6 and BrdU highlights the newly generated neurons in the dentate gyrus. As an ideal result compared to the control group, low GR activity will lead to a decrease in the AHN. For Experiment 2, 3 minor experiments will be constructed to test the GR activity and AHN of the mice in 3 different conditions (low, controllable, and uncontrollable stress). And Nanobit Assay that is separately attached to the GR and the ligands will present fluorescent when combined. Additionally, the method of CRISPR-CAS9 is used to knock down either GR or GR when the other one is measured, and BrdU is also used to light up the neurons to measure the degree of AHN. The ideal result will present a number greater than 1 for the ratio between GR/GR and AHN decreases for the low-stress group and uncontrollable-stress group. Oppositely, the ratio will be smaller than 1 for the controllable stress group, meaning AHN increases. Conclusively, the output will demonstrate a reversed U shape with the x-axis being the level of GR activity and the y-axis presenting the level of AHN. Despite the experiments that have proceeded on mice, the significance of them is people will have certain references to the influences of AHN to prevent those conditions or stress which will negatively affect AHN.

Double Dissociation of Cognitive Varies under Unilateral Radiation Exposure on the Hippocampus

Although the key position of the hippocampus (HP) in memory processes is not in doubt, the specifics of its participation in cognitive processes are far from being established. At the same time, the role of the HP in differentiating the novelty of impressions is often discussed in the context of adult HP neurogenesis. Radiation exposure to the HP, which inhibits the processes of neurogenesis, can serve as a model for studying this relationship. A homogeneous sample of 28 patients with meningiomas of the chiasmal-sellar area adjacent to the HP was studied. 15 patients were diagnosed with a left-sided location of the tumor and 13 patients with a right-sided one. The two groups were comparable in terms of demographic, clinical and morphometric characteristics. In order to stop the growth of the tumor, the patients underwent radiation therapy (RT), in which the HP on the side of the pathological process was forced to receive a dose comparable to the dose in the tumor. The study using the original technique was carried out before the start of RT, immediately after its completion, 6 and 12 months after the end of RT. Data were obtained on earlier changes in memory characteristics mediated by the right hippocampal region, but at the same time — more pronounced long-term cognitive consequences of ionizing effects on the HP of the left hemisphere.

Research progress on hippocampal neurogenesis in autism spectrum disorder.

Autism spectrum disorder (ASD) is a group of severe neurodevelopmental disorders with unclear etiology and significant heterogeneity that is emerging as a global public health concern. Increasing research suggests the involvement of hippocampal neurogenesis defects in the onset and development of ASD, drawing increasing amounts of attention to hippocampal neurogenesis issues in ASD. In this paper, we analyze relevant international studies on hippocampal neurogenesis in ASD, discuss the role of neurobiology in the pathogenesis of ASD, and explore the potential of improving hippocampal neurogenesis as a therapeutic approach for ASD. This review aims to provide new treatment perspectives and theoretical foundations for clinical practice.

Juvenile bright light exposure ameliorates adult behavioral abnormalities by enhancing neurogenesis in a N-methyl-D-aspartate receptor dysfunction mouse model relevant for cognitive impairment in schizophrenia

Exposure to light has been demonstrated to stimulate brain regions associated with cognition; however, investigations into its cognitive-enhancing effects have primarily focused on wild-type rodents. This study seeks to elucidate how bright light exposure mitigates cognitive deficits associated with schizophrenia by examining its impact on hippocampal neurogenesis and its potential to alleviate sub-chronic MK-801-induced cognitive impairments in mice. Following three weeks of juvenile bright light exposure (5–8 weeks old), significant increases in proliferating neurons (BrdU+) and immature neurons (DCX+ cells) were observed in the dentate gyrus (DG) and lateral ventricle of MK-801-treated mice. Long-term bright light treatment further promoted the differentiation of BrdU+ cells into immature neurons (BrdU+ DCX+ cells), mature neurons (BrdU+ NeuN+ cells), or astrocytes (BrdU+ GFAP+ cells) in the hippocampal DG. This augmented neurogenesis correlated with the attenuation of sub-chronic MK- 801-induced cognitive deficits, as evidenced by enhancements in Y-maze, novel object recognition (NOR), novel location recognition (NLR), and Morris water maze (MWM) test performances. These findings suggest a promising noninvasive clinical approach for alleviating cognitive impairments associated with neuropsychiatric disorders.

Adolescent alcohol exposure alters age-related progression of behavioral and neurotrophic dysfunction in the TgF344-AD model in a sex-specific manner.

Alzheimer's Disease (AD) and heavy alcohol use are widely prevalent and lead to brain pathology. Both alcohol-related brain damage (ABRD) and AD result in cholinergic dysfunction, reductions in hippocampal neurogenesis, and the emergence of hippocampal-dependent cognitive impairments. It is still unknown how ARBD caused during a critical developmental timepoint, such as adolescence, interacts with AD-related pathologies to accelerate disease progression later in life. The current study utilized a longitudinal design to characterize behavioral and pathological changes in a transgenic rat model of AD (TgF344-AD) following adolescent intermittent ethanol (AIE) exposure. We found that AIE accelerates cognitive decline associated with AD transgenes in female rats at 6 months of age, and male AD-rats are impaired on spatial navigation by 3-months with no additional deficits due to AIE exposure. Protein levels of various AD-pathological markers were analyzed in the dorsal and ventral hippocampus of male and female rats. The data suggests that AIE-induced alterations of the tropomyosin-related kinase A receptor (TrkA) / p75 neurotrophin receptor (p75NTR) ratio creates a brain that is vulnerable to age- and AD-related pathologies, which leads to an acceleration of cognitive decline, particularly in female rats.

Dandouchi Polypeptide Alleviates Depressive-like Behavior and Promotes Hippocampal Neurogenesis by Activating the TRIM67/NF-κB Pathway in CUMS-Induced Mice.

Background: Dandouchi polypeptide (DDCP) is derived from Semen Sojae Praeparatum (Dandouchi in Chinese), a fermented product of Glycine max (L.) Merr. Semen Sojae Praeparatum is widely used in the food industry for its unique flavor and nutritional value, and DDCP, as its derivative, also shows potential health benefits in food applications. However, the specific active substances responsible for Semen Sojae Praeparatum and the underlying mechanisms involved have not been fully elucidated. Methods: DDCP was extracted from Semen Sojae Praeparatum using enzymes, and its antidepressant effects were tested in chronic unpredictable mild stress (CUMS)-induced mice. Immunohistochemistry, immunofluorescence, and western blotting were used to analyze neurogenesis and the nuclear factor κB (NF-κB) pathway. Moreover, an adeno-associated virus (AAV) shRNA was used to induce tripartite motif-containing 67 (TRIM67) deficiency to examine the function of TRIM67 in the neuroprotective effects of DDCP in depressive disorders. Results: DDCP reduced depressive behaviors in CUMS mice and the expression of proinflammatory markers in the hippocampus. DDCP promoted neurogenesis and modulated the TRIM67/NF-κB pathway, with TRIM67 deficiency impairing its antidepressant effect. Conclusions: This research revealed that DDCP has a protective effect on countering depression triggered by CUMS. Notably, TRIM67 plays a crucial role in mitigating depression through DDCP, positioning DDCP as a potential therapeutic option for treating depressive disorders.

The therapeutic potential of curculigoside in poststroke depression: a focus on hippocampal neurogenesis and mitochondrial function.

To investigate the effects and mechanism of curculigoside against poststroke depression (PSD). In vivo, a PSD rat model was created by combining bilateral common carotid artery occlusion and chronic unpredictable mild stress stimulations. After 4-week modeling and intragastrically administration of curculigoside, the effects of curculigoside on behavior, hippocampal neurogenesis, and hippocampal mitochondrial oxidative phosphorylation (OxPhos) were investigated. In vitro, PSD-like primary neural stem cells (NSCs) model was established by oxygen-glucose deprivation/recovery (OGD/R) combing high-corticosterone (CORT) concentration, followed by treatment with curculigoside. The investigation subsequently examined the impact of curculigoside on mitochondrial OxPhos, proliferation, and differentiation of NSCs under OGD/R + CORT conditions. In vivo, PSD rats showed significantly depressive behaviors, dysfunctional neurogenesis in hippocampus, as well as decreased hippocampus adenosine triphosphate (ATP) levels, reduced electron transport chain complexes activity, and downregulates mitochondrial transcription factor A (TFAM) and PPAR-gamma coactivator 1 alpha (PGC-1α) expression in hippocampus. In vitro, OGD/R +CORT significantly injured the proliferation and differentiation, as well as impaired the mitochondrial OxPhos in NSCs. Curculigoside treatment was effective in improving these abnormal changes. Curculigoside may repair hippocampal neurogenesis in PSD rats by enhancing hippocampal mitochondrial OxPhos, and has shown a great potential for anti-PSD.

Residual Microglia Following Short-term PLX5622 Treatment in 5xFAD Mice Exhibit Diminished NLRP3 Inflammasome and mTOR Signaling, and Enhanced Autophagy.

Chronic neuroinflammation represents a prominent hallmark of Alzheimer's disease (AD). While moderately activated microglia are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations have indicated that the elimination of ∼80% of microglia through a month-long inhibition of the colony-stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration without impacting Aβ levels. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the immediate effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglial phenotype or metabolic fitness are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition in three-month-old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal Aβ plaques. We observed ∼65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia demonstrated a noninflammatory phenotype, with highly branched and ramified processes and reduced NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complexes. Moreover, plaque-associated microglia were reduced in number with diminished Clec7a (dectin-1) expression. Additionally, both microglia and neurons displayed reduced mechanistic target of rapamycin (mTOR) signaling and autophagy. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling, and enhanced autophagy. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, or hippocampal neurogenesis. Thus, short-term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.

Are the promnestic effects of neurokinin 3 receptor mediated by hippocampal neurogenesis in a Aβ-induced rat model of Alzheimer's disease?

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterised by cognitive dysfunction, memory loss and mood changes. Hippocampal neurogenesis has been suggested to play a role in learning and memory. Neurokinin 3 receptor (NK3R) has been shown to be prevalent in the hippocampus region. The aim of the project was to investigate the role of hippocampal neurogenesis in the promnestic effects of NK3R agonist administration in an amyloid beta-induced AD rat model. Wistar albino rats were divided into control, Alzheimer, NK3R agonist and Alzheimer + NK3R agonist groups. The open field (OF) test and Morris water maze (MWM) test were performed for locomotor activity and memory analysis. Peptide gene expression levels (Nestin, DCX, Neuritin, MASH1, Neun, BDNF) were analysed by quantitative reverse transcription polymerase chain reaction (RT-PCR). In the OF test, the group-time relationship was found to be statistically different in the parameters of distance travelled and percentage of movement (p< 0.05). In MWM, the time to reach the platform and the time spent in the target quadrant were statistically significant between the groups (p< 0.05). Statistically significant differences were observed in gene expression levels (Nestin, DCX, Neuritin, MASH1) in the hippocampal tissue of rats between the groups (p< 0.05). NK3 receptor agonism favourably affected hippocampal neurogenesis in AD model rats. It was concluded that NK3 receptor agonism in the hippocampus, which is the first affected region in the physiopathology of AD, may be effective in both the formation of neural precursor cells and the reduction of neuronal degeneration. The positive effect of NK3R on cognitive functions may be mediated by hippocampal neurogenesis.

Activation of angiotensin converting enzyme 2 promotes hippocampal neurogenesis via activation of Wnt/β-catenin signaling in hypertension

Hypertension-induced brain renin-angiotensin system (RAS) activation and neuroinflammation are hallmark neuropathological features of neurodegenerative diseases. Previous studies from our lab have shown that inhibition of ACE/Ang II/AT1R axis (by AT1R blockers or ACE inhibitors) reduced neuroinflammation and accompanied neurodegeneration via up-regulating adult hippocampal neurogenesis. Apart from this conventional axis, another axis of RAS also exists i.e., ACE2/Ang (1–7)/MasR axis, reported as an anti-hypertensive and anti-inflammatory. However, the role of this axis has not been explored in hypertension-induced glial activation and hippocampal neurogenesis in rat models of hypertension. Hence, in the present study, we examined the effect of ACE2 activator, Diminazene aceturate (DIZE) at 2 different doses of 10 mg/kg (non-antihypertensive) and 15 mg/kg (antihypertensive dose) in renovascular hypertensive rats to explore whether their effect on glial activation, neuroinflammation, and neurogenesis is either influenced by blood-pressure. The results of our study revealed that hypertension induced significant glial activation (astrocyte and microglial), neuroinflammation, and impaired hippocampal neurogenesis. However, ACE2 activation by DIZE, even at the low dose prevented these hypertension-induced changes in the brain. Mechanistically, ACE2 activation inhibited Ang II levels, TRAF6-NFκB mediated inflammatory signaling, NOX4-mediated ROS generation, and mitochondrial dysfunction by upregulating ACE2/Ang (1–7)/MasR signaling. Moreover, DIZE-induced activation of the ACE2/Ang (1–7)/MasR axis upregulated Wnt/β-catenin signaling, promoting hippocampal neurogenesis during the hypertensive state. Therefore, our study demonstrates that ACE2 activation can effectively prevent glial activation and enhance hippocampal neurogenesis in hypertensive conditions, regardless of its blood pressure-lowering effects.

The effects of brain serotonin deficiency on the behavioral and neurogenesis-promoting effects of voluntary exercise in tryptophan hydroxylase 2 (R439H) knock-in mice

Exercise is known to reduce depression and anxiety symptoms. Although the cellular and molecular mechanisms underlying this effect remain unknown, exercise-induced increases in neurotransmitter release and hippocampal neurogenesis have been hypothesized to play key roles. One neurotransmitter that has been implicated in both antidepressant-like effects and the regulation of hippocampal neurogenesis is serotonin (5-HT). Complete loss of function of the brain 5-HT synthesis enzyme (tryptophan hydroxylase 2, Tph2) has been reported to prevent exercise-induced increases in neurogenesis and to block a subset of antidepressant-like responses to selective serotonin reuptake inhibitors (SSRIs), but whether partial loss of Tph2 function blocks the behavioral and neurogenic effects of exercise has not been established. This study used four tests that are predictive of antidepressant efficacy to determine the impact of 5-HT deficiency on responses to exercise in male and female mice. Our results demonstrate that low 5-HT impairs the behavioral effects of exercise in females in the forced swim and novelty-suppressed feeding tests. However, genetic reductions in 5-HT synthesis did not significantly impact exercise-induced alterations in cellular proliferation or immature neuron production in the hippocampus in either sex. These findings highlight the importance of brain 5-HT in mediating behavioral responses to exercise and suggest that individual differences in brain 5-HT synthesis could influence sensitivity to the mental health benefits of exercise. Furthermore, the observed disconnect between neurogenic and behavioral responses to exercise suggests that increased neurogenesis is unlikely to be the primary driver of the behavioral effects of exercise observed here.

M1A demethylase Alkbh3 regulates neurogenesis through m1A demethylation of Mmp15 mRNA

BackgroundN1-Methyladenosine (m1A) is an abundant modification of transcripts regulating mRNA structure and translation efficiency. However, the characteristics and biological functions of mRNA m1A modification in adult hippocampal neurogenesis remain enigmatic.ResultsWe found that m1A demethylase Alkbh3 was dramatically enriched in neurons and neuronal genesis. Functionally, depletion of Alkbh3 in neural stem cells (NSCs) significantly decreased m1A modification, neuronal differentiation and proliferation coupling with increasing gliogenesis, whereas overexpressing Alkbh3 facilitated neuronal differentiation and proliferation. Mechanistically, the m1A demethylation of Mmp15 mRNA by Alkbh3 improved its RNA stability and translational efficacy, which promoted neurogenesis. Therapeutically, the silencing of Alkbh3 reduced hippocampal neurogenesis and impaired spatial memory in the adult mice.ConclusionsWe reveal a novel function of m1A demethylation on Mmp15 mRNA in Alkbh3-mediated neurogenesis, which shed light on advancing Alkbh3 regulation of neurogenesis as a novel neurotherapeutic strategy.

Increased spontaneous activity and progressive suppression of adult neurogenesis in the hippocampus of rat offspring after maternal exposure to imidacloprid

Imidacloprid (IMI) is a widely used neonicotinoid insecticide that poses risks for developmental neurotoxicity in mammals. The present study investigated the effects of maternal exposure to IMI on behaviors and adult neurogenesis in the hippocampal dentate gyrus (DG) of rat offspring. Dams were exposed to IMI via diet (83, 250, or 750 ppm in diet) from gestational day 6 until day 21 post-delivery on weaning, and offspring were maintained until adulthood on postnatal day 77. In the neurogenic niche, 750-ppm IMI decreased numbers of late-stage neural progenitor cells (NPCs) and post-mitotic immature granule cells by suppressing NPC proliferation and ERK1/2–FOS-mediated synaptic plasticity of granule cells on weaning. Suppressed reelin signaling might be responsible for the observed reductions of neurogenesis and synaptic plasticity. In adulthood, IMI at ≥ 250 ppm decreased neural stem cells by suppressing their proliferation and increasing apoptosis, and mature granule cells were reduced due to suppressed NPC differentiation. Behavioral tests revealed increased spontaneous activity in adulthood at 750 ppm. IMI decreased hippocampal acetylcholinesterase activity and Chrnb2 transcript levels in the DG on weaning and in adulthood. IMI increased numbers of astrocytes and M1-type microglia in the DG hilus, and upregulated neuroinflammation and oxidative stress-related genes on weaning. In adulthood, IMI increased malondialdehyde level and number of M1-type microglia, and downregulated neuroinflammation and oxidative stress-related genes. These results suggest that IMI persistently affected cholinergic signaling, induced neuroinflammation and oxidative stress during exposure, and increased sensitivity to oxidative stress after exposure in the hippocampus, causing hyperactivity and progressive suppression of neurogenesis in adulthood. The no-observed-adverse-effect level of IMI for offspring behaviors and hippocampal neurogenesis was determined to be 83 ppm (5.5–14.1 mg/kg body weight/day).

Carotid artery transplantation of brain endothelial cells enhances neuroprotection and neurorepair in ischaemic stroke rats.

Brain microvascular endothelial cells (BMECs), an important component of the neurovascular unit, can promote angiogenesis and synaptic formation in ischaemic mice after brain parenchyma transplantation. Since the therapeutic efficacy of cell-based therapies depends on the extent of transplanted cell residence in the target tissue and cell migration ability, the delivery route has become a hot research topic. In this study, we investigated the effects of carotid artery transplantation of BMECs on neuronal injury, neurorepair, and neurological dysfunction in rats after cerebral ischaemic attack. Purified passage 1 endothelial cells (P1-BMECs) were prepared from mouse brain tissue. Adult rats were subjected to transient middle cerebral artery occlusion (MCAO) for 30 min. Then, the rats were treated with 5 × 105 P1-BMECs through carotid artery infusion or tail vein injection. We observed that carotid artery transplantation of BMECs produced more potent neuroprotective effects than caudal injection in MCAO rats, including reducing infarct size and alleviating neurological deficits in behavioural tests. Carotid artery-transplanted BMECs displayed a wider distribution in the ischaemic rat brain. Immunostaining for endothelial progenitor cells and the mature endothelial cell markers CD34 and RECA-1 showed that carotid artery transplantation of BMECs significantly increased angiogenesis. Carotid artery transplantation of BMECs significantly increased the number of surviving neurons, decreased the cerebral infarction volume, and alleviated neurological deficits. In addition, we found that carotid artery transplantation of BMECs significantly enhanced ischaemia-induced hippocampal neurogenesis, as measured by doublecortin (DCX) and Ki67 double staining within 2 weeks after ischaemic injury. We conclude that carotid artery transplantation of BMECs can promote cerebral angiogenesis, neurogenesis, and neurological function recovery in adult rats after ischaemic stroke. Our results suggest that carotid injection of BMECs may be a promising new approach for treating acute brain injuries.