Enhancement Of Hippocampal Neurogenesis Research Articles

Tenuigenin ameliorates cognitive dysfunction in Alzheimer’s disease via hippocampal neurogenesis enhancement

A promising strategy for treating Alzheimer’s disease (AD) is hippocampal neurogenesis enhancement. Tenuigenin (TEN) is a bioactive compound extracted from Polygala tenuifolia that is widely used for treating amnesia in Chinese medicine. However, whether TEN is effective in treating AD through hippocampal neurogenesis is not fully clear. This study aimed to explore the pharmacologic effect and underlying mechanism of TEN on hippocampal neurogenesis and cognitive deficit amelioration in AD. In an in vivo study, TEN administration significantly ameliorated the cognitive decline in APP/PS1 transgenic AD mice via enhancement of hippocampal neurogenesis, which might be attributed to activation of the GSK-3β/β-catenin pathway. Furthermore, an in silico study suggested that TEN might be directly targeted to GSK-3β. Overall, TEN enhanced hippocampal neurogenesis and consequently ameliorated cognitive deficits via GSK-3β/β-catenin pathway activation, indicating that TEN might be a promising novel agent for AD treatment. • Tenuigenin ameliorates cognitive dysfunction in mouse model of Alzheimer’s disease. • Tenuigenin promotes hippocampal neurogenesis. • Tenuigenin shows potential GSK-3β inhibitory activity.

Moderate, intermittent voluntary exercise in a model of Gulf War Illness improves cognitive and mood function with alleviation of activated microglia and astrocytes, and enhanced neurogenesis in the hippocampus

Persistent cognitive and mood impairments in Gulf War Illness (GWI) are associated with chronic neuroinflammation, typified by hypertrophied astrocytes, activated microglia, and increased proinflammatory mediators in the brain. Using a rat model, we investigated whether a simple lifestyle change such as moderate voluntary physical exercise would improve cognitive and mood function in GWI. Because veterans with GWI exhibit fatigue and post-exertional malaise, we employed an intermittent voluntary running exercise (RE) regimen, which prevented exercise-induced stress. The GWI rats were provided access to running wheels three days per week for 13 weeks, commencing ten weeks after the exposure to GWI-related chemicals and stress (GWI-RE group). Groups of age-matched sedentary GWI rats (GWI-SED group) and naïve rats were maintained parallelly. Interrogation of rats with behavioral tests after the 13-week RE regimen revealed improved hippocampus-dependent object location memory and pattern separation function and reduced anxiety-like behavior in the GWI-RE group compared to the GWI-SED group. Moreover, 13 weeks of RE in GWI rats significantly reversed activated microglia with short and less ramified processes into non-inflammatory/antiinflammatory microglia with highly ramified processes and reduced the hypertrophy of astrocytes. Moreover, the production of new neurons in the hippocampus was enhanced when examined eight weeks after the commencement of RE. Notably, increased neurogenesis continued even after the cessation of RE. Collectively, the results suggest that even a moderate, intermittent physical exercise has the promise to improve brain function in veterans with GWI in association with suppression of neuroinflammation and enhancement of hippocampal neurogenesis.

Antidementia effects of Enterococcus faecalis 2001 are associated with enhancement of hippocampal neurogenesis via the ERK-CREB-BDNF pathway in olfactory bulbectomized mice

Our previous study showed that Enterococcus faecalis 2001 (EF-2001) suppresses colitis-induced depressive-like behavior through the enhancement of hippocampal neurogenesis in mice. In the present study, we investigated the effect of EF-2001 on the cognitive behavior of olfactory bulbectomized (OBX) mice and its molecular mechanisms. The OBX-induced cognitive dysfunction was significantly suppressed by EF-2001. Moreover, EF-2001 also recovered the reductions in p-ERK1/2, p-CREB, BDNF and DCX levels and in neurogenesis observed in the hippocampus of OBX mice. These results suggest that EF-2001-induced antidementia effects are associated with enhanced hippocampal neurogenesis through the ERK-CREB-BDNF pathway.

Treadmill running attenuates neonatal hypoxia induced adult depressive symptoms and promoted hippocampal neural stem cell differentiation via modulating AMPK-mediated mitochondrial functions

Neonatal hypoxia can induce the persisting brain dysfunctions and subsequently result in the behavioral abnormalities in adulthood. Improving mitochondrial functions were suggested as the effective strategy for brain functional recovery. In this study, we tested the effects of physical exercise, a well-established way benefits mitochondrion, for its functions to prevent hypoxia induced adult behavioral dysfunctions and the underlying molecular mechanism. Mice was induced with hypoxia and treadmill running were then administrated until the adulthood. The treadmill running resulted in the improved behavioral performance in depressive and anxiety tests together with the enhancement of hippocampal neurogenesis. We then detected treadmill running restored the mitochondrial morphology in adult neural stem cells (NSCs) as well as the ATP production in hippocampal tissue. In addition, activity of AMPK, which playing key roles in regulating mitochondrial functions, was also elevated by treadmill running. Blockage of AMPK with selective inhibitor compound C prohibited effects of treadmill running in attenuating neonatal hypoxia induced neurogenic impairment and antidepressant behavioral deficits in adulthood. In conclusion, treadmill running could prevent neonatal hypoxia induced adult antidepressant dysfunctions and neurogenic dampening via AMPK-mediated mitochondrial regulation.

Trajectories of brain remodeling in temporal lobe epilepsy.

Temporal lobe epilepsy has been usually associated with progressive brain atrophy due to neuronal cell loss. However, recent animal models demonstrated a dual effect of epileptic seizures with initial enhancement of hippocampal neurogenesis followed by abnormal astrocyte proliferation and neurogenesis depletion in the chronic stage. Our aim was to test for the hypothesized bidirectional pattern of epilepsy-associated brain remodeling in the context of the presence and absence of mesial temporal lobe sclerosis. We acquired MRIs from a large cohort of mesial temporal lobe epilepsy patients with or without hippocampus sclerosis on radiological examination. The statistical analysis tested explicitly for common and differential brain patterns between the two patients' cohorts and healthy controls within the computational anatomy framework of voxel-based morphometry. The main effect of disease was associated with continuous hippocampus volume loss ipsilateral to the seizure onset zone in both temporal lobe epilepsy cohorts. The post hoc simple effects tests demonstrated bilateral hippocampus volume increase in the early epilepsy stages in patients without hippocampus sclerosis. Early age of onset and longer disease duration correlated with volume decrease in the ipsilateral hippocampus. Our findings of seizure-induced hippocampal remodeling are associated with specific patterns of mesial temporal lobe atrophy that are modulated by individual clinical phenotype features. Directionality of hippocampus volume changes strongly depends on the chronicity of disease. Specific anatomy differences represent a snapshot within a progressive continuum of seizure-induced structural remodeling.

Abolition of aberrant neurogenesis ameliorates cognitive impairment after stroke in mice

Poststroke cognitive impairment is considered one of the main complications during the chronic phase of ischemic stroke. In the adult brain, the hippocampus regulates both encoding and retrieval of new information through adult neurogenesis. Nevertheless, the lack of predictive models and studies based on the forgetting processes hinders the understanding of memory alterations after stroke. Our aim was to explore whether poststroke neurogenesis participates in the development of long-term memory impairment. Here, we show a hippocampal neurogenesis burst that persisted 1 month after stroke and that correlated with an impaired contextual and spatial memory performance. Furthermore, we demonstrate that the enhancement of hippocampal neurogenesis after stroke by physical activity or memantine treatment weakened existing memories. More importantly, stroke-induced newborn neurons promoted an aberrant hippocampal circuitry remodeling with differential features at ipsi- and contralesional levels. Strikingly, inhibition of stroke-induced hippocampal neurogenesis by temozolomide treatment or using a genetic approach (Nestin-CreERT2/NSE-DTA mice) impeded the forgetting of old memories. These results suggest that hippocampal neurogenesis modulation could be considered as a potential approach for treatment of poststroke cognitive impairment.

Memantine produces antidepressant effect through the enhancement of hippocampal neurogenesis in olfactory bulbectomized mice

The work is concerned with this issue of multiple delay-dependent finite-time fault-tolerant control (FTC) for uncertain switched Takagi-Sugeno (T-S) fuzzy systems against state and input constraints. There exist intermittent faults (IFs), exogenous disturbances along with measurement noise in the models. There are few attempts for this theme. A nonlinear dynamic output feedback controller is explored for these uncertain switched T-S fuzzy systems first. And an augmented system with respect to realizing FTC is acquired. Moreover, sufficient conditions of robust finite-time H∞ control are constructed by piecewise fuzzy Lyapunov function. At the same time, finite-time boundedness (FTB) as well as input-output finite-time stability (IO-FTS) is achieved. The effectiveness as well as feasibility of this approach is verified through an example.

Functional and Structural Benefits Induced by Omega-3 Polyunsaturated Fatty Acids During Aging

BackgroundOmega-3 polyunsaturated fatty acids (n-3 PUFA) are structural components of the brain and are indispensable for neuronal membrane synthesis. Along with decline in cognition, decreased synaptic density and neuronal loss, normal aging is accompanied by a reduction in n-3 PUFA concentration in the brain in both humans and rodents. Recently, many clinical and experimental studies have demonstrated the importance of n-3 PUFA in counteracting neurodegeneration and age-related dysfunctions.MethodsMethods: This review will focus on the neuroprotective effects of n-3 PUFA on cognitive impairment, neuroinflammation and neurodegeneration during normal aging. Multiple pathways of n-3 PUFA preventive action will be examined.ResultsNamely, n-3 PUFA have been shown to increase the levels of several signaling factors involved in synaptic plasticity, thus leading to the increase of dendritic spines and synapses as well as the enhancement of hippocampal neurogenesis even at old age. In elderly subjects n-3 PUFA exert anti-inflammatory effects associated with improved cognitive functions. Interestingly, growing evidence highlights n-3 PUFA efficacy in preventing the loss of both gray and white matter volume and integrity.ConclusionThis review shows that n-3 PUFA are essential for a successful aging and appear as ideal cognitive enhancers to be implemented in nutritional interventions for the promotion of healthy aging.

Multiparity-induced enhancement of hippocampal neurogenesis and spatial memory depends on ovarian hormone status in middle age

Menopause is associated with cognitive decline, and previous parity can increase or delay the trajectory of cognitive aging. Furthermore, parity enables the hippocampus to respond to estrogens in middle age. The present study investigated how previous parity and estrogens influence cognition, neurogenesis, and neuronal activation in response to memory retrieval in the hippocampus of middle-aged females. Multiparous and nulliparous rats were ovariectomized (OVX) or received sham surgery and were treated with vehicle, 17β-estradiol, 17α-estradiol, or estrone. Rats were trained on the spatial working and reference memory versions of the Morris water maze. Multiparous rats had a significantly greater density of immature neurons in the hippocampus, enhanced acquisition of working memory, but poorer reference memory compared with nulliparous rats. Furthermore, OVX increased, while treatment with estrogens reduced, the density of immature neurons, regardless of parity. OVX improved reference memory only in nulliparous rats. Thus, motherhood has long-lasting effects on the neuroplasticity and function of the hippocampus. These findings have wide-ranging implications for the treatment of age-associated decline in women.

Fat cell-secreted adiponectin mediates physical exercise-induced hippocampal neurogenesis: an alternative anti-depressive treatment?

Psychological depression is drawing accumulating attention nowadays, due to the skyrocketing incidence worldwide and the enormous burdens it incurs. Physical exercise has been long recognized for its therapeutic effects on depressive disorders, although knowledge of the underlying mechanisms remains limited. Suppressed hippocampal neurogenesis in adult brains has been regarded, at least partly, contributive to depression, whereas physical exercise that restores neurogenesis accordingly exerts the anti-depressive action. Several recent publications have suggested the potential role of adiponectin, a protein hormone secreted by peripheral mature adipocytes, in mediating physical exercise-triggered enhancement of hippocampal neurogenesis and alleviation of depression. Here, we briefly review these novel findings and discuss the possibility of counteracting depression by modulating adiponectin signaling in the hippocampus with interventions including physical exercise and administration of pharmacological agents.

Ghrelin is required for dietary restriction-induced enhancement of hippocampal neurogenesis: lessons from ghrelin knockout mice.

Neurogenesis occurs in the adult hippocampus and is enhanced by dietary restriction (DR), and neurogenesis enhancement is paralleled by circulating ghrelin level enhancement. We have previously reported that ghrelin modulates adult neurogenesis in the hippocampus. In order to investigate the possible role of ghrelin in DR-induced hippocampal neurogenesis in adult mice, ghrelin knockout (GKO) mice and wild-type (WT) mice were maintained for 3 months on DR or ad libitum (AL) diets. Protein levels of ghrelin in the stomach and the hippocampus were increased by DR in WT mice. One day after BrdU administration, the number of BrdU-labeled cells in the hippocampal dentate gyrus was decreased in GKO mice maintained on the AL diet. DR failed to alter the proliferation of progenitor cells in both WT and GKO mice. Four weeks after BrdU injection, the number of surviving cells in the dentate gyrus was decreased in AL-fed GKO mice. DR increased survival of newborn cells in WT mice, but not in GKO mice. Levels of brain-derived neurotrophic factor protein in the hippocampus were similar between WT and GKO mice, and were increased by DR both in WT and GKO mice. These results suggest that elevated levels of ghrelin during DR may have an important role in the enhancement of neurogenesis induced by DR.

Intravenous immunoglobulin for Alzheimer's disease.

The foundation for using intravenous immunoglobulin (IVIg) to treat Alzheimer's disease (AD) can be traced back to the discovery, in the early 1990s, of naturally occurring anti-amyloid antibodies in human blood. A decade later, a number of independent investigators reported reduced levels of naturally occurring anti-amyloid antibodies in the spinal fluid and blood of AD patients relative to age-matched controls 1–3. Dodel subsequently reported that IVIg contained elevated levels of antibodies against amyloid-β (Aβ) monomers and proposed its use as a potential treatment for AD 4.

Epigenetic Modulation of Adult Hippocampal Neurogenesis by Extremely Low-Frequency Electromagnetic Fields

Throughout life, adult neurogenesis generates new neurons in the dentate gyrus of hippocampus that have a critical role in memory formation. Strategies able to stimulate this endogenous process have raised considerable interest because of their potential use to treat neurological disorders entailing cognitive impairment. We previously reported that mice exposed to extremely low-frequency electromagnetic fields (ELFEFs) showed increased hippocampal neurogenesis. Here, we demonstrate that the ELFEF-dependent enhancement of hippocampal neurogenesis improves spatial learning and memory. To gain insights on the molecular mechanisms underlying ELFEFs' effects, we extended our studies to an in vitro model of neural stem cells (NSCs) isolated from the hippocampi of newborn mice. We found that ELFEFs enhanced proliferation and neuronal differentiation of hippocampal NSCs by regulation of epigenetic mechanisms leading to pro-neuronal gene expression. Upon ELFEF stimulation of NSCs, we observed a significant enhancement of expression of the pro-proliferative gene hairy enhancer of split 1 and the neuronal determination genes NeuroD1 and Neurogenin1. These events were preceded by increased acetylation of H3K9 and binding of the phosphorylated transcription factor cAMP response element-binding protein (CREB) on the regulatory sequence of these genes. Such ELFEF-dependent epigenetic modifications were prevented by the Cav1-channel blocker nifedipine, and were associated with increased occupancy of CREB-binding protein (CBP) to the same loci within the analyzed promoters. Our results unravel the molecular mechanisms underlying the ELFEFs' ability to improve endogenous neurogenesis, pointing to histone acetylation-related chromatin remodeling as a critical determinant. These findings could pave the way to the development of novel therapeutic approaches in regenerative medicine.

Mild exercise model for enhancement of hippocampal neurogenesis: A possible candidate for promotion of neurogenesis

Mild exercise model for enhancement of hippocampal neurogenesis: A possible candidate for promotion of neurogenesis

Involvement of progranulin in the enhancement of hippocampal neurogenesis by voluntary exercise

We have previously suggested that progranulin mediates the stimulatory effects of estrogen on adult neurogenesis in the hippocampus. Neurogenesis in mature animals is enhanced by growth factors, environmental enrichment, and voluntary exercise. In this study, we investigated the role of progranulin in voluntary running-induced hippocampal neurogenesis. In the hippocampus of wild-type mice, the pyramidal neurons in the CA1 and CA3 regions and interneurons in the hilus were mainly immunoreactive for progranulin, and wheel running increased progranulin expression in these neurons. Wheel running also increased the number of proliferating cells in the hippocampus in wild-type mice, but not in progranulin-deficient mice. These results suggest that progranulin plays an indispensable role in enhancing the hippocampal neurogenesis induced by voluntary exercise.

The thyroid hormone, triiodothyronine, enhances fluoxetine-induced neurogenesis in rats: possible role in antidepressant-augmenting properties

The thyroid hormone triiodothyronine (T3) may accelerate and augment the action of antidepressants. Antidepressants up-regulate neurogenesis in adult rodent hippocampus. We studied the effect of T3 and T3+fluoxetine in enhancement of hippocampal neurogenesis beyond that induced by fluoxetine alone and the correlation with antidepressant behaviour in the novelty suppressed feeding test (NSFT). Rats were administered fluoxetine (5 mg/kg.d), T3 (50 mug/kg.d), fluoxetine (5 mg/kg.d)+T3 (50 mug/kg.d) or saline, for 21 d. Neurogenesis was studied by doublecortin (DCX) immunohistochemistry in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). In the NSFT, latency to feeding in animals deprived of food was measured. Fluoxetine and fluoxetine+T3 increased the number of doublecortin-positive (DCX+) cells in the SGZ compared to saline (p=0.00005, p=0.008, respectively). There was a trend towards an increased number of DCX+ cells by T3 compared to saline (p=0.06). Combined treatment with fluoxetine+T3 further increased the number of DCX+ cells compared to T3 or fluoxetine alone (p=0.001, p=0.014, respectively). There was no effect of any of the treatments on number of DCX+ cells in the SVZ. In the NSFT, all treatments (T3, fluoxetine+T3 and fluoxetine) reduced latency to feeding compared to saline (p=0.0004, p=0.00001, p=0.00009, respectively). Fluoxetine+T3 further reduced latency to feeding compared to T3 alone (p=0.05). The results suggest that enhancement of antidepressant action by T3 may be related to its effect of increasing hippocampal neurogenesis and that the antidepressant effect of these treatments is specific to the hippocampus and does not represent a general effect on cell proliferation.

Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide

Pharmacological enhancement of hippocampal neurogenesis is a therapeutic approach for improvement of cognition in learning and memory disorders such as Alzheimer's disease. Here we report the development of an 11-mer peptide that we designed based on a biologically active region of the ciliary neurotrophic factor. This peptide, Peptide 6, induced proliferation and increased survival and maturation of neural progenitor cells into neurons in the dentate gyrus of normal adult C57BL6 mice. Furthermore, Peptide 6 increased the MAP2 and synaptophysin immunoreactivity in the dentate gyrus. Thirty-day treatment of the mice with a slow release bolus of the peptide implanted subcutaneously improved reference memory of the mice in Morris water maze. Peptide 6 has a plasma half life of over 6 h, is blood-brain barrier permeable, and acts by competitively inhibiting the leukemia inhibitory factor signaling. The fact that Peptide 6 is both neurogenic and neurotrophic and that this peptide is effective when given peripherally, demonstrates its potential for prevention and treatment of learning and memory disorders.

Calmodulin activation is required for the enhancement of hippocampal neurogenesis following environmental enrichment

Objective: An enriched environmental exposure has been shown to promote hippocampal neurogenesis, which is an important mechanism underlying enrichment-induced memory improvement. The cAMP response element-binding protein is an important stimulus-inducible factor in the brain and is crucial for neurogenesis and memory ability. Calmodulin activation is important for activity-induced cAMP response element-binding protein phosphorylation. The aim of this study was to explore the effects of calmodulin activation on hippocampal neurogenesis and spatial memory improvement in rats exposed to enriched environment.Methods: Ninety-six neonatal pups were assigned to four groups: control group, enriched environment group, control + trifluoperazine (trifluoperazine, 5 mg/kg) group and enriched environment + trifluoperazine group. Pups in the enriched environment and enriched environment + trifluoperazine groups were exposed to enriched environments for 25 min from P10 to P24. Half of pups in each group were intraperitoneally injected with 50 mg/kg BrdU every other day from P10 to P24. Pups without BrdU injection were euthanized at P24, and hippocampal nuclear Ca2+-calmodulin and phosphorylated cAMP response element-binding protein were detected. Morris water maze acquisition and subsequent probe trial retention were performed in remained rats after P50 and immunohistochemistry was used to identify proliferating cells in the dentate gyrus 1 day after the probe trial.Results: The trifluoperazine injection could completely inhibit the environmental enrichment-induced activations of calmodulin and cAMP response element-binding protein. Enriched environmental exposure could improve Morris water maze performance and increase hippocampal BrdU-labeled cells, but the effects could be completely blocked by trifluoperazine injection.Conclusion: This study proves that the activation of calmodulin is essential for an enriched environmental exposure-induced cAMP response element-binding protein activation, hippocampal neurogenesis and spatial memory improvement.

Age-dependent decline in hippocampal neurogenesis is not altered by chronic treatment with fluoxetine

There has been ongoing controversy as to whether selective serotonin reuptake inhibitors (SSRIs) exhibit the same antidepressant efficacy and risk profile within different age groups. Although the etiology of such potential differences is currently not clear, age-dependent differences in the rate of hippocampal neurogenesis offer one possibility. In the current studies we have therefore examined whether fluoxetine, the prototypical selective serotonin reuptake inhibitor, differentially modulates neurogenesis in adolescent, young adult, and aged rats. Proliferation in the dentate gyrus was measured by assaying expression of the endogenous proliferative marker, Ki67. Survival of proliferating cells was assayed by staining with BrdU. We confirmed previous reports that the rate of neurogenesis, as well as the survival of proliferating cells, decreases significantly with age. Moderate decreases were found in young adult rats relative to adolescent rats, and profound decreases were found in aged rats. We additionally found that age did not alter the response to 25 days of treatment with fluoxetine. In fact, we did not observe enhancement of hippocampal neurogenesis, nor enhancement of proliferating cell survival, in any of the three age groups despite using doses of fluoxetine which have been reported to be effective. In addition to finding no age-dependent effects, our data question the general reproducibility of previously reported fluoxetine effects in animals.

Endogenous opioids inhibit ischemia‐induced generation of immature hippocampal neurons via the µ‐opioid receptor

It is established that hippocampal neurogenesis is dynamically regulated by physiological and pathological stimuli including learning, environmental complexity, mental disorders and brain lesion. Little is known about factors regulating adaptive changes in neurogenesis. Using mu-opioid receptor (MOP)-knockout mice we addressed whether endogenous opioids influence ischemia-induced enhancement of hippocampal neurogenesis. Permanent middle cerebral artery occlusion (MCAO) produced similar corticostriatal infarcts in MOP-knockout and wildtype mice. Analyses of BrdU/doublecortin-colabelled cells in the granule cell layer 14 days after MCAO showed that ischemic knockouts contained more immature neurons generated during days 9-11 than wildtypes. After 29 days, similar quantities of BrdU/NeuN-labelled cells were found in ischemic knockout and wildtype mice, suggesting that granule cells that were formed in excess during days 9-11 in the knockouts were eliminated by day 29. Neurogenesis was similar in knockout and wildtype mice subjected to sham operation. In addition to a transient increase in neurogenesis, MCAO caused a transient up-regulation of preprodynorphin and preproenkephalin mRNA expression in the granule cell layer. Our findings suggest that activated signalling via endogenous opioids and the MOP limits the enhanced generation of neuronal cells after ischemic corticostriatal lesions.