Suppression Of Hippocampal Neurogenesis Research Articles

Early-relief effects of tetrahedral DNA nanostructures-assisted depression therapy via modulates hippocampal neurogenesis and neuroplasticity

The delayed-onset effects of antidepressants may increase the risk of suicide in patients before they take full effect. Accumulating evidence indicates that the restriction of the blood–brain barrier (BBB), the inhibition of hippocampal neurogenesis, and the decrease in neuroplasticity play vital roles in this delayed response. This study utilizes tetrahedral DNA nanostructures (TDNs) as a drug delivery system, inherently facilitating the proliferation of neural precursor cells and effectively penetrating the BBB. The nanoscale complex, TDNs@FLX, is constructed by combining TDNs with the classic antidepressant fluoxetine (FLX). TDNs@FLX demonstrates the ability to alleviate depression symptoms in a mouse model during the early stages of treatment. In contrast, pure TDNs alone fail to provide long-lasting therapeutic benefits, and free FLX results in delayed therapeutic outcomes. The early efficacy of the TDNs@FLX complex in treating depression is closely related to the promotion of neural precursor cell proliferation, dendritic complexity, and spine density. Thus, this study addresses the limitations of classic antidepressants and presents exciting prospects for the application of DNA-based nanomedicine in the treatment of depressive disorders.

Hippocampal neurogenesis interferes with extinction and reinstatement of methamphetamine-associated reward memory in mice

Drugs of abuse, including morphine and cocaine, can reduce hippocampal neurogenesis (HN). Whereas promotion of HN is being increasingly recognized as a promising strategy for treating morphine and cocaine addiction. The present study is focused on exploring the changes of HN during methamphetamine (METH) administration and further clarify if HN is involved in METH-associated reward memory. After successfully establishing the conditioned place preference (CPP) paradigm to simulate the METH-associated reward memory in C57BL/6 mice, we observed that HN was significantly inhibited during METH (2 mg/kg, i. p.) administration and returned to normal after the extinction of METH CPP, as indicated by the immunostaining of bromodeoxyuridine (BrdU) and doublecortin (DCX) in the hippocampus. To promote/inhibit HN levels, 7,8-dihydroxyflavone (DHF), a small tyrosine kinase receptor B (TrkB) agonist and temozolomide (TMZ), an alkylating agent, were administered intraperitoneally (i.p.), respectively. The data showed that either DHF (5 mg/kg, i. p.) or TMZ (25 mg/kg, i. p.) pre-treatment before METH administration could significantly prolong extinction and enhance reinstatement of the reward memory. Notably, DHF treatment after METH administration significantly facilitated extinction and inhibited METH reinstatement, while TMZ treatment resulted in opposite effects. The present study indicated that METH administration could induce a temporal inhibitory effect on HN. More importantly, promotion of HN after the acquisition of METH-associated reward memory, but not inhibition of HN or promotion of HN before the acquisition of reward memory, could facilitate METH extinction and inhibit METH reinstatement, indicating the beneficial effect of HN on METH addiction by erasing the according reward memory.

Ocimum sanctum Linn. Extract Improves Cognitive Deficits in Olfactory Bulbectomized Mice via the Enhancement of Central Cholinergic Systems and VEGF Expression.

This study aimed to clarify the antidementia effects of ethanolic extract of Ocimum sanctum Linn. (OS) and its underlying mechanisms using olfactory bulbectomized (OBX) mice. OBX mice were treated daily with OS or a reference drug, donepezil (DNP). Spatial and nonspatial working memory performance was measured using a modified Y maze test and a novel object recognition test, respectively. Brain tissues of the animals were subjected to histochemical and neurochemical analysis. OS treatment attenuated OBX-induced impairment of spatial and nonspatial working memories. OBX induced degeneration of septal cholinergic neurons, enlargement of the lateral ventricles, and suppression of hippocampal neurogenesis. OS and DNP treatment also depressed these histological damages. OS administration reduced ex vivo activity of acetylcholinesterase in the brain. OBX diminished the expression levels of genes coding vascular endothelial growth factor (VEGF) and VEGF receptor type 2 (VEGFR2). Treatment with OS and DNP reversed OBX-induced decrease in VEGF gene and protein expression levels without affecting the expression of the VEGFR2 gene. These results demonstrate that the administration of OS can lessen the cognitive deficits and neurohistological damages of OBX and that these actions are, at least in part, mediated by the enhancement of central cholinergic systems and VEGF expression.

Inhibition of the CDK5/caspase-3 Pathway by p5-TAT Protects Hippocampal Neurogenesis and Alleviates Radiation-induced Cognitive Dysfunction

Radiation-induced cognitive dysfunction is a common complication associated with cranial radiation therapy. Inhibition of hippocampal neurogenesis and proliferation plays a critical role in this complication. Relieving hippocampal apoptosis may significantly protect hippocampal neurogenesis and proliferation. Previous studies have demonstrated that hyperactivity of cyclin-dependent kinase 5 (Cdk5) is closely related to apoptosis. The exact molecular changes and function of Cdk5 in radiation-induced cognitive dysfunction are still not clear. Whether inhibition of Cdk5 and the relevant caspase-3 could improve hippocampal neurogenesis and ameliorate radiation-induced cognitive dysfunction needs further exploration. We hypothesized that inhibition of the Cdk5/caspase-3 pathway by p5-TAT could protect hippocampal neurogenesis and alleviate radiation-induced cognitive dysfunction. In our study, we reported that radiation induced hyperactivity of Cdk5 accompanied by elevation of the levels of cleaved caspase-3, a marker of neuronal apoptosis. Inhibition of hippocampal neurogenesis and proliferation as well as cognitive dysfunction was also observed. p5-TAT, a specific inhibitor of Cdk5, decreased the overactivation of Cdk5 without affecting the levels of Cdk5 activators. Additionally, this treatment suppressed the expression of cleaved caspase-3. We further demonstrated that p5-TAT treatment reduced hippocampal dysfunction and improved behavioral performance. Therefore, Cdk5 inhibition by the small peptide p5-TAT is a promising therapeutic strategy for radiation-induced cognitive dysfunction.

Neonatal curcumin treatment restores hippocampal neurogenesis and improves autism-related behaviors in a mouse model of autism.

Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders characterized by deficits in social communication and interaction, repetitive stereotyped behaviors, and cognitive impairments. Curcumin has been indicated to be neuroprotective against neurological and psychological disorders. However, the role of curcumin in autistic phenotypes remains unclear. In the current study, we evaluated the effects of neonatal curcumin treatment on behavior and hippocampal neurogenesis in BTBRT+ltpr3tf/J (BTBR) mice, a model of autism. C57BL/6J (C57) and BTBR mouse pups were treated with 0.1% dimethyl sulfoxide (DMSO) or curcumin (20mg/kg) from postnatal day 6 (P6) to P8. Neural progenitor cells (NPCs) in the hippocampal dentate gyrus (DG) were evaluated on P8, and neurogenesis was measured on P24 by immunofluorescence. A battery of behavioral tests was carried out when the mice were 8weeks of age. Neonatal curcumin treatment improved autism-related symptoms in BTBR mice, enhancing sociability, reducing repetitive behaviors, and ameliorating cognitive impairments. Furthermore, the suppression of hippocampal neurogenesis in BTBR mice was greatly rescued after neonatal curcumin treatment, leading to an increase in neurogenic processes and an increase in NPC proliferation concomitant with an expansion of the NPC pool on P8, and NPC differentiation towards the neuronal lineage was promoted in the DG of BTBR mice on P24. Our findings suggest that neonatal curcumin treatment elicits a therapeutic response through the restoration of hippocampal neurogenesis in BTBR mice and thus may represent a promising novel pharmacological strategy for ASD treatment.

A Review of the Brain-Gut-Microbiome Axis and the Potential Role of Microbiota in Alzheimer’s Disease

Alzheimer's disease (AD) is a neurodegenerative process characterized by loss of neurons in the hippocampus and cerebral cortex, leading to progressive cognitive decline. Pathologically, the hallmark of AD is accumulation of "senile" plaques composed of amyloid-β (Aβ) protein surrounding neurons in affected regions. Despite extensive research into AD pathogenesis and therapeutic targets, there remains no breakthroughs in its management. In recent years, there has been a spark of interest in the connection between the brain and gastrointestinal tract, referred to as the brain-gut axis, and its potential implications for both metabolic and neurologic disease. Moreover, the gastrointestinal flora, referred to as the microbiome, appears to exert significant influence over the brain-gut axis. With the need for expanded horizons in understanding and treating AD, many have turned to the brain-gut-microbiome axis for answers. Here we provide a review of the brain-gut-microbiome axis and discuss the evidence supporting alterations of the axis in the pathogenesis of AD. Specifically, we highlight the role for the microbiome in disruption of Aβ metabolism/clearance, increased permeability of the blood-brain barrier and modulation of the neuroinflammatory response, and inhibition of hippocampal neurogenesis. The majority of the above described findings are the result of excellent, albeit basic and pre-clinical studies. Therefore, we conclude with a brief description of documented clinical support for brain-gut-microbiome axis alteration in AD, including potential microbiome-based therapeutics for AD. Collectively, these findings suggest that the brain-gut-microbiome axis may be a "lost link" in understanding and treating AD and call for future work.

Tooth loss early in life induces hippocampal morphology remodeling in senescence-accelerated mouse prone 8 (SAMP8) mice.

Long-term tooth loss is associated with the suppression of hippocampal neurogenesis and impairment of hippocampus-dependent cognition with aging. The morphologic basis of the hippocampal alterations, however, remains unclear. In the present study, we investigated whether tooth loss early in life affects the hippocampal ultrastructure in senescence-accelerated mouse prone 8 (SAMP8) mice, using transmission electron microscopy. Male SAMP8 mice were randomized into control or tooth-loss groups. All maxillary molar teeth were removed at 1 month of age. Hippocampal morphologic alterations were evaluated at 9 months of age. Tooth loss early in life induced mitochondrial damage and lipofuscin accumulation in the hippocampal neurons. A thinner myelin sheath and decreased postsynaptic density length were also observed. Our results revealed that tooth loss early in life may lead to hippocampal ultrastructure remodeling and subsequent hippocampus-dependent cognitive impairment in SAMP8 mice with aging.

Predator stress-induced depression is associated with inhibition of hippocampal neurogenesis in adult male mice

Stress has been suggested to disturb the 5-hydroxytryptamine system and decrease neurogenesis, which contribute to the development of depression. Few studies have investigated the effect of predator stress, a type of psychological stress, on depression and hippocampal neurogenesis in adult mice; we therefore investigated this in the present study. A total of 35 adult male Kunming mice were allocated to a cat stress group, cat odor stress group, cat stress + fluoxetine group, cat odor stress + fluoxetine group, or a control group (no stress/treatment). After 12 days of cat stress or cat odor stress, behavioral correlates of depression were measured using the open field test, elevated plus maze test, and dark-avoidance test. The concentrations of hippocampal 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were measured using high-performance liquid chromatography-electrochemical detection. Neurogenesis was also analyzed using a bromodeoxyuridine and doublecortin double-immunostaining method. Cat stress and cat odor stress induced depression-like behaviors; this effect was stronger in the cat stress model. Furthermore, compared with the control group, cat stress mice exhibited lower 5-hydroxytryptamine concentrations, higher 5-hydroxyindoleacetic acid concentrations, and significantly fewer bromodeoxyuridine+/doublecortin+-labeled cells in the dentate gyrus, which was indicative of less neurogenesis. The changes observed in the cat stress group were not seen in the cat stress + fluoxetine group, which suggests that the effects of predator stress on depression and neurogenesis were reversed by fluoxetine. Taken together, our results indicate that depression-like behaviors induced by predator stress are associated with the inhibition of hippocampal neurogenesis.

Carbofuran hampers oligodendrocytes development leading to impaired myelination in the hippocampus of rat brain

During the mammalian brain development, oligodendrocyte progenitor cells (OPCs) are generated from neuroepithelium and migrate throughout the brain. Myelination is a tightly regulated process which involves time framed sequential events of OPCs proliferation, migration, differentiation and interaction with axons for functional insulated sheath formation. Myelin is essential for efficient and rapid conduction of electric impulses and its loss in the hippocampus of the brain may result in impaired memory and long-term neurological deficits. Carbofuran, a carbamate pesticide is known to cause inhibition of hippocampal neurogenesis and memory dysfunctions in rats. Nonetheless, the effects of carbofuran on OPCs proliferation, fate determination, maturation/differentiation and myelination potential in the hippocampus of the rat brain are still completely elusive. Herein, we investigated the effects of sub-chronic exposure of carbofuran during two different time periods including prenatal and adult brain development in rats. We observed carbofuran hampers OPCs proliferation (BrdU incorporation) and oligodendroglial differentiation in vitro. Similar effects of carbofuran were also observed in the hippocampus region of the brain at both the time points. Carbofuran exposure resulted in reduced expression of key genes and proteins involved in the regulation of oligodendrocyte development and functional myelination. It also affects the survival of oligodendrocytes by inducing apoptotic cell death. The ultrastructural analysis of myelin architecture clearly depicted carbofuran-mediated negative effects on myelin compaction and g-ratio alteration. Conclusively, our study demonstrated that carbofuran alters myelination potential in the hippocampus, which leads to cognitive deficits in rats.

Ninjinyoeito Improves Behavioral Abnormalities and Hippocampal Neurogenesis in the Corticosterone Model of Depression.

Ninjinyoeito (NYT), a traditional Chinese medicine consisting of 12 herbs, is designed to improve fatigue, cold limbs, anorexia, night sweats, and anemia. Recently, NYT was reported to improve cognitive outcome and depression in patients with Alzheimer’s disease. However, little is known about how NYT alleviates depression and cognitive dysfunction. In this study, we investigated the effects and mechanisms of NYT in a corticosterone (CORT)-induced model of depression. Chronic NYT treatment ameliorated the depressive-like behaviors induced by CORT treatment in three types of behavioral tests. In addition, chronic NYT treatment also improved memory disruptions induced by CORT in both the Y-maze and novel object recognition tests, without affecting locomotor activity. Furthermore, we also showed that NYT treatment attenuated the CORT-induced reduction in cell proliferation and immature neuronal cell numbers in mouse hippocampal dentate gyrus. These results suggest that NYT has therapeutic effects on CORT-induced behavioral abnormalities and inhibition of hippocampal neurogenesis.

The Impact of Tianeptine in the Prevention of Radiation-Induced Neurogenesis Inhibition

Cranial radiotherapy (RT) is a frequently used treatment option, but its neurocognitive side effects emerge as a serious problem. Radiation inhibits hippocampal neurogenesis by induction of apoptosis and by decreasing the proliferation in the hippocampus. Tianeptine is an antidepressant drug and has been shown to induce hippocampal neurogenesis by reducing apoptosis and by providing a protective effect on proinflammatory cytokines. We aimed to demonstrate the effect of tianeptine on the inhibition of hippocampal neurogenesis and the apoptosis due to RT. Fifty six Wistar Albino rats were divided into 4 groups consisting of a control (n = 14), tianeptine (n = 14), RT (n = 14) and tianeptine + RT (n = 14) groups. Tianeptine and RT+tianeptine groups were administered tianeptine by oral gavage 3 weeks before the first sacrification and until day 120. Groups consisting of RT protocols received 10 Gy cranial RT. Hippocampal samples from the rats in each group were collected at 5th hour (early effects) and 120th day (late effects) after the RT. Morphological and immunohistochemical examinations were performed to detect cell proliferation with Ki67, apoptosis with TUNEL and immature neurons with doublecortin (DCX) selective antibody. At 5th-hour post-RT, there was no statistically significant difference between the RT+tianeptine and the RT groups in terms of Ki-67(+) cell counts (p = 0.246). Ki67(+) cell count in the RT group was reduced compared with the control group (p<0.001). The difference in the number of DCX(+) cells between RT and RT+tianeptine groups was not statistically significant (p = 0.39). In the RT group, however, the number of DCX(+) cells was lower than the control group (p <0.001). In the RT group, more TUNEL (+) cells were observed than RT+tianeptine and the other groups, and the difference was statistically significant (p <0.001). There was no statistically significant difference between groups in terms of Ki67(+) cell counts at 120 days post-RT (p = 0.1). The number of DCX (+) cells in the RT group was lower than the control group (p <0.001), but there was no statistically significant difference in the number of DCX (+) cells between RT and RT+tianeptine groups (p = 1). In the RT group, more TUNEL (+) cells were observed than RT+tianeptine and the other groups, and it was statistically significant (p <0.001). To the best of our knowledge, this is the first study in the literature examines the effect of tianeptine on neurogenesis induction observed in hippocampus due to RT. Our study showed that there is an increase in hippocampal apoptosis and a decrease in neurogenesis due to RT. Tianeptine reduced RT-induced apoptosis but did not have a statistically significant effect on neurogenesis. However, we believe that the effect of tianeptine on neurogenesis may be more pronounced in lower doses of cranial RT because of the fact that it has relieved inhibition of neurogenesis following 10 Gy cranial RT.

Effects of p21 on adult hippocampal neuronal development after irradiation

Inhibition of hippocampal neurogenesis is implicated in neurocognitive impairment after cranial irradiation. We recently demonstrated that disruption of neuronal development after DNA damage was regulated by p53. The cyclin-dependent kinase inhibitor 1 or p21, a downstream effector p53, mediates cell cycle arrest in response to DNA damage. There is evidence that p21 negatively regulates proliferation of neural progenitors (NPCs). Here we characterized the effects of p21 on disruption of neuronal development in the hippocampal dentate gyrus after irradiation. We irradiated young adult mice wild type (+/+) or knockout (−/−) of the Cdkn1a (p21) gene, and used different bromodeoxyuridine (BrdU) paradigms for cell fate mapping. The acute apoptotic response of NPCs in the subgranular zone of the dentate gyrus was independent of p21 after irradiation. In nonirradiated mice, p21 knockout resulted in an increase in neuroblast proliferation and neurogenesis. At 9 weeks after 5Gy, NPCs in the subgranular zone demonstrated increased p21 expression. Loss of newborn type-1 cells and disruption of hippocampal neurogenesis was evident at 9 weeks after irradiation, and these effects were independent of p21 genotype status. Within the developmental milestones of NPCs, irradiation resulted in loss of early intermediate NPCs (type-2a cells) in wild-type mice, whereas the principal effect of irradiation with p21 loss was culling of proliferating late intermediate (type-2b cells) and neuroblasts. These results suggest that p21 exerts differential effects on cell fate of NPCs after irradiation. p21 may serve to protect proliferating late NPCs but does not alter the ultimate inhibition of new neuron production after DNA damage.

P.3.011 - Hippocampal subfields volumes, endocrine stress axis and early life stress in major depressive disorder

Introduction Hippocampus (HC) volume reductions have been a consistent finding in major depression (MDD). One possible mechanism that contribute to these reductions might be the inhibition of hippocampal neurogenesis through increased glucocorticoid stimulation following the chronic activation of the hypothalamo-pituitary stress axis (HPA) [1,2]. This is also supported by the fact that the resulting volume reductions can be partially reversed with antidepressant treatment [1,2] Furthermore, preclinical studies suggest that the effect of HPA dysregulation on hippocampal volume reduction, neurogenesis and their reversal by antidepressant response vary across hippocampal regions and are especially present in CA1, CA3 (atrophy of dendrites) and dentate gyrus (neurogenesis) [2]. Compatibly with this hypothesis, genetic variants influencing the endocrine stress axis in MDD, such as the FKBP5 glucocorticoid receptor regulator, were shown to be associated with brain structural changes, especially in the presence of environmental stressors such as early life stress (ELS) [3,4]. In accordance with the above mentioned findings we hypothesized that there might be a differential effect of early life stress on hippocampal subfields volumes in MDD patients with different allelic variants of FKBP5. To answer this question, we investigated whether patients exposed to childhood adversity and carrying the high-risk T allele of the rs1360780 polymorphism of FKBP5 showed smaller hippocampal volumes compared to C homozygous patients. Since CA1, CA3 and the dentate gyrus are especially affected by HPA axis alterations, we decided to focus on these hippocampal subfields. Methods We processed structural MRI data from 65 healthy controls (HC) and 91 MDD patients with automated hippocampal subfields segmentation using Freesurfer 5.3 for whole brain segmentation, followed by hippocampal subfields segmentation using Freesurfer 6 developer version. A quality check was performed using the ENIGMA hippocampal subfield protocols. We selected the following subfields for analysis: granule cells/molecular layer/dentate gyrus (GCMLDG), CA1, CA3, whole hippocampus (WH). ELS was evaluated with the Childhood Trauma Questionnaire Short Form. At least one mild expression of sexual abuse (subscale score > 7), emotional abuse (subscale score > 12) or physical abuse (subscale score > 9) was seen as having had a history of childhood abuse. We predicted the volume of each subfield using generalized linear scale response models, testing for the significance of between-group (diagnosis, ELS, allele status, age, sex, site, total intractranial volume) and within-group (side) factors. Results MDD patients showed reduced volume in all the subfields and in the total HC (p Conclusion In MDD, volume of CA1, CA3, DG and total HC was reduced. Patients with a high-risk variant in a glucocorticoid receptor regulator gene display smaller CA1 volumes in presence of ELS.

Juvenile social defeat stress exposure persistently impairs social behaviors and neurogenesis

Adverse juvenile experiences, including physical abuse, often have negative health consequences later in life. We investigated the influence of social defeat stress exposure as juveniles on neuropsychological behaviors, and the causal role of glucocorticoids in abnormal behaviors and impairment of neurogenesis in mice exposed to the stress. The juvenile (24-day-old) and adult (70-day-old) male C57BL/6J mice were exposed to social defeat stress induced by an aggressive ICR mouse. Social defeat stress exposure as juveniles, even for 1 day, induced persistent social avoidance to the unfamiliar ICR mouse in the social interaction test, but that was not observed in mice exposed to the stress as adults. Social avoidance by the stress exposure as juveniles for 10 consecutive days was observed, when the target mouse was not only unfamiliar ICR but also another C57BL/J mouse, but not an absent or an anesthetized ICR mouse. The stress exposure did not induce anxiety- and depression-like behaviors in spontaneous locomotor activity, elevated plus-maze test, marble-burying test, forced swimming test, or sucrose preference test. Serum corticosterone levels increased immediately after the stress exposure. The hippocampal neurogenesis was suppressed 1 day and 4 weeks after the stress exposure. Administration of mifepristone, a glucocorticoid receptor antagonist, prior to each stress exposure, blocked the persistent social avoidance and suppression of neurogenesis. In conclusion, social avoidance induced by social defeat stress exposure as juveniles are more persistent than that as adults. These social avoidances are associated with suppression of hippocampal neurogenesis via glucocorticoid receptors.

Current research on molecular mechanism of ionizing radiation-induced neurogenesis disorders

With the development of modern radiotherapy techniques, radiotherapy has been widely used in the multimodality therapy for various malignant tumors, including head and neck cancers such as nasopharyngeal cancer and laryngeal cancer. A combination of surgery and radiochemotherapy significantly improves patients’ cure rate and survival time; however, with the increase in survival time, some patients receiving radiotherapy develop marked cognitive impairment. Ionizing radiation-induced cognitive impairment mainly manifests as hippocampus-dependent cognitive impairment, which is associated with inhibited hippocampal neurogenesis due to ionizing radiation. Therefore, it is necessary to investigate the mechanisms of the inhibition of hippocampal neurogenesis by ionizing radiation. This article reviews the molecular mechanism of neurogenesis disorders induced by ionizing radiation. Key words: Radiation; Neurogenesis; Neural stem/progenitor cell; Brain microenviorment; Inflammation

Maternal occlusal disharmony during pregnancy induces spatial memory deficits associated with the suppression of hippocampal neurogenesis in adult mouse offspring

Background and objectiveMaternal stress during pregnancy is an important factor affecting fetal brain development and leading to behavioral disorders such as spatial learning deficits and inhibition of hippocampal neurogenesis in the offspring. Occlusal disharmony induces cognitive deficits by suppressing hippocampal neurogenesis via increased plasma corticosterone levels. The present study aimed to explore the effects of maternal occlusal disharmony during pregnancy on hippocampal morphology and function in the adult mouse offspring. DesignOcclusal disharmony was induced in pregnant mice during the last week of gestation. Male offspring were raised until 4 months old, and then the Morris water maze was performed as a spatial memory test. Newborn cell proliferation in the hippocampal dentate gyrus was analyzed using 5-bromodeoxyuridine (BrdU) immunohistochemical method in separate groups of mice. ResultsPlasma corticosterone concentrations were significantly higher in dam with occlusal disharmony. In the adult offspring, maternal occlusal disharmony not only induced learning deficits, but also suppressed cell proliferation in the hippocampal dentate gyrus compared with control mice. ConclusionThese findings suggest that maternal occlusal disharmony during pregnancy increases plasma corticosterone concentrations in the dam, which leads to learning deficits and suppression of hippocampal cell proliferation in the offspring. Occlusal disharmony in the dam may be a risk factor for cognitive impairment in the offspring.

Role of proinflammatory cytokines in the inhibition of hippocampal neurogenesis in mesial temporal lobe epilepsy

BackgroundIn mesial temporal lobe epilepsy, reduced hippocampal neurogenesis correlates with severe impairment in declarative learning and memory. The proinflammatory cytokines interleukin 1β and high-mobility group box 1 (HMGB1) and their receptors have key roles in generating and perpetuating seizures. This study aimed to assess their potential role in inhibiting neurogenesis in patients with mesial temporal lobe epilepsy and whether any effect would be pharmacologically reversible as a possible mechanism to restore learning and memory deficits. MethodsWe generated three-dimensional (3D) stem-cell cultures (Hi-Spot, Capsant Neurotechnologies Ltd, UK), preserving the inflammatory microenvironment and key features of the in-vivo stem-cell niche, from sclerotic tissue obtained from patients undergoing surgery for epilepsy (n=23). Concentrations of interleukin 1β and HMGB1 and their receptors in sclerotic tissue were determined with PCR, western blot, ELISA, and immunohistochemistry and compared with normal cortical tissue. Neurogenesis in the presence or absence of interleukin 1β or HMGB1 antagonists was examined by quantifying the number of newly born neurons. FindingsWe expanded the use of air–liquid interphase technology previously used to generate Hi-Spots from the cortex of rats to generate 3D Hi-Spots from the adult human hippocampus. Using ELISA, we demonstrated that interleukin 1β concentrations were significantly elevated in sclerotic hippocampal Hi-Spots compared with control (mean 24·4 pg/mL [SD 2·3] vs 3·6 [1·4], p<0·01). Interleukin 1 receptor mRNA was four times higher than control with dense protein coexpression by nestine-positive neural stem cells. Blockade of interleukin 1 receptor increased the number of newly born neurons in sclerotic Hi-Spots (mean 14·23 cells per mm2 [SD 1·13] vs 4·8 [0·7], p<0·01) and significantly decreased HMGB1 activity (5·5 ng/mL [0·25] vs 7·7 [0·29], p<0·01). Treatment with the HMGB1 antagonist BoxA increased the percentage of newly born neurons and completely reversed the antineurogenic effects of interleukin 1β, indicating possible crosstalk between interleukin 1β and HMGB1 in modulating hippocampal neurogenesis. InterpretationWe provide a novel in-vitro molecular model that relies on the interleukin 1β–interleukin 1 receptor–HMGB1 axis. Whereas previous studies have elegantly shown that blockade of this axis renders epileptic animals free of seizures, our observations support the development of therapeutic interventions that counteract the microenvironment to promote hippocampal neurogenesis. This possibility could lead to pharmacological strategies to treat learning and memory deficits in mesial temporal lobe epilepsy. FundingEpilepsy Research UK.

Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression

Radiotherapy is common in the treatment of brain tumors in children but often causes deleterious, late-appearing sequelae, including cognitive decline. This is thought to be caused, at least partly, by the suppression of hippocampal neurogenesis. However, the changes in neuronal network properties in the dentate gyrus (DG) following the irradiation of the young, growing brain are still poorly understood. We characterized the long-lasting effects of irradiation on the electrophysiological properties of the DG after a single dose of 6-Gy whole-brain irradiation on postnatal day 11 in male Wistar rats. The assessment of the basal excitatory transmission in the medial perforant pathway (MPP) by an examination of the field excitatory postsynaptic potential/volley ratio showed an increase of the synaptic efficacy per axon in irradiated animals compared to sham controls. The paired-pulse ratio at the MPP granule cell synapses was not affected by irradiation, suggesting that the release probability of neurotransmitters was not altered. Surprisingly, the induction of long-term synaptic plasticity in the DG by applying 4 trains of high-frequency stimulation provoked a shift from long-term potentiation (LTP) to long-term depression (LTD) in irradiated animals compared to sham controls. The morphological changes consisted in a virtually complete ablation of neurogenesis following irradiation, as judged by doublecortin immunostaining, while the inhibitory network of parvalbumin interneurons was intact. These data suggest that the irradiation of the juvenile brain caused permanent changes in synaptic plasticity that would seem consistent with an impairment of declarative learning. Unlike in our previous study in mice, lithium treatment did unfortunately not ameliorate any of the studied parameters. For the first time, we show that the effects of cranial irradiation on long-term synaptic plasticity is different in the juvenile compared with the adult brain, such that while irradiation of the adult brain will only cause a reduction in LTP, irradiation of the juvenile brain goes further and causes LTD. Although the mechanisms underlying the synaptic alterations need to be elucidated, these findings provide a better understanding of the effects of irradiation in the developing brain and the cognitive deficits observed in young patients who have been subjected to cranial radiotherapy.

New horizon for the therapeutic modality of exercise on neuropsychiatric disorders

Since discovery of the possibility that neuronal precursors cells can differentiate into neurons (Reynolds and Weiss, 1992), neurogenesis in the olfactory bulb (Tarozzo et al., 1995) and hippocampus (Eriksson et al., 1998) of the adult mammals has been confirmed. The hippocampus plays a major role in spatial learning and memory in animals as well as humans. Neurogenesis in the hippocampus occurs throughout postnatal life, and is influenced by environment and behavior factors. Many studies have focused on the modulating factors of the neurogenesis. Enriched environment, learning, electroconvulsive therapy, anti-depressive agents, acupuncture, and exercise have been suggested as the increasing factor for neurogenesis. Adult hippocampal neurogenesis is considered to be composed of several development stages: proliferation, differentiation, migration, targeting and synaptic integration, and various characteristic neuronal markers are expressed during the specific stages. Adult hippocampal neurogenesis is closely implicated with hippocampal functions and decreased hippocampal neurogenesis is associated with neurodegenerative disorders. Exercise is known to have many beneficial effects on health, such as increasing of cardiovascular function, prevention of chronic diseases, and decreasing of body fat. Exercise improves learning ability and memory function, protects against neurodegenerative diseases, delays age-related cognitive decline, and alleviates symptoms of the developmental and neuropsychiatric disorders. Many studies have suggested the possibility that exercise can be a therapeutic modality for brain diseases. Neurogenesis induced by exercise is reported to be necessary in the hippocampal-dependent learning process. Suppression of hippocampal neurogenesis may contribute to cognitive dysfunction in aging, dementia, epilepsy, and other brain inflammatory conditions. The fact that exercise increases neurogenesis has enabled new research on the role of exercise. Most widely studied effect of exercise is on the depression. In our studies, treadmill exercise enhanced neurogenesis with increment of serotonin expression, which resulted in improvement of depressive symptoms (Baek et al., 2012). Treadmill exercise alleviated aging-induced memory impairment by enhancing neurogenesis (Kim et al., 2010). Kim et al. (2013) reported that exercise also accelerated maturation of neurons under the brain inflammatory conditions. These therapeutic efficacies of treadmill exercise can be ascribed to the enhancing effect of exercise on neurogenesis. Thus, the enhancing effect of exercise on neurogenesis may open new horizon for the treatment of many neuropsychiatric disorders.

방사선 유도 학습기억 장애에 대한 diethyldithiocarbamate의 효과

Evidence suggests that even low-dose irradiation can lead to progressive cognitive decline and memory deficits, which implicates, in part, hippocampal dysfunction in both humans and experimental animals. This study examined whether diethyldithiocarbamate (DDC) could attenuate memory impairment, using passive avoidance and object recognition test, and suppression of hippocampal neurogenesis, using the TUNEL assay and immunohistochemical detection with markers of neurogenesis (Kiel 67 (Ki-67) and doublecortin (DCX)) in adult mice treated with gamma radiation (0.5 or 2 Gy). DDC was administered intraperitonially at a dosage of 1,000 of body weight at 30 min. before irradiation. In passive avoidance and object recognition memory test, the mice, trained for 1 day after acute irradiation (2 Gy) showed significant memory deficits compared with the sham controls. The number of TUNEL-positive apoptotic nuclei in the dentate gyrus (DG) was increased 12 h after irradiation. In addition, the number of Ki-67- and DCX-positive cells were significantly decreased. DDC treatment prior to irradiation attenuated the memory defect, and blocked the apoptotic death. DDC may attenuate memory defect in a relatively low-dose exposure of radiation in adult mice, possibly by inhibiting a detrimental effect of irradiation on hippocampal neurogenesis.