Modulation Of Adult Neurogenesis Research Articles

In the pursuit of new social neurons. Neurogenesis and social behavior in mice: A systematic review.

Social behaviors have become more relevant to our understanding of the human nervous system because relationships with our peers may require and modulate adult neurogenesis. Here, we review the pieces of evidence we have to date for the divergence of social behaviors in mice by modulation of adult neurogenesis or if social behaviors and the social environment can drive a change in neurogenic processes. Social recognition and memory are deeply affected by antimitotic drugs and irradiation, while NSC transgenic mice may run with lower levels of social discrimination. Interestingly, social living conditions can create a big impact on neurogenesis. Social isolation and social defeat reduce the number of new neurons, while social dominance and enrichment of the social environment increase their number. These new "social neurons" trigger functional modifications with amazing transgenerational effects. All of these suggest that we are facing two bidirectional intertwined variables, and the great challenge now is to understand the cellular and genetic mechanisms that allow this relationship to be used therapeutically.

Adult Neurogenesis under Control of the Circadian System.

The mammalian circadian system is a hierarchically organized system, which controls a 24-h periodicity in a wide variety of body and brain functions and physiological processes. There is increasing evidence that the circadian system modulates the complex multistep process of adult neurogenesis, which is crucial for brain plasticity. This modulatory effect may be exercised via rhythmic systemic factors including neurotransmitters, hormones and neurotrophic factors as well as rhythmic behavior and physiology or via intrinsic factors within the neural progenitor cells such as the redox state and clock genes/molecular clockwork. In this review, we discuss the role of the circadian system for adult neurogenesis at both the systemic and the cellular levels. Better understanding of the role of the circadian system in modulation of adult neurogenesis can help develop new treatment strategies to improve the cognitive deterioration associated with chronodisruption due to detrimental light regimes or neurodegenerative diseases.

Association between Time Restricted Feeding and Cognitive Status in Older Italian Adults.

Background: Due to the increased life expectancy, the prevalence of aging-related health conditions, such as cognitive impairment, dementia and Alzheimer’s disease is increasing. Among the modifiable risk factors, dietary factors have proved to be of primary importance in preserving and improving mental health and cognitive status in older adults, possibly through the modulation of adult neurogenesis, neuronal plasticity and brain signaling. Feeding/fasting timing manipulation has emerged as an innovative strategy to counteract and treat cognitive decline. The aim of this study was to investigate the association between the timing of the feeding period and cognitive status in a cross-sectional cohort of adults living in the Mediterranean area. Methods: Demographic and dietary characteristics of 883 adults living in Southern Italy (Sicily) were analyzed. Food frequency questionnaires were used to calculate the time window between the first and the last meal of an average day. Participants with an eating time window duration of more than 10 h were then identified, as well as those with eating time restricted to less than 10 h (TRF). Results: After adjusting for potential confounding factors, individuals adherent to TRF were less likely to have cognitive impairment, compared to those with no eating time restrictions [odds ratio (OR) = 0.28; 95% confidence intervals (CI): 0.07–0.90]; a similar association was found for individuals having breakfast (OR = 0.37, 95% CI: 0.16–0.89), but not for those having dinner. Conclusions: The results of this study reveal that time restricted eating may be positively associated with cognitive status, and thus exert plausible effects on brain health.

Diet and Mental Health: Review of the Recent Updates on Molecular Mechanisms.

Over the last decades, there has been a substantial increase in the prevalence of mental health disorders, including an increased prevalence of depression, anxiety, cognitive, and sleep disorders. Diet and its bioactive components have been recognized among the modifiable risk factors, possibly influencing their pathogenesis. This review aimed to summarize molecular mechanisms underlying the putative beneficial effects toward brain health of different dietary factors, such as micro- and macronutrient intake and habits, such as feeding time and circadian rhythm. The role of hormonal homeostasis in the context of glucose metabolism and adiponectin regulation and its impact on systemic and neuro-inflammation has also been considered and deepened. In addition, the effect of individual bioactive molecules exerting antioxidant activities and acting as anti-inflammatory agents, such as omega-3 fatty acids and polyphenols, considered beneficial for the central nervous system via modulation of adult neurogenesis, synaptic and neuronal plasticity, and microglia activation has been summarized. An overview of the regulation of the gut–brain axis and its effect on the modulation of systemic inflammation and oxidative stress has been provided. Finally, the impact of bioactive molecules on inflammation and oxidative stress and its association with brain health has been summarized.

Histamine modulates hippocampal inflammation and neurogenesis in adult mice

Evidence points to a dual role of histamine in microglia-mediated neuroinflammation, a key pathological feature of several neurodegenerative pathologies. Moreover, histamine has been suggested as a modulator of adult neurogenesis. Herein, we evaluated the effect of histamine in hippocampal neuroinflammation and neurogenesis under physiological and inflammatory contexts. For that purpose, mice were intraperitoneally challenged with lipopolysaccharide (LPS) followed by an intrahippocampal injection of histamine. We showed that histamine per se triggered glial reactivity and induced mild long-term impairments in neurogenesis, reducing immature neurons dendritic volume and complexity. Nevertheless, in mice exposed to LPS (2 mg/Kg), histamine was able to counteract LPS-induced glial activation and release of pro-inflammatory molecules as well as neurogenesis impairment. Moreover, histamine prevented LPS-induced loss of immature neurons complexity as well as LPS-induced loss of both CREB and PSD-95 proteins (essential for proper neuronal activity). Altogether, our results highlight histamine as a potential therapeutic agent to treat neurological conditions associated with hippocampal neuroinflammation and neurodegeneration.

Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease

Alzheimer's disease (AD) patients display hippocampal atrophy, memory impairment, and cognitive decline. New neurons are generated throughout adulthood in 2 regions of the brain implicated in AD, the dentate gyrus of the hippocampus and the subventricular zone of the olfactory bulb. Disruption of this process contributes to neurodegenerative diseases including AD, and many of the molecular players in AD are also modulators of adult neurogenesis. However, the genetic mechanisms underlying adult neurogenesis in AD have been underexplored. To address this gap, we performed a gene-based association analysis in cognitively normal and impaired participants using neurogenesis pathway-related candidate genes curated from existing databases, literature mining, and large-scale genome-wide association study findings. A gene-based association analysis identified adenosine A2a receptor (ADORA2A) as significantly associated with hippocampal volume and the association between rs9608282 within ADORA2A and hippocampal volume was replicated in the meta-analysis after multiple comparison adjustments (p = 7.88 × 10−6). The minor allele of rs9608282 in ADORA2A is associated with larger hippocampal volumes and better memory.

Lack of riluzole efficacy in the progression of the neurodegenerative phenotype in a new conditional mouse model of striatal degeneration.

BackgroundHuntington’s disease (HD) is a rare familial autosomal dominant neurodegenerative disorder characterized by progressive degeneration of medium spiny neurons (MSNs) located in the striatum. Currently available treatments of HD are only limited to alleviating symptoms; therefore, high expectations for an effective therapy are associated with potential replacement of lost neurons through stimulation of postnatal neurogenesis. One of the drugs of potential interest for the treatment of HD is riluzole, which may act as a positive modulator of adult neurogenesis, promoting replacement of damaged MSNs. The aim of this study was to evaluate the effects of chronic riluzole treatment on a novel HD-like transgenic mouse model, based on the genetic ablation of the transcription factor TIF-IA. This model is characterized by selective and progressive degeneration of MSNs.MethodsSelective ablation of TIF-IA in MSNs (TIF-IAD1RCre mice) was achieved by Cre-based recombination driven by the dopamine 1 receptor (D1R) promoter in the C57Bl/6N mouse strain. Riluzole was administered for 14 consecutive days (5 mg/kg, i.p.; 1× daily) starting at six weeks of age. Behavioral analysis included a motor coordination test performed on 13-week-old animals on an accelerated rotarod (4–40 r.p.m.; 5 min). To visualize the potential effects of riluzole treatment, the striata of the animals were stained by immunohistochemistry (IHC) and/or immunofluorescence (IF) with Ki67 (marker of proliferating cells), neuronal markers (NeuN, MAP2, DCX), and markers associated with neurodegeneration (GFAP, 8OHdG, FluoroJade C). Additionally, the morphology of dendritic spines of neurons was assessed by a commercially available FD Rapid Golgi Stain™ Kit.ResultsA comparative analysis of IHC staining patterns with chosen markers for the neurodegeneration process in MSNs did not show an effect of riluzole on delaying the progression of MSN cell death despite an observed enhancement of cell proliferation as visualized by the Ki67 marker. A lack of a riluzole effect was also reflected by the behavioral phenotype associated with MSN degeneration. Moreover, the analysis of dendritic spine morphology did not show differences between mutant and control animals.DiscussionDespite the observed increase in newborn cells in the subventricular zone (SVZ) after riluzole administration, our study did not show any differences between riluzole-treated and non-treated mutants, revealing a similar extent of the neurodegenerative phenotype evaluated in 13-week-old TIF-IAD1RCre animals. This could be due to either the treatment paradigm (relatively low dose of riluzole used for this study) or the possibility that the effects were simply too weak to have any functional meaning. Nevertheless, this study is in line with others that question the effectiveness of riluzole in animal models and raise concerns about the utility of this drug due to its rather modest clinical efficacy.

Leptin-dependent neurotoxicity via induction of apoptosis in adult rat neurogenic cells.

Adipocyte-derived hormone leptin has been recently implicated in the control of neuronal plasticity. To explore whether modulation of adult neurogenesis may contribute to leptin control of neuronal plasticity, we used the neurosphere assay of neural stem cells derived from the adult rat subventricular zone (SVZ). Endogenous expression of specific leptin receptor (ObRb) transcripts, as revealed by RT-PCR, is associated with activation of both ERK and STAT-3 pathways via phosphorylation of the critical ERK/STAT-3 amino acid residues upon addition of leptin to neurospheres. Furthermore, leptin triggered withdrawal of neural stem cells from the cell cycle as monitored by Ki67 labeling. This effect was blocked by pharmacological inhibition of ERK activation thus demonstrating that ERK mediates leptin effects on neural stem cell expansion. Leptin-dependent withdrawal of neural stem cells from the cell cycle was associated with increased apoptosis, as detected by TUNEL, which was preceded by cyclin D1 induction. Cyclin D1 was indeed extensively colocalized with TUNEL-positive, apoptotic nuclei. Cyclin-D1 silencing by specific shRNA prevented leptin-induced decrease of the cell number per neurosphere thus pointing to the causal relationship between leptin actions on apoptosis and cyclin D1 induction. Leptin target cells in SVZ neurospheres were identified by double TUNEL/phenotypic marker immunocytofluorescence as differentiating neurons mostly. The inhibition of neural stem cell expansion via ERK/cyclin D1-triggered apoptosis defines novel biological action of leptin which may be involved in adiposity-dependent neurotoxicity.

Long-term treatment with l-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease

Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior.We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.

Activation of Type 1 Cannabinoid Receptor (CB1R) Promotes Neurogenesis in Murine Subventricular Zone Cell Cultures

The endocannabinoid system has been implicated in the modulation of adult neurogenesis. Here, we describe the effect of type 1 cannabinoid receptor (CB1R) activation on self-renewal, proliferation and neuronal differentiation in mouse neonatal subventricular zone (SVZ) stem/progenitor cell cultures. Expression of CB1R was detected in SVZ-derived immature cells (Nestin-positive), neurons and astrocytes. Stimulation of the CB1R by (R)-(+)-Methanandamide (R-m-AEA) increased self-renewal of SVZ cells, as assessed by counting the number of secondary neurospheres and the number of Sox2+/+ cell pairs, an effect blocked by Notch pathway inhibition. Moreover, R-m-AEA treatment for 48 h, increased proliferation as assessed by BrdU incorporation assay, an effect mediated by activation of MAPK-ERK and AKT pathways. Surprisingly, stimulation of CB1R by R-m-AEA also promoted neuronal differentiation (without affecting glial differentiation), at 7 days, as shown by counting the number of NeuN-positive neurons in the cultures. Moreover, by monitoring intracellular calcium concentrations ([Ca2+]i) in single cells following KCl and histamine stimuli, a method that allows the functional evaluation of neuronal differentiation, we observed an increase in neuronal-like cells. This proneurogenic effect was blocked when SVZ cells were co-incubated with R-m-AEA and the CB1R antagonist AM 251, for 7 days, thus indicating that this effect involves CB1R activation. In accordance with an effect on neuronal differentiation and maturation, R-m-AEA also increased neurite growth, as evaluated by quantifying and measuring the number of MAP2-positive processes. Taken together, these results demonstrate that CB1R activation induces proliferation, self-renewal and neuronal differentiation from mouse neonatal SVZ cell cultures.

The neuroprotective and neurogenic effects of neuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy induced by trimethyltin

The effects of intracerebroventricular administration of neuropeptide Y (NPY), which is believed to play an important role in neuroprotection against excitotoxicity and in the modulation of adult neurogenesis, were evaluated in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy represented by trimethyltin (TMT) intoxication. A single TMT injection (8 mg/kg) causes, in the rat brain, massive neuronal death, selectively involving pyramidal neurons, accompanied by glial activation and enhanced hippocampal neurogenesis. Our data indicate that intracerebroventricular administration of exogenous NPY (at the dose of 2 μg/2 μL, 4 days after TMT-administration), in adult rats, exerts a protective role in regard to TMT-induced hippocampal damage and a proliferative effect on the hippocampal neurogenic niche through the up-regulation of Bcl-2, Bcl2l1, Bdnf, Sox-2, NeuroD1, Noggin and Doublecortin genes, contributing to delineate more clearly the role of NPY in in vivo neurodegenerative processes.

Non-Coding RNAs Regulating Morphine Function: With Emphasis on the In vivo and In vitro Functions of miR-190

Non-coding RNAs (ncRNAs), especially microRNAs, are reported to be involved in a variety of biological processes, including several processes related to drug addiction. It has been suggested that the biological functions of opioids, one typical type of addictive drugs, are regulated by ncRNAs. In the current review, we examine a variety of mechanisms through which ncRNAs could regulate μ-opioid receptor (OPRM1) activities and thereby contribute to the development of opioid addiction. Using miR-23b as an example, we present the possible ways in which ncRNA-mediated regulation of OPRM1 expression could impact opioid addiction. Using miR-190 as an example, we demonstrate the critical roles played by ncRNAs in the signal cascade from receptor to systemic responses, including the possible modulation of adult neurogenesis and in vivo contextual memory. After discussing the possible targets of ncRNAs involved in the development of opioid addiction, we summarize the mechanisms underlying the interaction between ncRNAs and opioid addiction and present suggestions for further study.

MicroRNA - a contributor to age-associated neural stem cell dysfunction?

In the adult mammalian brain, new neurons are continuously generated from neural stem cells in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus [1]. Increasing evidence for the functional importance of adult-generated neurons in these regions for learning, complex behavior, and mood regulation, as well as a potential link of impaired adult neurogenesis to cognitive deficits in ageing and neurodegeneration have sparked great interest in the regulatory mechanisms underlying the coordinated generation of new functional neurons. Neurogenesis includes self-renewal and fate specification of neural stem cells, migration and maturation of young neurons, and functional integration of new neurons into the neural circuitry [1]. A large body of work has demonstrated that neurogenesis is regulated in a complex manner by the dynamic interplay of cell-extrinsic signals derived from the neurogenic “niche” and cell-intrinsic transcriptional and epigenetic regulators. More recently, microRNAs (miRNAs) have emerged as potent modulators of adult neurogenesis. miRNA 132 has been linked to the maturation and functional integration of newly generated hippocampal neurons and – in this context – is potentially regulated by hippocampal network activity and CREB-signalling [2]. Several miRNAs have also been implied in controlling the balance of stem cell maintenance and differentiation - a crucial checkpoint for sustaining adult neurogenesis throughout adulthood. In this context, miRNA-137 [3] and miRNA-184 [4] have been found to promote stem cell maintenance at the expense of differentiation, while miRNA-9 [5], miRNA lethal-7b (let-7b) [6, 7], and miRNA-124 [8] tip the balance from stem cell maintenance towards differentiation through the negative regulation of cyclin D1 and the stem cell maintenance factors TLX, Hmga2, and Sox9. Intriguingly, the latter factors are transcriptional regulators and thus are likely to control the expression of larger sets of genes, which may explain the profound effects of those miRNAs in stem cell maintenance and differentiation. In the February issue of Aging Brett and colleagues link the microRNA cluster miR-106b~25 to neural stem cell expansion and neuronal differentiation [9]. In this work, they demonstrate that miR-106b~25 promotes proliferation in primary neural stem cell cultures. Moreover they report that overexpression of miR-106b~25 enhances neural stem cell differentiation toward the neuronal lineage. Although the in vitro modulatory effects of miRNA-106b~25 on neural stem cell behaviour are relatively modest, the authors made several notable observations that imply this miRNA cluster as a critical regulator of adult neurogenesis and warrant further investigation of its function and regulation: Firstly, in silico predictions suggest that miRNA-25 may be involved in the modulation of transforming growth factor β (TGFβ)/bone morphogenic protein (BMP) and insulin/IGF signalling, i.e., signalling pathways that control neural stem cell quiescence, proliferation, and fate as well as age-related stem cell dysfunction in other organs. Secondly, the authors identify a functional FoxO3 binding site near the promoter for miR-106b~25, which modulates the activity of the miRNA cluster. Recent work identified FoxO transcription factors as crucial regulators of stem cell maintenance in the hematopoietic and the adult central nervous system, whose loss results in premature depletion of the stem cell pool. Notably, FoxO transcription factor-dependent pathways control ageing and longevity in C.elegans and Drosophila melanogaster and certain FoxO3 gene variants are associated with increased lifespan in people [10]. Hence, the miRNA-106b~25 cluster may emerge as an important modulator of ageing in neural stem cells and the neurogenic niches. The in vivo function of miRNA-106b~25 in neural stem cell behaviour and neurogenesis has to be determined and it will be particularly interesting to determine the impact of ageing on the activity of the miRNA-106b~25 cluster in neural stem cells and their progeny. Moreover, it will be important to understand if and how the miRNA-106b~25 cluster is controlled by signals derived from the neurogenic environment, given the evidence that major shifts in pathway activities contribute to stem cell dysfunction during ageing. In the long run, determining functional targets of miRNA-106b~25 in the adult neurogenic lineage may reveal novel pathways in the control of neurogenesis, which may be harnessed for treatment of age-associated cognitive deficits.

P166 Modulation of adult neurogenesis in the olfactory bulb in an acute mouse model of Parkinson’s disease

P166 Modulation of adult neurogenesis in the olfactory bulb in an acute mouse model of Parkinson’s disease

Aspartate racemase, generating neuronal D-aspartate, regulates adult neurogenesis

D-aspartic acid is abundant in the developing brain. We have identified and cloned mammalian aspartate racemase (DR), which converts L-aspartate to D-aspartate and colocalizes with D-aspartate in the brain and neuroendocrine tissues. Depletion of DR by retrovirus-mediated expression of short-hairpin RNA in newborn neurons of the adult hippocampus elicits profound defects in the dendritic development and survival of newborn neurons and survival. Because D-aspartate is a potential endogenous ligand for NMDA receptors, the loss of which elicits a phenotype resembling DR depletion, D-aspartate may function as a modulator of adult neurogenesis.

Subventricular zone microglia possess a unique capacity for massive in vitro expansion

Microglia, the resident immune cells of the brain, have recently been hypothesized to play a role both in neuronal diseases and age-related neurogenic decline, and are theorized to be modulators of adult neurogenesis. Current methods for the isolation of microglia from cultured primary brain tissue result in relatively poor yield, requiring a large tissue sample or multiple specimens to obtain a sufficient number of microglia for cell and molecular analysis. We report here a method for the repetitive isolation of microglia from established glial monolayer cultures from which it is possible to expand the initial population of microglia roughly 10,000-fold. The expanded population expresses appropriate microglial morphology and phenotype markers, and demonstrates functionally normal phagocytosis, thus providing a high-yield assay for the investigation and analysis of microglia from a single initial dissection of primary tissue. Furthermore, this massive expansion is limited to microglia derived from the subventricular zone as the fold expansion of isolatable microglia was found to be up to 20 times greater than cultures from other brain regions, indicating unique properties for this persistently neurogenic region.

Noninvasive and Quantitative Monitoring of Adult Neuronal Stem Cell Migration in Mouse Brain Using Bioluminescence Imaging

It is now generally accepted that continuous neurogenesis occurs in the adult mammalian brain, including that of humans. Modulation of adult neurogenesis can provide therapeutic benefits for various brain disorders, including stroke and Parkinson's disease. The subventricular zone-olfactory bulb pathway is one of the preferred model systems by which to study neural stem cell proliferation, migration, and differentiation in adult rodent brain. Research on adult neurogenesis would greatly benefit from reliable methods for long-term noninvasive in vivo monitoring. We have used lentiviral vectors encoding firefly luciferase to stably mark endogenous neural stem cells in the mouse subventricular zone. We show that bioluminescence imaging (BLI) allows quantitative follow-up of the migration of adult neural stem cells into the olfactory bulb in time. Moreover, we propose a model to fit the kinetic data that allows estimation of migration and survival times of the neural stem cells using in vivo BLI. Long-term expression of brain-derived neurotrophic factor in the subventricular zone attenuated neurogenesis, as detected by histology and BLI. In vivo monitoring of the impact of drugs or genes on adult neurogenesis is now within reach.

Lentiviral Vectors Mediate Efficient and Stable Gene Transfer in Adult Neural Stem CellsIn Vivo

Modulation of adult neurogenesis may offer new therapeutic strategies for various brain disorders. In the adult mammalian brain the subventricular zone (SVZ) of the lateral ventricle is a region of continuous neurogenesis. Lentiviral vectors stably integrate into dividing and nondividing cells, in contrast to retroviral vectors, which integrate only into dividing cells. We compared their potential for gene transfer into both quiescent and slowly dividing stem cells as well as into more rapidly dividing progenitor cells. In contrast to retroviral vectors, stereotactic injection of lentiviral vectors into the SVZ of adult mice resulted in efficient and long-term marker gene expression in cells with characteristics of both immature type B cells and migrating precursor cells. After migration along the rostral migratory stream and differentiation, the number of enhanced green fluorescent protein (eGFP)-expressing granular and periglomerular interneurons increased over time in the ipsilateral olfactory bulb. Moreover, the number of eGFP-labeled neuronal progenitor cells in the SVZ increased over time. By intraventricular injection of lentiviral vectors we could restrict gene transfer to ependymal cells and type B astroglial-like stem cells. In conclusion, lentiviral vectors surpass retroviral vectors in efficient long-term in vivo marking of subventricular zone stem cells for basic research and therapeutic applications.