Adult Hippocampal Neurogenesis Research Articles (Page 1)

Understudied orphan GPCRs lack identified natural ligands, yet understanding their function is critical for therapeutic development. GPRC5B is a brain-enriched, retinoic acid (RA)-induced orphan GPCR. While RA is used to treat severe acne, chronic exposure is associated with depression, likely due to its inhibition of adult hippocampal neurogenesis. Here, we tested whether GPRC5B plays a role in the molecular and cellular mechanisms underlying RA-induced depressive-like behaviors in mice by suppressing adult hippocampal neurogenesis. We found that Gprc5b knockout (KO) mice were resilient to RA-induced behavioral effects and that RA increased GPRC5B expression in the hippocampal neurogenic subgranular zone. This correlated with RA-mediated inhibition of adult hippocampal neurogenesis, an effect absent in Gprc5b KO mice, which also exhibited a larger pool of proliferative neuronal stem cells. Collectively, these findings suggest that GPRC5B mediates RA-induced anti-neurogenic effects and depressive-like behaviors.

While evidence is emerging that the temporal pattern of feeding may influence anxiety, it is unclear to what extent anxiety may itself impact spontaneous feeding behaviour. To address this, we have quantified spontaneous feeding, ghrelin secretion and adult hippocampal neurogenesis (AHN) in male low (LAB) and high (HAB) anxiety-behaviour rats. LAB and HAB rats showed the expected anxiogenic profile in the elevated plus-maze, HAB rats avoiding the open arms entirely. A 16% reduction in total food intake in HAB rats (p = .017) was due to a 35% reduction in light phase food consumption (p = .004). However, there were no significant changes in the number or duration of individual feeding events, and the 24-h feeding profile remained largely unaltered. Although basal circulating ghrelin was comparable in HAB and LAB rats, the 57% elevation in circulating ghrelin induced by a 24-h fast in LAB rats (p = .022) was completely abolished in HAB rats. In comparison with adult LAB rats, the number of newborn neurones (BrdU+/NeuN+) in the dentate gyrus of HAB rats was elevated by 68% and 103% in the sub-granular zone and granule cell layer, respectively (p = .0004 and p < .0001), these increases being observed across the rostro-caudal extent of the hippocampus. In contrast, the number of newborn non-neuronal (BrdU+/NeuN-) cells was unaltered. Thus, even in the context of the marked anxiety in HAB rats, mild hypophagia occurs without significant alteration in feeding patterns. Despite a blunting of fasting-induced ghrelin release, elevated AHN suggests an appropriate feedback response to the increased anxiety-related behaviour.

The perinatal environment has been suggested to participate in the development of tauopathies and Alzheimer's disease but the molecular and cellular mechanisms involved remain contradictory and under-investigated. Here, we evaluated the effects of a maternal high-fat diet (HFD) during lactation on the development of tauopathy in the THY-Tau22 mouse strain, a model of progressive tau pathology associated with cognitive decline. During lactation, dams were fed either a chow diet (13.6% of fat) or a HFD (58% of fat). At weaning, offspring were fed a chow diet until sacrifice at 4 months of age (the onset of tau pathology) or 7 months of age (the onset of cognitive impairment). During lactation, maternal HFD increased body weight gain in offspring. At 3 months of age, maternal HFD led to a mild glucose intolerance only in male offspring. Moreover, it impaired spatial memory in both male and female 6-month-old offspring, with males being more impacted. These cognitive deficits were associated with increased phosphorylation of hippocampal tau protein-observed at 4 months in males and at 7 months in females, highlighting a sex-specific temporal shift. Additionally, maternal HFD modified adult hippocampal neurogenesis (AHN), leading to an increase of mature neuronal cells number in females and of dendritic arborization length in males. Synaptic analysis further revealed that maternal HFD led to synaptic loss only in males. Finally, multi-omics approaches showed that maternal HFD has long-term consequences on both transcriptome, proteome and regulome, this effect being also sex-dependent with mitochondrial pathways, ribosomal activity, cilium and the extracellular matrix predominantly impacted in males, while gliogenesis, myelination and synaptic plasticity were primarily affected in females. Regulome analysis suggested that this sex-dependent phenotype was more related to a temporal shift rather than distinct sex-specific alterations. Collectively, our data suggest that maternal HFD accelerates the development of tauopathy in THY-Tau22 offspring, with sex-dependent effects, males being impacted earlier than females. These findings highlight that exposure to maternal HFD represents a critical window of vulnerability, and potentially of opportunity, for interventions aimed at preventing the development of neurodegenerative diseases.

Running ameliorates methamphetamine-associated cognitive impairment by regulating hippocampal neurogenesis through the GSK3β/β-catenin pathway.

TERT activator compound alleviates cigarette smoke-induced cognitive deficits by modulating hippocampal inflammation and neurogenesis: A comprehensive study integrating Mendelian randomization.

Platelet concentrate-derived extracellular vesicles promote adult hippocampal neurogenesis

Baicalin counteracts valproic acid-induced memory impairment by restoring neurogenesis in the hippocampus of adult rats.

Targeting adult-born neurons to correct early deficits in pattern separation in the Tg2576 mouse model of Alzheimer's disease.

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially-expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of cell proliferation. We found that the expression of sFRP3, a Wnt signaling inhibitor, is altered in a seizure-dependent manner and might be regulated by ΔFosB, a seizure-induced transcription factor. Increasing sFRP3 expression prevented NSC depletion and improved spatial discrimination, suggesting that the loss of sFRP3 might mediate seizure-driven impairment in cognition in AD model mice, and perhaps also in AD.Significance statement There is increased incidence of seizures in individuals with Alzheimer's disease (AD), but it is unclear how seizures contribute to cognitive decline. Here, we uncover a molecular mechanism by which seizures in AD induce expression of a long-lasting transcription factor in the hippocampal dentate gyrus that suppresses expression of sFRP3, an inhibitor of neural stem cell division, accelerating the depletion of a finite pool of neural stem cells and dysregulating adult hippocampal neurogenesis. We found that restoring sFRP3 expression prevents accelerated use and depletion of neural stem cells and improves performance in an adult neurogenesis-dependent cognitive task. Our findings have implications for AD, epilepsy, and other neurological disorders that are accompanied by seizures.

Wnt signaling plays a pivotal role in normal brain development and function. Dickkopf-related protein 2 (DKK2), a member of the DKK protein family (DKK1 - 4), modulates Wnt signaling either positively or negatively by interacting with the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (Lrp5/6). However, the role of DKK2 in the brain remains unclear. Here, we demonstrated that the DKK2-mediated suppression of Wnt signaling is essential for hippocampal function. Dkk2+/- mice exhibited impaired context discrimination and reduced adult hippocampal neurogenesis (AHN). Genetic disruption of Dkk2 (Dkk2+/- and Dkk2-/-) and chronic DKK2 administration into the brain affected AHN bidirectionally. Furthermore, homozygous and heterozygous Dkk2 deletions exerted differential effects on the Wnt signaling pathway in the hippocampus. Complete loss of Dkk2 enhanced both Wnt/β-catenin and Wnt/planar cell polarity (PCP) signaling, whereas haploinsufficiency primarily enhanced Wnt/PCP signaling. In hippocampal slices, DKK2 suppressed Wnt3a- and Wnt5a-mediated activation of Wnt/β-catenin and Wnt/PCP signaling, respectively. Chronic suppression of c-Jun N-terminal kinase(JNK) signaling rescued the impaired AHN and context discrimination in Dkk2+/- mice. Collectively, these findings identify DKK2 as a negative regulator of Wnt signaling that paradoxically promotes AHN and suggest that suppressing Wnt/PCP signaling may enhance AHN.

Pleiotrophin and receptor protein tyrosine phosphatase β/ζ as key modulators of high-fat diet-induced cognitive impairment and brain alterations.

A cafeteria diet high in saturated fat and sugar has been associated with increased anxiety-like and depressive-like behaviors and memory impairments, whereas exercise has been shown to promote antidepressant-like effects and enhance cognitive function in rodents. The mechanisms underlying the interactions between diet and exercise on mood, anxiety, and memory are not fully understood, but alterations in adult hippocampal neurogenesis (AHN), gut-derived metabolites, or plasma metabolic hormones may play a role. This study investigated whether voluntary exercise could mitigate the effects of concurrent exposure to a cafeteria diet on depression-like, anxiety-like, and cognitive behaviors in young adult male rats. Associated changes in AHN, metabolic hormones, and gut-derived metabolites were examined to identify potential mediators of behavioral changes. We found that exercise mitigated the cafeteria diet–induced increase in immobility in the forced swim test. This antidepressant-like effect of exercise in rats exposed to a cafeteria diet was accompanied by an attenuation of cafeteria diet–induced changes in plasma insulin and leptin, as well as in the abundance of caecal metabolites anserine, indole-3-carboxylate, and deoxyinosine. Exercise modestly improved spatial learning in the Morris water maze, promoted AHN and increased circulating levels of GLP-1, and these effects were blunted in animals exposed to a cafeteria diet suggesting that dietary composition plays a role in modulating the effects of exercise. Correlation analyses revealed that specific caecal metabolites were associated with depression- and cognition-related behaviors, independent of diet and exercise, highlighting the potential role of gut-derived metabolites in antidepressant-like behavior and cognitive function. Together these findings provide insight into potential metabolite and hormone-mediated mechanisms underlying the effects of a cafeteria diet and exercise on brain and behavior.

Amyotrophic lateral sclerosis (ALS) is a multisystem progressive neurodegenerative disease. A recent theory of ALS onsetting pathogenesis proposed that the initiating primary damage is an acquired irreversible intrafusal proprioceptive terminal PIEZO2 channelopathy with underlying genetic and environmental risk factors. This Piezo2 channelopathy may also disrupt the ultrafast proton-based oscillatory signaling to motor neurons through vesicular transporter 1 (VGLUT1) and to the hippocampus through VGLUT2. As a result, it may gradually degenerate motor neurons in which process Kv1.2 ion channels are gradually depleted. It also gradually depletes heat shock transcription factor-1 (HSF-1) in the hippocampus, hence negatively affecting adult hippocampal neurogenesis. Syndecans, especially syndecan-3 (SDC3) in the nervous system, may act as critical players in the maintenance of the crosstalk between Piezo ion channels. Hence, our goal was to reanalyze the potential pathogenic gene variants from the cohort of our previous ALS study with a special focus on the aforementioned genes. Reanalysis of data formerly acquired by whole-exome sequencing of 21 non-related adult ALS patients was carried out with a focus on 28 genes. Accordingly, we identified charge-altering variants of SDC3 in 13 patients out of 21 that may contribute to the impairment of the Piezo crosstalk, and the progressive loss of the proposed proton-based signaling to motor neurons and to the hippocampus. A variant of uncertain significance was identified in the KCNA2 gene that may facilitate the faster loss of Kv1.2 ion function on motor neurons when Piezo2 channelopathy prevails. Not to mention that one variant was identified in the potassium current rectifying ion channels encoding KCNK1 and KCNK16 genes that may also propel the ALS disease process and provide the autoimmune-like pathogenic background. Moreover, Piezo2 channelopathy likely promotes diminishing HSF1 function in the hippocampus in the presence of the identified HSF1 variant. The current findings may support the ALS onsetting acquired irreversible Piezo2 channelopathy-induced pathogenesis. However, the preliminary nature of these findings needs validation and further functional studies on cohorts with a larger sample size in the future.

The primary cilium is generally viewed as a sensory organelle that transduces chemical and mechanical stimuli from the environment. In the adult hippocampus, primary cilia mediate the effects of sonic hedgehog (Shh) and other signals on neurogenesis and hippocampal function, and loss of cilia leads to cognitive and behavioral deficits. The secreted peptide noggin is a bone morphogenetic protein (BMP) antagonist and plays a critical role in regulating adult hippocampal neurogenesis (AHN) and hippocampus-dependent behavior. Here, we show that noggin is expressed by mature granule cell neurons, that it is apically targeted and localized intracellularly near the pocket region of primary cilia, and that cilia regulate noggin release through Shh and somatostatin (SST) pathways. Further, granule cell activation modulates noggin dynamics both in vitro and in vivo. Together, these findings demonstrate synergy between Shh and noggin and the positive regulatory action of neuronal activity on regulating BMP antagonism within the neurogenic niche. Thus, the primary cilium is not only an organelle that transduces signals to neurons but also one that mediates extracellular signaling. Significance statement: Primary cilia are organelles that protrude from the surface of most vertebrate cell types. Defects in primary ciliary structure and function are associated with human disease. Primary cilia are generally viewed as exclusively sensory organelles that respond to environmental signals to regulate both cell development and adult cell function. This study demonstrates that the primary cilia in hippocampal granule cell neurons mediate the release of the BMP antagonist, noggin. These observations expand the current understanding of ciliary signaling and may inform future studies exploring the connection between hippocampal activity and cognition in ciliopathies.

In laboratory mice, ‘inactive but awake’ (IBA) home-cage behaviour involves animals being spontaneously motionless with eyes open, not interacting with their surroundings. Conventional (barren) housing typically triggers IBA more than comparatively enriched environments. Compellingly greater IBA is associated with some depression-like features in mice and we further explored this through three aims. First, we aimed to replicate previous results highlighting environmental and genetic (using two strains of mice: DBA/2J and C57BL/6J) aetiological contributors to IBA. Second, we explored whether the performance of IBA varied as the level of enrichment was either increased or reduced. Third, we opportunistically investigated whether elevated IBA predicted lower density of immature neurons in the dorsal (dDG) or ventral dentate gyrus (vDG) of the hippocampus. As expected, mice housed in conventional cages displayed more IBA than those in comparatively enriched cages and even more so in DBA/2J mice. As predicted, enrichment loss generally increased IBA while enrichment gain decreased IBA. Unsurprisingly, immature neuron density was lower in conventional compared with enriched cages, although only for vDG. Elevated IBA predicted reduced immature neuron density in the dDG, and this effect tended to be stronger for C57BL/6Js. We discuss the result implications, study limitations and future research directions.

Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wildtype (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes. In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.

Human adult hippocampal neurogenesis is shaped by neuropsychiatric disorders, demographics, and lifestyle-related factors.

Accumulating evidence showed the adult hippocampal neurogenesis (AHN) has played an essential role in regulating cognitive functions and emotions, while the other potential regulator such as the neuropeptides has still received less attention.. In the nestin-GFP mice, our data showed that the SP-overexpressed SuM neurons inhibited the proliferation of radial neural stem cells (rNSCs) and reduced the cell densities of immature and proliferating neurons in the dentate gyrus (DG). All of these processes were accompanied by depression and anxiety-like behaviours, including the reduced exploration, the lower sucrose preference, and the prolonged immobility. However, the neurokinin-1 receptor (NK1-R) antagonist could reversed those behavioural deficits. Together, our study demonstrated that SP was an essential inhibitor of AHN and emotional behaviours, while the NK1-R antagonism may provide a potential therapeutic strategy for depression and anxiety-like behaviours.

Hippocampal neurogenesis: Bridging stress, cognitive decline, and therapeutic strategies for neural health.

Sevoflurane-induced cognitive dysfunction in aged mice mediated by HDAC8-dependent suppression of adult hippocampal neurogenesis via the pCREB/BDNF pathway.