A novel derivative of xanomeline （EUK1001） facilitates the learning and memory in aging mice.

Aim： To investigate the effect of EUK1001, one of derivatives of xanomeline, on the learning and memory as well as hippocampal synaptic plasticity in aging mice. Methods： Mice were i.p.injected respectively with saline, xanomeline （0. 5mg/Kg ） and EUK1001 （0.5mg/Kg and 1 mg/kg） for 15 days before they were tested by a novel object recognition task. Effects of EUK1001 （0. 1 and 1μm） on the synaptic plasticity of CA3- CA1 in hippocampus were also investigated using in vitro electrophysiological technique. Results： The derivatives of xanomeline, such as EUK1001, improve the performance of aging mice in the novel object recognition test, like xamomeline. In addition, bath application of low concentration （0. 1 and lμm） of EUK1001 induced long term potentiation （LTP） in the hippocampus. This EUK1001-induced effect can be blocked completely by pirenzepine dihydrochloride （0. 25μm）, an antagonist of Ach receptor. Conclusion： EUK1001 ameliorates the normal aging related memory deficits. This effect on hippocampaldependent memory is mediated by enhancing synaptic plasticity of hippocampus.     

Dynorphin A enhances mitogen-induced proliferative response and interleukin-2 production of rat spenocytes

It has been well known that immune function is modulated by endogenous opioid peptides:βendorphin and enkephalins. However, the effect of dynorphin A on the immnune thnction has not been well documented.In this study, we investigated dynorphin A in the regulation of mitogen-induced proliferation and interleukin-2 (IL-2) production of rat splenocytes.The results showed that dynorphin A 1-13 as well as dynorphin A1- 17 enhanced concanavalin A-stimulated ~3H thyrnidine uptake 46%-112 % in a dose-dependent fashion.Dynorphin A also     

Effects of Liu-Wei-Di-Huang decoction, a typical traditional Chinese medicinal prescription, on learning and memory in senescence-accelerated mouse ( SAM) and hippocampal synaptic plasticity in rats

AIM: To investigate the effect of Lu-Wei-Di--Huang decoction(LW) on learning and memory in SAM and the hippocampalsynaptic plasticity in rats. METHODS: The behavioralexperiments including passive avoidance performance, shuttle boxand water maze tests wer conducted to assess the learning andmemory of mice and long-term potentiation (LTP) experimentwas employed as a model to examine the hippocampal synapticplasticity by recording the evoked potentials extracellularly inhippocampal dentate gyrus with tetanic stimulation to perforantpathway in anesthetized rats. RESULTS: Memory registrationand retention capacity, spatial memory as well as conditioned     

Protective effects of icariin on learning and memory deficits induced by aluminium in rats

This study examined the protective effects of icariin （ICA） on the learning and memory deficits in Aluminium （Al） -treated rats and potential mechanisms. The screened, qualified rats were treated with 1. 6 g/L AlCl3 in drinking water for 8 months, and the ability of spatial learning and memory was tested by Morris water maze. Aluminium （Al） administration significantly increased the mean escape latency searching distance in place navigation test, and decreased the searching time in the quadrant once the platform was in space probe test and adjusted searching distance in space probe test, indicative of brain spatial learning and memory deficits. ICA treatment （60, 120 mg/kg, i. g 3 month） significantly protected against Al-induced spatial learning and memory deficits, as evidenced by decreased escape latency and searching distance, and by increased the searching time in the quadrant once the platform was adjusted via searching distance compared with the Al alone group. To examine the mechanisms of the protection, the activities of superoxide dismuase （SOD） and the contents of maloidaldehyde （MDA） in hippocampus were assayed by commercial kits, and the level of Aβ1-40 in hippocampus was examined by immunohistochemistry （IHC）, respectively. ICA treatment significantly increased the activities of SOD, decreased the content of MDA and the level of Aβ1-40 in hippocampus in a dose - dependent manner. In summary, this study demonstrates that ICA is effective in improving the ability of spatial learning and memory of Al-intoxicated rats.     

The mechanism of ginsenosides Rg1 and Rb1 promoting neurotransmitters release

The root of Panax ginseng C. A. Meyer （Araliaceae） has been extensively used in traditional oriental medicine for prevention and treatment of aging - related disorders for over 2000 years. To study the mechanism of ginsennsides Rgl and Rb1 promoting neurotransmitters release , the amount of amino acids released from cell culture were measured by high performance liquid chromatography （HPLC）. Effects of Rg1 and Rbl on the phosphorylation of synapsins were detected with immunofluorescent staining and western blotting. Accumulating evidence suggests that ginsenosides such as Rgl and Rbl, which are the pharmacologically active ingredients of ginseng, modulate neurotransmission. Synapsins are abundant phosphoproteins essential for regulating neurotransmitter release. All synapsins contain a short amino - terminal domain A that is highly conserved and phosphorylated by cAMP- dependent protein kinase （PKA） , which plays a main role in regulating neurotransmitter release. In this study, we found that both Rgl and Rbl could increase glutamate releasing within physiological concentration. However, glutamate quantity was decreased by pre - incubating with PKA Inhibitor H89. When Rg1 joining again, glutamate quantity remained elevation as before, but Rb1 could not achieve it.     

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons： a modeling study

Aim： 3-Methyl-6-chloro-7,8-hydroxy-1-（3-methylphenyl）-2,3,4,5-tetrahydro-1H-3-benzazepine （SKF83959） have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation.
Methods： Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na^＋ channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability.
Results： SKF83959 （50 μmol/L） shifted the inactivation curve of Na^＋ current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 （examined with current injection at the soma） was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability （examined with current injection at the dendrite） was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency.
Conclusion： SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug’s anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.     

Mechanism of regulation of CaCC by the Mas-related G protein-coupled receptor D

MrgD is expressed almost exclusively in dorsal root ganglion(DRG) neurons.And its activation inhibited KCNQ/M-currents that contributes to an increase in excitability of DRG neurons and thus may enhance the signaling of primary afferent nociceptive neurons.Ca2+-activated chloride channels(CaCCs) are found in DRG neurons and regulate neuronal cell excitability as well.But the interaction between CaCCS and MrgD is still unknown.We here found that β-alanine-induced activation of MrgD resulted in eliciting Ca2+-activated chloride currents.The currents were inhibited by flufenamic acid(FFA) and by inhibition of phospholipase C and Ca2+ chelating agent EGTA.However,calphostin C,a PKC inhibitor,had no effect on the currents.These present data show that the inward currents induced by activation of MrgD were mediated through Gq-phospholipase C-IP3-Ca2+ release pathway,but not via Gi pathway.     

Effect of α-asarone on ethanol-induced learning and memory impairment in mice and its underlying mechanism

OBJECTIVE To investigate the effect ofα-asarone on ethanol-impaired cognitive ability and explore the underlying mechanism in mice. METHODS A mouse model of impaired learning and memory was created by ethanol(2.0 g · kg~(-1), ig). α-Asarone(7.5, 15 and 30 mg·kg~(-1), ip) was delivered 10 min prior to ethanol administration. After 40 min, the locomotor activity of mice with learning and memory impairment was evaluated by the open field test and the behavioral effect of α-asarone was evaluated using the novel object recognition test.Glutamate(Glu) and γ-aminobutyric acid(GABA) levels in the hippocampus were determined by ELISA, and the proteins expression levels of hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid(AMPA) receptor(Glu R2), N-methyl-D-aspartic acid(NMDA)receptor(NMDAR2 B), synaptophysin I(SYNΙ), glutamate transporter type 1(GLT-1) and calcium/calmodulindependent protein kinaseⅡ(Ca MKⅡ) were detected by Western blotting. RESULTS There was no significant difference in the horizontal or vertical locomotor activity between the ethanol and normal groups or the 7.5, 15 and 30 mg·kg~(-1)α-asarone groups[F(5, 48)=0.6536, P>0.05; F(5, 49)=1.995, P>0.05]. The recognition index in the ethanol group was significantly decreased as compared with that in the normal group[F(5, 46) =6.739, P<0.05]and was markedly increased in the α-asarone groups as compared with that in the ethanol group(P<0.05), with the exception of the 7.5 mg · kg~(-1)α-asarone group(P>0.05). The hippocampal Glu: GABA ratio in mice was significantly elevated in the ethanol group as compared with that in the normal group(33.42±0.8972 vs 30.79±0.2102, P<0.05) and significantly lower in the α-asarone groups(31.99±0.4986 vs. 33.42±0.8972; 30.97±0.1757 vs. 33.42±0.8972; 30.83 0.1723 vs. 33.42±0.8972, P<0.05). The expression levels of GluR2, NMDAR2B, pSYNⅠand p Ca MKII were significantly higher in the ethanol group as compared with those in the normal group(P<0.05) and obviously lower in the α-asarone groups(P<0.05), with the exception of GluR2, NMDAR2B and pCaMKⅡ in the 7.5 mg·kg~(-1)α-asarone group(P>0.05).And the expression level of GLT-1 was significantly lower in the ethanol group as compared with that in the normal group(P<0.05) and obviously higher in the α-asarone groups(P<0.05). CONCLUSION Pretreatment with α-asarone significantly improved the learning and memory impairment. A possible underlying mechanism is regulation of the calcium signaling cascade to correct functioning of related proteins, and thus, maintain the level of Glu.     

The study of dorsal hippocampal potential and neuronal activity during the spatial discrimination cognition in awaked guinea pigs

Abstract：This research is designed to study the characteristic changes of different hippocampal neural firing and potential during the spatial discrimination cognition in awaked guinea pigs, combining the linear and nonlinear analytical methods, so as to discuss the role of hippocampus during the spatial information encoding and spatial learning. The main results are as follows： 1. In the cognition state, the study reveals that there is significant difference between the active cognition group and passive cognition group in the firing frequency and complexity （ P 〈 0. 05 ）, but there is no significant difference between them in the spontaneous state （P 〉 0. 05 ）.     

PPARγ agonist pioglitazone reverses memory impairment and biochemical changes in a mouse model of type 2 diabetes

OBJECTIVE Pioglitazone,known as a peroxisome proliferator-activated receptor γ(PPARγ) agonist,is used to treat type 2 diabetes(T2DM).T2DM has been associated with reduced performance on numerous domains of cognitive function.Here,we investigated the effects of pioglitazone on memory impairment in a mouse model with defects in insulin sensitivity and secretion,namely high-fat diet(HFD) streptozotocin(STZ)-induced diabetic mice.METHODS ICR mice were fed an HFD for 4 weeks and then injected with a single low dose of STZ followed by continued HFD feeding for an additional 4 weeks.The diabetic mice were orally administered with pioglitazone(9,18 mg·kg-1) for 4-5 weeks.Y-maze test and Morris water maze test(MWM) were employed for testing learning and memory.Serum glucose,serum insulin,serum triglyceride,brain amyloid peptide-β(Aβ),brain β-site amyloid precursor protein cleaving enzyme(BACE1),brain nuclear factor κB(NF-κB),brain receptor for advanced glycation end products(RAGE) were also tested.RESULTS The STZ/HFD diabetic mice,characterized by hyperglycemia,hyperlipemia and hypoinsulinemia,performed poorly on Y-maze and MWM hence reflecting impairment of learning and memory behavior with increases of Aβ40/Aβ42,BACE1,NF-κB,and RAGE in brain.Treatment of PPARγ agonist,pioglitazone,significantly reversed diabetes-induced impairment of learning and memory behavior,which is involved in decreases of Aβ40/Aβ42 via inhibition of NF-κB,BACE1 and RAGE in brain as well as attenuation of hyperglycemia,hyperlipemia and hypoinsulinemia.CONCLUSION It is concluded that PPARγ agonist pioglitazone may be considered as potential pharmacological agents for the management of cognitive dysfunction in T2DM.     

Saponins from Panax japonicus ameliorates cognition deficits and attenuates oxidative damage in D-galactose-induced brain aging of mice

Aging is an inevitable process featured by intelligence decline,behavioral disorders and cognitive disability.Increasing evidence indicates that oxidative stress plays a key role in the senescent development.Our previous study demonstrated that Saponins from Panax japonicus has a significant anti-oxidative effect in vitro.So the aim of the present study was to investigate the brain protective role of Saponins from Panax japonicus and its underlying mechanism.Mice were subcutaneously injected with D-galactose(D-gal,150 mg·kg-1·d-1) for 8 weeks and administered Saponins from Panax japonicus simultaneously.After 8 weeks of treatment,the animal behavior was observed in the open field test and water maze test,and the morphology of hippocampus was detected.The activities and mRNA expressions of antioxidant enzymes as well as the level of malondialdehyde(MDA) were evaluated.The extent of apoptosis was examined by TUNEL assay.The results indicate that Saponins from Panax japonicus markedly ameliorates the D-gal induced learning and memory impairment in both open field test and Morris water maze.Biochemical examination and RT-PCR method revealed that Saponins from Panax japonicus significantly increases the decreased activities and mRNA expressions of superoxide dismutase(SOD),catalase(CAT) and glutathione peroxidase(GSH-Px) and decreases the raised malondialdehyde(MDA) content in the serum and brain of aging mice induced by D-gal.Furthermore,Saponins from Panax japonicus significantly attenuates the D-gal-induced neuronal degeneration and apoptosis in the hippocampus.These results indicate that Saponins from Panax japonicus has a potential protect role on brain aging mice induced by D-gal and its mechanism,at least in part,via modification of the redox system in the organism.     

Constructing and screening cDNA library of hippocampal differentially expressed genes correlated to morphine dependent memory in rats

Drug addiction has two aspects： physical dependence and psychological dependence. The development of psychological dependence is a special aberrant process of learning and memory, learning and memory play a key role in drug addiction, which is the totally new consensus of current international drug addiction research. Whether psychological dependence of drug abuser could be reduced or eliminated by blocking the process of long-term memory induced by repeatedly adminis-tered drugs to prevent relalase is a new persoective study field in drug addiction research.     

Synaptic Plasticity and Nociception

Synaptic plasticity is one of the fields that progresses rapidly and has a lot of success in neuroscience. The two major types of synaptie plasticity: long-term potentiation ( LTP and long-term depression (LTD are thought to be the cellular mochanisms of learning and memory. Recently, accumulating evidence suggests that, besides serving as a cellular model for learning and memory, the synaptic plasticity involves in other physiological or pathophysiological processes, such as the perception of pain and the regulation of cardiovascular system. This minireview will focus on the relationship between synaptic plasticity and nociception.     

Improved Learning and Memory of Pavlovian Context Fear Conditioning in Histidine Decarboxylase Knock- Out Mice

The hypothesis that histaminergic system is involved in learning and memory is supported by many studies. However, the functions of brain histamine in learning and memory are still controversial. To explore the exact role of histamine and related mechanisms, we trained wild-type （WT） and knock - out mice lacking the histidine decarboxylase gene （ HDC^-/- ） using Pavlovian fear conditioning.     

Effects of Kai - Xin - San, a traditional Chinese medicine, and its four herbal components on learning and memory

Senile dementia disease characterized by memory dysfunction and Alzheimer disease , are becoming more frequent in the aged populations . Modem medicine does not offer medical treatments to the amnesia and dementia. However , in the traditional Chinese medicines, several crude drugs created already thousand years ago , were thought to benefit the brain functions and to improve memory abilities . Kai - Xin -San, has been used since the Tang dynasty , and it has been applied in numerous compositions targeting senile dementia. Even in Japan, Kai - Xin - San has been used since the Heian dynasty . Kai- Xin- San contains ginseng （ panaxginseng C. A. Meyer） , polygala （ Polygala tenaifolia Wildenon） , acorus （ Acorus graminus Soland） , and hoelen （ Poria cocos Wolf） , at a ratio of 1： 1： 25：50 （ dry weight） . The traditional medicine suggested that Kai - Xin - San and four herbal components on memory dysfunctions using several behavioral animal models, as well as electrophysiological models of memory formation （ short - and long term potentiation） and hippocampal neuronal cell culture. Kai - Xin - San has protective effects against ischemia, ameliorated impairment of memory acquisitions induced by alcohol , enhanced recovery of memory functions of amygdale - lesioned mice , improved aging process in senile dementic animal model , and facilitated the hippocampul LTP - induction. Taken together , the resuits suggest that Kai - Xin - San directly -affected the hippocampal synaptic transmission,     

Beneficial effects of benzodiazepine diazepam on chronic stress-induced impairment of hippocampal structural plasticityand depression-like behavior in mice

Whether benzodiazepines(BZD) have beneficial effects on the progress of chronic stress-induced impairment of hippocampal structural plasticity and major depression is uncertain.The present study designed four preclinical experiments to determine the effects of BZD using chronic unpredictable stress model.In Experiment 1,several time course studies on behavior and hippocampus response to stress were conducted using the forced swim and tail suspension tests(FST and TST) as well as hippocampal structural plasticity markers.Chronic stress induced depression-like behavior in the FST and TST as well as decreased hippocampal structural plasticity that returned to normal within 3 week.In Experiment 2,mice received p.o.administration of three diazepam dosages prior to each variate stress session for 4 week.This treatment significantly antagonized the elevation of stress-induced corticosterone levels.Diazepam 0.5 and 1 mg·kg-1 blocked the detrimental effects of chronic stress.In Experiment 3,after 7 week of stress sessions,daily po diazepam administration during 1 week recovery phase dose-dependently accelerated the recovery of stressed mice.In Experiment 4,1 week diazepam administration to control mice enhanced significantly hippocampal structural plasticity and induced an antidepressant-like behavioral effect,whereas 4 week diazepam administration produced opposite effects.Hence,diazepam can slow the progress of chronic stress-induced detrimental consequences by normalizing glucocorticoid hormones.Considering the adverse effect of long-term diazepam administration on hippocampal plasticity,the preventive effects of diazepam may depend on the proper dose.Short-term diazepam treatment enhances hippocampal structural plasticity and is beneficial to recovery following chronic stress.     

Functional interactions between μ opioid and I1-imidazoline receptors

OBJECTIVE To study the role of I1-Imidazoline receptor(I1R) in opioid dependence.METHODS Subcellular location of μ opioid receptor(MOR) and IRAS was investigated by immunocytochemistry.The interaction between MOR and IRAS was studied by co-immunoprecipitation and fluorescence resonance energy transfer(FRET).Further more,whether the interactions between IRAS and MOR would affect the signaling and the adaptation of MOR was studied in the cells expressing MOR and IRAS.RESULTS We found that MOR and IRAS colocalized in the HEK293 cells transfected MOR and IRAS and in the neurons of the cerebral cortex and hippocampus.Coimmunoprecipitation and FRET assays showed that there were interactions between the IRAS and MOR.High concentration reductant DTT did not interrupt the interactions,suggesting that the interactions were not mediated by disulfide bond.Further more,we found that the interactions did not influence the expression and affinity of MOR,as well as the activation of G proteins,adenylate cyclase and extracellular signal-regulated kinase(ERK) phosphorylation coupled to MOR after stimulated by DAMGO.However,over-expression of IRAS could attenuate DAMGO-induced MOR desensitization and internalization,accelerate MOR resensitization in the cells co-expressing IRAS and MOR,which probably by increasing the rate of dephosphorylation and recycling of MOR.The molecular mechanisms for that were on studying.CONCLUSIONThese findings indicate I1R is an important molecular to modulate opioid functions,and provide the further evidence to support I1R as a new target for treating opioid addiction.     

Effects of the ephedra alkaloid methylephedrine on the basal evoked potential transportation and the long-term potentiation (LTP) in the rat hippocampal dentate granule cells in vivo

Objective The effect of the ephedra/ephedrine alkaloid methylephedrine(dl-methylephedrine hydrochloride for testing in this paper)on cognitive related synaptic plasticity was investigated by recording extracellular field evoked potentials and its LTP in hippocampal dentate granule cells in urethane-anaesthetized rats in vivo.Methods Single pathway recording of evoked field potentials was made from the dentate granule cells of hippocampal hemisphere in response to stimulation of the ipsilateral medial perforant path(MPP).Two parameters,the amplitude of population spike(PS amplitude)and the latency of the PS,were employed to evaluate the effects of drug on the overall changes in cellular responses.Results The present study show that methylephedrine 90 mg·kg-1 intraperitoneally,about 1/3 LD50,could increase the latency of the PS in hippocampal dentate granule cells by constant single stimulation of the MPP as the basal ransportation.However,the 30 mg·kg-1 and 10 mg·kg-1 dosage had no effect on the latency,and there are no influences of PS amplitude for all examinational groups.The methylephedrine 90 mg·kg-1 group significant enhanced the development of amplitude LTP in hippocampal dentate granule cells that induced by 60 Hz,60 pulses conditional tetanus in medial perforant path area.Also,the 30 mg·kg-1 group can promoted the maintenance of LTP induced by this tetanus,but no promotion on PS amplitude LTP appeared in this dosage and no any changes been found in 10 mg·kg-1 dosage group.Conclusions The ephedra/ephedrine alkaloid methylephedrine can modulate the synaptic plasticity in the lateral perforant path.A possible mechanism of methylephedrine on hippocampal LTP is been discussed.