Granular Cell Layer Of Dentate Gyrus Research Articles

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.

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.

Zinc supplementation normalizes gene expression and enhances neurogenesis in a rat model of traumatic brain injury

New interventions are needed to improve resilience to traumatic brain injury (TBI). To examine the role of zinc, rats were fed a zinc adequate (30 ppm) or supplemented (180 ppm) diet for 4 wks followed by a frontal cortex TBI using controlled cortical impact. Chronic zinc supplementation significantly improved spatial learning and memory, and reduced anxiety and depression‐like behaviors. Mechanistically, we hypothesized that zinc supplementation would prevent injury‐induced changes in gene expression and enhance hippocampal stem cell proliferation and survival. Hippocampal RNA was extracted 48 h after TBI to analyze mRNA abundance via the NimbleGen platform microarray. TBI altered the expression of over 170 mRNAs, approximately 70 of which were normalized in rats supplemented with zinc (p<0.01). We identified genes involved in cell proliferation, apoptosis, survival, repair, and differentiation. Rats were also injected with the thymidine analogue EdU to label proliferating cells in the hippocampus. TBI doubled the number of proliferating cells in the dentate gyrus granular cell layer 24 h post‐injury (p<0.05), and supplemental zinc increased this number by an additional 2 fold (p<0.05). Ongoing work is characterizing the long‐term fate of these cells. These data show that zinc can be a novel and effective strategy for preventing adverse cellular, molecular, and behavioral outcomes associated with TBI.Grant Funding Source: Department of Defense/US Army MRMC

Expression of Steroid Receptor Coactivator-1 Was Regulated by Postnatal Development but Not Ovariectomy in the Hippocampus of Rats

Female steroids such as estrogens and progestins, through their nuclear receptors, play important roles in regulation of the structure and function of the hippocampus. Steroid receptor coactivator-1 (SRC-1) has been detected in embryonic and/or adult hippocampus of rodents, and SRC-1 null mice showed significantly longer escape latency in the Morris maze test, indicating a role of this coactivator in the regulation of hippocampus function. Whether this is regulated by development and circulating ovary hormones remains unclear. In this study, postnatal development and ovariectomy for regulation of hippocampal SRC-1 in female rats were investigated by Western blot and immunohistochemistry. The results showed that SRC-1-immunopositive materials were predominantly detected in the CA1 pyramidal cell layer and dentate gyrus granular cell layer. Very low levels of SRC-1 were detected at postnatal day 0, but they increased with development. The highest levels of SRC-1 were detected at postnatal day 14, then they decreased to adult levels from postnatal day 30; significantly lower levels of SRC-1 were detected in the middle-aged (18-month-old) hippocampus when compared with that of the adult. Western blot and immunohistochemistry demonstrated that hippocampal SRC-1 expression was unchanged after ovariectomy, no significant differences were noticed from day 3 to 8 weeks postsurgery when compared with sham animals. The above results showed that hippocampal SRC-1 is regulated by postnatal development but not ovariectomy, and that the exact role of SRC-1 in the estradiol regulation of hippocampus needs further investigation.

Expressions of GAP43, P38 mRNA and protein in insular electrical kindled rats and its significance

To investigate the expression of neural growth-associated protein (GAP-43) and synaptophysin (P38) gene and protein in insular electrical kindled epileptic rats and its significance. Seventy-two male adult rats were divided into kindled group (n = 36) and sham group (n = 36) randomly. Each group was further divided into 1, 3, 7, 15, 30 and 60 d sub-groups (n = 6) respectively. After kindling with immunohistochemical staining and hybridization in situ, the altered expressions of GAP-43 and P38 were detected in hippocampus of insular electrical kindled epilepsy rats. Epilepsy day 1: GAP-43 mRNA and protein expression at hippocampus dentate gyrus granular cell layer, hilus and CA3 pyramidal layer in the kindled group were higher than the sham group (P < 0.05). The expressions declined at Day 3 (P > 0.05). Expressions became elevated again at Day 7 and they were significantly higher than those in the sham group at Days 15 and 30 (P < 0.05). There was no statistical difference between two groups at Day 60 (P > 0.05). Expressions of P38 mRNA and protein: hybridization signal and immunostaining at hippocampus dentate gyrus granular cell layer, hilus and CA3 pyramidal layer began to rise at Day 7 and peaked at Day 15 (P < 0.01). They lasted 4 weeks and then began to decline. Insular epilepsy is closely related with temporal hippocampus. GAP-43 and P38 may be the pathological basis of insular epilepsy and the key molecular mechanism of synaptic plasticity.

Is the dentate gyrus an independent generator of in vitro recorded theta rhythm?

In this study we investigated the ability of the dentate gyrus to independently generate cholinergically induced theta rhythm in vitro. Two different experiments were performed. In Experiment I, new laminar profiles of theta phase, amplitude, and current sources and sinks were constructed. In this experiment a gradual phase shift of theta waves in the CA1 stratum radiatum was observed. Simultaneously, two amplitude maxima were detected: the first in the CA1 stratum oriens, and the second in the CA1 stratum lacunosum-moleculare. Moreover, during the positive peak of theta in the CA1 stratum oriens, two large sinks were observed: the first localized in the stratum oriens and the second in the stratum lacunosum-moleculare. In Experiment II the EEG activity of three different transected hippocampal slices (CA1 transected slices, CA3c transected slices, and DG transected slices) was recorded. It was demonstrated that the dentate gyrus granular cell body layer was not able to independently produce in vitro theta rhythm. Data obtained in both experiments provide strong evidence that in cholinegically treated hippocampal formation maintained in vitro there is no independent generator of theta rhythm in the region of the dentate gyrus granular cell layer.

Prior neonatal isolation reduces induction of NGF mRNA and decreases GDNF mRNA in the hippocampus of juvenile and adult rodents subjected to immobilization stress

Numerous studies have demonstrated that early adverse experiences are associated with the development of susceptibility to stress later in life. Although it is known that early experience of adversity, such as neonatal isolation, maternal separation, and low maternal care, enhances the activity of the hypothalamo-pituitary-adrenalaxis in rodents, the detailed mechanism underlying stress susceptibility induced by early adversity remains to be elucidated. Since neurotrophins have been shown to have a neuroprotective effect, we examined the influence of repeated neonatal isolation on expression of nerve growth factor (NGF), glia cell-derived neurotrophic factor (GDNF), and neurotrophin-3 mRNA in the hippocampus of juvenile and adult rats subsequently exposed immobilization stress, using real-time quantitative PCR and in situ hybridization. Neonatal isolation did not affect the basal hippocampal expression of these neurotrophin mRNAs in either juvenile or adult rats not subsequently exposed to immobilization. Similarly, there was a significant interaction between neonatal isolation and immobilization that affected the expression of NGF and GDNF mRNAs. Neonatal isolation attenuated the induction of NGF mRNA in both groups of rats and decreased GDNF mRNA in juvenile rats in response to immobilization. The decreased induction of NGF mRNA and reduced GDNF mRNA in response to immobilization was found in the CA3 pyramidal cell layer and dentate gyrus granular cell layer in the hippocampus of adult rats that had been subjected to neonatal isolation. These findings suggest that susceptibility to stress arising from prior neonatal isolation might be a result of decreased neuroprotective support through NGF and GDNF.

Effect of neonatal isolation on the noradrenergic transduction system in the rat hippocampal slice.

Numerous studies suggest that early adverse experiences induce neurochemical, morphological, and functional changes in the hippocampus in adolescence and adulthood. The aim of this study was to identify the influence of neonatal isolation (NI) on noradrenaline (NA)-mediated intracellular calcium ([Ca(2+)](i)) mobilization. To measure [Ca(2+)](i), we used the Ca(2+)-sensitive dye fura-2 and analysis by fluorescence microscopy. First, we examined the contributions of adrenergic receptor subtypes to the NA-stimulated increase in [Ca(2+)](i) in the granule cell layers of the dentate gyrus (DG) and in the pyramidal cell layers of the CA3 in the hippocampus. Second, we found that the NA-stimulated [Ca(2+)](i) increment was significantly decreased in response to NI in these hippocampal regions. In addition, we examined the influence of environmental enrichment (EE) after weaning on the decrease in the NA-stimulated [Ca(2+)](i) increment induced by NI. The administration of EE reversed the influence of NI on the NA-stimulated [Ca(2+)](i) increment in the CA3 pyramidal cell layer but not in the DG granular cell layer in the hippocampus. These findings suggest that NI and EE after weaning may modulate hippocampal function by altering adrenergic receptor-mediated signal transduction during adolescence.

Delayed effects of chronic variable stress during peripubertal-juvenile period on hippocampal morphology and on cognitive and stress axis functions in rats.

Animal studies on the effects of chronic variable stress during the peripubertal-juvenile period on hippocampal structure and function are lacking. Twenty-eight-day-old Sprague-Dawley rats were subjected to random, variable physical or social stress regimens for 4 weeks. Hippocampal volume was found to continue to grow in all lamina examined during the transition into young adulthood. Our variable physical stress paradigm led to inhibition of this growth in the CA1 pyramidal cell layer (PCL) and in the dentate gyrus-granular cell layer (DG-GCL), which reached full arrest in the CA3-PCL. Volume deficits were first observed after chronic stress exposure when 3 weeks, but not 24 h, of recovery had elapsed. Moreover, these volume deficits were associated with impairments in the Morris water-maze navigation, sustained down-regulation in the basal hippocampal glucocorticoid receptor gene expression, and deficits in the shutdown of acute stress-induced corticosterone secretion. Volume changes both due to normal maturation and after chronic stress exposure were independent of neuron number. Thus, a peripubertal-juvenile chronic stress paradigm that leads to significant alterations in the limbic-hypothalamic-pituitary-adrenal axis can produce robust effects in hippocampal structure and cognitive ability, lasting into adulthood.