阿托伐他汀可增强血管性痴呆模型中大鼠海马CA1区发动蛋白1的表达

The current study examined a rat model of vascular dementia.The model rats exhibited obvious morphological and ultrastructural changes in neurons in the brain,and significantly reduced dynamin 1 expression in hippocampal CA1 region along with decreased learning and memory performance.Following atorvastatin treatment,the morphology and ultrastructure of cells in the model rat brain were significantly improved,dynamin 1 expression in hippocampal CA1 region was significantly enhanced,and learning and memory ability was significantly improved.The results demonstrated that impaired learning and memory abilities in vascular dementia model rats were closely correlated with decreased dynamin 1 expression.These findings indicate that atorvastatin can protect model rats against cognitive impairment by increasing dynamin 1 expression.     

Impaired myelination of the human hippocampal formation in Down syndrome

Myelination is considered as one of the last steps of neuronal development and is essential to the physiologically matured function of afferent and efferent pathways. In the present study, myelin formation was examined in the human fetal, postnatal and adult hippocampal formation in Down syndrome and in age-matched controls with immunohistochemistry detecting a protein component of the myelin sheath, the myelin basic protein synthesized by oligodendroglial cells. Myelination is mainly a postnatal event in the hippocampal formation of both healthy controls and in patients with Down syndrome. In patients with Down syndrome the sequence of myelination of the hippocampal formation followed a similar developmental pattern to that in controls. However, myelin formation was generally delayed in Down syndrome compared to age-matched controls. In addition, in the hilus of the dentate gyrus a decreased density of myelinated axons was detected from the start of myelination until adulthood. The majority of local axons (mossy fibers) are not myelinated in the hilar region and myelinated fibers arriving in the hilus come mainly from the subcortical septal nuclei. Since intact septo-hippocampal connections are necessary for memory formation, we hypothesize that decreased myelination in the hilus may contribute to the mental retardation of Down syndrome patients.     

Cellular resolution anatomical and molecular atlases for prenatal human brains

Increasing interest in studies of prenatal human brain development, particularly using new single-cell genomics and anatomical technologies to create cell atlases, creates a strong need for accurate and detailed anatomical reference atlases. In this study, we present two cellular-resolution digital anatomical atlases for prenatal human brain at postconceptional weeks (PCW) 15 and 21. Both atlases were annotated on sequential Nissl-stained sections covering brain-wide structures on the basis of combined analysis of cytoarchitecture, acetylcholinesterase staining, and an extensive marker gene expression dataset. This high information content dataset allowed reliable and accurate demarcation of developing cortical and subcortical structures and their subdivisions. Furthermore, using the anatomical atlases as a guide, spatial expression of 37 and 5 genes from the brains, respectively, at PCW 15 and 21 was annotated, illustrating reliable marker genes for many developing brain structures. Finally, the present study uncovered several novel developmental features, such as the lack of an outer subventricular zone in the hippocampal formation and entorhinal cortex, and the apparent extension of both cortical (excitatory) and subcortical (inhibitory) progenitors into the prenatal olfactory bulb. These comprehensive atlases provide useful tools for visualization, segmentation, targeting, imaging, and interpretation of brain structures of prenatal human brain, and for guiding and interpreting the next generation of cell census and connectome studies.     

p21Cip restrains hippocampal neurogenesis and protects neuronal progenitors from apoptosis during acute systemic inflammation

Altered neurogenesis in adult hippocampus is implicated in cognition impairment and depression. Inflammation is a potent inhibitor of neurogenesis. The cyclin‐dependent kinase inhibitor p21^Cip1 (p21) restrains cell cycle progression and arrests the cell in the G1 phase. We recently showed that p21 is expressed in neuronal progenitors and regulates proliferation of these cells in the subgranular zone of the dentate gyrus of hippocampus where adult neurogenesis occurs. The current study suggests that p21 is induced in vivo in the hippocampus of WT mice in response to acute systemic inflammation caused by LPS injections, restrains neuronal progenitor proliferation and protects these cells from inflammation‐induced apoptosis. In intact p21^?/? hippocampus, neuronal progenitors proliferate more actively as assessed by BrdU incorporation, and give rise to increased number of DCX positive neuroblasts. However, when mice were treated with LPS, the number of neuroblasts decreased due to induced subgranular zone apoptosis. In vitro, differentiating Tuj‐1 positive neuroblasts isolated from p21^?/? hippocampus exhibited increased proliferation rate, measured by Ki‐67 staining, as compared to WT cells (p<0.05). In WT neuronal progenitors treated with IL‐6, the number of p21‐positive cells was increased (p<0.05), and this led to Tuj‐1⁺ cell proliferation restraint, whereas the number of proliferating GFAP⁺ astrocytes was increased ～ 2‐fold. Thus, when p21 is intact, inflammation might divert neuronal progenitors towards astrogliogenesis by inducing p21. At the same time, when p21 is lacking, no effects of IL‐6 on proliferation of Tuj‐1⁺ cells or GFAP⁺ cells are detected in differentiating p21^?/? neuronal progenitors. These results underscore the important role of p21 controlling hippocampal neuronal differentiation during inflammation. © 2013 Wiley Periodicals, Inc.     

Regulation of mitochondrial dynamics and distribution by synapse position and neuronal activity in the axon

Proper distribution of axonal mitochondria is critical for multiple neuronal functions. To understand the underlying mechanisms for population behavior, quantitative characterisation of elemental dynamics on multiple time scales is required. Here we investigated the stability and transport of axonal mitochondria using live‐cell imaging of cultured mouse hippocampal neurons. We first characterised the long‐term stability of stationary mitochondria. At a given moment, about 10% of the mitochondria were in a state of transport and the remaining 90% were stationary. Among these stationary mitochondria, 40% of them remained in the same position over several days. The rest of the mitochondria transited to mobile state stochastically and this process could be detected and quantitatively analysed by time‐lapse imaging with intervals of 30 min. The stability of axonal mitochondria increased from 2 to 3 weeks in culture, was decreased by tetrodotoxin treatment, and was higher near synapses. Stationary mitochondria should be generated by pause of moving mitochondria and subsequent stabilisation. Therefore, we next analysed pause events of moving mitochondria by repetitive imaging at 0.3 Hz. We found that the probability of transient pause increased with field stimulation, decreased with tetrodotoxin treatment, and was higher near synapses. Finally, by combining parameters obtained from time‐lapse imaging with different time scales, we could estimate transition rates between different mitochondrial states. The analyses suggested specific developmental regulation in the probability of paused mitochondria to transit into stationary state. These findings indicate that multiple mitochondrial behaviors, especially those regulated by neuronal activity and synapse location, determine their distribution in the axon.     

Blocking brain‐derived neurotrophic factor inhibits injury‐induced hyperexcitability of hippocampal CA3 neurons

Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin‐related kinase B (TrkB), a receptor for brain‐derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF‐mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury‐induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB‐Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB‐Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two‐fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB‐Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB‐Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury‐induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post‐traumatic epilepsy. Therefore, our data suggest that blocking the BDNF–TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post‐traumatic epilepsy.     

Effects of Low‐Frequency Hippocampal Stimulation on Gamma‐Amino Butyric Acid Type B Receptor Expression in Pharmacoresistant Amygdaloid Kindling Epileptic Rats

Objective: To observe the effect of low‐frequency hippocampal stimulation on gamma‐amino butyric acid type B (GABA‐B) receptor expression in hippocampus pharmacoresistant epileptic rats. Materials and Methods: Sixteen pharmacoresistant epileptic rats were selected by testing their seizure response to phenytoin and phenobarbital, and they were randomly divided into a pharmacoresistant control group (PRC group, eight rats) and a pharmacoresistant stimulation group (PRS group, eight rats). Another 16 pharmacosensitive epileptic rats were served as control, also divided randomly into a pharmacosensitive control group (PSC group) and a pharmacosensitive stimulation group (PSS group). A stimulation electrode was implanted into the rats' hippocampus in the four groups. Low‐frequency hippocampal stimulation was administered twice per day for two weeks. Following these weeks of stimulation, GABA‐B receptor‐positive neurons were counted and the gray values of GABA‐B receptor expression in the rats' hippocampal tissues were measured. Results: The amygdale stimulus‐induced epileptic seizures were decreased significantly in the PRS group compared with the PRC group. The parameters of the amygdale after discharge also were improved after hippocampal stimulation. Simultaneously, the GABA‐B receptor‐positive neurons increased and the GABA‐B expression gray values decreased markedly in the PRS group compared with the PRC group. The same phenomenon also was observed between the PSS group and the PSC group. However, no significant difference was found in the GABA‐B receptor‐positive neurons and the gray values of GABA‐B between the PRS group and the PSC group. Conclusions: The low‐frequency hippocampal stimulation may inhibit the amygdale stimulus‐induced epileptic seizures and the after discharges. The antiepileptic effects of the hippocampal stimulation may be achieved partly by increasing the expression of the GABA‐B receptor.     

Surgical pathology of epilepsy‐associated non‐neoplastic cerebral lesions: A brief introduction with special reference to hippocampal sclerosis and focal cortical dysplasia

Among epilepsy‐associated non‐neoplastic lesions, mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE‐HS) and malformation of cortical development (MCD), including focal cortical dysplasia (FCD), are the two most frequent causes of drug‐resistant focal epilepsies, constituting about 50% of all surgical pathology of epilepsy. Several distinct histological patterns have been historically recognized in both HS and FCD, and several studies have tried to perform clinicopathological correlations. However, results have been controversial, particularly in terms of post‐surgical seizure outcome. Recently, the International League Against Epilepsy constituted a Task Forces of Neuropathology and FCD within the Commission on Diagnostic Methods, to establish an international consensus of histological classification of HS and FCD, respectively, based on agreement with the recognition of the importance of defining a histopathological classification system that reliably has some clinicopathological correlation. Such consensus classifications are likely to facilitate future clinicopathological studies. Meanwhile, we reviewed the neuropathology of 41 surgical cases of mTLE, and confirmed three type/patterns of HS along with no HS, based on the qualitative evaluation of the distribution and severity of neuronal loss and gliosis within hippocampal formation, that is, HS type 1 (61%) equivalent to “classical” Ammon's horn sclerosis, HS type 2 (2%) representing CA1 sclerosis, HS type 3 (17%) equivalent to end folium sclerosis, and no HS (19%). Furthermore, we performed a neuropathological comparative study on mTLE‐HS and dementia‐associated HS (d‐HS) in the elderly, and confirmed that neuropathological features differ between mTLE‐HS and d‐HS in the distribution of hippocampal neuronal loss and gliosis, morphology of reactive astrocytes and their protein expression, and presence of concomitant neurodegenerative changes, particularly Alzheimer type and TDP‐43 pathologies. These differences may account, at least in part, for the difference in pathogenesis and epileptogenicity of HS in mTLE and senile dementia. However, the etiology and pathogenesis of most epileptogenic lesions are yet to be elucidated.     

Anomalous expression of chloride transporters in the sclerosed hippocampus of mesial temporal lobe epilepsy patients

The Na+-K+-Cl-cotransporter 1 and K+-Cl-cotransporter 2 regulate the levels of intracellular chloride in hippocampal cells.Impaired chloride transport by these proteins is thought to be involved in the pathophysiological mechanisms of mesial temporal lobe epilepsy.Imbalance in the relative expression of these two proteins can lead to a collapse of Cl-homeostasis,resulting in a loss of gamma-aminobutyric acid-ergic inhibition and even epileptiform discharges.In this study,we investigated the expression of Na+-K+-Cl-cotransporter 1 and K+-Cl-cotransporter 2 in the sclerosed hippocampus of patients with mesial temporal lobe epilepsy,using western blot analysis and immunohistochemistry.Compared with the histologically normal hippocampus,the sclerosed hippocampus showed increased Na+-K+-Cl-cotransporter 1 expression and decreased K+-Cl-cotransporter 2 expression,especially in CA2 and the dentate gyrus.The change was more prominent for the Na+-K+-Cl-cotransporter 1 than for the K+-Cl-cotransporter 2.These experimental findings indicate that the balance between intracellular and extracellular chloride may be disturbed in hippocampal sclerosis,contributing to the hyperexcitability underlying epileptic seizures.Changes in Na+-K+-Cl-cotransporter 1 expression seems to be the main contributor.Our study may shed new light on possible therapies for patients with mesial temporal lobe epilepsy with hippocampal sclerosis.     

Effects of diazepam on glutamatergic synaptic transmission in the hippocampal CA1 area of rats with traumatic brain injury

The activity of the Schaffer collaterals of hippocampal CA3 neurons and hippocampal CA1 neurons has been shown to increase after fluid percussion injury. Diazepam can inhibit the hyperexcitability of rat hippocampal neurons after injury, but the mechanism by which it affects excitatory synaptic transmission remains poorly understood. Our results showed that diazepam treatment significantly increased the slope of input-output curves in rat neurons after fluid percussion injury. Diazepam significantly decreased the numbers of spikes evoked by super stimuli in the presence of 15 μmol/L bicuculline, indicating the existence of inhibitory pathways in the injured rat hippocampus. Diazepam effectively increased the paired-pulse facilitation ratio in the hippocampal CA1 region following fluid percussion injury, reduced miniature excitatory postsynaptic potentials, decreased action-potential-dependent glutamine release, and reversed spontaneous glutamine release. These data suggest that diazepam could decrease the fluid percussion injury-induced enhancement of excitatory synaptic transmission in the rat hippocampal CA1 area.