miR-429-3p mediates memory decline by targeting MKP-1 to reduce surface GluA1-containing AMPA receptors in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2AAPP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

N,N-dimethyltryptamine,a natural psychedelic,rap-idly improves spatial memory and hippocampal long-term potentiation:a potential rapid-acting therapy for dementia-associated wandering / 中国药理学与毒理学杂志

There is no fast-acting treatment strate-gies against Alzheimer's disease(AD),in particular dementia-related wandering.N,N-dimethyltryptamine(DMT)is a natural psychedelic that may have rapid-onset nootropic effects.In this study,5×FAD transgenic mice which recapitulated amyloid neuropathological features of AD received one single injection of 6 or 12 mg·kg-1 DMT and tested at 0.5,1,and 2 h thereafter in Y-maze for spatial memory.5×FAD transgenic mice exhibited pro-nounced decreases in time spent,number entered,and distance travelled in the novel arm of Y-maze.DMT at 12 mg·kg-1 partially or completely reversed the three behavioral indices at multiple time points,up to 2 h post injection.The rapid-onset behavioral improvement was consistent with pharmacokinetic analysis of DMT,showing approximately 30 min to reach the maximum concentra-tion in the brain tissue.The transgenic mice also displayed dramatically impaired hippocampal long-term potentiation(LTP),an electrophysiological feature of memory forma-tion and consolidation.DMT potently enhanced LTP and restored intracellular calcium activity,expression and phosphorylation of calcium/calmodulin-dependent protein kinase Ⅱ(CaMK Ⅱ)and AMPA-type glutamate receptor 1(GluR1),the two key calcium-activated mediators involved in LTP induction.Adenosine triphosphate(ATP)is purinergic signalling molecules that are involved in LTP induction and maintenance.DMT rapidly increased mito-chondrial ATP dynamics in in vivo and in vitro models.These results suggest that DMT rapidly improve spatial memory and hippocampal LTP by restoring the CaMK Ⅱ-GluR1 signaling pathway and mitochondrial ATP produc-tion.It may be served as a fast-acting nootropic agent for the treatment of AD in particular wandering.

Mechanism of Dihuang Yinzi in Improving Astrocyte Injury and Regulating Synaptic Structure and Function in AD Mice / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of Dihuang Yinzi in improving astrocyte injury and protecting synaptic structure and function in the brain of Alzheimer's disease （AD） mice. MethodForty male APP/PS1 transgenic mice aged four months were randomly divided into a model group and a model + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. Forty C57BL/6J mice with the same background and same age were randomly divided into a control group and a control + Dihuang Yinzi （0.25 g·kg-1） group， with 20 mice in each group. The mice in the control + Dihuang Yinzi group and the model + Dihuang Yinzi group were administered with Dihuang Yinzi by gavage， and those in the control group and the model group received an equal volume of sterilized normal saline， once a day for 150 days. The learning and memory ability of mice was tested by the light-dark box test and Y-maze spontaneous alternation test. The content of glutamate （Glu） and glutamine （Gln） was measured by liquid chromatography-tandem mass spectrometry （LC-MS）. Long-term potentiation （LTP） assay was used to detect synaptic plasticity in brain tissues. The protein expression levels of excitatory amino acid transporter 2 （EAAT2）， postsynaptic density protein95 （PSD95）， and synaptophysin （SYN） in brain tissues were measured by Western blot. Immunofluorescence was used to assess the localization and expression of EAAT2. Colorimetry was performed to detect Na+-K+ ATPase activity in mouse brain tissues. ResultAs compared with the control group， the model group showed shortened residence latency （P<0.01）， increased number of errors （P<0.01） in the light-dark box test， reduced spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， down-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， blunted activity of Na+-K+ ATPase （P<0.01）， up-regulated Glu level （P<0.01）， down-regulated Gln level （P<0.01）， and reduced relative population spike （PS） amplitude and the slope of excitatory postsynaptic potential （EPSP） （P<0.05， P<0.01）， while the above experimental indexes were not significantly different in the control + Dihuang Yinzi group. Compared with the model group， the model + Dihuang Yinzi group displayed prolonged residence latency （P<0.05）， decreased number of errors （P<0.01） in the light-dark box test， increased spontaneous alternation behaviors （P<0.01）， no significant difference in the total number of arm entries in the Y-maze spontaneous alternation test， up-regulated expression of EAAT2， PSD95， and SYN （P<0.01）， potentiated activity of Na+-K+ ATPase （P<0.01）， reduced Glu level （P<0.01）， up-regulated Gln level （P<0.01）， and increased PS amplitude and EPSP slope （P<0.01）. ConclusionDihuang Yinzi can improve cognitive dysfunction in AD mice by protecting astrocytes， increasing Glu uptake to reduce its abnormal accumulation， and protecting synaptic structure and function.

Disrupted Maturation of Prefrontal Layer 5 Neuronal Circuits in an Alzheimer's Mouse Model of Amyloid Deposition / 神经科学通报·英文版

Mutations in genes encoding amyloid precursor protein (APP) and presenilins (PSs) cause familial forms of Alzheimer's disease (AD), a neurodegenerative disorder strongly associated with aging. It is currently unknown whether and how AD risks affect early brain development, and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology. Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis. Among these lines, the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloid β (Aβ)-induced neurodegeneration. We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons, and performed detailed synaptic physiological characterization of layer 5 (L5) neurons from the prefrontal cortex (PFC) of 5XFAD and wild-type littermate controls. L5 PFC neurons from 5XFAD mice show early APP/Aβ immunolabeling. Whole-cell patch-clamp recording at an early post-weaning age (P22-30) revealed functional impairments; although 5XFAD PFC-L5 neurons exhibited similar membrane properties, they were intrinsically less excitable. In addition, these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs. These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation. Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A. Consistent with this, patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio, and an increased level of AMPAR-lacking silent synapses. These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.

Evaluation of antidepressant activity of ondansetron in rodent models of depression

Background: At present, there is an escalating concern regarding possible role of 5-HT3 receptor in psychopharmacology and the therapeutic potential of their antagonists. Moreover, inclusion of 5-HT3 receptor antagonist may curtail the antidepressant-induced LTP decrease causing memory deficits, thereby improving efficacy of current antidepressants. Aim and Objective: This study aims to evaluate the antidepressant activity of 5-HT3 antagonist, that is, ondansetron (OND) in rodent models of depression. Materials and Methods: Male Swiss albino mice (20–30 g bw) and Wistar rats (100–200 g bw) were divided into five groups. Animals received either OND p.o. (0.1, 0.5 and 1 mg/kg), venlafaxine (10 mg/kg), or vehicle (1 ml distilled water p.o.) in control. Tail suspension and forced swim test were used to evaluate the effects of drugs and control after 60 min of their administration. Furthermore, assessment of locomotor activity (LA) was done by photoactometer after 24 h of drug administration. Results: Ondansetron exhibited significant antidepressants activity (P < 0.05) in rodent models. However, LA was not significantly altered by OND. Conclusion: Ondansetron exhibited significant antidepressant activity in rodent models hence paving the way for exploration of 5-HT3 receptor antagonist in future researches and its therapeutic application in depression.

Mejora del rendimiento post-activación con banco plano o landmine en la fuerza del golpe recto / Melhoria do desempenho de pós-ativação com banco plano ou landmine na força do golpe reto / Post-activation performance enhancement with bench press or landmine on straight punch strength

RESUMEN La presente investigación centró sus esfuerzos en descubrir alternativas metodológicas que beneficien la posibilidad de aplicar altos niveles de fuerza en el golpe recto, favoreciendo con ello la probabilidad de una victoria por la vía del knock out. La hipótesis de trabajo planteó que, si se emplean ejercicios con un efecto de mejora del rendimiento postactivación, se puede incrementar la fuerza aplicada al golpe recto. Este cuasi-experimento tuvo como objetivo determinar los efectos agudos de la mejora del rendimiento postactivación en la fuerza aplicada en el golpe recto, utilizando el banco plano o el Landmine como actividad condicionante. Se trabajó con 20 boxeadores (ocho profesionales y 12 amateur), y dividió la población en dos grupos, emparejados según el peso corporal. Se evaluó la fuerza máxima de impactocon una celda de carga modelo WLCC01, luego se determinó la fuerza máxima dinámica para cada ejercicio, y a partir de estos datos, se colocó una carga a movilizar del 60 % de la fuerza máxima dinámica, ejecutando repeticiones hasta que la velocidad del movimiento disminuyó más del 10 %. Seguidamente, se volvió a evaluar la fuerza máxima de impacto. Se tomaron registros inmediatamente después, al minuto uno, dos, tres, cuatro y cinco. Los resultados expresaron un aumento del 9.3 % en el grupo de banco plano y del 12,46 % en el grupo de Landmine. Se concluyó que ambos ejercicios, al ser utilizados como actividad condicionante, generan un incremento significativo (p 0.05) de la fuerza máxima de impacto en el golpe recto.

RESUMO A presente investigação centrou os seus esforços na descoberta de alternativas metodológicas que beneficiem a possibilidade de aplicar níveis elevados de força no golpe reto, favorecendo assim a probabilidade de uma vitória por knock-out. A hipótese de trabalho propôs que, se forem utilizados exercícios com um efeito de melhoria do desempenho pós-ativação, a força aplicada ao golpe reto pode ser aumentada. Esta quase-experimentação visava determinar os efeitos agudos do melhoramento do desempenho pós-ativação sobre a força aplicada ao golpe reto, utilizando como atividade condicionadora a bancada plana ou Landmine. Trabalhámos com 20 pugilistas (oito profissionais e 12 amadores). A força máxima de impacto foi avaliada com uma célula de carga modelo WLCC01, depois a força dinâmica máxima foi determinada para cada exercício, e a partir destes dados, foi colocada uma carga para mobilizar 60 % da força dinâmica máxima, executando repetições até a velocidade do movimento diminuir mais de 10 %. Depois, a força máxima de impacto foi reavaliada. Os registos foram tirados imediatamente após, aos um, dois, três, quatro e cinco minutos. Os resultados mostraram um aumento de 9,3 % no grupo dos bancos planos e de 12,46 % no grupo das minas terrestres. Concluiu-se que ambos os exercícios, quando utilizados como atividade condicionante, geram um aumento significativo (p 0,05) da força máxima de impacto no soco reto.

ABSTRACT The present research focused its efforts on discovering methodological alternatives that benefit the possibility of applying high levels of strength in the straight punch, thus favoring the probability of a victory by knockout. The working hypothesis proposed that, if exercises with a post-activation performance enhancement effect are used, the strength applied to the straight punch can be increased. This quasi-experiment aimed to determine the acute effects of post activation performance enhancement on the strength applied to the straight punch, using the bench press or the Landmine as the conditioning activity. It was worked with 20 boxers (eight professional and 12 amateur), and the population was divided into two groups, matched according to body weight. The maximum impact strength was evaluated with a load cell model WLCC01, then the maximum dynamic strength was determined for each exercise, and from this data, a load was placed to mobilize 60 % of the maximum dynamic strength, performing repetitions until the speed of the movement decreased by more than 10 %. Then, the maximum impact strength was re-evaluated. Records were taken immediately after, at one, two, three, four and five minutes. The results showed an increase of 9.3 % in the bench press group and 12.46 % in the Landmine group. It was concluded that both exercises, when used as conditioning activity, generate a significant increase (p 0.05) of the maximum impact strength in the straight punch.

Performance of brazilian university handball players in the vertical jump after maximum strength training

This study aimed to analyze the performance of the vertical jump with counter movement (CMJ), in university handball athletes, immediately after the maximum strength training in multiple series and after 10 and 15min of rest. Twelve male athletes participated, age 20.9±2.4 years old, height 1.78±0.05m and Body Mass Index (BMI) 28.74±8.1kg/m2. After the tests and retests of 1 repetition maximum (1RM) for the dominant and non-dominant sides, in the leg extension, the volunteers performed crossover after 48 hours of the training sessions. CMJ measurements were collected before and immediately after each training protocol and after 10 and 15min of rest. Passive recovery between sets was three minutes. The intervals between training protocols were at least 45min. There were no statistical differences for the CMJ between the moments pre-, post-training session, 10 and 15min of rest in the different protocols, but progressive increases in the CMJ variables were observed, extending up to the 15th minute of rest, in all training protocols when comparing the results of the means of the CMJ variables of the moments post-training session, 10 and 15min of rest with the averages of the variables from the pre-training session, being more evident in the alternate unilateral protocol, which, unlike the other protocols of the study, performed series with the two lower limbs. It was evidenced that the training protocols of short duration and with high dynamic efforts, previously performed, influenced the performance of the CMJ, favoring for the transient improvement of the explosive muscular strength of the athletes.

Corticosterone induced D-serine release deficit play an important role in long-term potentiation impairment by corticosterone in perforant path-dentate gyrus pathway / 中国药理学与毒理学杂志

OBJECTIVE Previous studies showed that over activation of NMDA receptors may be a crucial cause of long-term potentiation (LTP) and cognitive impairment induced by stress or corticosterone. However, other studies showed that the function of NMDA receptors is insufficient since the NMDA receptors co-agonist D-serine could improve stress-induced cognitive impairment. The purpose of this study is to clarify whether over activation of NMDA receptors or hypofunction of NMDA receptors is involved in hippocampal impairment of LTP by corticosterone and the underlying mechanisms. METHODS Cort was injected subcutaneously 1 h before the high-frequency stimulation (HFS) to induce LTP impairment. NMDA receptor antagonists and agonists were administrated by icv. RESULTS Hippocampal LTP and object location recognition memory were impaired in corticosterone-treated mice. Corticosterone increased the gluta?mate level in hippocampal tissues, neither NMDA receptors antagonist nor its subtype antagonists alleviated impairment of LTP, while enhancing the function of NMDA receptors by D-serine did alleviate impairment of LTP by corticosterone, suggesting that hypofunction of NMDA receptors might be one of the main reasons for impairment of LTP by corticoste?rone. Further results showed that the level of D-serine and its precursor L-serine did not change. D-serine release-related protein Na+-independent alanine-serine-cysteine transporter-1 (ASC-1) in the cell membrane was decreased and increas?ing D-serine release by the selective activator of ASC-1 antiporter activity alleviated impairment of LTP by corticoste?rone. CONCLUSION Taken together, this study demonstrates that hypofunction of NMDA receptors may be involved in impairment of LTP by corticosterone and reduced D-serine release may be an important reason for its hypofunction, which is an important complement to existing mechanisms of corticosterone-induced LTP and cognitive impairment.

Induction of long-term potentiation at Schaffer collateral-CA1 synapses in mice hippocampus after IMPX977 administration / 中草药·英文版

Objective: To investigate the effects of IMPX977 on long term potentiation (LTP) at Schaffer collateral-CA1 synapses in vitro and on methyl CpG binding protein 2 (Mecp2) expression in mice cortex and hippocampus. Methods: Thirty-two C57BL/6 mice were randomly divided into four groups: control, olive oil (vehicle), IMPX977 low (5 mg/kg) and high (15 mg/kg) groups. Mice were administrated every other day orally for two weeks. Extracellular recording technique in vitro was used to record the effects of IMPX977 on Schaffer collateral-CA1 LTP pathway in acute mice hippocampal slices. The Mecp2 protein expression level was detected by Western blotting. Results: Compared to the control group, vehicle did not alter the synaptic transmission in Schaffer collateral-CA1 synapses, however, IMPX977 at concentrations of 5 mg/kg and 15 mg/kg significantly enhanced fEPSP (field excitatory postsynaptic potential) slope in Schaffer collateral-CA1 pathway to (179.6 ± 17.8)% and (191.4 ± 21.4)%, individually 60 min after HFS, IMPX977 improved LTP induction significantly at Schaffer collateral-CA1 pathway at least. Also, IMPX977 significantly elevated MeCP2 protein level in cortex. Conclusion: The effects of IMPX977 on synaptic transmission and Mecp2 protein expression provided convincing evidence that IMPX977 could be promising new drug candidates for Rett syndrome treatment.

Short-Term Visual Experience Leads to Potentiation of Spontaneous Activity in Mouse Superior Colliculus / 神经科学通报·英文版

Spontaneous activity in the brain maintains an internal structured pattern that reflects the external environment, which is essential for processing information and developing perception and cognition. An essential prerequisite of spontaneous activity for perception is the ability to reverberate external information, such as by potentiation. Yet its role in the processing of potentiation in mouse superior colliculus (SC) neurons is less studied. Here, we used electrophysiological recording, optogenetics, and drug infusion methods to investigate the mechanism of potentiation in SC neurons. We found that visual experience potentiated SC neurons several minutes later in different developmental stages, and the similarity between spontaneous and visually-evoked activity increased with age. Before eye-opening, activation of retinal ganglion cells that expressed ChR2 also induced the potentiation of spontaneous activity in the mouse SC. Potentiation was dependent on stimulus number and showed feature selectivity for direction and orientation. Optogenetic activation of parvalbumin neurons in the SC attenuated the potentiation induced by visual experience. Furthermore, potentiation in SC neurons was blocked by inhibiting the glutamate transporter GLT1. These results indicated that the potentiation induced by a visual stimulus might play a key role in shaping the internal representation of the environment, and serves as a carrier for short-term memory consolidation.

Tweety-Homolog 1 Facilitates Pain via Enhancement of Nociceptor Excitability and Spinal Synaptic Transmission / 神经科学通报·英文版

Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.

Single Exposure to Cocaine Impairs Reinforcement Learning by Potentiating the Activity of Neurons in the Direct Striatal Pathway in Mice / 神经科学通报·英文版

Plasticity in the glutamatergic synapses on striatal medium spiny neurons (MSNs) is not only essential for behavioral adaptation but also extremely vulnerable to drugs of abuse. Modulation on these synapses by even a single exposure to an addictive drug may interfere with the plasticity required by behavioral learning and thus produce impairment. In the present work, we found that the negative reinforcement learning, escaping mild foot-shocks by correct nose-poking, was impaired by a single in vivo exposure to 20 mg/kg cocaine 24 h before the learning in mice. Either a single exposure to cocaine or reinforcement learning potentiates the glutamatergic synapses on MSNs expressing the striatal dopamine 1 (D1) receptor (D1-MSNs). However, 24 h after the cocaine exposure, the potentiation required for reinforcement learning was disrupted. Specific manipulation of the activity of striatal D1-MSNs in D1-cre mice demonstrated that activation of these MSNs impaired reinforcement learning in normal D1-cre mice, but inhibition of these neurons reversed the reinforcement learning impairment induced by cocaine. The results suggest that cocaine potentiates the activity of direct pathway neurons in the dorsomedial striatum and this potentiation might disrupt the potentiation produced during and required for reinforcement learning.

Effects of lead exposure and chelation therapy in different developmental stages on mouse short-term and long-term cognitive functions / 环境与职业医学

Background Lead (Pb) exposure impairs cognitive functions of children. Whether Pb exposure in different developmental stages induces long-term cognitive impairment, and whether chelation therapy could mitigate the cognitive impairment is rarely reported. Objective This experiment is designed to investigate effects of Pb exposure and chelation therapy during different developmental stages (breastfeeding, weaning, and early puberty periods) on mouse short-term and long-term cognitive functions. Methods C57BL/6 male mice in breastfeeding period, weaning period, and early puberty period (postnatal day 2, 21, and 41; PND 2, PND 21, and PND 41, n=30, respectively) were randomly divided into control, Pb exposure, and Pb+dimercaptosuccinic acid (DMSA) treatment groups (n=10 in each group). The control groups received standard food and deionized water. The Pb exposure mice received standard food and free drinking water containing Pb acetate (0.1% for dams, and 0.05% for pups). After receiving Pb acetate for 19 d, the Pb+DMSA treatment groups were given 1 mmol·kg−1·d−1 DMSA for 6 d with gastric infusion. Whole blood Pb levels were measured after DMSA treatment on experimental day 25. The effects on short-term cognitive function were tested in the Morris Water Maze task by the analyses of escape latency on PND 75−79, as well as target quadrant time and times of platform-crossing on PND 80. Hippocampal long-term potentiation of field excitatory postsynaptic potential (fEPSP) of mice on PND 365 was induced to demonstrate the effects on long-term cognitive function. Results The blood Pb levels among the Pb, Pb+DMSA, and control groups were statistically different for each developmental stage (Fbreastfeeding period=43.47, Fweaning period=228.6, Fearly period of puberty=274.2, all P<0.001). Compared to the counterpart control groups, blood Pb levels of the pb exposure groups (386.4, 265.0, and 178.1 μg·L−1 in breastfeeding period, weaning period, and early puberty period, respectively) were significantly higher for all stages. After the chelation therapy, the blood Pb significantly decreased for all stages (28.68, 47.29, and 20.93 μg·L−1 in the three periods, respectively, all P<0.001) and the Pb levels of the mice exposed in the breastfeeding period decreased most (by 92.58%, 82.15%, and 88.25% in the three periods, respectively, P<0.01). In the water maze task, the mice exposed to Pb in the breastfeeding period had a gentler decrease in escape latency (from 54.20 s on day 1 to 30.54 s on day 5, by 43.65 % decrease) than the control group (from 32.44 s on day 1 to 15.20 s on day 5, by 53.14 % decrease) (P<0.01) and a significant decrease in target quadrant time (P<0.05). After the chelation therapy, the escape latency of the DMSA-treated mice in the breastfeeding period (from 40.94 s on day 1 to 20.87 s on day 5, by 48.99 % decrease) was steeper than that of the Pb-exposed mice (P<0.05). The differences in the escape latency, target quadrant time, and times of platform-crossing were not significant between the Pb-exposed mice and the control mice in the weaning period and early period of puberty (all P>0.05). After the chelation therapy, such differences were also not significant compared with before therapy. Due to the small sample size, data were merged for different developmental stages in the long-term potentiation test. The amplitudes of fEPSP induced in the control, Pb-exposed, and DMSA treatment groups were significantly different (Fgroups=212.2, Ftime=11.36. P<0.001). The average fEPSP amplitude induced in the last 10 min recorded in the hippocampal slices in the Pb exposure group was significantly lower than that in the control group (P<0.05). After the DMSA treatment, no significant differences were observed in the fEPSP amplitudes between the Pb exposure group and the DMSA treatment group (P>0.05). When observing the fEPSP data by developmental stages, the fEPSP amplitude in the breastfeeding Pb-exposure group was 27.2% lower than that of the breastfeeding control group, while such changes were not obvious in the weaning period or in the early period of puberty. The fEPSP amplitude in breastfeeding DMSA treatment group was 44.3% higher than that of the breastfeeding Pb exposure group, while such changes were not observed in the weaning period or in early period of puberty. Conclusion Pb exposure during different developmental stages, especially in breastfeeding period, could affect short-term and long-term cognitive functions of mice. The harmful effects may be partially reversed by DMSA chelation therapy, especially being treated in breastfeeding period.

Sub-chronic aluminum exposure inhibits synaptic plasticity in hippocampus of rats via inhibiting PI3K/AKT/mTOR signaling pathway / 中国职业医学

OBJECTIVE: To study the effect of sub-chronic aluminum exposure on synaptic plasticity in the hippocampus of rats and to explore the mechanism of phosphatidylinositol 3 kinase(PI3 K)/protein kinase B(AKT)/rapamycin target protein(mTOR) signaling pathway. METHODS: Specific pathogen free adult healthy male SD rats were randomly divided into control group and low-, medium-and high-dose groups based on body weight, with 10 rats in each group. Rats were treated with maltol aluminum solution at the concentrations of 0, 10, 20 and 40 μmol/kg body weight by intraperitoneal injection, 5 days per week for 3 months. After the exposure, rats were weighed. Morris water maze was used to test the learning and memory ability, and the two-electrode binding technique was used to record the long-term potentiation(LTP) amplitude in the hippocampus CA1 area of rats. The protein expression of PI3 K, AKT and mTOR in rat hippocampus tissues was detected by Western blot. RESULTS: After the exposure, the body weights of rats in the medium-and high-dose groups were lower than that of the control group(P<0.05). The results of the positioning navigation experiment showed that the escape latencies of the rats in the medium-and high-dose groups were shorter than that in the control group during the 2 nd to 4 th days of the experiment(P<0.05). The results of space exploration experiments showed that there was no statistical difference on the target quadrant retention time and the number of crossing the platform among the 4 groups(P>0.05). At 1, 30, and 60 min after high-frequency stimulation, the LTP amplitudes in the hippocampus CA1 area of the aluminum-treated groups were lower than that of the control group at the same time point(P<0.05), and the LTP amplitudes of hippocampus CA1 area of rats decreased with the increase of maltol aluminum exposure dose(P<0.01). The relative expression of PI3 K, AKT and mTOR protein in the hippocampus tissues of the aluminum-treated groups was lower than that of the control group(P<0.05), and the relative expression of the above three proteins decreased with the increase of the maltol aluminum exposure dose(P <0.01). CONCLUSION: Sub-chronic aluminum exposure could lead to dose-dependent inhibition of hippocampus synaptic plasticity in rats, thereby impairing the spatial learning ability of rats. This process may be related to inhibition of PI3 K/AKT/mTOR signaling pathway by aluminum.

Effects of intra-dentate gyrus microinjection of myokine irisin on long-term potentiation in male rats / Efeitos da microinjeção da miocina irisina no giro denteado sobre a potenciação a longo prazo em ratos machos

ABSTRACT Induction of long-term potentiation (LTP) increases the storage capacity of synapses in the hippocampal dentate gyrus (DG). Irisin is a myokine generated from FNDC5 (a gene precursor) during exercise. Although intra-cornu ammonis 1 administration of irisin fortifies LTP in mice with Alzheimer's disease, the effects of intra-DG injection of irisin on the LTP in rats remains to be elucidated in vivo. In this study, male Wistar rats were randomly divided into a control group (saline), irisin (0.5, 1, and 1.5 μg/rat), and dimethyl sulfoxide (DMSO). After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the DG of rats in vivo. Moreover, following completion of the experiments, the stimulating and recording sites in the hippocampus were confirmed histologically from brain sections. Furthermore, biochemical assays like malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS) were evaluated (the antioxidant markers were analyzed in the plasma). Our results suggest that all doses of irisin (0.5, 1, 1.5 μg/rat) caused an increase in the EPSP slope and PS amplitude when compared with the control group. In addition, the results obtained showed that irisin decreased TOS and MDA levels while increasing TAC levels as a marker of lipid peroxidation in plasma. The present report provides direct evidence that irisin affects the activity-dependent synaptic plasticity in the dentate gyrus.

RESUMO A indução de potenciação de longo prazo (LTP) aumenta a capacidade de armazenamento das sinapses no giro denteado (DG) do hipocampo. A irisina é uma miocina gerada a partir do FNDC5 (um precursor genético) durante o exercício. Embora a administração intra-Cornu Ammonis1 de irisina fortaleça a LTP em camundongos com doença de Alzheimer, os efeitos da injeção intra-denteada de irisina sobre a LTP em ratos ainda precisam ser elucidados in vivo. Neste estudo, ratos Wistar machos foram divididos aleatoriamente em um grupo controle (solução salina), irisina (0,5, 1 e 1,5 μg / rato) e dimetilsulfóxido (DMSO). Após o tratamento, a amplitude do pico populacional (PS) e a variação dos potenciais pós-sinápticos excitatórios (EPSP) foram medidos no DG de ratos in vivo. Além disso, após a conclusão das experiências, os locais de estimulação e registro no hipocampo foram confirmados histologicamente a partir de secções do cérebro. Adicionalmente, ensaios bioquímicos como malondialdeído (MDA), capacidade antioxidante total (TAC) e status oxidante total (TOS) foram avaliados (os marcadores antioxidantes foram analisados no plasma). Nossos resultados sugerem que todas as doses de irisina (0,5, 1, 1,5 μg / rato) causaram um aumento na variação da EPSP e na amplitude da PS quando comparadas com o grupo controle. Além disso, os resultados obtidos mostraram que a irisina diminuiu os níveis de TOS e MDA, enquanto aumentou os níveis de TAC como um marcador da peroxidação lipídica no plasma. O presente estudo fornece evidências diretas de que a irisina afeta a plasticidade sináptica dependente de atividade no DG.

Prescribing patterns of tramadol in hemodialysis patients

Background: Pain is the most common complaint in hemodialysis patients. Tramadol had become analgesic of choice in these patients, and its prescription is increasing day by day. With this background, we evaluated the prescribing trends of tramadol in patients undergoing maintenance hemodialysis.Methods: A total of 70 prescriptions were audited to assess the prescribing trends of tramadol (usually prescribed as a combination of 37.5 mg tramadol and 325 mg of paracetamol two times a day). Included prescriptions were from both male and female patients above 18 years of age undergoing maintenance hemodialysis. Demographic, clinical and medication use were recorded from the patients.Results: The mean age of patients was 48±11.7 years, duration of dialysis 2.2±1.4 years. Tramadol consumptions were observed in 40/70 (56%) of patients. Majority of tramadol consumption was found in 30/40 (75%) males, 23/40 (59%) between 40-59 years and 28/40 (70%) undergoing two dialyses per week and 13/40 (32.5) were diabetics. During our exploratory analysis, we found that 15/40 (38%) of tramadol users, were concurrently prescribed with clonidine as add on antihypertensive. We noticed that the tramadol pill count during the preceding week was 81 in patients concurrently using clonidine and 139 in the patients who were not using clonidine (p>0.05).Conclusions: In our study, tramadol consumptions were observed in 56% of patients. We also noticed analgesic interaction between clonidine and tramadol.

La metáfora energética del ser humano y su incidencia en el auge de la neurastenia, la neurosis y la depresión / The energy metaphor for the human body and its effect on the rise of neurasthenia, neurosis and depression

Resumen El artículo tiene por objetivo realizar una historia crítica del auge de tres categorías diagnósticas: la neurastenia (fin del siglo XIX), la neurosis (primera mitad del siglo XX) y la depresión (segunda mitad del siglo XX hasta nuestros días). La hipótesis es que su amplia difusión se explicaría debido al vínculo que ellas han tenido con la metáfora energética del ser humano. Desde mediados del siglo XIX, la concepción energética se difundió por la cultura occidental, habilitando ciertas ficciones acerca de lo que somos - dimensión ontológica - y lo que podríamos llegar a ser - dimensión ética. El artículo muestra que estas patologías han codificado y tornado inteligible determinadas trayectorias vitales que no cumplían con los imperativos de tales ficciones onto-éticas.

Abstract This article aims to provide a historical critique of the rise of three diagnostic categories: neurasthenia (late nineteenth century), neurosis (first half of the twentieth century) and depression (mid-twentieth century to the present). The hypothesis is that their broad dissemination can be explained through their link to the energy metaphor for the human body. From the mid-nineteenth century on, the concept of energy spread through western culture, encouraging certain fictions about what we are - the ontological dimension - and what we could be - the ethical dimension. The article shows that these pathologies have codified and made intelligible a set of life trajectories that did not obey the imperatives of those onto-ethical fictions.

Effects of Chronic and Acute Lithium Treatment on the Long-term Potentiation and Spatial Memory in Adult Rats

OBJECTIVE: Although, accumulating evidence is delineating a neuroprotective and neurotrophic role for lithium (Li), inconsistent findings have also been reported in human studies especially. Moreover, the effects of Li infusion into the hippocampus are still unknown. The aims of this work were (a) to assess whether basal synaptic activity and long-term potentiation (LTP) in the hippocampus are different in regard to intrahippocampal Li infusion; (b) to assess spatial learning and memory in rats chronically treated with LiCO₃ in the Morris water maze. METHODS: Field potentials were recorded form the dentate gyrus, stimulating perforant pathways, in rats chronically (20 mg/kg for 40 days) or acutely treated with LiCO₃ and their corresponding control rats. In addition, performance of rats in a Morris water maze was measured to link behaviour of rats to electrophysiological findings. RESULTS: LiCO₃ infusion into the hippocampus resulted in enhanced LTP, especially in the late phases, but attenuated LTP was observed in rats chronically treated with Li as compared to controls. Li-treated rats equally performed a spatial learning task, but did spend less time in target quadrant than saline-treated rats in Morris water maze. CONCLUSION: Despite most data suggest that Li always yields neuroprotective effects against neuropathological conditions; we concluded that a 40-day treatment of Li disrupts hippocampal synaptic plasticity underlying memory processes, and that these effects of prolonged treatment are not associated with its direct chemical effect, but are likely to be associated with the molecular actions of Li at genetic levels, because its short-term effect preserves synaptic plasticity.

Educando en un ambiente enriquecido: porque todos estamos conectados / Educating in an enriched environment: because we are all connected

El objetivo de esta revisión es dar a conocer las diferentes vertientes que sustentan el proceso del aprendizaje en base a un concepto que ha alcanzado una gran importancia en los últimos años, el Ambiente Enriquecido (AE). Un término que ha sido emanado desde la biología, con diversos estudios de laboratorio realizados por científicos de renombre mundial y que, progresivamente ha ido incorporándose a disciplinas como la Psicología y la Pedagogía. En este artículo proponemos la descripción del impacto de este concepto en el proceso de aprendizaje experimentado por los seres humanos y su abordaje desde una perspectiva multidisciplinaria. Comenzamos por describir las bases neurofisiológicas del aprendizaje, con los fundamentos de la teoría neuronal como principal protagonista, pasando por la importancia de la Plasticidad Sináptica (PS) en el proceso de aprendizaje, el fenómeno de la Potenciación a Largo Plazo (PLP), como proceso generador de redes neuronales efectivas y sólidas. Posteriormente abordamos la génesis del Ambiente Enriquecido, con su origen en los experimentos con ratones de laboratorio, para posteriormente describir los conceptos y términos que han emanado del mismo que han sido aplicables a la Psicología Educacional tales como el Ambiente Desafiante, los instrumentos necesarios para su implementación y también el importante rol de las emociones en el proceso de aprendizaje de los sujetos. Finalmente, describimos el rol de la Pedagogía en la aplicación de actividades efectivas que conduzcan a un aprendizaje significativo en base al Ambiente Enriquecido.

The aim of this review is to present different strands that sustain the learning process based on a concept that has reached a major importance in recent years, the Enriched Environment (EE). A term that has been emerged from biology, with various laboratory studies conducted by world-renowned scientists and that has progressively been incorporated into disciplines such as Psychology and Education. In this article, we propose the description of the impact of this concept on the learning process experienced by human beings and its approach from a multidisciplinary perspective. We begin by describing the neurophysiological bases of learning, with the fundamentals of neuronal theory as the main protagonist, passing through the importance of Synaptic Plasticity (SP) in the learning process, the phenomenon of Long Term Potentiation (LTP), as a generating process of effective and solid neural networks. Subsequently, we covered the genesis of the Enriched Environment, with its origin in the experiments with laboratory mice, to later describe the concepts and terms that have emanated from it and have been applicable to Educational Psychology, such as Challenging Environment, the necessary instruments for its implementation and the important role of emotions in the subjects' learning process. Finally, we describe the role of Education in the implementation of effective activities that lead to meaningful learning based on the Enriched Environment.