Granular Cells Of Dentate Gyrus Research Articles

Does Fibromyalgia Affect the Structure of the Dentate Gyrus?

Abstract Background The hippocampus is considered an important component of the limbic system of the brain. It is involved in memory and functional diversities. The term hippocampus typically refers to the dentate gyrus and the hippocampus proper, the cornu ammonis (CA). Fibromyalgia is known to cause memory and cognitive function impairment and is characterized by causing chronic widespread muscular pain. Aim of the Work The aim of this work was to study the possible structural and morphometric changes in rats’ hippocampal dentate gyrus induced by repeated intramuscular injections of acidic saline in the left gastrocnemius and to compare it with the control. Material and Methods Fifty-four adult female albino Swiss rats were divided into three equal groups (18 rats each): control group (I), natural saline group (II) and acidic saline group (III). Group I received no medication, group II received two i.m. injections of 100 μl saline (pH 7.4) into the left gastrocnemius muscle at day 0 and 5 respectively under sedation with halothane (2-4%), while group III received two i.m. injections of 100 μl saline (pH 4) into the left gastrocnemius muscle at day 0 and 5 respectively under sedation with halothane (2-4%). Rats of each group were further subdivided into 3 subgroups (a, b, c) 6 rats each. Rats were sacrificed by decapitation at day 7, 14, 21 from the start of experiment and their brains were excised. Results Histological examination of H&E-stained sections of groups I and II showed no difference and were both considered control groups. The dentate region was formed of three laminae: the molecular, granular and polymorphic. The granular cell layer is the principal layer separating the molecular and polymorphic layers and was formed of aggregation of granular cells. They were rounded to oval with large vesicular nuclei and .prominent nucleoli The examination of the H&E-stained sections of rats’ dentate gyrus granular cells (DG) appeared darkly stained with pyknotic nuclei I group III as compared to the control. Glial cells slightly increased especially among molecular and polymorphic layers. Neurofibrillary tangles and vacuolations started to appear in silver-stained sections. The neurodegenerative findings started to be more notable in subgroup (b) then became more prevalent in subgroup(c) together with the appearance of clear areas among the sub granular zone. Morphometric studies detected non-significant difference in mean area percentage of astrocytes between group I and group II subgroups. The statistical analysis demonstrated high significant difference in mean area percentage of astrocytes between control groups and acidic saline groups. Evident gliosis was confirmed in group IIIc when the astrocytes percentage areas become very highly significantly increased compared to groups I and II. Conclusion In conclusion, repeated acidic saline injection induced dentate gyrus alterations obvious but minimal at week 1 and become intense at week 3 after the first injection. This effect ended with neuronal death and gliosis.

The effects of carvacrol and p-cymene on Aβ1-42 -induced long-term potentiation deficit in male rats.

Alzheimer's disease (AD) is the most common type of dementia in which oxidative stress plays an important role. In this disease, learning and memory and the cellular mechanism associated with it, long-term potentiation (LTP), are impaired. Considering the beneficial effects of carvacrol (CAR) and p-cymene against AD, their effect was assessed on in vivo hippocampal LTP in the perforant pathway (PP)-dentate gyrus (DG) pathway in an Aβ1-42 -induced rat model of AD. Male Wistar rats were randomly assigned to five groups: sham: intracerebroventricular (ICV) injection of phosphate-buffered saline, Aβ: ICV Aβ1-42 injections, Aβ + CAR (50 mg/kg), Aβ + p-cymene (50 mg/kg), and Aβ + CAR + p-cymene. Administration of CAR and p-cymene was done by gavage daily 4 weeks before and 4 weeks after the Aβ injection. The population spike (PS) amplitude and field excitatory postsynaptic potentials (fEPSP) slope were determined in DG against the applied stimulation to the PP. Aβ-treated rats exhibited impaired LTP induction in the PP-DG synapses, resulting in significant reduction in both fEPSP slope and PS amplitude compared to the sham animals. Aβ-treated rats consumed either CAR or p-cymene separately (but not their combination), and showed an enhancement in fEPSP slope and PS amplitude of the DG granular cells. These data indicate that CAR or p-cymene can ameliorate Aβ-associated changes in synaptic plasticity. Surprisingly, the combination of CAR and p-cymene did not yield the same effect, suggesting a potential interaction between the two substances.

Neuroprotective Effects of Ferrostatin and Necrostatin Against Entorhinal Amyloidopathy-Induced Electrophysiological Alterations Mediated by voltage-gated Ca2+ Channels in the Dentate Gyrus Granular Cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aβ) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aβ25-35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aβ25-35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aβ25-35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca2+ channels in their effects. After inducing Aβ25-35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aβ25-35 neurotoxicity induced a considerable reduction in input resistance (Rin), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aβ on the Ca2+ channel current and neuronal function, which might take place in neurons during the development of AD.

Nanoscale‐alumina induced cognitive dysfunction in mice related to hippocampal structural changes: A stereological study

AbstractBackgroundAluminum (Al) is known to induce neurotoxicity in both humans and rodents. Recent evidence has indicated that the toxicity of Al Oxide (Al2O3) Nanoparticles (Al‐NP), one of the most abundantly used engineered nanoparticles, is far greater than that of Al itself. To date, however, no information is available regarding the effect of Al‐NP on the stereological parameters of hippocampus. In particular, no stereological studies have evaluated the effect of Al‐NP on hippocampal CA1, dentate gyrus volume, and number of pyramidal and granular cells.MethodAdult male NMRI mice were treated with AlNP in dose 10 mg/kg/oral gavage for 5 days. The test session of novel object recognition (NOR) task was performed on day 5. Following the NOR test, the hippocampi were analyzed for stereological and apoptotic.ResultThe results demonstrated that the five‐day Al‐NP ingestion elicited a reduced preference to explore a novel object in the novel object recognition test (a hippocampal‐dependent task). Perhaps contributing to this memory deficit, Al‐NP induced additional alterations in the hippocampus of male NMRI mice in terms of (1) hippocampal volume (decreased the volume of the whole hippocampus, CA1, and dentate gyrus regions), (2) cell number (decreased the number of CA1 pyramidal neurons and dentate gyrus granular cells), and (3) increased cleaved caspase‐3 in the whole hippocampus.ConclusionThese results provided new mechanistic insight to understand the impairing effect of AL‐NP on the hippocampal function and structure.

A stereological study reveals nanoscale-alumina induces cognitive dysfunction in mice related to hippocampal structural changes

Aluminum (Al) is known to induce neurotoxicity in both humans and rodents. Recent evidence has indicated that the toxicity of Al Oxide (Al2O3) nanoparticles (Al-NP), one of the most abundantly used engineered nanoparticles, is far greater than that of Al itself. To date, however, no information is available regarding the effect of Al-NP on the stereological parameters of hippocampus. In particular, no stereological studies have evaluated the effect of Al-NP on hippocampal CA1, dentate gyrus volume, and number of pyramidal and granular cells. Thus, the present study aimed to take a multidimensional approach to assess the concomitant cognitive, stereological, and apoptotic changes induced by a five-day Al-NP ingestion (10 mg/kg/day) in mice. The results demonstrated that the five-day Al-NP ingestion elicited a reduced preference to explore a novel object in the novel object recognition test (a hippocampal-dependent task). Perhaps contributing to this memory deficit, Al-NP induced additional alterations in the hippocampus of male NMRI mice in terms of (1) hippocampal volume (decreased the volume of the whole hippocampus, CA1, and dentate gyrus regions), (2) cell number (decreased the number of CA1 pyramidal neurons and dentate gyrus granular cells), and (3) increased cleaved caspase-3 in the whole hippocampus. These results provided new mechanistic insight to understand the impairing effect of AL-NP on the hippocampal function and structure.

The effects of febrile status epilepticus on hippocampal circuit function

Rationale . Febrile status epilepticus (FSE) in children has been linked to cognitive deficits and epileptogenesis later in life. Recent evidence in the experimental hyperthermia animal model of FSE (eFSE) has shown that spatial memory deficits may be a result of structural and functional changes to specific cells types in the hippocampal circuit. Experimentally, the effects of FSE on cognitive deficits are mitigated by the blockade of neuron-restrictive silencing factor (NRSF) binding to its target chromatin. The goal of the current study is to understand the relationship between cognitive outcomes and the efficacy of hippocampal circuit throughput and whether this relationship is altered by NRSF treatment post FSE. Methods . Postnatal day 10–11 male Sprague-Dawley rat pups (N = 13) underwent procedures for eFSE hyperthermia induction. Pups were placed, two at a time, inside a 3 L flask, the bottom of which was lined with absorbent paper. Prior to hyperthermia, a glycerin-based hydrating ointment was applied to the paws, ears, and tail of the pups to mitigate potential hyperthermic skin injury. Pups were subjected to a continuous stream of warm air until hyperkinesis and chewing automatisms were identified. Seizure behaviors typically progressed to clonic movements and eventual tonic extension. After approximately 60 min of hyperthermia, eFSE pups were immersed in cool water (−23.0 °C) to aid in the return of core temperature to normothermia and to promote seizure cessation. Pups were then placed on a euthermic pad maintained at 37 °C for 30 min, and then were returned to their home cage and dam. An intact NRSE or a scrambled (SCR) NRSE sequence oligodeoxynucleotide (ODN) was infused ICV 3 h post eFSE (Sigma-Aldrich). Four experimental groups were used in these experiments. The first was a non-eFSE control animal that received a scrambled sequence of NRSE (CTL-SCR). The second was a non-eFSE control who received the NRSE sequenced ODN (CTL-NRSE). The third were eFSE animals infused with scrambled ODN (eFSE-SCR). Finally, there was a group of eFSE animals infused with NRSE ODNs (eFSE-NRSE). 2.5 nmol of either NRSE or SCR ODN were infused bilaterally into the ventricles at a rate of 0.5 l/min and a volume of 2.5 l/hemispheres. ICV infusions were repeated 24 h after eFSE. While blind to treatment group, treated and untreated rats were trained on an active avoidance spatial task on a rotating arena in order to measure cognitive outcomes in relation to treatment condition. To measure circuit throughput in the dorsal hippocampus across experimental conditions, we utilized 64-channel silicon probes to measure EEGs and neuronal action potentials across synaptic input regions along the apical and basal dendrites of CA1 pyramidal cells and dentate gyrus granular cells under urethane-anesthesia. Following acute probe recording experiments, animals were perfused with fixative and brain tissue was harvested for immunohistochemical procedures. Results . Preliminary data suggests group differences in the ability to learn the active avoidance spatial task while analysis of cell spiking data suggests interhemispheric differences in neuronal activity across all groups. Acute recordings also revealed that there were notable hallmarks during EEG recordings across animals and groups in theta-, beta-, and gamma- range oscillations in deep CA1; dentate gyrus EEGs; and also the response to mechanical perturbation when the probe was lowered.

Glial Cell Architecture Dynamics in Dentate Gyrus and CA4 Area of Wistar Rat Hippocampus Following 20-minute Occlusion of Common Carotid Arteries

Aim. To study the distribution and spatial organization of dentate gyrus (DG) astrocytes and CA4 area of hippocampus of Wistar rats following 20-minute occlusion of common carotid arteries (OCCA) compared to sham-operated control animals.Material and methods. Histological (Nissl staining with hematoxylin and eosin), immunohistochemical (GFAP, MAP-2) and morphometric methods were used. Astrocytes and neurons in control (sham-operated animals, n = 5) group, after 6 hours (n=5), 1 days (n=5), 3 days (n=5), 7 days (n=5), 14 days (n=5) and 30 days (n=5) after 20-minute OCCA were studied on thin (4 µm) serial frontal sections of the hippocampus. Fractal analysis (ImageJ 1.52; fraclac 2.5 plugin) was used to obtain additional quantitative information on the spatial organization of astrocyte networks. Statistical hypotheses were tested using nonparametric criteria.Results. 30 days after the 20-minute OCCA, only 5.3% of CA4 neurons were irreversibly destroyed and the total numerical density of DG granular cells remained at the control level. Hypertrophy and increased complexity of the spatial organization of astrocyte processes were observed 6 hours and 1 day after OCCA and persisted for 30 days. Astrogliosis was accompanied by an increased relative area of GFAP-positive material and fractal dimension and reduced lacunarity of the astrocyte network. The latter was especially evident in 1, 14 and 30 days after the OCCA.Conclusion. After the 20-minute OCCA, the density of GFAP-positive material increased, the fibroarchitecture reorganized and gained more complexity due to the branching of astrocyte processes. At the same time, the total numerical density of neurons changed only slightly. All this indicated the probable role of astrocytes in post-ischemic activation of natural neuroprotection mechanisms.

Coenzyme Q10 supplementation reverses diabetes-related impairments in long-term potentiation induction in hippocampal dentate gyrus granular cells: An in vivo study

Diabetes mellitus (DM) is associated with impaired hippocampal synaptic plasticity. Coenzyme Q10 (CoQ10) acts as an antioxidant and exerts neuroprotective effects. Accordingly, this study aimed at evaluating the effects of CoQ10 on hippocampal long-term potentiation (LTP) and paired-pulse facilitation (PPF) in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were randomly divided into six groups (n = 8 per group) as follows and treated for 90 days: the control, control + low dose of CoQ10 (100 mg/kg), control + high dose of CoQ10 (600 mg/kg), diabetic, diabetic + low dose of CoQ10, and diabetic + high dose of CoQ10 groups. Diabetes was induced by a single intraperitoneal injection of 50 mg/kg STZ. The population spike (PS) amplitude and slope of excitatory post synaptic potentials (EPSPs) were measured in dentate gyrus (DG) area in response to the stimulation applied to the perforant path (PP). The results showed that the STZ-induced diabetes impaired LTP induction in the PP-DG synapses. This finding is supported by the decreased EPSP slope and PS amplitude of LTP (P < 0.05). Both low- and high-dose CoQ10 supplementation in the control and diabetic animals enhanced EPSP slope and PS amplitude of LTP in the granular cells of DG (P < 0.05). PPF was affected by LTP induction in diabetic animals receiving the high dose of CoQ10 (P < 0.05). It is suggested that CoQ10 administration could attenuate deteriorative effect of STZ-induced diabetes on in vivo LTP in the DG. The enhanced transmitter release can be partly one of the possible underlying mechanism(s) responsible for the LTP induction in the diabetic animals treated with CoQ10.

Preconditioning with toll-like receptor agonists attenuates seizure activity and neuronal hyperexcitability in the pilocarpine rat model of epilepsy

Neuroinflammation plays an important role in epileptic disorders. Toll-like receptors (TLRs) are the key signal transduction tools by which neuroinflammation may promote epileptogenesis. Depending on the stimulus nature, TLRs may engage a distinct signaling pathway. We examined the impact of early minor activation of TLR4 and TLR2 on the severity of seizure in the pilocarpine rat model of temporal lobe epilepsy (TLE). One μg of Lipopolysaccharides (LPS), Monophosphoryl lipid A (MPL), Pam3Cysor or vehicles were microinjected into the right lateral ventricle of the male Wistar rats. 24 h later, seizures were induced by intraperitoneal injection of pilocarpine, and seizure-related behaviors were monitored. 24 h after seizure induction, the hippocampal level of pro/anti-inflammatory mediators and electrophysiological properties of the dentate gyrus (DG) granular cells were investigated by western blot and whole cell patch clamp techniques, respectively. Pretreatment with TLR ligands resulted in decreased seizure severity, lower hippocampal pro-inflammatory (IL-1β and IL-6) cytokines and higher anti-inflammatory (IL-10 and TGF- β) mediators in the pilocarpine-treated rats. Pilocarpine induced profound hyperexcitability in the DG granule cells accompanied by potentiated excitatory postsynaptic currents (EPSCs) and dampened inhibitory postsynaptic currents (IPSCs), in contrast to the control group. However, pretreatment with TLR ligands preserved almost normal excitability and synaptic transmission against the pilocarpine. In conclusion, early activation of TLR4 and TLR2, probably through preserving normal hippocampal cytokine profile and neuronal function attenuates seizure severity in the rat model of TLE.

ADAMTS18 Deficiency Affects Neuronal Morphogenesis and Reduces the Levels of Depression-like Behaviors in Mice

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that modify extracellular matrix components and play crucial roles in development and numerous diseases. ADAMTS18 is a member of the ADAMTS family, and genome-wide association studies made an initial association of ADAMTS18 with white matter integrity in healthy people of 72–74 years old. However, the potential roles of ADAMTS18 in central nervous system remain unclear. In this study, we showed that Adamts18 mRNA is highly abundant in developing brains, especially in the cerebellum granular cell layer and the hippocampus dentate gyrus (DG) granular cell layer. Adamts18 knockout (KO) mice displayed higher dendritic branching complexity and spine density on hippocampal DG granular cells. Behavioral tests showed that Adamts18 KO mice had reduced levels of depression-like behaviors compared to their wild-type (WT) littermates. The increased neurite formation could be attributed in part to reduced phosphorylation levels of the collapsin response mediator protein-2 (CRMP2) due to activation of the laminin/PI3K/AKT/GSK-3β signaling pathway. Our findings revealed a critical role of ADAMTS18 in neuronal morphogenesis and emotional control in mice.

Coriolus versicolor biomass increases dendritic arborization of newly-generated neurons in mouse hippocampal dentate gyrus.

Brain cognitive reserve refers to the ability of the brain to manage different challenges that arise throughout life, making it resilient to neuropathology. Hippocampal adult neurogenesis has been considered to be a relevant contributor for brain cognitive reserve and brain plasticity. Coriolus versicolor (CV), a common healthful mushroom, has been receiving increasing attention by its antitumoral, anti-inflammatory, antioxidant, antibacterial, and immunomodulatory properties, including in the hippocampus. Herein, we evaluated whether CV biomass oral administration for 2.5 months enhances hippocampal neurogenic reserve under normal/physiological conditions, by quantifying hippocampal dentate gyrus (DG) granular cell layer (GCL) and subgranular zone (SGZ) volumes, proliferation, number and dendritic complexity features of hippocampal newly-generated neurons. We also analyzed β-catenin levels in DG newly-generated immature neurons, because it plays a major role in neurogenesis. Although no differences were observed in the volume of GCL and SGZ layers, in proliferation and in the number of newly-generated neurons of controls and CV-administered mice, we found that CV administration promotes a significant increase in dendritic length and branching and total dendritic volume of immature neurons, suggesting a positive effect of oral CV administration in the hippocampal neurogenic reserve. We also observed that β-catenin levels are increased both in the nucleus and cytoplasm of DG immature neurons, suggesting that Wnt/β-catenin signalling may play an important role in the CV positive effect on the differentiation of these cells. These data unveil a so far unexplored neurogenic potential of CV supplementation, which emerges as a possible preventive strategy for different neurological conditions.

The impact of epilepsy duration in a series of patients with mesial temporal lobe epilepsy due to unilateral hippocampal sclerosis

PurposeTo evaluate if the duration of epilepsy influences MRI volumes of the hippocampus, amygdala, parahippocampal gyrus, entorhinal cortex and temporal pole of both hemispheres and epileptogenic hippocampus neuronal cell density and dentate gyrus granular cells distribution in patients with refractory mesial temporal lobe epilepsy due to hippocampal sclerosis (MTLE/HS). MethodsSeventy-seven patients with refractory MTLE/HS submitted to surgery were included. Histopathological analysis included: (1) quantitative: hippocampal subfields and total estimated hippocampal cell density (HCD), thickness of the dentate gyrus – normal, thinning or dispersion; (2) qualitative: type of HS and granule cells pathology in the dentate gyrus (normal, neuronal cell loss, dispersion and bilamination). Automated MRI-derived measurements from bilateral temporal structures (hippocampus, amygdala, parahippocampal gyrus, temporal pole, entorhinal cortex) were obtained for 58 subjects. Histopathological and imaging findings were compared with data from specimens obtained in autopsies of age-matched individuals and living controls, respectively, and the data were adjusted for the age at epilepsy onset and the frequency of focal impaired awareness seizures/month. ResultsForty-two (54.5%) patients presented right HS. The greater the duration of epilepsy, the smaller the total estimated HCD (p = 0.025; r = −0.259). Patients with a normal distribution of the granular cells had a shorter epilepsy duration than those with dispersion (p = 0.018) or thinning (p = 0.031). A reduced ipsilateral hippocampal volume (r = −0.551, p = 0.017) and a smaller hippocampal asymmetry index (r = −0.414, p = 0.002) were correlated to a longer epilepsy duration. The estimated HCD was correlated to the volume of the ipsilateral hippocampus (r = 0.420, p = 0.001). ConclusionOur study showed an increasing atrophy of the ipsilateral hippocampus in patients with a longer epilepsy duration. Our data suggest that this reduction in hippocampal volume is related to neuronal loss. Besides that, we also showed an increased probability of exhibiting an abnormal distribution of the granular cells in the dentate gyrus in patients with longer epilepsy duration.

Decreased hippocampal cell proliferation in mice with experimental antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, which may trigger vascular thrombosis with consecutive infarcts. However, cognitive dysfunctions representing one of the most commonest neuropsychiatric symptoms are frequently present despite the absence of any ischemic brain lesions. Data on the structural and functional basis of the neuropsychiatric symptoms are sparse. To examine the effect of APS on hippocampal neurogenesis and on white matter, we induced experimental APS (eAPS) in adult female Balb/C mice by immunization with β2-glycoprotein 1. To investigate cell proliferation in the dentate gyrus granular cell layer (DG GCL), eAPS and control mice (n = 5, each) were injected with 5-bromo-2'-deoxyuridine (BrdU) once a day for 10 subsequent days. Sixteen weeks after immunization, eAPS resulted in a significant reduction of BrdU-positive cells in the DG GCL compared to control animals. However, double staining with doublecortin and NeuN revealed a largely preserved neurogenesis. Ultrastructural analysis of corpus callosum (CC) axons in eAPS (n = 6) and control mice (n = 7) revealed no significant changes in CC axon diameter or g-ratio. In conclusion, decreased cellular proliferation in the hippocampus of eAPS mice indicates a limited regenerative potential and may represent one neuropathological substrate of cognitive changes in APS while evidence for alterations of white matter integrity is lacking.

Hippocampal involvement in nonpathological déjà vu: Subfield vulnerability rather than temporal lobe epilepsy equivalent.

IntroductionMorphological correlates of nonpathological déjà vu (DV) have been identified recently within the human brain. Significantly reduced gray matter volume (GMV) within a set of cortical and subcortical regions reported in subjects experiencing DV seems to mirror the distribution of GMV reduction in mesial temporal lobe epilepsy (MTLE) patients but vary in terms of the hippocampus. Another condition associated with hippocampal GMV reduction and DV alike disturbance in memory processing is schizophrenia (SCH). Here, we tested the hypothesis that hippocampal involvement in nonpathological DV resembles more closely the pattern of GMV decrease observed in MTLE compared with that occurring in SCH.MethodsUsing automated segmentation of the MRI data we compared the medians of GMV within 12 specific hippocampal subfields in healthy individuals that do (DV+; N = 87) and do not report déjà vu experience (DV−; N = 26), and patients with MTLE (N = 47) and SCH (N = 29). By Pearson correlation, we then evaluated the similarity of MTLE and SCH groups to DV+ group with respect to spatial distribution of GMV deviation from DV− group.ResultsSignificant GMV decrease was found in MTLE group in most of the subfields. There were just trends in the hippocampal GMV decrease found in DV+ or SCH groups. Concerning the spatial distribution of GMV decrease, we revealed statistically significant correlation for the left hippocampus for SCH vs DV+. Otherwise there was no statistically significant correlation.ConclusionsOur findings reveal structural features of hippocampal involvement in nonpathological DV, MTLE, and SCH. Despite our expectations, the pattern of GMV reduction in the DV+ relative to the DV− group does not resemble the pattern observed in MTLE any more than that observed in SCH. The highly similar patterns of the three clinical groups rather suggest an increased vulnerability of certain hippocampal subfields; namely, Cornu Ammonis (CA)4, CA3, dentate gyrus granular cell layer (GC‐DG), hippocampal–amygdaloid transition area (HATA) and subiculum.

Orexin 1 and orexin 2 receptor antagonism in the basolateral amygdala modulate long-term potentiation of the population spike in the perforant path-dentate gyrus-evoked field potential in rats.

Involvement of amygdalo-hippocampal substructures in patients with narcolepsy due to deficiencies in the orexinergic system, and the presence of hippocampus-dependent memory impairments in this disorder, have led us to investigate the effects of orexin 1 and 2 receptor antagonism in the basolateral amygdala (BLA) on long-term potentiation (LTP) of dentate gyrus (DG) granular cells. We used a 200-Hz high-frequency stimulation protocol in anesthetized rats. We studied the long-term synaptic plasticity of perforant path-dentate gyrus granule cells following the inactivation of orexin receptors before and after tetanic stimulation. LTP of the DG population spike was attenuated in the presence of orexin 1 and 2 receptor antagonism (treatment with SB-334867-A and TCS-OX2-29, respectively) in the BLA when compared to that observed following treatment with dimethyl sulfoxide (DMSO). However, the population excitatory post-synaptic potentials were not affected. Moreover, when orexin 1 and 2 receptors in the BLA were blocked after LTP induction, there were no differences between the DMSO and treatment groups. Our findings suggest that the orexinergic system of the BLA plays a modulatory role in the regulation of hippocampal plasticity in rats.

Restorative effects of curcumin on sleep-deprivation induced memory impairments and structural changes of the hippocampus in a rat model

The present study examined the consequences of rapid eye-movement sleep-deprivation (REM-SD) with or without curcumin treatment. The outcome measures comprised quantitative features in the three-dimensional reconstruction (3DR) CA1 and dentate gyrus in experimental and control animals using stereological procedures.Male rats were arbitrarily assigned to nine groups based on the intervention and treatment administered including: 1-cage control+distilled water, 2-cage control+curcumin (100mg/kg/day), 3-cage control+olive oil, 4-REM-SD+distilled water, 5-REM-SD+curcumin, 6-REM-SD+olive oil, 7-grid-floor control+distilled water, 8-grid-floor control+curcumin, and 9-grid-floor control+olive oil. Animals in the latter three groups were placed on wire-mesh grids in the sleep-deprivation box. REM-SD was induced by an apparatus comprising a water tank and multiple platforms. After a period of 21days, rats were submitted to the novel object-recognition task. Later, their brains were excised and evaluated using stereological methods.Our results indicated a respective 29% and 31% reduction in the total volume of CA1, and dentate gyrus in REM-SD+distilled water group as compared to the grid-floor control+distilled water group (p<0.05). Other than the above, the overall number of the pyramidal cells of CA1 and granular cells of dentate gyrus in the sleep-deprived group were found to be reduced by 48% and 25%, respectively. The REM-SD+distilled water group also exhibited impaired object recognition memory and deformed three-dimensional reconstructions of these regions. The volume, cell number, reconstruction, object recognition time, and body weight were however recovered in the REM-SD+curcumin compared to the REM-SD+distilled water group. This suggests the potential neuro-restorative effects of curcumin in our model.

FTY720/fingolimod, an oral S1PR modulator, mitigates radiation induced cognitive deficits.

This study evaluates FTY720/Fingolimod, modulator of sphingosine-1-phosphate (S1P) receptor, as a potential mitigator of radiation-induced neurocognitive dysfunction. To study radiation-induced neurocognitive deficits, 6 week-old C57/Bl/6J mice received 0 or 7Gy cranial irradiation and were treated with FTY720 or vehicle for seven weeks. Fear conditioning and Morris water maze were then employed to test learning and memory. Immunohistochemical staining for neural progenitor cells (NPCs) and mature neurons was used to assess changes in hippocampal neurogenesis. To test effects on tumor growth, mice harboring brain tumor xenografts were treated with FTY720 or vehicle for six weeks. In irradiated mice, learning deficits were manifested by significantly longer latency times in the Morris Water Maze compared to non-irradiated controls (p=0.001). The deficits were fully restored by FTY720. In irradiated brains, FTY720 maintained the cytoarchitecture of the dentate gyrus granular cell layer and partially restored the pool of NPC. In mice harboring brain tumor stem cell (BTSC) xenografts FTY720 delayed tumor growth and improved survival (p=0.012). FTY720 mitigates radiation-induced learning dysfunction. A partial restoration of neurogenesis was observed. Furthermore, FTY720 appears to delay tumor growth and improve survival in a xenograft glioma mouse model.

Overexpression of Mineralocorticoid Receptors in the Mouse Forebrain Partly Alleviates the Effects of Chronic Early Life Stress on Spatial Memory, Neurogenesis and Synaptic Function in the Dentate Gyrus.

Evidence from human studies suggests that high expression of brain mineralocorticoid receptors (MR) may promote resilience against negative consequences of stress exposure, including childhood trauma. We examined, in mice, whether brain MR overexpression can alleviate the effects of chronic early life stress (ELS) on contextual memory formation under low and high stress conditions, and neurogenesis and synaptic function of dentate gyrus granular cells. Male mice were exposed to ELS by housing the dam with limited nesting and bedding material from postnatal day (PND) 2 to 9. We investigated the moderating role of MRs by using forebrain-specific transgenic MR overexpression (MR-tg) mice. Low-stress contextual (i.e., object relocation) memory formation was hampered by ELS in wildtype but not MR-tg mice. Anxiety like behavior and high-stress contextual (i.e., fear) memory formation were unaffected by ELS and/or MR expression level. At the cellular level, an interaction effect was observed between ELS and MR overexpression on the number of doublecortin-positive cells, with a significant difference between the wildtype ELS and MR-tg ELS groups. No interaction was found regarding Ki-67 and BrdU staining. A significant interaction between ELS and MR expression was further observed with regard to mEPSCs and mIPSC frequency. The ratio of evoked EPSC/IPSC or NMDA/AMPA responses was unaffected. Overall, these results suggest that ELS affects contextual memory formation under low stress conditions as well as neurogenesis and synaptic transmission in dentate granule cells, an effect that can be alleviated by MR-overexpression.

Abstract PR144

Background & Objectives: Normal hippocampal neurogenesis and function rely on the elaborate balance between proliferation and differentiation of neural progenitor cells (NPCs). Yet, the relationship between proliferation and differentiation of NPCs in anesthesia-induced impaired neurogenesis and cognitive deficits in the developing brain is still poorly understood. The canonical Wnt signaling pathway is critical to the regulation of the cell fate decision of hippocampal NPCs. This study was designed to investigate the effects of isoflurane on the initial cell fate of NPCs and Wnt signaling in the hippocampus of neonatal rats. Materials & Methods: Bromodeoxyuridine (BrdU), an S-phase marker, was injected before and after 4 h of 1.5% isoflurane anesthesia in postnatal day 7 (P7) rats to label NPCs and their progeny in dentate gyrus. Proliferation and neuronal differentiation of NPCs were assessed 24h after exposure, and survival of newborn neurons was quantified one week after exposure using immunofluorescence. Rat hippocampi were harvested at the end of anesthesia for western blot to determine the levels of β-catenin and GSK3β. At 4 weeks of age, rats were evaluated for spatial learning and memory using Morris water maze. Results: Isoflurane significantly decreased proliferation but increased precocious neuronal differentiation of NPCs, leading to decreased numbers of newborn granular cells in dentate gyrus one week after exposure. Isoflurane decreased the hippocampal β-catenin level and enhanced GSK3β activity by suppressing the phosphorylation of GSK3β on Ser9. Neonatal exposure to isoflurane impaired the spatial learning performance in rats later in life.Conclusion: Our findings suggest that isoflurane anesthesia in neonatal rats may disrupt the homeostatic control on the hippocampal progenitors by switching the balance from proliferation to premature neuronal differentiation, which is associated with an inhibition of Wnt signaling in the hippocampus. Disclosure of Interest: None declared

MiR-155 Is Essential for Inflammation-Induced Hippocampal Neurogenic Dysfunction.

Peripheral and CNS inflammation leads to aberrations in developmental and postnatal neurogenesis, yet little is known about the mechanism linking inflammation to neurogenic abnormalities. Specific miRs regulate peripheral and CNS inflammatory responses. miR-155 is the most significantly upregulated miR in primary murine microglia stimulated with lipopolysaccharide (LPS), a proinflammatory Toll-Like Receptor 4 ligand. Here, we demonstrate that miR-155 is essential for robust IL6 gene induction in microglia under LPS stimulation in vitro. LPS-stimulated microglia enhance astrogliogenesis of cocultured neural stem cells (NSCs), whereas blockade of IL6 or genetic ablation of microglial miR-155 restores neural differentiation. miR-155 knock-out mice show reversal of LPS-induced neurogenic deficits and microglial activation in vivo. Moreover, mice with transgenic elevated expression of miR-155 in nestin-positive neural and hematopoietic stem cells, including microglia, show increased cell proliferation and ectopically localized doublecortin-positive immature neurons and radial glia-like cells in the hippocampal dentate gyrus (DG) granular cell layer. Microglia have proliferative and neurogenic effects on NSCs, which are significantly altered by microglial miR-155 overexpression. In addition, miR-155 elevation leads to increased microglial numbers and amoeboid morphology in the DG. Our study demonstrates that miR-155 is essential for inflammation-induced neurogenic deficits via microglial activation and induction of IL6 and is sufficient for disrupting normal hippocampal development.