Hippocampal Neurogenesis Research Articles

Abnormal hippocampal neurogenesis and impaired social recognition memory in two neurodevelopmental models of schizophrenia.

Schizophrenia is a mental disorder characterized by cognitive impairments, specifically deficits in social recognition memory (SRM). Abnormal hippocampal neurogenesis has been implicated in these deficits. Due to the pathogenetic heterogeneity of schizophrenia, studying the hippocampal neurogenesis and SRM in two models with prenatal and postnatal defects could enhance our understanding of the developmental aspects of the biological susceptibility to schizophrenia. Here, we examined SRM and hippocampal neurogenesis in two developmental models of schizophrenia: gestational exposure to methylazoxymethanol acetate (MAM) and postweaning social isolation (SI). Our findings revealed that gestational MAM exposure induced a decay of social memory while postweaning SI led to impaired social memory formation and decay. In both models, we observed a correlation between impaired SRM and reduced number, and abnormal differentiation and less complex morphology of hippocampal neurons. These results indicate that aberrant hippocampal neurogenesis may contribute to the deficits of SRM in both models, and these abnormalities may be a shared underlying pathogenic factor in developmental models of schizophrenia, regardless of prenatal and postnatal pathogenesis.

RBIO-09. EFFECTS OF RADIATION ON THE HIPPOCAMPUS AND HIPPOCAMPAL NEUROGENESIS: A SYSTEMATIC REVIEW OF INJURY MECHANISMS AND INTERVENTION STRATEGIES

Abstract PURPOSE To understand how radiation affects the hippocampus and hippocampal neurogenesis. Radiotherapy is a common modality in the treatment of brain tumors that targets malignant cells with radiation. However, unintended iatrogenic injury may extend to adjacent healthy cells. The hippocampus is a particular area of concern, given its vital role in memory and learning and capacity for neurogenesis. METHODS We searched the PubMed, Embase, and Web of Science databases for studies assessing the effects of radiation on the hippocampus and hippocampal neurogenesis, adhering to PRISMA guidelines. Animal studies were evaluated according to the ARRIVE guidelines for pre-clinical studies. The SYRCLE risk of bias tool was utilized to examine potential bias among studies. Study characteristics, including study design, sample size, experimental methods, radiation dose, and results were collected and synthesized. RESULTS Ninety-two studies met inclusion criteria, and the majority of studies investigated rat and/or mouse models (n = 91, 98.9%). Across studies, cranial irradiation was consistently found to be associated with detrimental effects on hippocampal function and structure through molecular alterations to gene and protein expression, neuronal cell apoptosis, disruption of dendritic spines, and initiation of pro-inflammatory processes. The consequences for neurogenesis were mostly focused on the dentate gyrus of the hippocampus. These effects manifested as cognitive deficits in hippocampus-dependent tasks such as memory and learning. Behavioral (e.g., running) and pharmacological (e.g., PPARα agonists) interventions against the deleterious effects of radiation suggest the potential to address radiation-induced hippocampal disruption and cognitive deficits. The majority of studies were found to have an unclear risk of bias. CONCLUSIONS This systematic review highlights the effects of cranial radiation on hippocampal neurogenesis and their association with disruptions in memory and learning. Future research should continue to focus on delivering radiotherapy that spares susceptible regions in the brain, preserving patients’ cognitive function and quality of life.

Environmental Affordance for Physical Activity, Neurosustainability, and Brain Health: Quantifying the Built Environment’s Ability to Sustain BDNF Release by Reaching Metabolic Equivalents (METs)

Background/Objectives: Unlike enriched environments for rodents, human-built environments often hinder neuroplasticity through sedentary lifestyles, to which exercise can merely overcome its adverse effects. This paper introduces "environmental affordance for physical activity" to quantify the potential of spatial layout designs to stimulate activity and sustain neuroplasticity, mainly hippocampal neurogenesis. Methods: A novel framework links metabolic equivalents (METs) that can be afforded by the spatial layout of the built environment to its role in increasing the brain-derived neurotrophic factor (BDNF)—a biomarker that promotes and sustains adult hippocampal neurogenesis and synaptic plasticity. Equations are developed to assess the built environment’s affordance for physical activity through BDNF changes measurable after brief exposure to the built environment for 20–35 min. Results: The developed equations are evidenced to be feasible to cause BDNF release through low- to moderate-intensity physical activity. This model provides a feasible assessment tool to test the built environment’s effectiveness towards neurosustainability. Conclusions: By sustaining neurogenesis, the environmental affordance for physical activity holds promise for improving mental health and preventing cognitive decline.

Dexmedetomidine Attenuates Neuroinflammation-Mediated Hippocampal Neurogenesis Impairment in Sepsis-Associated Encephalopathy Mice through Central α2A-Adrenoceptor.

Sepsis-associated encephalopathy (SAE), one of the common complications of sepsis, is associated with higher ICU mortality, prolonged hospitalization, and long-term cognitive decline. Sepsis can induce neuroinflammation, which negatively affects hippocampal neurogenesis. Dexmedetomidine has been shown to protect against SAE. However, the potential mechanism remains unclear. In this study, we added lipopolysaccharide (LPS)-stimulated astrocytes-conditioned media (LPS-CM) to neural stem cells (NSCs) culture, which were pretreated with dexmedetomidine in the presence or absence of the α2-adrenoceptor antagonist yohimbine or the α2A-adrenoceptor antagonist BRL-44408. LPS-CM impaired the neurogenesis of NSCs, characterized by decreased proliferation, enhanced gliogenesis, and declined viability. Dexmedetomidine alleviated LPS-CM-induced impairment of neurogenesis in a dose-dependent manner. Yohimbine, as well as BRL-44408, reversed the effects of dexmedetomidine. We established a mouse model of SAE via cecal ligation and perforation (CLP). CLP-induced astrocyte-related neuroinflammation and hippocampal neurogenesis deficits, accompanied by learning and memory decline, which were reversed by dexmedetomidine. The effect of dexmedetomidine was blocked by BRL-44408. Collectively, our findings support the conclusion that dexmedetomidine can protect against SAE, likely mediated by the combination of inhibiting neuroinflammation via the astrocytic α2A-adrenoceptor with attenuating neuroinflammation-induced hippocampal neurogenesis deficits via NSCs α2A-adrenoceptor.

Decreased Brain pH Underlies Behavioral and Brain Abnormalities Induced by Chronic Exposure to Glucocorticoids in Mice.

Depressed patients may exhibit glucocorticoid hypersecretion, suggesting that elevated levels of glucocorticoids may play an important role in the pathophysiology of depression. Some postmortem brain studies have shown decreased pH and increased lactate levels in psychiatric patients, implying involvement of these factors in the pathogenesis. To investigate the effects of glucocorticoids on brain pH and lactate levels, and their roles in depressive symptoms, brain pH and lactate were examined in mice treated with corticosterone (CORT), the major bioactive glucocorticoid in rodents. A single administration of CORT decreased hippocampal pH after 24 h. Three weeks of CORT treatment decreased pH in the prefrontal cortex (PFC), striatum, and hippocampus (HC), whereas intake of pH 9.0 drinking water increased pH in these brain regions. pH and lactate levels were correlated in the PFC and HC of mice treated with CORT for 3 weeks. The suppression of body weight gain and decrease in adrenal weight observed after 3 weeks of CORT treatment were not alleviated by pH 9.0 water. However, an increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus were alleviated. The decrease in brain pH and increase in immobility time in the forced swim test and a decrease in neurogenesis in the hippocampus induced by CORT treatment were abolished by co-treatment with the glucocorticoid receptor (GR) antagonist mifepristone. These findings indicate that decreased brain pH via GRs may be related to glucocorticoid-induced depression-like behavior and decreased hippocampal neurogenesis.

Taohe Chengqi decoction improves diabetic cognitive dysfunction by alleviating neural stem cell senescence through HIF1α-driven metabolic signaling

ObjectiveType 2 diabetes mellitus (T2DM) is characterized by numerous long-term complications, in which progressive cognitive decline represents a significant risk factor for dementia and other neurodegenerative disorders. Taohe Chengqi decoction (THCQ) is a common traditional Chinese formula for treating T2DM; however, the neuroprotective effect of THCQ on diabetes-associated cognitive dysfunction remains unclear. Hence, the present study investigated the therapeutic effects of THCQ on cognitive impairment associated with T2DM and elucidated the underlying mechanisms. MethodsA stable high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM mouse model was established and received intragastrical THCQ administration. Blood and tissue samples were investigated for biochemical parameters and neuropathology, whereas hippocampal tissue underwent transcriptome analyses and the role of neural stem cell (NSC) senescence was detected both in vivo and in vitro. Network pharmacology analysis and subsequent primary NSC experiments were conducted to explore the involvement of the HIF1α signaling pathway in THCQ-mediated hippocampal NSC senescence. Furthermore, a lentivirus vector overexpressing HIF1α was used to verify the THCQ potential therapeutic effects on HIF1α/PDKs metabolic signaling that influenced NSC senescence. ResultsTHCQ alleviated cognitive dysfunction and metabolic abnormalities in HFD/STZ mice, and relieved hippocampal neurodegeneration. Transcriptome analyses and validation experiments revealed THCQ-induced neuroprotective effects by targeting high glucose-mediated hippocampal neuropathy and NSC senescence. Bioinformatic analysis indicated that HIF1α signaling played a significant role in THCQ therapeutic outcomes; while HIF1α overexpression impaired the effects of THCQ on high glucose-induced metabolic disorders and NSC senescence. ConclusionThe present study demonstrated that THCQ improved diabetic cognitive dysfunction and hippocampal neurogenesis, the effects of which were mainly attributed to the restoration of metabolic homeostasis and inhibition of NSC senescence through HIF1α signaling. Our results provide novel insights into the therapeutic framework for diabetic neuropathy and indicate that THCQ might be a promising candidate for the management of T2DM-related cognitive disorders.

Captopril prevents depressive-like behavior in an animal model of depression by enhancing hippocampal neurogenesis via activation of the ACE2/Ang (1–7)/Mas receptor/AMPK/BDNF pathway

Captopril prevents depressive-like behavior in an animal model of depression by enhancing hippocampal neurogenesis via activation of the ACE2/Ang (1–7)/Mas receptor/AMPK/BDNF pathway

Taurine Reverses Arsenic-Induced Inhibition of Hippocampal Neurogenesis and Depression-Like Behavior in Mice.

Arsenic exposure results in damage to the neurological system. We previously demonstrated the arsenic-induced inhibition of hippocampal neurogenesis and its reversibility after exposure is terminated. The present study aimed to reveal whether arsenic-induced inhibition of hippocampal neurogenesis was ameliorated when taurine was co-administered, and we also investigated depression-like behavioral changes using the forced swim test. Mice were randomly divided into four groups. The first group received distilled water only for 4 months (control group), the second group received 4.0 mg/L As2O3 via drinking water for 4 months (arsenic group), the third group received 4.0 mg/L As2O3 and taurine (150 mg/kg body weight, by gavage, twice a week) for 4 months (arsenic + taurine group), and the fourth group received taurine only by gavage for 4 months (taurine group). The percentage of new mature neurons decreased in the arsenic group compared with the control group (64% ± 0.90% vs. 76% ± 1.9%, p < 0.01); however, this percentage was reversed to control levels in the arsenic + taurine group (76% ± 1.4%, p > 0.05). In the forced swim test, the immobility time during the last 4 min was significantly increased in the arsenic group, but restored to control levels in the arsenic + taurine group. The possible mechanisms of this taurine amelioration of hippocampal damage were further investigated, and included a reduction in oxidative stress as indicated by carbonyl content, inflammation, and aquaporin1, 4, and 8 expressions, as well as an increase in Wnt3a and brain-derived neurotrophic factor expression in western blot analyses.

Perinatal running training reversed postnatal anxiety and depressive-like behavior and cognitive impairment in mice following prenatal subchronic variable stress.

Pregnancy is a very complex and highly stressful time in women. Despite the high prevalence of postpartum depression, more than 50 % of mothers are undiagnosed or untreated, showing an urgent need to explore an effective preventive strategy. Regular physical activity has been suggested to be associated with an increased quality of life in pregnant and postpartum women. The purpose of this study was to determine whether perinatal running training can affect maternal care stress-related anxiety, depressive-like behavior, and cognitive changes in postpartum dams and to explore the possible underlying mechanism. 40 female C57BL/6J mice were divided into four groups: prenatal control (NC) and running training (EX) group (NC+EX), prenatal control and nonrunning training (RE) group (NC+RE), prenatal subchronic variable stress (SCVS) and running training group (SCVS+EX) and prenatal SCVS and non-running training group (SCVS+RE). Mice in prenatal stress groups were subjected to SCVS after pregnancy confirmed. Mice in running training groups subjected to running training throughout pregnancy and lactation. Then after the delivery, maternal behavior, cognitive changes, anxiety and depressive-like behaviors were tested. Then we measured the serum prolactin (PRL), hypothalamic-pituitary adrenal (HPA) axis activity, and adult hippocampus neurogenesis (AHN) in dams. Compared to NC+RE, prenatal SCVS caused cognitive impairments, the decrease in maternal behavior, and anxiety and depressive-like behavior in SCVS+RE dams, accompanying increase in HPA axis activity and decreased the PRL levels and AHN in postpartum period. Then compared to SCVS+RE, perinatal running training mitigates cognitive impairments, increased maternal behavior, and alleviates anxiety and depressive-like behavior in SCVS+EX dams, accompanying the decreased HPA axis activity, and the increased PRL levels and AHN in postpartum period. Overall, this study suggests that perinatal running training might improve maternal care and reverse prenatal stress-related cognitive impairment and anxiety and depressive-like behavior in postpartum dams.

The Deficiency of the ASD-Related Gene CHD8 Disrupts Behavioral Patterns and Inhibits Hippocampal Neurogenesis in Mice.

Chromodomain helicase DNA-binding 8 (CHD8) is a gene that poses a high risk for autism spectrum disorder (ASD) and neurological development delay. Nevertheless, the impact of CHD8 haploinsufficiency on both hippocampus neurogenesis and behavior remains uncertain. Here, we performed behavioral assessments on male and female CHD8 heterozygous mice. The study discovered that both male and female CHD8 heterozygous mice displayed an impairment in preference for social novelty. Concurrently, CHD8 heterozygous mice exhibited anxiety-like behavior. However, its cognitive capacity for learning and memory is within the expected range. Furthermore, we discovered a reduction in the number of both immature and mature new neurons in mice with CHD8 heterozygous, resulting in an impeded neurogenesis process in the hippocampus. Taken together, our findings indicate that CHD8 plays a crucial role in the regulation of hippocampal neurogenesis, and further suggest that ASD-like behaviors observed in CHD8 heterozygous mice may be associated with disruptions in hippocampal neurogenesis.

Stress-induced obesity in mice causes cognitive decline associated with inhibition of hippocampal neurogenesis and dysfunctional gut microbiota.

Effects of stress on obesity have been thoroughly studied in high-fat diet fed mice, but not in normal diet fed mice, which is important to clarify because even on a normal diet, some individuals will become obese under stress conditions. Here we compared mice that showed substantial weight gain or loss under chronic mild stress while on a normal diet; we compared the two groups in terms of cognitive function, hypothalamic-pituitary-adrenal signaling, neurogenesis and activation of microglia in hippocampus, gene expression and composition of the gut microbiome. Chronic mild stress induced diet-independent obesity in approximately 20% of animals, and it involved inflammatory responses in peripheral and central nervous system as well as hyperactivation of the hypothalamic-pituitary-adrenal signaling and of microglia in the hippocampus, which were associated with cognitive deficits and impaired hippocampal neurogenesis. It significantly increased in relative abundance at the phylum level (Firmicutes), at the family level (Prevotellaceae ucg - 001 and Lachnospiraceae NK4a136), at the genus level (Dubosiella and Turicibacter) for some enteric flora, while reducing the relative abundance at the family level (Lactobacillaceae and Erysipelotrichaceae), at the genus level (Bacteroidota, Alistipes, Alloprevotella, Bifidobacterium and Desulfovibrio) for some enteric flora. These results suggest that stress, independently of diet, can induce obesity and cognitive decline that involve dysfunctional gut microbiota. These insights imply that mitigation of hypothalamic-pituitary-adrenal signaling and microglial activation as well as remodeling of gut microbiota may reverse stress-induced obesity and associated cognitive decline.

Using fluorescence, PET, and fMRI to detect the alteration of patterns and activation of specific neurons in the subiculum in response to hippocampus neurogenesis

In this paper, the questions started with “What will happen to the brain if AHN(adult hippocampus neurogenesis) increases” and then going further on the question became “How would certain neurons in the hypothalamus and subiculum change if AHN increases”. Therefore, this paper will address this question and propose three experiments and a conclusion. For the experiments, PET and fMRI are used to scan the brain and see the levels of glucose and therefore the activation of neurons. Furthermore, FosTRAP2 with fluoresce allows a better in-depth look at the parts where neurons were active, or in this case, activated due to stress. The three experiments should show more activity/fluorescence in the hypothalamus and subiculum in groups with neurogenesis compared to the control groups with CORT injection. In conclusion, if the results are in accordance with the hypothesis, this allows a better insight into the mechanism and link between anxiety and AHN. This will also mean a correlation with the subiculum, HPA, and AHN.

Increasing Adult Hippocampal Neurogenesis affects Neuronal Output Pattern from the Ventral Subiculum to the Hypothalamus

Adult Hippocampal Neurogenesis, or AHN, has been discovered to alleviate anxiety and depressive behavior, thus leading to the presumption that the mechanisms underlying it might be somewhat linked to the regulatory circuitry of anxiety and depression. The subiculum is a region of the Hippocampus connecting the CA1 neurons and the Entorhinal cortex. It is the main output region of the Hippocampus. A great portion of the subiculum neurons form neuronal projections to the lateral hypothalamus, which is known to play a crucial role in the regulation of anxiety via hormone secretion in both rodents and humans. Thus, we hypothesize that Adult Hippocampal Neurogenesis regulates anxiety via altering the neural output from the subiculum to the lateral hypothalamus. In this research proposal we aim to prove that increasing AHN causes a direct impact on neuronal activity in the main output region of the Hippocampus--the subiculum region, under the effect of anxiety. This study uses the Fos-TRAP2 model to induce tdTomato expression in neurons with high recent activity while the mice was under the effect of corticosterone-induced anxiety. We compare the amount of TRAPed neurons in the subiculum region of the brain during anxiety, in mice with and without weeks of voluntary exercise (running), which leads to an increased neurogenesis. This provides insight into the effects of AHN on the subiculum-hypothalamus pathway, thus the mechanisms underlying its effect of anxiety alleviation.

Impact of Adult Hippocampal Neurogenesis on Neuronal Output Patterns from the Subiculum to the Lateral Hippocampus During Anxiety

Adult hippocampal neurogenesis (AHN) has an effect on mood regulations. Promoting AHN could recover stressed-induced symptoms such as depression and anxiety. In this study, we used voluntary physical exercise, fosTRAP2, functional magnetic resonance imaging (FMRI) and positron emission tomography (PET) technology to evaluate the effect of AHN on mice during unpredictable chronic mild stress (UCMS). Additionally, we inject fluoxetine to increase AHN.

Corticosterone-Mediated BDNF Changes and Their Effects on Adult Neurogenesis in Depression

Adult neurogenesis, the process of generating functional neurons from neural precursor cells in the adult brain, is essential for cognitive function and emotional regulation. Major Depressive Disorder (MDD), characterized by persistent sadness and decreased psychosocial function, is associated with impaired adult hippocampal neurogenesis (AHN). Elevated levels of corticosterone (CORT), a glucocorticoid released in response to stress, have been shown to downregulate brain-derived neurotrophic factor (BDNF), a crucial regulator of neurogenesis, thereby inhibiting AHN. Despite significant advances in understanding the impact of CORT and BDNF on neurogenesis, the precise molecular and cellular pathways involved remain unclear. This review highlights key gaps in the research, particularly the need for a deeper understanding of how glucocorticoid and mineralocorticoid receptors regulate BDNF transcription, the role of autophagic pathways in BDNF degradation, and the influence of glutamatergic signaling on these processes. Future research should focus on elucidating these mechanisms to develop targeted therapeutic strategies, including pharmacological interventions that modulate BDNF and CORT levels and lifestyle modifications like exercise and adequate sleep to enhance neurogenesis. Understanding these complex interactions will be crucial for advancing treatments for depression and improving mental health outcomes.

Effects of Increased Adult Hippocampal Neurogenesis on Neuronal Output from the Subiculum to the Lateral Hippocampus under Anxiety

Numerous studies assessed the important involvement of adult hippocampal neurogenesis (AHN) in the regulation of stress. Although the precise processes underlying the promotion of AHN on the recovery of anxiety-induced symptoms have been thoroughly examined, they are still unclear.We observed the subiculum region and its neuronal output to the lateral hippocampal formation, which may serve as a conduit between AHN and the recovery from depression.In order to cultivate AHN with exercise and fluoxetine injection independently, we employed a mouse model. We then used FosTRAP2, PET, and fMRI to measure the subiculum’s neural activity during anxiety.When considered collectively, our findings imply that raising AHN in anxious mice modifies the way some subiculum neurons in the lateral hippocampal region output.

Gut microbiota dysbiosis-mediated ceramides elevation contributes to corticosterone-induced depression by impairing mitochondrial function

The role of gut microbiota (GM) dysbiosis in the pathogenesis of depression has received widespread attention, but the mechanism remains elusive. Corticosterone (CORT)-treated mice showed depression-like behaviors, reduced hippocampal neurogenesis, and altered composition of the GM. Fecal microbial transplantation from CORT-treated mice transferred depression-like phenotypes and their dominant GM to the recipients. Fecal metabolic profiling exposed remarkable increase of gut ceramides in CORT-treated and recipient mice. Oral gavage with Bifidobacterium pseudolongum and Lactobacillus reuteri could induce elevations of gut ceramides in mice. Ceramides-treated mice showed depressive-like phenotypes, significant downregulation of oxidative phosphorylation-associated genes, and hippocampal mitochondrial dysfunction. Our study demonstrated a link between chronic exposure to CORT and its impact on GM composition, which induces ceramides accumulation, ultimately leading to hippocampal mitochondrial dysfunction. This cascade of events plays a critical role in reducing adult hippocampal neurogenesis and is strongly associated with the development of depression-like behaviors.

The impact of voluntary wheel-running exercise on hippocampal neurogenesis and behaviours in response to nicotine cessation in rats.

The literature indicates that nicotine exposure or its discontinuation impair adult hippocampal neurogenesis in rats, though the impact of exercise on this process remains unclear. We have previously shown that disturbances in the number of doublecortin (DCX, a marker of immature neurons)-positive (DCX+) cells in the dentate gyrus (DG) of the hippocampus during nicotine deprivation may contribute to a depression-like state in rats. This study aimed to investigate the effect of running on hippocampal neurogenesis, depression-like symptoms, and drug-seeking behaviour during nicotine deprivation. The rats were subjected to nicotine (0.03mg/kg/inf) self-administration via an increasing schedule of reinforcement. After 21 sessions, the animals entered a 14-day abstinence phase during which they were housed in either standard home cages without wheels, cages equipped with running wheels, or cages with locked wheels. Wheel running increased the number of Ki-67+ and DCX+ cells in the DG of both nicotine-deprived and nicotine-naive rats. Wheel-running exercise evoked an antidepressant effect on abstinence Day 14 but had no effect on nicotine-seeking behaviour on abstinence Day 15 compared to rats with locked-wheel access. In summary, long-term wheel running positively affected the number of immature neurons in the hippocampus, which corresponded with an antidepressant response in nicotine-weaned rats. One possible mechanism underlying the positive effect of running on the affective state during nicotine cessation may be the reduction in deficits in DCX+ cells in the hippocampus.

Suppressing DUSP16 overexpression induced by ELK1 promotes neural progenitor cell differentiation in mouse models of Alzheimer's disease.

Emerged evidence indicated that stimulating hippocampal neurogenesis is a potential strategy for restoring cognition in AD. Mitogen-activated protein kinases (MAPKs) play an essential role in neurogenesis. Meanwhile, the enzymatic power of the phosphatases is much greater than that of kinases. Dual-specificity phosphatase 16 (DUSP16), known to as a phosphatase negatively regulate MAPKs, may be implicated in neural differentiation. Nevertheless, the effect of DUSP16 on cognitive disorders by stimulating neural progenitor cell (NPC) differentiation in AD mice remains unclear. Our study demonstrates an association between DUSP16 SNPs and clinical progression in individuals with mild cognitive impairment (MCI). Besides, increased DUSP16 expression was detected in both 3xTg and SAMP8 mouse models of AD, accompanied by NPC neural differentiation impairments. By silencing DUSP16, the induction of neural differentiation, synaptic transmission, and cognitive benefits were observed in both AD mice. Furthermore, DUSP16 was involved in the process of NPC differentiation through regulating c-Jun N-terminal kinase (JNK) phosphorylation and SOX2 expression. Moreover, ETS transcription factor (ELK1) was involved in the DUSP16 transcription, which resulted in the upregulation of DUSP16 at the state of AD. Our data uncovers a potential regulatory role for DUSP16 in adult hippocampal neurogenesis (AHN) and provides a possibility to find a novel strategy for AD intervention.

Spatial transcriptomic analysis of adult hippocampal neurogenesis in the human brain.

Adult hippocampal neurogenesis has been extensively characterized in rodent models, but its existence in humans remains controversial. We sought to assess the phenomenon in postmortem human hippocampal samples by combining spatial transcriptomics and multiplexed fluorescent in situ hybridization. We computationally examined the spatial expression of various canonical neurogenesis markers in postmortem dentate gyrus (DG) sections from young and middle-aged sudden-death males. We conducted in situ assessment of markers expressed in neural stem cells, proliferative cells, and immature granule neurons in postmortem DG sections from infant, adolescent, and middle-aged males. We examined frozen DG tissue from infant (n = 1, age 2 yr), adolescent (n = 1, age 16 yr), young adult (n = 2, mean age 23.5 yr), and middle-aged (n = 2, mean age 42.5 yr) males, and frozen-fixed DG tissue from middle-aged males (n = 6, mean age 43.5 yr). We detected very few cells expressing neural stem cell and proliferative markers in the human DG from childhood to middle age. However, at all ages, we observed a substantial number of DG cells expressing the immature neuronal marker DCX. Most DCX + cells displayed an inhibitory phenotype, while the remainder were non-committed or excitatory in nature. The study was limited by small sample sizes and included samples only from males. Our findings indicate very low levels of hippocampal neurogenesis throughout life and the existence of a local reserve of plasticity in the adult human hippocampus. Overall, our study provides important insight into the distribution and phenotype of cells expressing neurogenesis markers in the adult human hippocampus.