Electrical induction of spikes in the hippocampus impairs recognition capacity and spatial memory in rats

In clinical studies, interictal EEG spikes (IS) have been associated with numerous neuropsychological abnormalities, ranging from transitory cognitive impairment to epileptic encephalopathies. Understanding the pathophysiological mechanisms of IS has been hampered by the lack of validated animal models. To mimic IS, a stimulating microelectrode was implanted in the ventral hippocampal commissure and a recording microelectrode in the CA1 region of the hippocampus of normal male rats. Spike patterns were induced using a series of electrical pulses 10-30 ms in duration with a frequency of 0.5-2Hz and a current of 0.2mA. The commissural stimulation-evoked population discharges in the hippocampus resembled naturally occurring IS in epileptic rats and, in no cases, resulted in behavioral seizures. For behavioral testing, the Morris water maze, radial arm maze, and object recognition tasks were used. Spikes were induced during sleep between the two sets of water maze trials; during the trials in the radial arm maze task; and prior to the sample phase and during the delay periods in the object recognition task. We demonstrated that rats that received spikes took longer to reach the escape platform in the second set of water maze trials; had significantly more reference errors and required more trials to complete the radial arm maze task; and had lower investigation ratios in the object recognition task. The results indicate that induction of spikes in the hippocampus results in impairment of spatial reference and nonspatial object recognition memory.     

Prenatal exposure to lambda-cyhalothrin impairs memory in developing rats: Role of NMDA receptor induced post-synaptic signalling in hippocampus

Effect of prenatal exposure to lambda-cyhalothrin (LCT) has been assessed on the integrity of NMDA receptors and associated post-synaptic signalling in hippocampus of developing rats. Decrease in the binding of [3H]-MK 801, known to label NMDA receptors was observed in hippocampus of rats prenatally exposed to LCT (1 and 3 mg/kg body weight) on PD22, compared to controls. Consistent with this, decrease in the mRNA and protein expression of NR1 and NR2B subunits of NMDA receptors was evident in rats prenatally exposed to LCT (1 and 3 mg/kg body weight) on PD22. There was no change in mRNA and protein expression of NR2A subunit of NMDA receptors. Prenatal exposure to LCT (1 and 3 mg/kg body weight) decreased the expression of positive regulators (PSD95, pERK1/2, CaMKIIα & pCREB) and increased the expression of negative regulators (Cdk5 & SynGAP) associated with NMDA receptor dependent synaptic plasticity in hippocampus and impaired learning and memory of rats on PD22. The neurobehavioral changes continued to persist in rats exposed to LCT at high dose (3 mg/kg body weight) while exhibited trend of recovery in those exposed at moderate dose (1 mg/kg body weight) on PD45, compared to controls. No change in any of the neurobehavioral endpoint was observed in developing rats prenatally exposed to LCT at low dose (0.5 mg/kg body weight) on PD22 and PD45. The results exhibit that alterations in NMDA receptors on prenatal exposure to LCT may affect postsynaptic signalling associated with impaired learning and memory in developing rats.     

电针干预自发性高血压大鼠主动脉丝裂原活化蛋白激酶磷酸酶1及磷酸化细胞外信号调节激酶1/2蛋白的表达

背景：近年来大量临床研究表明针刺风池、太冲、曲池等穴位能有效降低血压,可用于高血压,但对其治疗的分子机制尚未阐明。 目的：观察针刺大鼠风池、太冲、曲池等穴位对丝裂原活化蛋白激酶信号转导调控系统的影响,从而探讨针刺治疗高血压的分子机制。 方法：选取8月龄自发性高血压雄性Wistar大鼠14只,随机分为针刺组和模型组,每组7只;另选取同月龄正常血压雄性Wistar-Kyoto大鼠7只作为对照组。对针刺组大鼠采用电针针刺双侧风池、曲池和三阴交穴,毫针刺太溪和太冲穴。3周后采用RT-PCR方法检测各组大鼠主动脉组织丝裂原活化蛋白激酶磷酸酶1 mRAN的表达,Western blot方法检测丝裂原活化蛋白激酶磷酸酶1、磷酸化细胞外信号调节激酶1/2蛋白表达。 结果与结论：与对照组比较,模型组主动脉组织磷酸化细胞外信号调节激酶1/2蛋白表达水平升高,丝裂原活化蛋白激酶磷酸酶1 mRNA及其蛋白表达水平降低(P < 0.01);与模型组比较,针刺组主动脉组织磷酸化细胞外信号调节激酶1/2蛋白表达水平降低,丝裂原活化蛋白激酶磷酸酶1 mRNA及其蛋白表达水平升高(P < 0.05)。提示针刺治疗自发性高血压大鼠可能是通过调控丝裂原活化蛋白激酶信号转导途径,增强磷酸化细胞外信号调节激酶1/2蛋白表达,降低丝裂原活化蛋白激酶磷酸酶1蛋白表达,从而改善血管重塑,降低血压。     

In vivo microdialysis measures of extracellular serotonin in the rat hippocampus during sleep–wakefulness

We investigated extracellular 5-hydroxytryptamine (5-HT) levels in rat hippocampus during different stages of the sleep–waking cycle using in vivo microdialysis. The extracellular 5-HT level was highest in active waking (AW) and, when compared to AW, 5-HT level was progressively lower in quiet waking (QW; 78%), quiet sleep (QS; 50%) and REM (which we termed active sleep (AS); 40%). Functional implications of AS related-decreased 5-HT in the hippocampus are discussed.     

Lateral ventricle injection of the protein synthesis inhibitor anisomycin impairs long-term memory in a spatial memory task

Although protein synthesis inhibition has been shown to affect long-term memory in a wide variety of animal species, cases have been reported in which protein synthesis inhibition failed to affect memory consolidation [S. Wittstock, R. Menzel, Color learning and memory in honey bees are not affected by protein synthesis inhibition, Behav. Neural Biol., 62 (1994) 224–229.]. Most findings argue that the critical time for protein synthesis is during or immediately after training. However, other reports show a second time window, hours after training, where protein synthesis inhibition can cause amnesia [F.M. Freeman, S.P.R. Rose, A.B. Scholey, Two time windows of anisomycin-induced amnesia for passive avoidance training in the day-old chick, Neurobiol. Learn. Mem., 63 (1995) 291–295.][G. Grecksch, H. Matthies, Two sensitive periods for the amnesic effect of anisomycin, Pharmacol. Biochem. Behav., 12 (1980) 663–665.]. In this study, we addressed two questions: (1) Is protein synthesis essential for spatial memory? and (2) At what injection time window(s) will protein synthesis inhibition cause spatial memory amnesia? We report that bilateral intraventricular microinjection of anisomycin (Ani) impairs consolidation of long-term memory, in the hippocampal-dependent Morris water maze spatial memory task. Memory was impaired in a dose-dependent manner without affecting short-term memory. Spatial memory was affected only if Ani was injected 20 min before performing the task and not in any other time window before or after the behavioral test. The inhibition did not affect pre-existing memories or the capability to memorize once the effect of the inhibition diminished.     

Effects of anesthesia on immunohistochemical detection of phosphorylated extracellular signal-regulated kinase in cerebral cortex

During attempts to examine the phosphorylation status of extracellular signal-regulated kinase (ERK) in cerebral cortex immunohistochemically, we determined whether deep anesthesia for euthanasia disturbs the phosphorylation status of ERK, because the anesthesia might influence activity-dependent phosphorylation of ERK. We compared effects of short (2 and 5 min) and long (>10 min) anesthesia by pentobarbital on the immunoreactivity for phosphorylated ERK in the visual and entorhinal cortices of rat. The long anesthesia drastically reduced the density of phosphorylated ERK immunopositive cells to about 15% of the short anesthesia condition. The reduction was observed in all cortical regions. We found no significant difference in pERK immunoreactivity between 2 and 5 min groups. A reduction of similar degree was induced by long anesthesia with isoflurane. Even if a similar duration of anesthesia is given, the immunohistochemical results possibly contain a variation due to the individual difference in the sensitivity to the anesthetics. We demonstrated that the variation of pERK immunopositive cell density in the visual cortex was significantly reduced by normalizing the values to the density in the nonvisual area in the entorhinal cortex, thus enabling us to detect differences between animals under different visual conditions with higher sensitivity. Therefore, the variation could be reduced by calculating the ratio of immunoreactivity in the area of interest to that in other cortical area as reference.     

睡眠剥夺对大鼠脑干和海马大麻素CB-1受体的影响

目的探讨快速眼动(REM)睡眠剥夺(SD)对大鼠脑干和海马大麻素CB-1受体的影响。方法采用改良多平台睡眠剥夺法建立REM睡眠剥夺模型。将40只Sprague-Dawley大鼠随机分为空白对照组(CC)、环境对照组(TC),以及睡眠剥夺1d(SD1d)、3d(SD3d)和5d(SD5d)组,每组8只。应用逆转录-聚合酶链反应方法检测大鼠脑干及海马CB-1受体mRNA的表达,电镜观察其超微结构的改变。结果SD各组大鼠脑干与海马超微结构均有神经元凋亡,SD3d和SD5d组尤著。(1)脑干CB-1受体mRNA表达值SD1d组(0.789±0.139)和SD3d组(1.264±0.182)均高于CC组(0.420±0.054),且SD3d组高于SD1d组(P<0.05),SD5d组(0.678±0.145)与CC组的差异无统计学意义(P>0.05)。(2)海马CB-1受体mRNA表达值SD1d组(0.598±0.098)高于CC组(0.374±0.064),SD3d组(0.258±0.072)低于CC组,且SD3d组低于SD1d组(P<0.05);SD5d组(0.448±0.177)与CC组的差异无统计学意义(P>0.05)。结论REM睡眠剥夺能造成脑干及海马神经元的损伤,在不同睡眠剥夺时期CB-1受体mRNA表达不同,其中CB-1受体表达增强可能是一种自身稳定调节的保护机制。     

Activation of extracellular signal-regulated kinase- mitogen-activated protein kinase cascade in the amygdala is required for memory reconsolidation of auditory fear conditioning

Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of amygdala (LA). Recently we have demonstrated that consolidated fear memories, when reactivated, return to a labile state which is sensitive to disruption by the protein synthesis inhibitor anisomycin. The specific molecular mechanisms that underlie this reconsolidation of fear memories are still largely unknown. The activation of extracellular signal-regulated kinase-mitogen-activated protein kinase (ERK-MAPK) pathway in the LA is required for the consolidation of auditory fear memories. In the present study, we examined the role of ERK-MAPK cascade in the LA during reconsolidation of auditory fear conditioning. We show that intra-LA infusions of the MAPK kinase (MEK) inhibitor U0126, a manipulation which inhibits activation of ERK-MAPK, impairs postreactivation long-term memory (PR-LTM) but leaves the postreactivation short-term memory (PR-STM) intact. The same treatment with U0126, in the absence of memory reactivation, has no effect. Furthermore, we verified that reconsolidation requires translation using a second protein synthesis inhibitor, cycloheximide. Post-reactivation infusions of cycloheximide blocked PR-LTM but not PR-STM and, in the absence of reactivation, had no effect. Our data show that activation of ERK-MAPK signalling pathway and protein synthesis in the LA are required for reconsolidation of auditory fear memories.     

Permanent and temporary inactivation of the hippocampus impairs T-maze footshock avoidance acquisition and retention

The hippocampus is widely recognized as playing an important role in learning and memory. Lesions of the hippocampus can disrupt spatial navigational learning and memory and injection of drugs into the hippocampus can affect both spatial navigational and nonspatial tasks. In the current studies we tested the effects of bilateral of electrolytic lesions and reversible inactivation of the hippocampus on acquisition and retention of T-maze footshock avoidance conditioning. Electrolytic lesions, which destroyed 31+/-0.04% of the hippocampus, significantly impaired acquisition and retention for T-maze footshock avoidance. No differences were found in motivation to avoid shock, open field activity, or foot shock sensitivity between lesion and control groups. Temporary inactivation of the hippocampus with lidocaine administered immediately before training disrupted acquisition and retention for T-maze footshock avoidance. Temporary hippocampal inactivation performed just prior to retention testing and post-training inactivation in mice trained to first avoidance had no effect on retention. However, temporary post-training inactivation in 'undertrained' (enough trials to remember 1 week later if treated with saline, but not allowed to make the avoidance response) mice impaired retention. The current findings indicate that the hippocampus plays an important role in learning and memory processing in the aversive T-maze paradigm.     

Anesthetic propofol normalized the increased release of glutamate and γ-amino butyric acid in hippocampus after paradoxical sleep deprivation in rats

Objective: Multiple lines of evidence suggest that general anesthesia helps the recovery from sleep deprivation. However, little is known about the underlying neurochemical mechanisms. In the current study, we investigated the effect of anesthetic propofol on the release of glutamate (Glu) and γ-amino butyric acid (GABA) in the hippocampal CA1 region of rat with 24 h-paradoxical sleep deprivation (PSD).

Methods: A guide cannula for microdialysis was inserted into the CA1 region of hippocampus in rats. At six days after cannula implantation, rats received 24 h-PSD by using the platform–water tank method. The rats were then subjected to natural sleep or propofol anesthesia (100 mg/kg, i.p.), respectively, after 24-h PSD. Microdialysis samples from hippocampus were collected before and at the end of PSD, and also at 1, 3, 6, and 8 h post-PSD. The concentrations of Glu and GABA in collected samples were determined by using high performance liquid chromatography.

Results: The current study showed that 24 h-PSD significantly increased the release of Glu and GABA in the hippocampus in rats. In both natural sleep and propofol anesthesia groups, the upregulated Glu and GABA levels after PSD gradually decreased and returned to the baseline level by 8 h post-PSD.

Conclusion: Our data indicate that propofol anesthesia promotes the restoration of disturbed excitatory and inhibitory neurotransmitter release in the hippocampus after PSD, similar to the beneficial effects of natural sleep. This finding suggests that propofol anesthesia may be a viable pharmacotherapeutic strategy for the treatment of certain sleep disorders that share similar mechanisms with PSD.     

Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats

Acetylcholine (ACh) systems have been widely shown to be important for memory. In particular, ACh hippocampal neurons are critical for memory formation, though ACh innervation of other areas such as the nucleus accumbens may also be important. There has also been increasing interest in ACh and dopaminergic (DA) interactions with regard to short-term spatial memory. In a series of studies, we have found that ACh and DA agonists and antagonists given systemically interact to influence memory. The critical neural loci of these interactions are not currently known. In the present study, we used local infusion techniques to examine the role of ACh and DA transmitter systems in the nucleus accumbens and the ventral hippocampus on radial-arm maze (RAM) working memory performance. Into the nucleus accumbens of rats, we infused the nicotinic ACh agonist nicotine, the nicotinic ACh antagonist mecamylamine, the DA agonist apomorphine, or the DA antagonist haloperidol. Into the ventral hippocampus, we infused nicotine, mecamylamine, the muscarinic ACh agonist pilocarpine, or the muscarinic ACh antagonist, scopolamine. The nicotinic ACh and DA interaction was tested by a hippocampal infusion of mecamylamine alone or together with the DA D₂ agonist quinpirole given via subcutaneous injection. The results confirmed that both nicotinic and muscarinic ACh receptors in the ventral hippocampus play a significant role in spatial working memory. Blockade of either nicotinic or muscarinic ACh receptors caused significant impairments in RAM choice accuracy. However, infusion of either nicotinic or muscarinic agonists failed to improve choice accuracy. The interaction of DA D₂ systems is different with hippocampal nicotinic blockade than with general nicotinic blockade. Systemic administration of quinpirole potentiated the amnestic effect of mecamylamine infused into the ventral hippocampus, whereas it was previously found to reverse the amnestic effect of systemically administered mecamylamine. In contrast to the significant effects of mecamylamine in the hippocampus, no effects were found after infusion into the nucleus accumbens. Nicotine also was not found to have a significant effect on memory after intra-accumbens infusion. Neither the DA agonist apomorphine nor the DA antagonist haloperidol had a significant effect on memory after infusion into the nucleus accumbens. This study provides support for the involvement of nicotinic and muscarinic receptors in the ventral hippocampus in memory function. Ventral hippocampal nicotinic systems have significant interactions with D₂ systems, but these differ from their systemic interactions. In contrast, nicotinic ACh and DA systems in the nucleus accumbens were not found in the current study to be important for working memory performance in the RAM.     

Galanin in the medial septal area impairs working memory

Galanin, a peptide of 29 amino acids, is co-localized with acetylcholine in a subpopulation of neurons of the medial septal area (MSA) that project to the hippocampus. Galanin reverses the actions of acetylcholine in several biochemical and behavioral procedures, and may be involved in memory processes. To test the possibility that galanin acts on the cell bodies of MSA neurons, two measures of septohippocampal function were assessed following intra-septal microinfusion of galanin or two synthetic fragments of galanin (1–16 and 21–29). The behavioral measure was choice accuracy in a working memory task in a T-maze. The electrophysiological measure was hippocampal theta activity recorded from the dentate hilus. The galanin fragment, 1–16, and the complete peptide, 1–29, decreased choice accuracy and decreased hippocampal theta activity in a dose-dependent fashion. Saline and the 21–29 fragment had no effect on choice accuracy and hippocampal theta. Sensorimotor performance was unaffected. These findings demonstrate that galanin impairs working memory when administered directly into the MSA and suggest that galanin inhibits MSA neural activity.     

In utero exposure of mice to diesel exhaust particles affects spatial learning and memory with reduced N-methyl-d-aspartate receptor expression in the hippocampus of male offspring

Diesel exhaust consists of diesel exhaust particles (DEPs) and gaseous compounds. Previous studies reported that in utero exposure to diesel exhaust affects the central nervous system. However, there was no clear evidence that these effects were caused by diesel exhaust particles themselves, gaseous compounds, or both. Here, we explored the effects of in utero exposure to DEPs on learning and memory in male ICR mice. DEP solutions were administered subcutaneously to pregnant ICR mice at a dose of 0 or 200 μg/kg body weight on gestation days 6, 9, 12, 15, and 18. We examined learning and memory in 9-to-10-week-old male offspring using the Morris water maze test and passive avoidance test. Immediately after the behavioral tests, hippocampi were isolated. Hippocampal N-methyl-d-aspartate receptor (NR) expression was also measured by quantitative RT-PCR analysis. Mice exposed to DEPs in utero showed deficits in the Morris water maze test, but their performance was not significantly different from that of control mice in the passive avoidance test. In addition, DEP-exposed mice exhibited decreased hippocampal NR2A expression. The present results indicate that maternal DEP exposure disrupts learning and memory in male offspring, which is associated with reduced hippocampal NR2A expression.     

Time-limited role of the hippocampus in the memory for trace eyeblink conditioning in mice

We examined the role of the hippocampus in memory retention after trace eyeblink conditioning in mice. After establishing the conditioned response (CR) in the trace paradigm, mice received a bilateral aspiration of the dorsal hippocampus and its overlying neocortex on the next day (1-day group) or after 4 weeks (4-week group). Control mice received a neocortical aspiration on the same schedule as the hippocampal-lesion group. After 2 weeks of recovery, these groups received additional conditioning for 3 days. Frequency of the CR of the 1-day group was as low as spontaneous values on the first day in the post-lesion session and never reached pre-surgical level during the post-lesion sessions, while that of the control group did reach pre-surgical level during the post-lesion sessions although there was a transient decline just after lesion. In contrast to the 1-day group, the 4-week-hippocampal lesion group retained the CR and showed a further increase, without significant difference from the control group. The temporal pattern of the CR also was unchanged by the hippocampal lesion 4 weeks after learning. These results suggest a time-limited role for the hippocampus in memory retention after trace conditioning in mice: the CR acquired recently requires an intact hippocampus for its retention, but the CR acquired remotely does not. This is similar to the result reported in rabbits. Therefore, the mechanism and time course of memory consolidation after trace eyeblink conditioning may be similar in mice and rabbits.     

β-淀粉样蛋白25-35杏仁核注射对大鼠空间学习记忆及海马突触素表达的影响

目的探讨β-淀粉样蛋白25-35（Aβ25-35）杏仁核注射所造痴呆模型大鼠海马突触素的改变及其与空间学习记忆力的关系。方法雄性Sprague-Dawley大鼠24只，随机分为正常对照组、假手术组（颅内注射5．0nmol 0．1％三氟乙酸）、痴呆模型组（颅内注射5．0nmol Aβ25-35），每组各8只。采用杏仁核注射Aβ25-35的方法建立大鼠痴呆模型；通过Morris水迷宫测试观察大鼠空间学习记忆能力的改变；应用免疫组织化学染色测定模型大鼠海马突触素表达的水平。结果大鼠痴呆模型建立6周后，痴呆模型组大鼠存在明显的空间学习记忆力障碍，为期6d水迷宫测试的平均潜伏期均明显长于正常对照组及假手术组，其中第4～6天与正常对照组的差异有统计学意义（P〈0．01）。免疫组织化学染色，痴呆模型组大鼠海马突触索表达的阳性数及着色密度均明显少于正常对照组及假手术组，其中与正常对照组的差异均有统计学意义（P均〈0．01）。结论Aβ25-35杏仁核注射所造痴呆模型的大鼠海马突触数量明显减少，其空间学习记忆力功能障碍可能与突触的减少有关。     

Amygdala kindling effects on sleep and memory in rats

Sleep disturbances accompany the development of amygdaloid-kindled seizures in cats. Some of these sleep deficits resemble those seen in aged rats; these latter changes in sleep patterns are correlated with memory impairments in the aged animals. In the present study, we examined the hypothesis that sleep deficits after kindling may be related to memory impairments. Rats were kindled for 4 weeks (2-2.5 weeks after stage 5 seizures) and were then allowed a one week recovery period. Sleep patterns were assessed through-out the kindling and recovery periods. The animals were then trained on an inhibitory avoidance apparatus and tested for retention 24 h later. Only transient sleep changes occurred during the development of kindling (to stage 5 seizures). However, continued kindling resulted in significant reductions in several sleep measures which remained depressed for at least one week after the termination of the kindling trials. As a group, kindled rats were impaired in retention of the inhibitory avoidance learned response. In kindled animals, retention performance was significantly correlated with total paradoxical sleep, the ratio of paradoxical/total sleep, and paradoxical sleep, the ratio of paradoxical/total sleep, and paradoxical sleep bout duration. These correlations are consistent with the view that deficits in paradoxical sleep may be related to deficits in some forms of memory.     

Anti-apoptotic actions of vasopressin in H32 neurons involve MAP kinase transactivation and Bad phosphorylation

Vasopressin (VP) secreted within the brain modulates neuronal function acting as a neurotransmitter. Based on the observation that VP prevented serum deprivation-induced cell death in the neuronal cell line, H32, which expresses endogenous V1 receptors, we tested the hypothesis that VP has anti-apoptotic properties. Flow cytometry experiments showed that 10 nM VP prevented serum deprivation-induced cell death and annexin V binding. Serum deprivation increased caspase-3 activity in a time and serum concentration dependent manner, and VP prevented these effects through interaction with receptors of V1 subtype. The signaling pathways mediating the anti-apoptotic effect of VP involve mitogen activated protein (MAP) kinase and extracellular signal-regulated kinases (ERK), Ca²⁺/calmodulin dependent kinase (CaMK) and protein kinase C (PKC). Western blot analyses revealed time-dependent decreases of Bad phosphorylation and increases in cytosolic levels of cytochrome c following serum deprivation, effects which were prevented by 10 nM VP. These data demonstrate that activation of endogenous V1 VP receptors prevents serum deprivation-induced apoptosis, through phosphorylation-inactivation of the pro-apoptotic protein, Bad, and consequent decreases in cytosolic cytochrome c and caspase-3 activation. The data suggest that VP has anti-apoptotic activity in neurons and that VP may act as a neuroprotective agent in the brain.     

Lead stimulates ERK1/2 and p38MAPK phosphorylation in the hippocampus of immature rats

Lead (Pb(2+)) is widely recognized as a neurotoxicant whose mechanisms of action are not completely established. We have previously demonstrated that Pb(2+) can activate the p38(MAPK) pathway and increase the phosphorylation of Hsp27 in bovine adrenal chromaffin cells and human SH SY5Y cells over a short incubation period (1 h). In the present work we analyzed the effects of Pb(2+) administered in vivo on the level and the phosphorylation state of ERK1/2 and p38(MAPK) in the hippocampus of immature rats. Rats were treated with lead acetate (2, 8 or 12 mg/kg, i.p.) or saline (control) over the 8th to 12th postnatal days, and hippocampal slices were prepared on the 14th day. The Pb(2+) level in the lead-treated animals increased 2.5-6-fold in the blood (3.0-6.0 microg/dl) and 2.0-3.0-fold in the forebrain (78-103 ng/g wet weight), compared to control (saline). The phosphorylation of both ERK1/2 and p38(MAPK) was significantly increased by prior exposure to Pb(2+) in vivo. In in vitro experiments, hippocampal slices from 14-day-old rats were exposed to Pb(2+) (1-10 microM) for 1 and 3 h. There were no changes in the phosphorylation state of ERK and p38(MAPK) for 1-h incubation, whereas a significant increase of ERK1/2 and p38(MAPK) phosphorylation by Pb(2+) (5 microM) was observed for the 3-h incubation. Cell viability measured using MTT was not modified in any of the conditions tested. These results indicate that the phosphorylation of hippocampal ERK1/2 and p38(MAPK) is stimulated by lead in a period of rapid brain development, an effect that may underlie, at least in part, the neurotoxicty elicited by this metal.     

Estradiol potentiates acetylcholine and glutamate-mediated post-trial memory processing in the hippocampus

There is increasing evidence that estrogen is involved in CNS activity, particularly memory. Several studies have suggested that estrogen improves memory by enhancing cholinergic and glutamatergic activity. In the present studies, we examined the effects of administration into the hippocampus of 17 beta-estradiol and estrone on retention of T-maze footshock avoidance in female ovariectomized mice. Both 17 beta-estradiol and estrone improved retention on an equimolar basis in a dose-dependent fashion. We then used the T-maze footshock paradigm to test whether a dose of 17 beta-estradiol ineffective as a single injection (subthreshold) could potentiate the effects of arecoline, a cholinergic agonist, or L-glutamate, a glutamatergic agonist, on retention. The dose of either arecoline or L-glutamate needed to improve retention was reduced at least ten-fold by the low dose of 17 beta-estradiol. These findings support the concept that estrogen improves memory by potentiating the activity of the cholinergic and glutamatergic systems.