U1 small nuclear RNA (snRNA) is selectively enriched in 100% of familial Alzheimer’s disease (AD) resulting from presenilin1 (PS1) and amyloid precursor protein (APP) mutations. However, it remains unknown what gene or protein cause the U1 snRNA overexpression and then resulted in AD. Using SH-SY5Y cells, we discovered that PS1 induced the overexpression of U1 snRNA, which increased the production of Aβ. Moreover, the U1 snRNA overexpression induced the upregulation of apoe and clu transcripts. In addition, the levels of phosphorylation of tau protein at Thr212 were significantly elevated in U1 snRNA overexpression cells. Immunofluorescence using antibodies reactive with the phosphorylation of tau at Thr212 site demonstrated the hyperphosphorylated tau localization with α-tubulin, the main component of cytoskeleton. Importantly, the increased levels of Bax, Bcl2, and Bax/Bcl2 ratio showed that the overexpression of U1 snRNA could cause cell apoptosis. Conclusively, these findings suggest that PS1 considerably increases the level of U1snRNA accompanied with the adverse change of Aβ level, AD-related tau cytoskeletal pathology, and cell apoptosis.

•PS impairs cognitive flexibility in adolescent offspring.•PS reduces in vivo hippocampal LTP and DEP capacities in adolescent offspring.•Hippocampal expressions of NR2A, NR2B and PSD-95 were significantly altered by PS.•Level of hippocampal cell death and autophagy was effectively elevated by PS.•Autophagy may be involved in the effect of PS on the offspring.Prenatal stress (PS) brings numerous outcomes on offspring, including anxiety, depression-like behavior and other cognitive disorder. In this study, a rat model of PS was established by using restraint stress for 45 min three times per day from the 15th to 21st day of pregnancy. Behavioral tests, including open field test (OPT), elevated plus-maze (EPM) and Morris water-maze (MWM), were performed in adolescent male-offspring. The bidirectional synaptic plasticity, including long-term potential (LTP) and depotentiation (DEP), from the hippocampal Schaffer collaterals to CA1 region was subsequently measured. Furthermore, Western blot assay, immunofluorescence staining and hematoxylin-eosin (HE) staining were employed. The MWM test showed that the cognitive flexibility was remarkably damaged in PS offspring. Meanwhile, PS considerably aggravated the anxiety and depression-like behavior in OPT and EPM. Both LTP and DEP were significantly inhibited by PS. Furthermore, PS considerably altered the expression of synaptic-related proteins NR2A, NR2B and PSD-95 in adolescent male-offspring. Interestingly, PS significantly elevated the autophagy level in the hippocampus of male-offspring. In order to investigate the role of autophagy on the negative impacts of PS in adolescent male-offspring, both in vitro and in vivo studies were performed. It was found that autophagy inhibitors significantly eliminated the alterations in gene expression induced by corticosterone. The results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by PS in adolescent male-offspring.

Our previous investigation demonstrated that autophagy significantly reduced melamine-induced cell death in PC12 cells via inhibiting the excessive generation of ROS. In the present study, we further examine if rapamycin, used as an autophagy activator, can play a significant role in protecting neurons and alleviating the impairment of spatial cognition and hippocampal synaptic plasticity in melamine-treated rats. Male Wistar rats were divided into three groups: control, melamine-treated, and melamine-treated + rapamycin. The animal model was established by administering melamine at a dose of 300 mg/kg/day for 4 weeks. Rapamycin was intraperitoneally given at a dose of 1 mg/kg/day for 28 consecutive days. The Morris water maze test showed that spatial learning and reversal learning in melamine-treated rats were considerably damaged, whereas rapamycin significantly impeded the cognitive function impairment. Rapamycin efficiently alleviated the melamine-induced impairments of both long-term potentiation (LTP) and depotentiation, which were damaged in melamine rats. Rapamycin further increased the expression level of autophagy markers, which were significantly enhanced in melamine rats. Moreover, rapamycin noticeably decreased the reactive oxygen species level, while the superoxide dismutase activity was remarkably increased by rapamycin in melamine rats. Malondialdehyde assay exhibited that rapamycin prominently reduced the malondialdehyde (MDA) level of hippocampal neurons in melamine-treated rats. In addition, rapamycin significantly decreased the caspase-3 activity, which was elevated by melamine. Consequently, our results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by melamine.

The aim of this study was to examine if nicotine was able to improve cognition deficits in a mouse model of chronic mild stress. Twenty-four male C57BL/6 mice were divided into three groups: control, stress, and stress with nicotine treatment. The animal model was established by combining chronic unpredictable mild stress (CUMS) and isolated feeding. Mice were exposed to CUMS continued for 28 days, while nicotine (0.2 mg/kg) was also administrated for 28 days. Weight and sucrose consumption were measured during model establishing period. The anxiety and behavioral despair were analyzed using the forced swim test (FST) and open-field test (OFT). Spatial cognition was evaluated using Morris water maze (MWM) test. Following behavioral assessment, both long-term potentiation (LTP) and depotentiation (DEP) were recorded in the hippocampal dentate gyrus (DG) region. Both synaptic and Notch1 proteins were measured by Western. Nicotine increased stressed mouse’s sucrose consumption. The MWM test showed that spatial learning and reversal learning in stressed animals were remarkably affected relative to controls, whereas nicotine partially rescued cognitive functions. Additionally, nicotine considerably alleviated the level of anxiety and the degree of behavioral despair in stressed mice. It effectively mitigated the depression-induced impairment of hippocampal synaptic plasticity, in which both the LTP and DEP were significantly inhibited in stressed mice. Moreover, nicotine enhanced the expression of synaptic and Notch1 proteins in stressed animals. The results suggest that nicotine ameliorates the depression-like symptoms and improves the hippocampal synaptic plasticity closely associated with activating transmembrane ion channel receptors and Notch signaling components.

•Mice were exposed to hindlimb unloading for 14 days.•Behavior test, neural oscillatory analysis, Western and HPLC were performed.•Microgravity mice show anxiety-like behaviors, NR2A/2B and glutamate levels decrease.•There were significant differences of oscillatory patterns between two groups.•Neural oscillations as a bridge between glutamatergic system and emotional behaviors.This study aims to investigate if neural oscillations can play a role as a bridge between the alteration of glutamatergic system and emotional behaviors in simulated microgravity (SM) mice. Adult male C57BL/6J mice were randomly divided into two groups: SM and control groups. The animal model was established by hindlimb unloading (HU). The mice were exposed to HU continued for 14 days. Weight and sucrose consumption were measured. The degree of anxious and depressive was evaluated by Open field test and Elevated plus maze test. Local field potentials were recorded in the hippocampal perforant path (PP) and dentate gyrus (DG) regions. The NMDAR2A/2B (NR2A/2B) subunits expression and glutamate level were measured by Western and high performance liquid chromatography (HPLC), respectively. After 14 days, SM mice exhibited depressive-like and anxiety-like behaviors, while the expression of NR2A/2B subunits and the glutamate level were significantly decreased in the SM group. Moreover, the power distribution of theta (3–8 Hz) was decreased by HU, which further significantly attenuated the identical-frequency strength of phase synchronization and the neural information flow at theta rhythm on the PP-DG pathway. The theta-gamma phase synchronization strength was also significantly reduced by HU. The data imply that the neural oscillations measurements is a sign of the emotional behaviors impairment and the glutamatergic system change induced by HU.

Melamine is an industrial chemical that can cause central nervous system disorders including excitotoxicity and cognitive impairment. Its illegal use in powdered baby formula was the focus of a milk scandal in China in 2008. One of our previous studies showed that melamine impaired glutamatergic transmission in rat hippocampal CA1 pyramidal cells. However, the underlying mechanism of action of melamine is unclear, and it is unknown if the CA3–CA1 pathway is directly involved. In the present study, a whole-cell patch-clamp technique was employed to investigate the effect of melamine on the hippocampal CA3–CA1 pathway in vitro. Both the evoked excitatory postsynaptic current (eEPSC) and the paired-pulse ratio (PPR) were recorded. Furthermore, we examined whether autophagy was involved in glutamatergic transmission alterations induced by melamine. Our data showed that melamine significantly increased the amplitude of eEPSCs in a dose-dependent manner. Inhibition of the N-methyl-d-aspartic acid receptor did not prevent the increase in eEPSC amplitude. In addition, the PPR was remarkably decreased by a melamine concentration of 5 × 10−5 g/mL. It was found that autophagy could be activated by melamine and an autophagy inhibitor, 3-MA, prevented the melamine-induced increase in eEPSC amplitude. Overall, our results show that melamine presynaptically alters glutamatergic synaptic transmission of hippocampal CA3–CA1 synapses in vitro and this is likely associated with autophagy alteration.

Our previous investigation showed that melamine in offspring hippocampus appeared to not be the critical factor for cognitive defects. The present study was to investigate whether the cognitive impairments induced by prenatal and postnatal melamine exposure and persisted into adulthood, and to evaluate the differences of the exposures in affecting hippocampus-depended cognition and synaptic plasticity. Wistar rats were exposed to melamine through the whole gestational period or from postnatal day (PD) 21 to PD41, and then tested on PD90. The experiments of water maze and hippocampal synaptic plasticity in vivo were performed to assess the effects on spatial cognition and synaptic impairments. The results indicated that cognitive defects were induced by exposures to either prenatal or postnatal melamine, whereas there was a more serious damage in prenatal. Histological evidence further showed that there were the detrimental effects of both prenatal and postnatal effects. Paired-pulse facilitation ratio and post-tetanic potentiation were severely impacted in prenatal-exposed rats but not postnatal-exposed ones. Both exposures to prenatal and postnatal melamine impaired long-term potentiation, while there was severe damage to prenatal animals. These data suggest that the detrimental effects of prenatal and postnatal melamine on cognition and hippocampal synaptic plasticity could persist into adulthood, and the impairment of prenatal exposure was to some extent more severe. Hence, prenatal and postnatal exposures to melamine may have different effects on hippocampus-dependent learning and memory, which would most likely result from differentially adversely properties on the hippocampal CA1 synaptic function.

Theta and gamma oscillations are believed to play an important role in cognition and memory, and their phase coupling facilitates the information transmission in hippocampal-cortex network. In a rat model of chronic stress, the phase coupling of both theta and gamma oscillations between ventral hippocampal CA1 (vCA1) and medial prefrontal cortex (mPFC) was found to be disrupted, which was associated with the impaired synaptic plasticity in the pathway. However, little was known about the mechanisms underlying the process. In order to address this issue, both dopamine and serotonin as monoaminergic neurotransmitters were involved in this study, since they were crucial factors in pathological basis of depressive disorder. Local field potentials (LFPs) were recorded simultaneously at both vCA1 and mPFC regions under anesthesia, before and after the injection of dopamine D1 receptor antagonist and 5-HT1A receptor agonist, respectively. The results showed that the blockage of D1 receptor could lead to depression-like decrement on theta phase coupling. In addition, the activation of 5-HT1A receptor enhanced vCA1–mPFC coupling on gamma oscillations, and attenuated CA1 theta-fast gamma cross frequency coupling. These data suggest that the theta phase coupling between vCA1 and mPFC may be modulated by dopamine system that is an underlying mechanism of the cognitive dysfunction in depression. Besides, the serotonergic system is probably involved in the regulation of gamma oscillations coupling in vCA1–mPFC network.

An increasing number of studies pays attention to cross-frequency coupling in neuronal oscillations network, as it is considered to play an important role in exchanging and integrating of information. In this study, two generalized algorithms, phase–amplitude coupling-evolution map approach and phase–amplitude coupling-conditional mutual information which have been developed and applied originally in an identical rhythm, are generalized to measure cross-frequency coupling. The effectiveness of quantitatively distinguishing the changes of coupling strength from the measurement of phase–amplitude coupling (PAC) is demonstrated based on simulation data. The data suggest that the generalized algorithms are able to effectively evaluate the strength of PAC, which are consistent with those traditional approaches, such as PAC-PLV and PAC-MI. Experimental data, which are local field potentials obtained from anaesthetized SD rats, have also been analyzed by these two generalized approaches. The data show that the theta–low gamma PAC in the hippocampal CA3–CA1 network is significantly decreased in the glioma group compared to that in the control group. The results, obtained from either simulation data or real experimental signals, are consistent with that of those traditional approaches PAC-MI and PAC-PLV. It may be considered as a proper indicator for the cross frequency coupling in sub-network, such as the hippocampal CA3 and CA1.

Our previous study showed that hydrogen sulfide (H2S) could alleviate the cognitive deficits in vascular dementia (VD) rats associated with the improvement of synaptic plasticity. Neural oscillations are reported to interact with each other through either identical-frequency or cross-frequency coupling. This study examined whether impaired neural couplings could be alleviated by H2S in the hippocampal CA3–CA1 of VD rats and explored its possible mechanism. A VD rat model was established by two-vessel occlusion. Sodium hydrosulfide (NaHS), a kind of H2S donor, was administered intraperitoneally (5.6 mg/kg/day) for 3 weeks. Local field potentials were simultaneously collected in the hippocampal CA3 and CA1. The effects of NaHS on the modulation of theta–gamma coupling were evaluated by using the measurements of both phase–phase coupling and phase–amplitude coupling, while several other approaches including behavior, electrophysiology, western blot, immunofluorescence staining were also employed. The results showed that NaHS significantly prevented spatial learning and memory impairments (p < 0.01). NaHS considerably alleviated the impairment of neural coupling in VD rats in an identical-frequency rhythm and between cross-frequency bands. Moreover, the expression of cystathionine-β-synthase (CBS) was markedly attenuated in VD rats. NaHS elevated the expression of CBS to maintain the intrinsic balance of H2S. Interestingly, it was observed that NaHS increased the protein expression of N-methyl-d-aspartic acid receptor 2A (NMDAR2A) in VD rats. In conclusion, the data suggest that NaHS played the neuroprotective role partly via modulating the expression of NMDAR2A in order to alleviate the impairments of neural couplings in VD rats.

Vascular endothelial growth factor (VEGF) has recently been proved to be a potential therapeutic drug in ischemic disorders depending on the dose, route and time of administration, especially in focal cerebral ischemia. Whether VEGF could exert protection in a long-term total cerebral ischemic model is still uncertain, and the cellular mechanism has not been clarified so far. In order to answer the above issue, an experiment was performed in non-invasively giving exogenous VEGF to a total cerebral ischemic model rats and examining their spatial cognitive function by performing Morris water maze and long-term potential test. Moreover, we performed in vitro experiment to explore the cellular mechanism of VEGF protection effect. In an in vitro ischemia model oxygen–glucose deprivation (OGD), whole-cell patch-clamp recording was employed to examine neuronal function. Additionally, hematoxylin–eosin and propidium iodide staining were applied in vivo and in vitro in the neuropathological and viability study, separately. Our results showed that intranasal administration of VEGF could improve the cognitive function, synaptic plasticity and damaged hippocampal neurons in a global cerebral ischemia model. In addition, VEGF could retain the membrane potential, neuronal excitability and spontaneous excitatory postsynaptic currents in the early stage of ischemia, which further demonstrated that there was an acute effect of VEGF in OGD-induced pyramidal neurons. Simultaneously, it was also found that the death of CA1 pyramidal neuronal was significantly reduced by VEGF, but there was no similar effect in VEGF coexists with SU5416 group. These results indicated that VEGF could ameliorate cognitive impairment and synaptic plasticity via improving neuronal viability and function through acting on VEGFR-2.

Alterations in oscillatory brain activity are strongly correlated with cognitive performance in various physiological rhythms, especially the theta and gamma rhythms. In this study, we investigated the coupling relationship of neural activities between thalamus and medial prefrontal cortex (mPFC) by measuring the phase interactions between theta and gamma oscillations in a depression model of rats. The phase synchronization analysis showed that the phase locking at theta rhythm was weakened in depression. Furthermore, theta-gamma phase locking at n:m (1:6) ratio was found between thalamus and mPFC, while it was diminished in depression state. In addition, the analysis of coupling direction based on phase dynamics showed that the unidirectional influence from thalamus to mPFC was diminished in depression state only in theta rhythm, while it was partly recovered after the memantine treatment in a depression model of rats. The results suggest that the effects of depression on cognitive deficits are modulated via profound alterations in phase information transformation of theta rhythm and theta-gamma phase coupling.

Alterations in oscillatory brain activity are strongly correlated with cognitive performance in various physiological rhythms. The present study investigated whether the directionality of neural information flow (NIF) could be used to characterize the synaptic plasticity in thalamocortical (TC) pathway, and examined which frequency field oscillations were mostly related to the cognitive deficiency in depression. Two novel algorithms were employed to determine the coupling interaction between the LD thalamus and medial prefrontal cortex (mPFC) in five frequency bands, using the phase signals of local field potentials (LFP) in these two regions. The results showed that the power of neural activity in mPFC was increased in delta, theta and beta frequency bands in depression. However, the nonlinear characteristics of LFP activity were weakened in depression by means of sample entropy measurements. In the analysis of phase dynamics, the phase synchronization values were reduced in theta rhythm in stressed rats. Importantly, the coupling direction index d and the unidirectional influence from LD thalamus to mPFC were significantly reduced at the theta rhythm in rats in depression, and increased after memantine treatment, which were associated with the LTP alterations and cognitive impairment in our previous report. Moreover, the fact that the reduced entropy value was only found in mPFC might implicate postsynaptic effect involved in synaptic plasticity alteration in the depression model. The results suggest that the effects of depression on cognitive deficits are mediated via profound alterations in information flow in the TC pathway, and the directional index at theta rhythm could be used as a measurement of synaptic plasticity.

This study sets to examine the effects of ionic products from silicon-substituted hydroxyapatite (Si-HA) on brain activity in Wistar rats. Animals were treated intraperitoneally with leaching liquor of Si-HA once a day for 2 weeks. Morris water maze (MWM) test was employed to evaluate the spatial memory. The long term potentiation (LTP) of synaptic responses in the CA1 area was recorded. The expressions of growth associated protein-43 (GAP-43), glial fibrillary acidic protein (GFAP) and Nestin were identified by immunohistochemistry. The MWM test showed that the escape latency was markedly shortened by ionic products from Si-HA, meanwhile it produced a statistically significant improvement (p < 0.05) in the retention phase, implying a considerable improvement of spatial memory in Si-HA group. Moreover, LTP was significantly enhanced in Si-HA group as compared with that of control group. The GFAP expression was not upregulated in Si-HA group, but the expressions of GAP-43 and Nestin were increased. The findings suggested that there could be beneficial effects of Si-HA ionic products on rat brain function rather than to cause undesirable cerebral injury. The study provides the basis for further investigation into the biological applications of Si-HA.Highlights► Examine effect of ionic products from Si-HA on brain activity in Wistar rats. ► MWM test, hippocampus LTP and immunohistochemistry were used in the study. ► LTP was significantly enhanced and spatial memory was improved by Si-HA. ► Expressions of GAP-43 and Nestin were increased in Si-HA group. ► There could be beneficial effects of Si-HA ionic products on rat brain function.

For many glioblastoma multiforme patients, cognitive deficits are part of the disease process. In this study we attempted to determine the role of synaptic plasticity and glutamate (Glu) in C6 glioma-bearing rats. Male Sprague–Dawley (SD) rats were subjected to tumor implantation in the right caudate putamen nucleus. At 17 days after tumor implantation, animals were exposed to an open field test. The numbers of crossings and rearings were used as measures of exploration processes. An input/output (I/O) curve was first determined using the measurements of field excitatory postsynaptic potential (fEPSP) slope in response to a series of stimulation intensities. The short-term potentiation (STP) and long-term potentiation (LTP) induced by high-frequency stimulation (HFS) in the CA1 region of the contralateral hippocampus to the tumor were recorded. The glutamate and γ-aminobutyric acid (GABA) content of contralateral hippocampus were quantified by high-performance liquid chromatography (HPLC). C6 glioma-bearing rats showed a trend for a rightward shift of input/output relationship and significant deficits in maintenance of STP and LTP. Quantitative analysis by HPLC of glutamate and γ-aminobutyric acid revealed that Glu concentration and Glu/GABA ratio were increased significantly in contralateral hippocampus, suggesting impairment of excitatory and inhibitory synaptic transmission. The results suggest that the neurocognitive deficits in C6 glioma-bearing rats may be mediated via profound changes in neuroplasticity and elevated Glu concentration and Glu/GABA ratio in hippocampus area of the brain.

•Effect of vitamins C and E on neurotoxicity induced by melamine was evaluated.•MWM task, electrophysiological recordings and ELISA method were employed.•Combined vitamins significantly improved the spatial cognition of rats.•Combined vitamins alleviated melamine-induced synaptic plasticity impairments.Albeit the pathogenesis of cognitive impairment after exposure to melamine has not been fully elucidated, factors such as oxidative stress is thought to play potential roles. In the present study, we investigated the effect of treatment with vitamin C (150 mg/kg) and vitamin E (200 mg/kg) on the impairment induced by melamine. Three-week-old male Wistar rats were submitted to oral gavage with 300 mg/kg melamine in 1% carboxymethylcellulose (CMC) for 28 days (MEL-SAL group). After treatment with melamine, animals received administration of a combination of vitamin C and vitamin E once a day for 7 days (MEL-VIT group). Both control (CT-SAL) group and pair-fed (CT-VIT) group received the same dosage of CMC and vitamin complex, respectively. Melamine-treated rats presented a marked decrease in learning and memory in the Morris water maze (MWM) as well as a reduced efficiency to find the platform in the reversal learning task. The rats treated with vitamins E and C had part of the above effects rescued in MWM tests, with mitigating the melamine-induced deficit in the learning and memory but slightly improving the reversal learning ability. The vitamins C plus E regimen mitigated melamine-induced impairment of hippocampal synaptic plasticity. It showed that the modulation of oxidative stress with vitamins E and C reduced melamine-induced damage. The data suggested that there was a novel therapeutic strategy to the cognitive dysfunction observed in melamine-induced neuropathy.

•Investigating the mechanism of improving spatial cognition induced by rTMS.•rTMS facilitates spatial learning and memory abilities in normal rats.•rTMS significantly enhances synaptic plasticity in the hippocampus.•rTMS considerably increases the level of BDNF expression in the hippocampus.•rTMS significantly increases the levels of SYP and NR2B in the hippocampus.Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique, by which cognitive deficits can be alleviated. Furthermore, rTMS may facilitate learning and memory. However, its underlying mechanism is still little known. The aim of this study was to investigate if the facilitation of spatial cognition and synaptic plasticity, induced by rTMS, is regulated by enhancing pre- and postsynaptic proteins in normal rats. Morris water maze (MWM) test was performed to examine the spatial cognition. The synaptic plasticity, including long-term potentiation (LTP) and depotentiation (DEP), presynaptic plasticity paired-pulse facilitation (PPF), from the hippocampal Schaffer collaterals to CA1 region was subsequently measured using in vivo electrophysiological techniques. The expressions of brain-derived neurotrophic factor (BDNF), presynaptic protein synaptophysin (SYP) and postsynaptic protein NR2B were measured by Western blot. Our data show that the spatial learning/memory and reversal learning/memory in rTMS rats were remarkably enhanced compared to that in the Sham group. Furthermore, LTP and DEP as well as PPF were effectively facilitated by 5 Hz-rTMS. Additionally, the expressions of BDNF, SYP and NR2B were significantly increased via magnetic stimulation. The results suggest that rTMS considerably increases the expressions of BDNF, postsynaptic protein NR2B and presynaptic protein SYP, and thereby significantly enhances the synaptic plasticity and spatial cognition in normal animals.Download full-size image

•Study focuses on the neurotoxic effects of prenatal melamine exposure (PME).•Using MWM test, electrophysiological recording and ELISA methods.•PME has negative effects on CNS development, hippocampus-dependent spatial cognition.•PME inhibits fEPSPs amplitudes and enhances PPF ratio of hippocampal CA1 area.•An underlying mechanism could be that PME impaired hippocampal synaptic function.Our previous studies showed that chronic melamine exposure could affect hippocampal synaptic plasticity and impair learning and memory on adult rats. In this study, we investigated whether prenatal melamine exposure (PME) induced cognitive deficits and impairment of synaptic plasticity in postnatal offspring. An animal model was produced by melamine exposure throughout gestational period with 400 mg/kg/day, while male offspring rats were employed. Rats’ performance in Morris water maze (MWM) was tested to evaluate learning and memory. To examine the variations of paired-pulse facilitation (PPF) and synaptic plasticity, field excitatory postsynaptic potentials (fEPSPs) were recorded in hippocampal CA1 by stimulating Schaffer collaterals path. The result showed that PME probably impaired spatial learning and memory. The fEPSPs amplitudes of LTP were much lower and the PPF ratio was significantly higher in PME group than controls. These data suggested that PME impaired hippocampal synaptic function, which was partly involved in spatial cognition impairments.

Zinc is one of trace elements that play essential roles in several cell functions, and is unquestionably important to the normal health and function of the central nervous system. Growing evidence suggests that Zn2+ can become a pathogenic agent in certain neurological disease states, such as ischemia, seizures, and trauma. The main role of the Zn2+ may serve as an endogenous neuromodulator in the brain. In the present study, we used the electrophysiology method to investigate the effects of Zn2+ on the excitability of hippocampus CA1 region. Our results have demonstrated that the Zn2+ activates the Wistar rat hippocampal CA1 region network by significantly enhancing the spike rate of the spontaneous firing. In addition, Zn2+ can increase the intrinsic membrane excitability by enhancing the firing rate and half-width of the evoked action potential. Meanwhile, our results also indicate that Zn2+ can effectively inhibit voltage-dependent potassium currents (both transient outward potassium currents and delayed rectifier potassium currents). On the other hand, Zn2+ also inhibits excitatory neurotransmitter release by decreasing the inter-event interval and the total charge transfer of the excitatory postsynaptic currents. The present results, in combination with other works, suggest that Zn2+ can influence neuronal excitability, intrinsic membrane excitability and synaptic transmission in the hippocampus CA1 neurons by multiple mechanisms.

Increasing of peroxynitrite (ONOO−) production during ischemia in the immature brain was considered to be associated with impaired cognitive function. GABAergic synapses played an important role in memory formation including the induction of long-term potentiation (LTP) and long-term depression (LTD) in hippocampus. In the present study, we examined the effects of acute exposure of the ONOO− donor, SIN-1 on GABAergic synaptic transmission in immature rat hippocampal slices with whole-cell patch-clamp recordings. The results showed that SIN-1 increased the peak amplitude of evoked inhibitory postsynaptic currents (eIPSCs) and decreased paired pulse ratio via the formation of ONOO−. In addition, it also increased the frequency of spontaneous (but not miniature) IPSCs in a dose-dependent manner without altering amplitudes or rise and decay times of both (sIPSCs and mIPSCs). It further demonstrated that the presynaptic action of SIN-1 was external calcium dependent and was not related to the changes of interneuron excitability. This study provides electrophysiological evidences from developing hippocampal slices to support that SIN-1 enhances action potential-dependent GABA release. It suggests that the potentiation effect of ONOO− may contribute to hyperexcitability and seizures and may underlie one of the mechanisms by which ischemia increases seizure susceptibility in the immature brain.Highlights► The ONOO− donor, SIN-1 reversibly enhanced eIPSCs via the formationin of ONOO−. ► SIN-1 presynaptically increased GABAergic transmission in a dose-dependent manner. ► SIN-1 could enhance sIPSCs via presynaptic voltage-gated calcium channels (VGCCs). ► Effect of SIN-1 was not related to the changes of interneuron excitability.

The effects of two cypermethrin insecticides, alpha-cypermethrin and theta-cypermethrin on the transient outward potassium (IA) channels in freshly dissociated hippocampal CA3 neurons of rat, were studied using whole-cell patch clamp technique. The results indicate that alpha-cypermethrin increased the amplitude of IA and theta-cypermethrin decreased the amplitude of IA, and both of them shifted steady activation curve of IA towards negative potential. Theta-cypermethrin contributed in the inactivation of IA. Alpha-cypermethrin prolonged the time constants for the recovery from inactivation kinetics of IA. These results imply that transient outward potassium (IA) channels are the target of cypermethrin, which may explain the mechanism of toxical effects of cypermethrin on mammalian animals.

Our previous studies reported that hippocampus was one of the target sites of melamine, by which the spatial cognition and hippocampal long-term potentiation (LTP) could be impaired. The aim of present study was to investigate whether cognitive behavior impairment induced by melamine was associated with the alteration of hippocampal long-term depression (LTD), and try to interpret the potential underlying mechanism. Wistar rats were used to establish an animal model and melamine administered at a dose of 300 mg/kg/day for 4 weeks. Water maze behavior and long-term depression (LTD) in hippocampal CA3-CA1 pathway were measured, followed by enzyme linked immunosorbent assay (ELISA), by which acetylcholine (ACh) level and acetylcholinesterase (AChE) activity were determined. Results showed that learning and reversal learning abilities were significantly impaired by melamine. The field excitatory postsynaptic potential (fEPSP) slopes were significantly higher in melamine group compared to that in control group. Furthermore, the function of cholinergic system was damaged associated with decreased Ach level and enhanced AChE activity in melamine-treated rats. It suggested that melamine induced abnormal inhibitory effect on synaptic plasticity of hippocampus, which partly resulted in reduced LTD and further damaged cognitive flexibility. Melamine could also induce dysfunctional cholinergic system, which was associated with the poor performance of animals in MWM (Morris water maze) tests.Highlights► Investigating rat’s cognitive impairment induced by melamine in vivo. ► Performing MWM test, electrophysiological test and ELISA methods. ► Learning and reversal learning abilities were significantly weakened. ► Long-term depression and cholinergic neurotransmission were impaired. ► Poor performance is associated with synaptic plasticity and cholinergic system damage.

Since the melamine-contamination event happened in September 2008, there have been lots of studies about melamine toxicity, but very limited studies focused on central nervous system (CNS). In the present study, we investigated the effects of melamine (5 × 10−4, 5 × 10−5 and 5 × 10−6 g/ml) on voltage-gated sodium channels (VGSCs) in hippocampal CA1 neurons using whole-cell patch-clamp recordings technique. The results showed that only 5 × 10−4 g/ml melamine reduced the amplitude of voltage-gated sodium current (INa). At the concentrations of 5 × 10−5 and 5 × 10−4 g/ml, melamine produced a hyperpolarizing shift in the steady-state activation curve of INa and also enhanced the steady-state inactivate processing of INa. Action potential properties and the pattern of repetitive firing were examined using current-clamp recording, which indicated that peak amplitude and overshoot of the evoked single action potential were decreased. The half-width and the firing rate of repetitive firing were increased in a concentration-dependent manner. The data suggest that melamine alters the action potential of hippocampal CA1 neurons by impairing the functional properties of VGSCs, which may be the underlie mechanisms of neurotoxicity induced by melamine.

Many studies reported that infants and animals were affected by food containing melamine, and the renal pathology was the main manifestation in intoxicated case. Our previous studies showed that melamine could impair hippocampal function and inhibited differentiated PC12 cell proliferation in vitro. The present study aimed to examine the effect on hippocampus and the possible mechanism induced by melamine in vivo. To address the hypothesis that melamine would impair the hippocampal function in vivo and then induce cognitive deficits, male Wistar rats were used to establish an animal model and melamine administered at a dose of 300 mg kg/day for 4 weeks. Morris water maze (MWM) test was employed to evaluate the learning and memory. The long term potentiation (LTP) from Schaffer collaterals to CA1 region in the hippocampus was recorded. The result of MWM test showed that there were significant deficits of learning and memory induced by melamine. LTP test presented that field excitatory postsynaptic potentials (fEPSPs) slopes were significantly lower in melamine group compared to that in control group. In conclusion, melamine had a toxic influence on hippocampus, which induced the learning and memory deficits. It suggested that the potential mechanism was associated with impairments of synaptic plasticity.Highlights► We examine cognitive deficits of rats induced by melamine in vivo. ► We use MWM test, LTP recording and ELISA method. ► Melamine has toxic effects on hippocampus, induced learning and memory deficits. ► Mechanism may be impairment of synaptic plasticity.

Growing evidence suggests the involvement of stress in the pathophysiology of depression. This study was designed to test behavioral and electrophysiological changes in a stressed model of depression. Rats were randomly divided into control and stressed groups. Chronic unpredictable stress combined with isolation rearing was applied in rats of stressed group for three weeks. Weight and sucrose consumption were measured during the model establishing period. Behavior was measured by Morris water maze. Electroencephalography (EEG) of thalamus and prefrontal cortex was recorded after behavioral tests, followed by recording long-term potentiation (LTP) of the same thalamocortical pathway. Results showed that rats’ weight and sucrose intake were significantly lower in stressed group than those in control group. In stressed group, escape latency of reversal training stage in water maze test was significantly prolonged, and platform crossings of reversal probe trials were significantly decreased. EEG test showed that the extent of thalamus driving prefrontal cortex was decreased in stressed group. LTP test showed lower postsynaptic potential amplitude in stressed group as compared to that in control group. In conclusion, chronic stress could cause certain behavioral changes in rats, with possible mechanism of impairing EEG of certain thalamocortical pathway and prefrontal cortical synaptic plasticity.Highlights► Chronic unpredictable stress combined with isolation was used as animal model. ► Chronic stress impaired rats’ reversal learning ability. ► EEG of thalamocortical pathway may be related to stress induced behavioral changes. ► Prefrontal cortical synaptic plasticity might be involved in reversal learning.

To further disclose the underlying mechanisms of protein β-sheet formation, studies were made on the rules of β-strands alignment forming β-sheet structure using statistical and machine learning approaches. Firstly, statistical analysis was performed on the sum of β-strands between each β-strand pairs in protein sequences. The results showed a propensity of near-neighbor pairing (or called “first come first pair”) in the β-strand pairs. Secondly, based on the same dataset, the pairwise cross-combinations of real β-strand pairs and four pseudo-β-strand contained pairs were classified by support vector machine (SVM). A novel feature extracting approach was designed for classification using the average amino acid pairing encoding matrix (APEM). Analytical results of the classification indicated that a segment of β-strand had the ability to distinguish β-strands from segments of α-helix and coil. However, the result also showed that a β-strand was not strongly conserved to choose its real partner from all the alternative β-strand partners, which was corresponding with the ordination results of the statistical analysis each other. Thus, the rules of “first come first pair” propensity and the non-conservative ability to choose real partner, were possible important factors affecting the β-strands alignment forming β-sheet structures.Highlights► Investigating β-strands alignment by statistical and machine learning methods. ► The rule of “first come first pair” propensity of β-strands was found. ► A β-strand was not conserved to choose real partner from the alternative partner.

To further disclose the underlying mechanisms of protein β-sheet formation, studies were made on the rules of β-strands alignment forming β-sheet structure using statistical and machine learning approaches. Firstly, statistical analysis was performed on the sum of β-strands between each β-strand pairs in protein sequences. The results showed a propensity of near-neighbor pairing (or called “first come first pair”) in the β-strand pairs. Secondly, based on the same dataset, the pairwise cross-combinations of real β-strand pairs and four pseudo-β-strand contained pairs were classified by support vector machine (SVM). A novel feature extracting approach was designed for classification using the average amino acid pairing encoding matrix (APEM). Analytical results of the classification indicated that a segment of β-strand had the ability to distinguish β-strands from segments of α-helix and coil. However, the result also showed that a β-strand was not strongly conserved to choose its real partner from all the alternative β-strand partners, which was corresponding with the ordination results of the statistical analysis each other. Thus, the rules of “first come first pair” propensity and the non-conservative ability to choose real partner, were possible important factors affecting the β-strands alignment forming β-sheet structures.Highlights► Investigating β-strands alignment by statistical and machine learning methods. ► The rule of “first come first pair” propensity of β-strands was found. ► A β-strand was not conserved to choose real partner from the alternative partner.

This investigation examined whether the directionality of neural information flow could be used to index the measurement of synaptic plasticity in the chronic unpredictable stress (CUS) animals. Evolution map approach (EMA) was employed to determine the direction of information flow between the cortex and thalamus, while the experiment was performed by inducing long-term potentiation of the thalamocortical pathway after recording intracranial EEG at the same two positions in Wistar rats of both normal and stressed groups. The results showed that the coupling direction index was significantly diverted in stressed state compared to that in normal state, while the strength of thalamus driving frontal cortex was considerably reduced in the rats of CUS model. Moreover, the data obtained from LTP experiment exhibited that chronic stress decreased medial prefrontal cortex (mPFC) synaptic plasticity, which was certainly in accordance with the EEG findings. These results demonstrated that using EMA measurement, directionality index of neural information flow may be as a measure of synaptic plasticity.Research highlights▶ Coupling direction index was significantly diverted in CUS. ▶ Strength of thalamus driving frontal cortex was considerably reduced in CUS. ▶ Chronic stress was decreased mPFC synaptic plasticity. ▶ Directionality index of information flow may be as a measure of synaptic plasticity.

In this study we employed both detrended fluctuation analysis (DFA) and multiscale entropy (MSE) measurements to compare the long-range temporal correlation (LRTC) of multifibre renal sympathetic nerve activity (RSNA) between conscious and anesthetized Wistar rats. It was found that both methods showed the obvious LRTC properties in conscious state. Moreover, the scaling exponent of the RSNA in conscious rats was significantly higher than that in anesthetized rats. The results of MSE analysis showed that the entropy values, derived from the conscious group, increased on small time scales and then stabilized to a relatively constant value whereas the entropy measure, derived from anesthetized animals, almost monotonically decreased. This suggests that the fractal properties of underlying dynamics of the system have been reduced by anesthesia. The results demonstrate that apparently random fluctuations in multifibre RSNA are dictated by a complex deterministic process that imparts “long-term” memory to the dynamic system. However, this memory is significantly weakened by anesthesia.

Highlight•Study focuses on sex-specific effects of prenatal ethanol exposure.•MWM test and electrophysiological recording were performed.•A new index to measure the impairment of synaptic plasticity balance was developed.•Ethanol has sexually dimorphism on spatial cognition and synaptic plasticity balance.•Imbalance synaptic plasticity could be an underlying mechanism of cognitive deficits.Prenatal ethanol exposure can lead to long-lasting impairments in the ability of rats to process spatial information, as well as produce long-lasting deficits in long-term potentiation (LTP), a biological model of learning and memory processing. The present study aimed to examine the sexually dimorphic effects of chronic prenatal ethanol exposure (CPEE) on behavior cognition and synaptic plasticity balance (SPB), and tried to understand a possible mechanism by evaluating the alternation of SPB. The animal model was produced by ethanol exposure throughout gestational period with 4 g/kg bodyweight. Offspring of both male and female were selected and studied on postnatal days 36. Subsequently, the data showed that chronic ethanol exposure resulted in birth weight reduction, losing bodyweight gain, microcephaly and hippocampus weight retardation. In Morris water maze (MWM) test, escape latencies were significantly higher in CPEE-treated rats than that in control ones. They also spent much less time in the target quadrant compared to that of control animals in the probe phase. In addition, it was found that there was a more severe impairment in females than that in males after CPEE treatment. Electrophysiological studies showed that CPEE considerably inhibited hippocampal LTP and facilitated depotentiation in males, while significantly enhanced LTP and suppressed depotentiation in females. A novel index, developed by us, showed that the action of CPEE on SPB was more sensitive in females than that in males, suggesting that it might be an effective index to distinguish the difference of SPB impairment between males and females.