Dentate Gyrus Region Of Hippocampus Research Articles

Role of extracellular signal-regulated kinase in rubrofusarin-enhanced cognitive functions and neurite outgrowth

Memory-enhancing agents have long been required for various reasons such as for obtaining a good score in a test in the young and for retaining memory in the aged. Although many studies have found that several natural products may be good candidates for memory enhancement, there is still a need for better agents. The present study investigated whether rubrofusarin, an active ingredient in Cassiae semen, enhances learning and memory in normal mice. Passive avoidance and Morris water maze tests were performed to determine the memory-enhancing ability of rubrofusarin. To investigate synaptic function, hippocampal long-term potentiation (LTP) was measured. Western blotting was performed to determine protein levels. To investigate neurite outgrowth, DCX immunohistochemistry and cell culture were utilised. Rubrofusarin (1, 3, 10, 30 mg/kg) enhanced memory in passive avoidance and Morris water maze tests. Moreover, rubrofusarin ameliorated scopolamine-induced memory impairment. In the rubrofusarin-treated group, high-frequency stimulation induced higher LTP in the hippocampal Schaffer-collateral pathway compared to the control group. The rubrofusarin-treated group showed a higher number of DCX-positive immature neurons with an increase in the length of dendrites compared to the control group in the hippocampal dentate gyrus region. In vitro experiments showed that rubrofusarin facilitated neurite outgrowth in neuro2a cells through extracellular signal-regulated kinase (ERK). Finally, we found that extracellular signal-regulated kinase (ERK) is required for rubrofusarin-induced enhancement of neurite outgrowth, learning and memory. These results demonstrate that rubrofusarin enhances learning and memory and neurite outgrowth, and these might need activation of ERK pathway.

Identification and functional characterization of CD133+GFAP+CD117+Sca1+ neural stem cells.

Neural stem cells (NSCs) are responsible for maintaining the nervous system and repairing damages. Utility of NSCs could provide a novel solution to treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. However, we have no idea the exact phenotypic and functional characteristics of NSCs and their precise role in geriatric neurological and aging-related diseases. In this study, C57BL/6 mice were used to isolate and identify CD133+GFAP+CD117+Sca1+ cells in the hippocampal dentate gyrus region of the mouse brain as a novel neural stem cellpopulation, in terms of cell phenotype, self-renewal capacity, and differentiation capability. With increasing in aging, the function, total cell number, and self-renewal capacity of CD133+GFAP+CD117+Sca1+ cells decreased, and the activity of differentiated cells also decreased. Meanwhile, we investigated differentially expressed genes in order to further classify their gene signature and pathways associated with their functional changes. Taken together, these findings demonstrate the existence of a rare population of NSCs in the hippocampal dentate gyrus region. Identification ofspecific NSCs offers ample opportunities foralleviating neural diseases.

Bee Venom Activates the Nrf2/HO-1 and TrkB/CREB/BDNF Pathways in Neuronal Cell Responses against Oxidative Stress Induced by Aβ1-42.

Honeybee venom has recently been considered an anti-neurodegenerative agent, primarily due to its anti-inflammatory effects. The natural accumulation of amyloid-beta (Aβ) in the brain is reported to be the natural cause of aging neural ability downfall, and oxidative stress is the main route by which Aβ ignites its neural toxicity. Anti-neural oxidative stress is considered an effective approach for neurodegenerative therapy. To date, it is unclear how bee venom ameliorates neuronal cells in oxidative stress induced by Aβ. Here, we evaluated the neuroprotective effect of bee venom on Aβ-induced neural oxidative stress in both HT22 cells and an animal model. Our results indicate that bee venom protected HT22 cells against apoptosis induced by Aβ1–42. This protective effect was explained by the increased nuclear translocation of nuclear factor erythroid 2-like 2 (Nrf2), consequently upregulating the production of heme oxygenase-1 (HO-1), a critical cellular instinct antioxidant enzyme that neutralizes excessive oxidative stress. Furthermore, bee venom treatment activated the tropomyosin-related kinase receptor B (TrkB)/cAMP response element-binding (CREB)/brain-derived neurotrophic factor (BDNF), which is closely related to the promotion of cellular antioxidant defense and neuronal functions. A mouse model with cognitive deficits induced by Aβ1–42 intracerebroventricular (ICV) injections was also used. Bee venom enhanced animal cognitive ability and enhanced neural cell genesis in the hippocampal dentate gyrus region in a dose-dependent manner. Further analysis of animal brain tissue and serum confirmed that bee venom reduced oxidative stress, cholinergic system activity, and intercellular neurotrophic factor regulation, which were all adversely affected by Aβ1–42. Our study demonstrates that bee venom exerts antioxidant and neuroprotective actions against neural oxidative stress caused by Aβ1–42, thereby promoting its use as a therapeutic agent for neurodegenerative disorders.

Betaine Ameliorates Depressive-Like Behaviors in Zinc Oxide Nanoparticles Exposed Mice.

The aim of the current study was to determine protective effects of betaine on depressive-like behaviors in zinc oxide nanoparticles (ZnO NPs) exposed mice. Forty male mice randomly allocated into four experimental groups. Group 1 kept as control and groups 2-4 received oral administration of betaine (30 mg/kg), ZnO NPs (600 mg/kg), and ZnO NPs (600 mg/kg) 1 h after pre-administration of betaine (30 mg/kg) for 7 days, respectively. Then, forced swimming test (FST), tail suspension test (TST), open field test (OFT), and rotarod tests were done. Furthermore, serum malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), and total antioxidant capacity (TAC) levels were determined. Hippocampal tissue samples were collected for histopathological assessment. According to the results, treatment with ZnO NPs significantly increased immobility time in the FST and TST (P<0.05). Betaine significantly decreased immobility time in the FST and TST (P<0.05). Pretreatment with betaine significantly decreased ZnO NPs-induced alterations in the FST and TST (P<0.05). The duration of staying on the rotarod and the numbers of crossings in the OFT significantly decreased in the mice that received ZnO NPs (P<0.05). These results were significantly improved in betaine+ZnO NPs treated mice as compared to the ZnO NPs group (P<0.05). Treatment with ZnO NPs significantly increased serum MDA level while decreased SOD and GPx compared to the control group (P<0.05). These changes were effectively ameliorated by pretreatment with betaine compared to the ZnO NPs group (P<0.05). No significant effect on serum TAC level was observed in all groups (P˃0.05). Administration of ZnO NPs decreased the thickness of hippocampus and pyramidal neurons in the hippocampal dentate gyrus (DG) and CA1 regions were sparsely arranged. Pretreatment with betaine caused an improvement in the histological features of the hippocampus when compared with ZnO NPs-treated mice. Taken together, these results suggest that betaine has protective role against ZnO NPs-induced toxicity in mice.

Reduced GABAergic neuropil and interneuron profiles in schizophrenia: Complementary analysis of disease course-related differences

BackgroundGABAergic interneuron dysfunction has been implicated in the pathophysiology of schizophrenia. Expression of glutamic acid decarboxylase (GAD), a key enzyme in GABA synthesis, may also be altered. Here, we have simultaneously evaluated GAD-immunoreactive (GAD-ir) neuropil and cell profiles in schizophrenia-relevant brain regions, and analysed disease-course related differences. MethodsGAD65/67 immunoreactivity was quantified in specific brain regions for profiles of fibres and cell bodies of interneurons by automated digital image analysis in post-mortem brains of 16 schizophrenia patients from paranoid (n = 10) and residual (n = 6) diagnostic subgroups and 16 matched controls. Regions of interest were superior temporal gyrus (STG) layers III and V, mediodorsal (MD) and laterodorsal (LD) thalamus, and hippocampal CA1 and dentate gyrus (DG) regions. ResultsA reduction in GAD-ir neuropil profiles (p < 0.001), particularly in STG layer V (p = 0.012) and MD (p = 0.001), paralleled decreased GAD-ir cell profiles (p = 0.029) in schizophrenia patients compared to controls. Paranoid schizophrenia patients had lower GAD-ir neuron cell profiles in STG layers III (p = 0.007) and V (p = 0.001), MD (p = 0.002), CA1 (p = 0.001) and DG (p = 0.043) than residual patients. There was no difference in GAD-ir neuropil profiles between paranoid and residual subgroups (p = 0.369). ConclusionsThese results support the hypothesis of GABAergic dysfunction in schizophrenia. They show a more prominent reduction of GAD-ir interneurons in paranoid versus residual patients, suggestive of more pronounced GABAergic dysfunction in the former. Fully automated analyses of histological sections represent a step towards user-independent assessment of brain structure.

MicroRNA-204-5p reduction in rat hippocampus contributes to stress-induced pathology via targeting RGS12 signaling pathway

BackgroundNeuroinflammation occupies a pivotal position in the pathogenesis of most nervous system diseases, including depression. However, the underlying molecular mechanisms of neuroinflammation associated with neuronal injury in depression remain largely uncharacterized. Therefore, identifying potential molecular mechanisms and therapeutic targets would serve to better understand the progression of this condition.MethodsChronic unpredictable stress (CUS) was used to induce depression-like behaviors in rats. RNA-sequencing was used to detect the differentially expressed microRNAs. Stereotactic injection of AAV virus to overexpress or knockdown the miR-204-5p. The oxidative markers and inflammatory related proteins were verified by immunoblotting or immunofluorescence assay. The oxidative stress enzyme and products were verified using enzyme-linked assay kit. Electron microscopy analysis was used to observe the synapse and ultrastructural pathology. Finally, electrophysiological recording was used to analyze the synaptic transmission.ResultsHere, we found that the expression of miR-204-5p within the hippocampal dentate gyrus (DG) region of rats was significantly down-regulated after chronic unpredicted stress (CUS), accompanied with the oxidative stress-induced neuronal damage within DG region of these rats. In contrast, overexpression of miR-204-5p within the DG region of CUS rats alleviated oxidative stress and neuroinflammation by directly targeting the regulator of G protein signaling 12 (RGS12), effects which were accompanied with amelioration of depressive-like behaviors in these CUS rats. In addition, down-regulation of miR-204-5p induced neuronal deterioration in DG regions and depressive-like behaviors in rats.ConclusionTaken together, these results suggest that miR-204-5p plays a key role in regulating oxidative stress damage in CUS-induced pathological processes of depression. Such findings provide evidence of the involvement of miR-204-5p in mechanisms underlying oxidative stress associated with depressive phenotype.Graphical

Effect of gap junction blockers on hippocampal ripple energy expression in rats with status epilepticus.

To study the effect of gap junction blockers, quinine (QUIN) and carbenoxolone (CBX), on hippocampal ripple energy expression in rats with status epilepticus (SE). A total of 24 rats were randomly divided into four groups: model, QUIN, valproic acid (VPA), and CBX (n=6 each). A rat model of SE induced by lithium-pilocarpine (PILO) was prepared. The QUIN, VPA, and CBX groups were given intraperitoneal injection of QUIN (50 mg/kg), VPA by gavage (200 mg/kg), and intraperitoneal injection of CBX (50 mg/kg) respectively, at 3 days before PILO injection. Electroencephalography was used to analyze the change in hippocampal ripple energy before and after modeling, as well as before and after chloral hydrate injection to control seizures. Ripple expression was observed in the hippocampal CA1, CA3, and dentate gyrus regions of normal rats. After 10 minutes of PILO injection, all groups had a gradual increase in mean ripple energy expression compared with 1 day before modeling, with the highest expression level before chloral hydrate injection in the model, VPA and CBX groups (P<0.05). The QUIN group had the highest expression level of mean ripple energy 60 minutes after PILO injection. The mean ripple energy returned to normal levels in the three intervention groups immediately after chloral hydrate injection, while in the model group, the mean ripple energy returned to normal levels 1 hour after chloral hydrate injection. The mean ripple energy remained normal till to day 3 after SE in the four groups. The changing trend of maximum ripple energy was similar to that of mean ripple energy. The change in ripple energy can be used as a quantitative indicator for early warning of seizures, while it cannot predict seizures in the interictal period. Gap junction blockers can reduce ripple energy during seizures.

Hippocampal asymmetry and regional dispersal of nAChRs alpha4 and alpha7 subtypes in the adult rat

To better comprehend the relationship between left/right (L/R) differences and hippocampus functions is necessary knowledge of lateral asymmetry and regional distribution. This research was design to examine hippocampal L/R asymmetry and regional distribution profile of the alpha7 and alpha4 subtypes of nicotinic acetylcholine receptors (nAChRs) in the adult rat.10–12-week-old twenty-four male wistar rats were randomly selected. After removing the brains, immunohistochemistry, real-time PCR, and western blot methods were applied to distinguish the presence of the receptors in the hippocampus. Outcomes stated that the mentioned receptors expression profile was spatial-dependent. As, the hippocampal dispersal of alpha7 and alpha4 subtypes in the left hippocampus (LH) was remarkably maximum compare with the right hippocampus (RH) (p = 0.001, p = 0.005 respectively). Furthermore, the alpha7 optical density (OD) was not significantly different in the diverse regions in hippocampus of adult rat (p = 0.057), while the maximum OD of the alpha4 was detected in the hippocampal dentate gyrus and CA3 regions of LH (p = 0.007, p = 0.009 respectively) and the minimum OD was in the CA1 of the RH (p = 0.019). In real time PCR evaluation, there is a significantly higher expression of alpha7 and alpha4 in LH compared to RH (p = 0.043, p = 0.049 respectively), also, for western blot (p = 0.042, p = 0.030 respectively). According to present data, the alpha7 and alpha4 nAChR subtypes expression profile demonstrated lateral asymmetry, the uniform regional dispersal for alpha7 and different regional dispersal for alpha4 in the adult rat hippocampus.

Repeated Neonatal Isoflurane Exposure is Associated with Higher Susceptibility to Chronic Variable Stress-induced Behavioural and Neuro-inflammatory Alterations

Numerous studies have reported that prolonged or multiple exposures to anaesthetics in early life lead to detrimental effects on brain function, most having focused on neurocognitive function, and relatively few on long term neuropsychiatric performance. The present study investigated the impact of repeated neonatal isoflurane exposure on chronic variable stress (CVS)-induced psychiatric and behavioural outcomes together with CVS-related neuronal activity and neuro-inflammatory reactivity in relevant brain circuits. In the present study, C57BL/6J mice received either three exposures to isoflurane at postnatal days 7, 8, and 9 or a control exposure. From postnatal day 45, mice were exposed to a mild, 3-week, CVS paradigm or none and the CVS-related neuropsychiatric performance was evaluated using a series of behavioural tests. The neuronal activity in relevant brain regions was measured by ΔFosB immunopositivity and CVS-related neuroinflammation was assessed by analysing levels of pro-inflammatory cytokines IL-1α, IL-1β, IL-6, and TNF-α. In mice experiencing serial neonatal isoflurane exposure, we detected a significant enhancement in anxiety levels following CVS procedures, together with enhanced neuronal activity, and exacerbated neuroinflammation in the basolateral amygdaloid nuclei (BLA) and hippocampal dentate gyrus (DG) regions. No such change was found in control mice. These results indicate an association between early multiple isoflurane exposures in infant mice and susceptibility to a CVS-evoked anxious phenotype accompanied by enhanced neuronal activity in BLA and DG regions and high inflammatory reactivity in response to CVS.

Oral Herb Medicine Paste Improves Learning and Memory Function in Elderly Spontaneous Hypertensive Rats

Background: Oral herb medicine paste (Gao-Zi-Yao) has long been a unique way for treating various diseases. The present study is to explore the effect of Gao-Zi-Yao on learning and memory function in elderly spontaneous hypertensive rats (SHR) and its possible mechanism. Methods: Male elderly SHR were received different doses of Gao-Zi-Yao for 4 weeks. Systolic blood pressure (SBP) and heart rate were monitored. Morris water maze was performed to test the learning and memory function of the rats. Number of neurons in hippocampus was counted by Nissl staining. Western blot was applied to detect the expressions of learning and memory function related proteins, N-methyl-d-aspartate receptor 2B (NMDAR 2B), glutamate receptor 1 (GluR1), phosphorylated-calmodulin-dependent protein kinase II (p-CaMK II), and phosphorylated-cAMP responsive element-binding protein (p-CREB) in rat hippocampus. Findings: Data showed that Gao-Zi-Yao reduced SBP in elderly SHR. The results of Morris water maze experiment showed that Gao-Zi-Yao dose-dependently improved learning and memory function. Number of neurons in the hippocampal dentate gyrus (DG) region of the elderly SHR was increased by Gao-Zi-Yao treatment. In addition, Gao-Zi-Yao elevated the protein expressions of NMDAR 2B, GluR1, p-CaMK II, and p-CREB in hippocampus. Interpretation: Gao-Zi-Yao decreases SBP and improves the learning and memory function of the elderly SHR by regulation of neuron number in hippocampal DG area and the expressions of learning and memory function related proteins. Funding Statement: This work was supported by the National Natural Science Foundation of China (81970422), Suzhou Municipal Science and Technology Bureau (SS201745, GSWS2019022, SYSD2020210), and 5th 333 Project of Jiangsu Province. Declaration of Interests: The authors stated 'not applicable.' Ethics Approval Statement: The experiments were performed in according with the National Institutes of Health Guidelines for the Use of Laboratory Animals (NIH, publication number 85-23, revised 1996.), which were approved by and performed according to guidelines for the care and use of animals established by Soochow University. All the herbs and other materials used in the preparation of Gao-Zi Yao were approved by National Health Commission of the People’s Republic of China.

Atorvastatin Prevents the Neuron Loss in the Hippocampal Dentate Gyrus Region through its Anti-Oxidant and Anti-Apoptotic Activities.

Atorvastatin is a member of statins, which has shown positive vascular effects, anti-oxidant, anti-platelet, and anti-apoptotic properties. In this study, we hypothesized that atorvastatin could prevent the neurons lost in the hippocampal dentate gyrus region after transient global Ischemia/Reperfusion (I/R) through its anti- oxidant and anti-apoptotic activities. Twenty-four male Wistar rats, 12-13 weeks old and weighing 250-300 g, were divided randomly into four groups: control, I/R, vehicle (I/R treated with NaCl) and experiment (I/R treated with atorvastatin, 10 mg/kg); rats were sacrificed 96 hours after I/R. Quantitative expression of genes (caspase 8, p53, bax, bcl2, cytochrome c) was studied. The MDA level, SOD, CAT, and GPx activities were measured with biochemical tests. To detect apoptotic cells, TUNEL and Nissl staining were performed. Mitochondria were prepared from the hippocampus rats and used for the quantification of mitochondrial ROS, ATP level, GSH content, membrane potential, cytochrome c release, and determination of mitochondrial swelling. Atorvastatin attenuated the overexpression of bax, cytochrome C, p53, and caspase8 mRNAs and induced expression of bcl-2 mRNA (P<0.001). Atorvastatin treatment increased anti-oxidant enzyme levels (P<0.01). Treatment with atorvastatin reduced the number of TUNEL-positive cells. It could decrease the cytochrome c release (P<0.01), inhibit the decrease of MMP (P<0.001) and increase the ATP level (P<0.001) in hippocampal mitochondria compared with the I/R group. Atorvastatin treatment in I/R rats decreases oxidative stress, production of ROS, apoptosis rate in neuronal cells, and improves the mitochondrial function. Hence, atorvastatin has a proper neuronal protective effect against the I/R injury in the brain.

Enriched Environment and Social Isolation Affect Cognition Ability via Altering Excitatory and Inhibitory Synaptic Density in Mice Hippocampus

The purpose of the study was to examine whether the underlying mechanism of the alteration of cognitive ability and synaptic plasticity induced by the housing environment is associated with the balance of excitatory/inhibitory synaptic density. Enriched environment (EE) and social isolation (SI) are two different housing environment, and one is to give multiple sensory environments, the other is to give monotonous and lonely environment. Male 4-week-old C57 mice were divided into three groups: CON, EE and SI. They were housed in the different cage until 3 months of age. Morris water maze and novel object recognition were performed. Long term potentiation (LTP), depotentiation (DEP) and local field potentials were recorded in the hippocampal perforant pathway and dentate gyrus (DG) region. The data showed that EE enhanced the ability of spatial learning, reversal learning and memory as well as LTP/DEP in the hippocampal DG region. Meanwhile, SI reduced those abilities and the level of LTP/DEP. Moreover, there were higher couplings of both phase-amplitude and phase-phase in the EE group, and lower couplings of them in the SI group compared to that in the CON group. Western blot and immunofluorescence analysis showed that EE significantly enhanced the level of PSD-95, NR2B and DCX; however, SI reduced them but increased GABAARα1 and decreasedDCX levels. The data suggests that the cognitive functions, synaptic plasticity, neurogenesis and neuronal oscillatory patterns were significantly impacted by housing environment via possibly changing the balance of excitatory and inhibitory synaptic density.

Neuroprotective Effects of Fluoxetine Against Chronic Stress-Induced Neural Inflammation and Apoptosis: Involvement of the p38 Activity

Depression is considered a widespread neuropsychiatric disease associated with neuronal injury within specific brain regions. Fluoxetine, a selective serotonin reuptake inhibitor, has been widely used in depressed patients. Recently, fluoxetine has demonstrated neuroprotective effects apart from the effect on serotonin. However, the underlying mechanism involved in this neuroprotection remains unclear, in particular, whether fluoxetine exerts antidepressant effects via protecting against neuronal injury. Here, we found that treatment with fluoxetine (10 mg/kg, i.p.) for 2 weeks ameliorated depression-like behaviors in a chronic unpredictable mild stress (CUMS)-induced rat model of depression and was accompanied with an alleviation of glia activation and inhibition of interleukin-1β (IL-1β), interferon gamma (IFN-γ), and tumor necrosis factor-α (TNF-α) expression in the hippocampal dentate gyrus (DG) region. Meanwhile, CUMS rats treated with fluoxetine showed reductions in neuronal apoptosis and a downregulation of the apoptotic protein Bax, cleaved caspase 3, and caspase 9 levels. These effects appear to involve a downregulation of p38 mitogen-activated protein kinase (MAPK) signaling within the DG hippocampus as the specific inhibitor of p38 MAPK, SB203580, significantly suppressed apoptosis, as well as ameliorated depressive behaviors resulting from CUMS exposure. Moreover, fluoxetine could rescue neuronal deterioration and depression-like phenotypes caused by overexpression of p38 in DG. This finding extends our knowledge on the antidepressant-like effects of fluoxetine, which appear to at least partially profit from neuroprotection against inflammation and neuronal apoptosis via downregulation of the p38 MAPK pathway. The neuroprotective mechanisms of fluoxetine may provide some novel therapeutic avenues for stress-related neurological diseases.

Extracellular Matrix (ECM)-Mimicking Neuroprotective Injectable Sulfo-Functionalized Peptide Hydrogel for Repairing Brain Injury

Brain injury can lead to the loss of neuronal functions and connections, along with the damage of the extracellular matrix (ECM). Thus, it ultimately results in devastating long-term damage, and recovery from this damage is a challenging task. To address this issue, we have designed a sulfo-group-functionalized injectable biocompatible peptide hydrogel, which not only mimics the ECM and supports the damaged neurons but also releases a neurotrophic factor around the injured sites of the brain in the presence of the matrix metalloproteinase 9 (MMP9) enzyme. It has also been observed that the driving force of hydrogel formation is a β-sheet secondary structure and π-π stacking interactions between Phe-Phe moieties. The hydrogel is able not only to promote neurite outgrowth of PC12-derived neurons and primary neurons cultured in its presence but also to nullify the toxic effects of anti-nerve growth factor (Anti-NGF)-induced neurons. It also promotes the expression of vital neuronal markers in rat cortical primary neurons, displays substantial potential in neuroregeneration, and also promotes fast recovery of the sham injured mice brain. Increased expression of reactive astrocytes in the hippocampal dentate gyrus region of the sham injured brain clearly suggests its tremendous ability in the neural repair of the damaged brain. Thus, we can convincingly state that our hydrogel is capable of repairing brain injury by mimicking an ECM-like environment and providing neuroprotection to the damaged neurons.

The small GTPase ARF6 regulates GABAergic synapse development

ADP ribosylation factors (ARFs) are a family of small GTPases composed of six members (ARF1–6) that control various cellular functions, including membrane trafficking and actin cytoskeletal rearrangement, in eukaryotic cells. Among them, ARF1 and ARF6 are the most studied in neurons, particularly at glutamatergic synapses, but their roles at GABAergic synapses have not been investigated. Here, we show that a subset of ARF6 protein is localized at GABAergic synapses in cultured hippocampal neurons. In addition, we found that knockdown (KD) of ARF6, but not ARF1, triggered a reduction in the number of GABAergic synaptic puncta in mature cultured neurons in an ARF activity-dependent manner. ARF6 KD also reduced GABAergic synaptic density in the mouse hippocampal dentate gyrus (DG) region. Furthermore, ARF6 KD in the DG increased seizure susceptibility in an induced epilepsy model. Viewed together, our results suggest that modulating ARF6 and its regulators could be a therapeutic strategy against brain pathologies involving hippocampal network dysfunction, such as epilepsy.

NF-κB "decoy" inhibits COX-2 expression in epileptic rat brain.

There is a need to investigate the role of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression in the epileptic rat brain and cultured hippocampal neurons. Immunofluorescence and polymerase chain reaction was used to detect the expression of nuclear factor kappa B and cyclooxygenase-2. In cultured hippocampal neurons and rat brain: the control group compared with the normal group, nuclear factor kappa B expression in the hippocampal dentate gyrus, cerebral cortex, the piriform cortex brain regions were significantly increased (P < 0.01). This is accompanied by a significant increase in cyclooxygenase-2 protein and mRNA expressions in the hippocampus (P < 0.01). In the experimental group compared to the control group, the nuclear factor-kappa B expression in the hippocampal dentate gyrus, cerebral cortex, piriform cortex, and other brain regions was significantly lower (P < 0.01), with the accompanying decrease in cyclooxygenase-2 protein and mRNA expression (P < 0.01) in the hippocampus. In conclusion, κB-decoy can inhibit nuclear factor kappa B activation in epileptic rat brain and cyclooxygenase-2 overexpression.

High Dietary Iron Disrupts Iron Homeostasis and Induces Amyloid-β and Phospho-τ Expression in the Hippocampus of Adult Wild-Type and APP/PS1 Transgenic Mice

ABSTRACTBackgroundBrain iron deposition is a feature of Alzheimer disease and may contribute to its development. However, the relative contribution of dietary iron remains unclear.ObjectivesWe investigated the impact of high dietary iron on brain pathological changes and cognitive function in adult wild-type (WT) mice and amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice.MethodsMale WT mice and APP/PS1 mice aged 10 wk were fed either a control diet (66 mg Fe/kg) (WT-Ctrl and APP/PS1-Ctrl) or a high iron diet (14 g Fe/kg) (WT-High Fe and APP/PS1-High Fe) for 20 wk. Iron concentrations in brain regions were measured by atomic absorption spectrophotometry. Brain iron staining and amyloid-β (Aβ) immunostaining were performed. Protein expressions in the hippocampus were determined by immunoblotting. Superoxide dismutase (SOD) activity and malondialdehyde concentration were examined. Cognitive functions were tested with the Morris water maze system.ResultsIn the hippocampus, APP/PS1-High Fe mice had significantly higher iron concentration (2.5-fold) and ferritin (2.0-fold) than APP/PS1-Ctrl mice (P < 0.001), and WT-High Fe mice had significantly higher ferritin (2.0-fold) than WT-Ctrl mice (P < 0.001). Interestingly, APP/PS1 mice had significantly higher iron concentration (2–3-fold) and ferritin (2–2.5-fold) than WT mice fed either diet (P < 0.001). Histological analysis indicated that iron accumulated in the hippocampal dentate gyrus region in APP/PS1 mice, consistent with the pattern of Aβ deposition. For both mouse strains, iron treatment induced Aβ and phospho-τ expression (1.5–3-fold) in the hippocampus, but had little impact on oxidative stress and cognitive function. Furthermore, APP/PS1 mice had significantly lower SOD activity and higher malondialdehyde concentration than WT mice in the hippocampus (P < 0.0001), paralleled by apparent cognitive dysfunction.ConclusionsDietary iron overload induces iron disorder and Aβ and phospho-τ expression in the hippocampus of adult WT and APP/PS1 transgenic mice.

Resveratrol reserved hypoxia-ischemia induced childhood hippocampal dysfunction and neurogenesis via improving mitochondrial dynamics

Early life stress usually causes the abnormal brain development and results in the onset of cognitive and emotional disorders in later childhood. Neonatal hypoxic ischemia (HI) causes dramatic brain damage in early life and resulted in serious impairment to brain development. Hippocampal neurogenesis, as one of the key structural plasticity to mediate animal behaviors, can be impact by neonatal HI until child stage. In our study, we identified the natural product resveratrol (RES) as the potential alternative therapy to improve brain functions of childhood mice after underwent neonatal HI. Treatment of RES improved the spatial learning and memory in morris water maze and increased the recognize ability in objective recognition task. Moreover, RES also attenuate the depressive and anxiety like mood in child mice after experiencing neonatal HI. Brain morphological study showed RES promote the proliferation of neural stem cells and increase the neuronal differentiation in hippocampal dentate gyrus (DG) region. Our in vitro study in C17.2 neural stem cell line demonstrated RES could prevent the mitochondrial fragmentation induced by hypoxia. Moreover, same effect was also observed in primary cultural neurons. To summarize, RES could prevent the cognitive deficit and depressive/anxiety mood in childhood with experience of neonatal HI via promoting hippocampal neurogenesis. Improving mitochondrial dynamics could be one of the key biological mechanisms underlying such effects of RES.

CXCR7 regulates epileptic seizures by controlling the synaptic activity of hippocampal granule cells

C–X–C motif chemokine receptor 7 (CXCR7), which mediates the immune response in the brain, was recently reported to regulate neurological functions. However, the role of CXCR7 in epilepsy remains unclear. Here, we found that CXCR7 was upregulated in the hippocampal dentate gyrus (DG) of mice subjected to kainic acid (KA)-induced epilepsy and in the brain tissues of patients with temporal lobe epilepsy. Silencing CXCR7 in the hippocampal DG region exerted an antiepileptic effect on the KA-induced mouse model of epilepsy, whereas CXCR7 overexpression produced a seizure-aggravating effect. Mechanistically, CXCR7 selectively regulated N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic neurotransmission in hippocampal dentate granule cells by modulating the cell membrane expression of the NMDAR subunit2A, which requires the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Thus, CXCR7 may regulate epileptic seizures and represents a novel target for antiepileptic treatments.

Microglia Activated by Excess Cortisol Induce HMGB1 Acetylation and Neuroinflammation in the Hippocampal DG Region of Mice Following Cold Exposure.

Cold stress can induce neuroinflammation in the hippocampal dentate gyrus (DG), but the mechanism underlying neuronal apoptosis induced by cold stress is not well-understood. To address this issue, male and female C57BL/6 mice were exposed to a temperature of 4 °C for 3 h per day for 1 week, and glial cell activation, neuronal apoptosis, and neuroinflammation were evaluated by western blotting, immunofluorescence, terminal deoxynucleotidyl transferase 2’-deoxyuridine 5’-triphosphate (dUTP) nick end labeling, Nissl staining, and immunohistochemistry. Additionally, BV2 cells were treated with different concentrations of cortisol (CORT) for 3 h to mimic stress and molecular changes were assessed by western blotting, immunofluorescence, and co-immunoprecipitation. We found that excess CORT activated glial cells and increased neuroinflammation in the DG of mice exposed to cold temperatures, which was associated with increased acetylation and nuclear factor-κB signaling. These effects were mediated by the acetylation of lysine 9 of histone 3 and lysine 310 of p65, which resulted in increased mitogen-activated protein kinase phosphorylation, nuclear translocation of p65, microglia activation, and acetylation of high-mobility group box 1. Neuroinflammation was more severe in male compared to female mice. These findings provide new insight into the mechanisms of the cold stress response, which can inform the development of new strategies to combat the effects of hypothermia.