Deficits In Hippocampal Neurogenesis Research Articles

Caffeic Acid Alleviates Memory and Hippocampal Neurogenesis Deficits in Aging Rats Induced by D-Galactose

Hippocampal neurogenesis occurs throughout life, but it declines with age. D-galactose (D-gal) enhances cellular senescence through oxidative stress leading to neurodegeneration and memory impairment. Caffeic acid (CA) acts as an antioxidant via decreasing brain oxidative stress. This study aims to investigate the advantages of CA in alleviating the loss of memory and neurogenesis production in the hippocampus in aged rats activated by D-gal. Fifty-four male Sprague-Dawley rats were unpredictably arranged into six groups. In the D-gal group, rats were administered D-gal (50 mg/kg) by intraperitoneal (i.p.) injection. For the CA groups, rats received 20 or 40 mg/kg CA by oral gavage. In the co-treated groups, rats received D-gal (50 mg/kg) and CA (20 or 40 mg/kg) for eight weeks. The results of novel object location (NOL) and novel object recognition (NOR) tests showed memory deficits. Moreover, a decline of neurogenesis in the hippocampus was detected in rats that received D-gal by detecting rat endothelial cell antigen-1 (RECA-1)/Ki-67, 5-bromo-2′-deoxyuridine (BrdU)/neuronal nuclear protein (NeuN), doublecortin (DCX) by means of staining to evaluate blood vessel associated proliferating cells, neuronal cell survival and premature neurons, respectively. By contrast, CA attenuated these effects. Our results postulate that CA attenuated the impairment of memory in D-gal-stimulated aging by up-regulating levels of hippocampal neurogenesis.

Eucommiae cortex polysaccharides mitigate obesogenic diet-induced cognitive and social dysfunction via modulation of gut microbiota and tryptophan metabolism.

Rationale: The high fat and sucrose diet, known as the obesogenic diet (OD), has been related to low-grade chronic inflammation and neurodevelopmental disorders. Emerging evidence suggests that OD influences cognitive and social function via the gut-brain axis. However, the effects of OD during adolescence on future health have been unclear. Meanwhile, the underlying mechanisms and effective interventions are not fully understood. Polysaccharides, one of the most abundant substances in the Eucommiae cortex, exhibit potential immunomodulatory and neuroprotective effects. Here, we aimed to investigate the impact of OD on adolescents, explore the modulating roles of Eucommiae cortex polysaccharides (EPs) on OD-induced behavioral dysfunction, and elucidate the underlying molecular mechanisms.Methods: In the present study, four-week-old mice were fed with OD for four weeks to simulate persistent OD in adolescents. The behavioral features were accessed by open field test and Morris water maze. The gut bacterial structure was identified by 16S rRNA gene amplicon sequencing. The gene and protein expression in colonic tissues and hippocampus were detected by qRT-PCR, immunoblotting, enzyme-linked immunosorbent assay, and immunofluorescence staining. Detection of biological metabolites in serum and hippocampal tissues was performed by widely targeted metabolomics and targeted metabolomics.Results: We found that OD-fed mice showed cognitive and social-behavioral deficits accompanied by gut dysbiosis and systematic tryptophan (Trp) metabolism disorders, which increased kynurenine (Kyn) concentration in the hippocampus. Bacteria-derived lipopolysaccharide (LPS, endotoxin) induced microglia-mediated neuroinflammation, directing the metabolism of Kyn in the hippocampus toward quinolinic acid (QA), which led to glutamate-mediated hyperactivation of mossy cells (MCs) in hippocampal hilus. Furthermore, OD impaired parvalbumin (PV) interneurons-related local circuits in the hippocampal granule cell layer. These resulted in hippocampal neurogenesis deficits and related behavioral dysfunction in mice. EPs supplementation ameliorated OD-induced gut dysbiosis, as evidenced by inhibiting the expansion of Escherichia coli (E.coli) and reducing the concentration of LPS in colonic contents and serum, thereby inhibiting the subsequent neuroinflammation. In addition, oral EPs suppressed the peripheral Kyn pathway to reduce the concentration of QA and glutamic acid in the hippocampus of OD-fed mice, thereby rescuing the glutamic acid-triggered neuroexcitotoxicity. These contributed to remodeling the rhythm of hippocampal neurogenesis and mitigated behavioral dysfunction in OD-fed mice.Conclusions: The present study addresses a gap in the understanding of neuronal dysfunction associated with OD during adolescence and provides the first evidence that EPs improved cognitive and social behavior via modulation of gut microbiota and tryptophan metabolism in adolescent mice fed with OD, which may represent novel preemptive therapy for neurodevelopmental disorders via manipulation of the tryptophan metabolite.

Effect of Heat Stress on Hippocampal Neurogenesis: Insights into the Cellular and Molecular Basis of Neuroinflammation-Induced Deficits.

Heat stress is known to result in neuroinflammation, neuronal damage, and disabilities in learning and memory in animals and humans. It has previously been reported that cognitive impairment caused by neuroinflammation may at least in part be mediated by defective hippocampal neurogenesis, and defective neurogenesis has been linked to aberrantly activated microglial cells. Moreover, the release of cytokines within the brain has been shown to contribute to the disruption of cognitive functions in several conditions following neuroinflammation. In this review, we summarize evolving evidence for the current understanding of inflammation-induced deficits in hippocampal neurogenesis, and the resulting behavioral impairments after heat stress. Furthermore, we provide valuable insights into the molecular and cellular mechanisms underlying neuroinflammation-induced deficits in hippocampal neurogenesis, particularly relating to cognitive dysfunction following heat stress. Lastly, we aim to identify potential mechanisms through which neuroinflammation induces cognitive dysfunction, and elucidate how neuroinflammation contributes to defective hippocampal neurogenesis. This review may therefore help to better understand the relationship between hippocampal neurogenesis and heat stress.

Postnatal Cytoarchitecture and Neurochemical Hippocampal Dysfunction in Down Syndrome.

Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volume, which are later associated with memory deficits, little is known about the effects of trisomy 21 on postnatal hippocampal cellular development in Down syndrome (DS). We examined postnatal hippocampal neuronal profiles from autopsies of DS and neurotypical (NTD) neonates born at 38-weeks’-gestation up to children 3 years of age using antibodies against non-phosphorylated (SMI-32) and phosphorylated (SMI-34) neurofilament, calbindin D-28k (Calb), calretinin (Calr), parvalbumin (Parv), doublecortin (DCX) and Ki-67, as well as amyloid precursor protein (APP), amyloid beta (Aβ) and phosphorylated tau (p-tau). Although the distribution of SMI-32-immunoreactive (-ir) hippocampal neurons was similar at all ages in both groups, pyramidal cell apical and basal dendrites were intensely stained in NTD cases. A greater reduction in the number of DCX-ir cells was observed in the hippocampal granule cell layer in DS. Although the distribution of Calb-ir neurons was similar between the youngest and oldest NTD and DS cases, Parv-ir was not detected. Conversely, Calr-ir cells and fibers were observed at all ages in DS, while NTD cases displayed mainly Calr-ir fibers. Hippocampal APP/Aβ-ir diffuse-like plaques were seen in DS and NTD. By contrast, no Aβ1–42 or p-tau profiles were observed. These findings suggest that deficits in hippocampal neurogenesis and pyramidal cell maturation and increased Calr immunoreactivity during early postnatal life contribute to cognitive impairment in DS.

Knockdown of long non-coding RNA SOX2OT downregulates SOX2 to improve hippocampal neurogenesis and cognitive function in a mouse model of sepsis-associated encephalopathy

BackgroundAberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy. In the current study, we examined the potential role of the long noncoding RNA (lncRNA) sex-determining region Y-box 2 (SOX2) overlapping transcript (SOX2OT), a known regulator of adult neurogenesis in sepsis-induced deficits in hippocampal neurogenesis and cognitive function.MethodsSepsis was induced in adult C57BL/6 J male mice by cecal ligation and perforation (CLP) surgery. Randomly selected CLP mice were transfected with short interfering RNAs (siRNAs) against SOX2OT or SOX2, or with scrambled control siRNA. Cognitive behavior was tested 8–12 days post-surgery using a Morris water maze. Western blotting and RT-qPCR were used to determine expression of SOX2, Ki67, doublecortin (DCX), nestin, brain lipid-binding protein, and glial fibrillary acidic protein (GFAP) in the hippocampus. The number of bromodeoxyuridine (BrdU)+/DCX+ cells, BrdU+/neuronal nuclei (NeuN)+ neurons, and BrdU+/GFAP+ glial cells in the dentate gyrus were assessed by immunofluorescence.ResultsCLP mice showed progressive increases in SOX2OT and SOX2 mRNA levels on days 3, 7, and 14 after CLP surgery, accompanied by impaired cognitive function. Sepsis led to decrease in all neuronal markers in the hippocampus, except GFAP. Immunofluorescence confirmed the decreased numbers of BrdU+/DCX+ cells and BrdU+/NeuN+ neurons, and increased numbers of BrdU+/GFAP+ cells. SOX2OT knockdown partially inhibited the effects of CLP on levels of SOX2 and neuronal markers, neuronal populations in the hippocampus, and cognitive function. SOX2 deficiency recapitulated the effects of SOX2OT knockdown.ConclusionSOX2OT knockdown improves sepsis-induced deficits in hippocampal neurogenesis and cognitive function by downregulating SOX2 in mice. Inhibiting SOX2OT/SOX2 signaling may be effective for treating or preventing neurodegeneration in sepsis-associated encephalopathy.

Deltamethrin Exposure Inhibits Adult Hippocampal Neurogenesis and Causes Deficits in Learning and Memory in Mice.

Deficits in learning and memory are often associated with disruption of hippocampal neurogenesis, which is regulated by numerous processes, including precursor cell proliferation, survival, migration, and differentiation to mature neurons. Recent studies demonstrate that adult born neurons in the dentate gyrus (DG) in the hippocampus can functionally integrate into the existing neuronal circuitry and contribute to hippocampal-dependent learning and memory. Here, we demonstrate that relatively short-term deltamethrin exposure (3 mg/kg every 3 days for 1 month) inhibits adult hippocampal neurogenesis and causes deficits in learning and memory in mice. Hippocampal-dependent cognitive functions were evaluated using 2 independent hippocampal-dependent behavioral tests, the novel object recognition task and Morris water maze. We found that deltamethrin-treated mice exhibited profound deficits in novel object recognition and learning and memory in water maze. Deltamethrin exposure significantly decreased bromodeoxyuridine (BrdU)-positive cells (39%) and Ki67+ cells (47%) in the DG of the hippocampus, indicating decreased cellular proliferation. In addition, deltamethrin-treated mice exhibited a 44% decrease in nestin-expressing neural progenitor cells and a 38% reduction in the expression of doublecortin (DCX), an early neuronal differentiation marker. Furthermore, deltamethrin-exposed mice exhibited a 25% reduction in total number of granule cells in the DG. These findings indicate that relatively short-term exposure to deltamethrin causes significant deficits in hippocampal neurogenesis that is associated with impaired learning and memory.

CXCR5 Knockdown Attenuates Hippocampal Neurogenesis Deficits and Cognitive Impairment in a Mouse Model of Sepsis-associated Encephalopathy

In this study, we investigated the potential role of C-X-C chemokine receptor type (CXCR) 5 in neurocognitive function in a mouse model of sepsis-associated encephalopathy (SAE). Adult male C57BL/6J mice received intracerebroventricular injections of small interfering RNAs (siRNAs) against CXCR5 or scrambled control siRNA. After 3 days, SAE was induced by cecal ligation and puncture (CLP, n = 16 per group). Memory and learning ability were tested using the Morris water maze (MWM) on days 5–9 after CLP. Hippocampal expression of CXCR5, interleukin (IL)-1β and IL-6 were measured by western blot. Cell proliferation and the numbers of immature and mature neurons in the dentate gyrus were assessed by immunohistochemistry. CLP mice had deficits in memory and learning, as shown by increased latency in the MWM training sessions and decreased time spent in and crossing the target quadrant on day 9. CLP also increased the number of proliferating and immature neurons and decreased the number of mature neurons. This was accompanied by increased expression of CXCR5, IL-1β and IL-6 in the hippocampus. CXCR5 knockdown attenuated the memory and learning deficits induced by CLP and partially reversed the effects of CLP on numbers of proliferating, immature and mature neurons, and on expression of IL-1β and IL-6 in the hippocampus. These results suggest that CXCR5 knockdown can attenuate sepsis-induced deficits in hippocampal neurogenesis and cognitive function in mice with SAE.

Dexmedetomidine attenuates ethanol-induced inhibition of hippocampal neurogenesis in neonatal mice

Background/AimsEthanol (EtOH) exposure during a period comparable to the third trimester in human results in obvious neurotoxicity in the developing hippocampus and persistent deficits in hippocampal neurogenesis. Dexmedetomidine (DEX), a highly selective α-2-adrenergic agonist has been demonstrated to restore the impaired neurogenesis and neuronal plasticity in the dentate gyrus (DG) that follows neurological insult. However, the protective roles of DEX in the EtOH-induced deficits of postnatal neurogenesis in the hippocampus are still unknown. MethodsMice were pretreated with DEX prior to EtOH exposure to determine its protective effects on impaired postnatal hippocampal neurogenesis. Six-day-old neonatal mice were treated with DEX (125 μg/kg) or saline, followed by EtOH at a total of 5 g/kg or an equivalent volume of saline on P7. Immunohistochemistry and immunofluorescence were used to evaluate the neurogenesis and activated microglia in the DG. Quantitative real time PCR (qRT-PCR) was utilized to assess the expression of inflammatory factors in the hippocampus. ResultsDEX pretreatment attenuated the inhibition of EtOH-mediated hippocampal neurogenesis and the reduction of hippocampal neural precursor cells (NPCs). We further confirmed that DEX pretreatment reversed the EtOH-induced microglia activation in the DG as well as the upregulation of the hippocampal TNFα, MCP-1, IL-6, and IL-1β mRNA levels. ConclusionOur findings indicate that DEX pretreatment protects against EtOH-mediated inhibition of hippocampal neurogenesis in postnatal mice and reverses EtOH-induced neuroinflammation via repressing microglia activation and the expression of inflammatory cytokines.

Cell-extrinsic requirement for sulfate in regulating hippocampal neurogenesis.

ABSTRACTSulfate is a key anion required for a range of physiological functions within the brain. These include sulfonation of extracellular proteoglycans to facilitate local growth factor binding and to regulate the shape of morphogen gradients during development. We have previously shown that mice lacking one allele of the sulfate transporter Slc13a4 exhibit reduced sulfate transport into the brain, deficits in social behaviour, reduced performance in learning and memory tasks, and abnormal neurogenesis within the ventricular/subventricular zone lining the lateral ventricles. However, whether these mice have deficits in hippocampal neurogenesis was not addressed. Here, we demonstrate that adult Slc13a4+/− mice have increased neurogenesis within the subgranular zone (SGZ) of the hippocampal dentate gyrus, with elevated numbers of neural progenitor cells and intermediate progenitors. In contrast, by 12 months of age there were reduced numbers of neural stem cells in the SGZ of heterozygous mice. Importantly, we did not observe any changes in proliferation when we isolated and cultured progenitors in vitro in neurosphere assays, suggestive of a cell-extrinsic requirement for sulfate in regulating hippocampal neurogenesis. Collectively, these data demonstrate a requirement for sulfate transport during postnatal brain development to ensure normal adult hippocampal neurogenesis.

Chronic Circadian Misalignment without Circadian Arrhythmicity or Sleep Deprivation Does Not Impair Adult Hippocampal Neurogenesis.

Artificial light in modern society has led to the ubiquity of light exposure at night as individuals work night shifts and use light-emitting electronic devices before bedtime. These aberrant light conditions have detrimental consequences on cognitive and mental health, compelling the need to understand the mechanisms by which light affects brain functions. Although it was believed that aberrant light impairs health by first disrupting circadian rhythms and sleep, we showed that chronic exposure to a light cycle termed T7 (3.5 h of darkness, 3.5 h of light) caused mood and learning dysfunction in adult mice independent of sleep deprivation or circadian arrhythmicity, suggesting the direct effects of aberrant light on brain function. However, the mechanisms by which light directly causes mood and learning dysfunction remain poorly understood. In this study, we sought to determine whether exposure to the T7 cycle disrupts adult hippocampal neurogenesis, given that suppressed neurogenesis has been correlated with mood and learning dysfunction. After exposing adult mice to the T7 light cycle, we analyzed adult hippocampal neurogenesis by examining cellular proliferation and number of adult-born neurons. Contrary to our hypothesis that T7 would suppress neurogenesis, we found that adult mice exposed to 2 or 10 weeks of the T7 light cycle did not exhibit deficits in hippocampal neurogenesis. Our findings suggest that the direct effects of light on mood and learning do not depend on adult hippocampal neurogenesis.

Salvianolic acid B promotes microglial M2-polarization and rescues neurogenesis in stress-exposed mice

Although accumulating evidence suggests that activated microglia are associated with deficits in neurogenesis and contribute to the physiopathology of major depressive disorder, the role of microglia in treating depression remains poorly understood. Our previous study showed that salvianolic acid (SalB) has the regulation of neuroinflammatory responses and antidepressant-like effects. Here, we hypothesized that SalB’s therapeutic effects occur because it modulates microglial phenotypes that are associated with neurogenesis. To test this hypothesis, we treated CMS-exposed C57BL/6 mice with SalB (20mg/kg, intraperitoneally, once daily) for 3weeks and investigated microglial phenotypic profiles and hippocampal neurogenesis. The results showed that the SalB treatment skewed M1 microglial polarization toward M2 activation in the hippocampus and cortex and remedied CMS-induced deficits in hippocampal neurogenesis. SalB (40µM) inhibited LPS-stimulated microglial M1 activation as well as induced M2 activation in vitro, and the cultured microglia with the SalB treatment showed enhanced neural precursor cell proliferation, differentiation, and survival. SalB treatment also ameliorated the depressive-like behaviors of the CMS-treated mice in sucrose preference, forced swimming, and tail suspension tests. These findings suggest a possible antidepressive mechanism for anti-inflammatory agents that is correlated with microglial polarization and hippocampal neurogenesis and which may provide a new microglia-targeted strategy for depression therapy.

847. Hippocampal Neurogenesis in Primates and Its Relations to in vivo and Postmortem Measures of Hippocampal Volume

Deficits in hippocampal neurogenesis and alterations in hippocampal volume are associated with depression and other stress-related psychopathology. Here, we used bromodeoxyuridine (BrDU) labeling and postmortem histology in conjunction with deformation-based morphometry (DBM) to understand how in vivo and ex vivo measurements of hippocampal volume relate to primate neurogenesis.

Age-related decline in BubR1 impairs adult hippocampal neurogenesis.

SummaryAging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age‐related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain. Using established progeroid mice expressing low amounts of BubR1, we demonstrate these mice exhibit deficits in neural progenitor proliferation and maturation, leading to reduction in new neuron production. Collectively, our identification of BubR1 as a new and critical factor controlling sequential steps across neurogenesis raises the possibility that BubR1 may be a key mediator regulating aging‐related hippocampal pathology. Targeting BubR1 may represent a novel therapeutic strategy for age‐related cognitive deficits.

Adolescent cocaine exposure enhances goal-tracking behavior and impairs hippocampal cell genesis selectively in adult bred low-responder rats.

Environmental challenges during adolescence, such as drug exposure, can cause enduring behavioral and molecular changes that contribute to life-long maladaptive behaviors, including addiction. Selectively bred high-responder (bHR) and low-responder (bLR) rats represent a unique model for assessing the long-term impact of adolescent environmental manipulations, as they inherently differ on a number of addiction-related traits. bHR rats are considered "addiction-prone," whereas bLR rats are "addiction-resilient," at least under baseline conditions. Moreover, relative to bLRs, bHR rats are more likely to attribute incentive motivational value to reward cues, or to "sign-track." We utilized bHR and bLR rats to determine whether adolescent cocaine exposure can alter their inborn behavioral and neurobiological profiles, with a specific focus on Pavlovian conditioned approach behavior (i.e., sign- vs. goal-tracking) and hippocampal neurogenesis. bHR and bLR rats were administered cocaine (15mg/kg) or saline for 7days during adolescence (postnatal day, PND 33-39) and subsequently tested for Pavlovian conditioned approach behavior in adulthood (PND 62-75), wherein an illuminated lever (conditioned stimulus) was followed by the response-independent delivery of a food pellet (unconditioned stimulus). Behaviors directed toward the lever and the food cup were recorded as sign- and goal-tracking, respectively. Hippocampal cell genesis was evaluated on PND 77 by immunohistochemistry. Adolescent cocaine exposure impaired hippocampal cell genesis (proliferation and survival) and enhanced the inherent propensity to goal-track in adult bLR, but not bHR, rats. Adolescent cocaine exposure elicits long-lasting changes in stimulus-reward learning and enduring deficits in hippocampal neurogenesis selectively in adult bLR rats.

Presenilin-1 familial Alzheimer's disease mutation alters hippocampal neurogenesis and memory function in CCL2 null mice.

Aberrations in hippocampal neurogenesis are associated with learning and memory, synaptic plasticity and neurodegeneration in Alzheimer's disease (AD). However, the linkage between them, β-amyloidosis and neuroinflammation is not well understood. To this end, we generated a mouse overexpressing familial AD (FAD) mutant human presenilin-1 (PS1) crossed with a knockout (KO) of the CC-chemokine ligand 2 (CCL2) gene. The PS1/CCL2KO mice developed robust age-dependent deficits in hippocampal neurogenesis associated with impairments in learning and memory, synaptic plasticity and long-term potentiation. Neurogliogenesis gene profiling supported β-amyloid independent pathways for FAD-associated deficits in hippocampal neurogenesis. We conclude that these PS1/CCL2KO mice are suitable for studies linking host genetics, immunity and hippocampal function.

Prenatal ethanol exposure differentially affects hippocampal neurogenesis in the adolescent and aged brain

Exposure to ethanol in utero is associated with a myriad of sequelae for the offspring. Some of these effects are morphological in nature and noticeable from birth, while others involve more subtle changes to the brain that only become apparent later in life when the individuals are challenged cognitively. One brain structure that shows both functional and structural deficits following prenatal ethanol exposure is the hippocampus. The hippocampus is composed of two interlocking gyri, the cornu ammonis (CA) and the dentate gyrus (DG), and they are differentially affected by prenatal ethanol exposure. The CA shows a more consistent loss in neuronal numbers, with different ethanol exposure paradigms, than the DG, which in contrast shows more pronounced and consistent deficits in synaptic plasticity.In this study we show that significant deficits in adult hippocampal neurogenesis are apparent in aged animals following prenatal ethanol exposure. Deficits in hippocampal neurogenesis were not apparent in younger animals. Surprisingly, even when ethanol exposure occurred in conjunction with maternal stress, deficits in neurogenesis did not occur at this young age, suggesting that the capacity for neurogenesis is highly conserved early in life. These findings are unique in that they demonstrate for the first time that deficits in neurogenesis associated with prenatal ethanol consumption appear later in life.

Sustained running in rats administered corticosterone prevents the development of depressive behaviors and enhances hippocampal neurogenesis and synaptic plasticity without increasing neurotrophic factor levels.

We have previously shown that voluntary running acts as an anxiolytic and ameliorates deficits in hippocampal neurogenesis and spatial learning. It also reduces depression-like behaviors that are normally observed in rats that were administered either low (30 mg/kg) or moderate (40 mg/kg) doses of corticosterone (CORT). However, the protective effects of running were absent in rats treated with a high (50 mg/kg) dose of CORT. We examined whether allowing animals to exercise for 2 weeks prior and/or concurrently with the administration of 50 mg/kg CORT treatment could have similar protective effects. We examined hippocampal neurogenesis using immunohistochemical staining of proliferative and survival cells with the thymidine analogs (BrdU, CIdU, and IdU). In addition, we monitored synaptic protein expression and quantified the levels of neurotrophic factors in these animals as well as performing behavioral analyses (forced swim test and sucrose preference test). Our results indicate that the depressive phenotype and reductions in neurogenesis that normally accompany high CORT administration could only be prevented by allowing animals to exercise both prior to and concurrently with the CORT administration period. These animals also showed increases in both synaptophysin and PSD-95 protein levels, but surprisingly, neither brain-derived neurotrophic factor (BDNF) nor insulin-like growth factor 1 (IGF-1) levels were increased in these animals. The results suggest that persistent exercise can strengthen resilience to stress by promoting hippocampal neurogenesis and increasing synaptic protein levels, thereby reducing the deleterious effects of stress.

159. Increased microglia activation may contribute to age-related decline in hippocampal neurogenesis and cognitive function

Age-related priming of microglia and the subsequent increased release of inflammatory molecules is implicated in the low-grade neuroinflammation and cognitive decline associated with aging. The current study evaluated whether chronic treatment with minocycline, a tetracycline antibiotic that inhibits microglia activation, attenuates age-related deficits in hippocampal neurogenesis and spatial learning. Adult (3 months) and aged (22 months) male BALB/c mice were randomly assigned to minocycline or control groups. The minocycline group received minocycline in their drinking water for 20 days whereas control mice received plain water. On average, aged mice consumed 70 mg/kg/day minocycline and adults 85 mg/kg/day. One week into treatment, mice received Bromodeoxyuridine (BrdU) injections to label dividing cells. Spatial learning was assessed using the water maze. Following perfusion, immunofluorescence was conducted to assess new neuron survival and differentiation. Chronic minocycline treatment improved spatial learning in aged, but not adult, mice. New cell survival was reduced in aged mice but unaffected by minocycline. Measures of cellular differentiation are currently in progress. We hypothesize that aging will reduce differentiation of new cells into neurons compared to adults, and that minocycline treatment will increase the proportion of new cells that differentiate into neurons. Findings indicated that basal changes in microglia activation may contribute to age-related cognitive decline. Additional work is underway to determine whether alterations in microglia activation contribute to age-related reductions in hippocampal neurogenesis.

Diabetes Impairs Hippocampal Function via Advanced Glycation End Product Mediated New Neuron Generation in Animals with Diabetes-Related Depression

The diabetes-induced reduction of neurogenesis in hippocampal dentate and its reversal with antidepressant medications implies a potential mechanism for diabetes-related depression and cognitive decline. In the following article, the role of advanced glycation end products (AGEs) in hippocampal neurogenesis deficits in diabetic animals with depression has been further explained in the light of an in vitro study. Diabetes was induced in animals with the use of streptozotocin (55 mg/kg, i.p.), and the animals then divided into those with and those without depression-like behaviors as analyzed by behavioral tests. The AGE formation inhibitor aminoguanidine (10 mg/kg) was administrated for an additional 4 weeks. Proliferating cells, their survival, and their phenotype fate were monitored with bromodeoxyuridine labeling and confocal laser microscopy. The presence of AGE peptides was determined with the use of a flow injection assay. Animals with diabetes and depressive symptoms displayed a reduction in hippocampal neurogenesis and an elevated serum level of AGE peptides, both of which were reversed by a 4-week regimen of aminoguanidine (10 mg/kg, i.p.), which inhibits AGE formation; in addition, the depressive behaviors were improved. These findings provided in vivo evidence that diabetes impairs hippocampal function via the AGE-mediated generation of new neurons. This likely represents a putative mechanism that is responsible for diabetes-related depression and cognitive decline, and it suggests a potential approach for future research.

Postnatal Stimulation of the Pups Counteracts Prenatal Stress-Induced Deficits in Hippocampal Neurogenesis

Postnatal Stimulation of the Pups Counteracts Prenatal Stress-Induced Deficits in Hippocampal Neurogenesis