Memory Retention Deficits Research Articles

Organization of WAVE-1 in hippocampal dendritic spines

Event Abstract Back to Event Organization of WAVE-1 in hippocampal dendritic spines R. Szudóczky1, R. Weinberg2, S. Soderling3, P. Sótonyi1 and B. Rácz1* 1 St. István University, Dept. Anatomy & Histology, Hungary 2 University of North Carolina, Dept. Cell & Developmental Biology, United States 3 Duke University Medical Center, Dept. Cell Biology, United States Recent in vitro studies have shown that theWAVE (Wiskott–Aldrich syndrome Verprolin-homology) family of actin binding proteins play an important role in modulating synaptic plasticity. Moreover, dysregulation of WAVEs has been implicated in a syndromic form of mental retardation in humans, reproduced in WAVE-1 knockout (KO) mice. Loss of WAVE-1 leads to abnormalities in synaptic plasticity and deficits in memory retention, suggesting that WAVE-1 plays a key role in spine functions associated with synaptic plasticity. Here we studied EM sections from WT and WAVE-1 KO mice. Spine dimensions did not differ significantly between WT and KO, but we found significantly more trafficking endosomes in spines from KO mice than in WT controls. We also studied the organization of WAVE-1 in hippocampus. LM immunostaining revealed WAVE-1 in dendrites of pyramidal neurons; high-resolution EM labeling techniques showed that WAVE-1 extended into dendritic spines. Quantitative analysis of the gold label confirmed a close association of WAVE-1 with the spine plasma membrane. Density was especially high in the so-called “endocytic zone.” We hypothesize that WAVE-1 plays a pivotal role in the organization of the actin cytoskeleton necessary for intraspinoplasmic vesicle trafficking. Keywords: Neurophysiology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neurophysiology Citation: Szudóczky R, Weinberg R, Soderling S, Sótonyi P and Rácz B (2011). Organization of WAVE-1 in hippocampal dendritic spines. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00050 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. B. Rácz, St. István University, Dept. Anatomy & Histology, Budapest, Hungary, racz.bence@aotk.szie.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers R. Szudóczky R. Weinberg S. Soderling P. Sótonyi B. Rácz Google R. Szudóczky R. Weinberg S. Soderling P. Sótonyi B. Rácz Google Scholar R. Szudóczky R. Weinberg S. Soderling P. Sótonyi B. Rácz PubMed R. Szudóczky R. Weinberg S. Soderling P. Sótonyi B. Rácz Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

A free-radical scavenger protects the neural progenitor cells in the dentate subgranular zone of the hippocampus from cell death after X-irradiation

It has been elucidated that cognitive dysfunction following cranial radiotherapy might be linked to the oxidative stress-induced impairment of hippocampal neurogenesis that is mediated by proliferating neural stem or progenitor cells. The novel free-radical scavenger edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) has been clinically used to reduce neuronal damage following ischemic stroke. Previously, we reported that the free-radical scavenger, edaravone, which is currently used to treat patients with brain ischemia, protected cultured human neural stem cells (NSCs) from radiation-induced cell death; the protective effect was observed more significantly in NSCs than in brain tumor cells. Here, in animal models, we demonstrate that edaravone protects neurons in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus from cell death after irradiation. Moreover, edaravone protected spatial memory retention deficits as determined by Morris water maze tests. Our study may shed some light on the beneficial effects of free-radical scavengers in impaired neurogenesis following cranial radiation therapy.

Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A

We have reported recently that inhibition of protein phosphatase (PP)-2A and PP-1 by calyculin A, a specific inhibitor of PP-2A and PP-1, induced Alzheimer-like hyperphosphorylation of tau and spatial memory retention impairment. In this study, we tested the in vivo effects of melatonin on these Alzheimer-like changes. We found that administration of melatonin intraperitoneally for 9 consecutive days before injection of calyculin A could prevent calyculin A-induced synaptophysin loss, memory retention deficits, as well as hyperphosphorylation of tau and neurofilaments. Furthermore, melatonin partially reversed the phosphorylation of the catalytic subunit of PP-2A at Tyrosine 307 (Y307), a crucial site negatively regulating the activity of PP-2A, and reduced the levels of malondialdehyde, a marker of oxidative stress, induced by calyculin A. These results suggest that melatonin could serve as a potential therapeutic agent for preventing Alzheimer-like pathological changes and behavioral abnormality via modulating the activity of PP-2A and oxidative stress.

Ascorbic Acid Protects Against Restraint Stress-Induced Memory Deficits in Wistar Rats

OBJECTIVE:Chronic stress has been shown to cause oxidative damage in the central nervous system. Although stress-induced impairments in learning and memory have been studied extensively, very few studies have investigated possible ways to prevent their ill effects. The present work was designed to study the protective effects of ascorbic acid in memory loss induced by chronic restraint stress.METHODS:Adult male Wistar rats were designated into the following groups: (i) Normal control, (ii) Ascorbic acid treatment, (iii) Vehicle control, (iv) Restraint stress, (v) Restraint stress + vehicle, and (vi) Restraint stress + ascorbic acid treatment. At the end of 21 days, animals of all groups were subjected to memory tests using Morris water maze and passive avoidance apparatus. Then, the results obtained were compared between the experimental groups.RESULTS:Rats exposed to restraint stress alone and those pretreated with vehicle solution before restrained stress showed deficits in learning and impaired memory retention in the memory tests when compared to animals in other experimental groups. Animals pretreated with ascorbic acid before restraining showed significant improvement in memory retention in the same memory tests.CONCLUSIONS:Results of this study suggest the possibility of using ascorbic acid as a dietary supplement to prevent stress-induced memory impairments.

Calcineurin inhibition eliminates the normal inverted U curve, enhances acquisition and prolongs memory in a mammalian 3′-5′-cyclic AMP–dependent learning paradigm

The role protein phosphatase 2B (calcineurin, CaN) plays in learning and memory has received a significant amount of attention due to its promotion of the dephosphorylation of 3′-5′-cyclic AMP response element binding protein (CREB). Researchers have ascertained that overexpression of CaN is associated with memory retention deficits [Foster TC, Sharrow KM, Masse JR, Norris CM, Kumar A (2001) Calcineurin links Ca2+ dysregulation with brain aging. J Neurosci 21:4066–4073; Mansuy IM, Mayford M, Jacob B, Kandel ER, Bach ME (1998) Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell 92:39–49], while CaN inhibition enhances learning and memory [Gerdjikov TV, Beninger RJ (2005) Differential effects of calcineurin inhibition and protein kinase A activation on nucleus accumbens amphetamine-produced conditioned place preference in rats. Eur J Neurosci 22:697–705; Ikegami S, Inokuchi K (2000) Antisense DNA against calcineurin facilitates memory in contextual fear conditioning by lowering the threshold for hippocampal long-term potentiation induction. Neuroscience 98:637–646]. The present study hypothesized that infusion of a CaN inhibitor (FK506) bilaterally into the olfactory bulbs of postnatal day 6 Sprague Dawley rat pups would prolong the duration of a conditioned odor preference and retard cyclic AMP response element binding protein dephosphorylation. A 2 mg/kg s.c. injection of isoproterenol (ISO, β-adrenoceptor agonist) was paired with a 10 min exposure to peppermint and subsequently an infusion of FK506. Immunohistochemistry for phosphorylated 3′-5′-cyclic AMP response element binding protein (pCREB) revealed that unilateral infusion of FK506 resulted in an amplification of phosphorylated CREB in the olfactory bulb 40 min after training compared with saline-infused bulbs. Pups infused bilaterally with FK506 maintained a learned preference for peppermint 48, 72 and 96 h after training. CaN inhibition also modified the conventional inverted U curve obtained when ISO is used to replace stroking, as the unconditioned stimulus. When pups were infused with FK506, learning occurred with sub- and supra-optimal doses of ISO indicating that CaN overcomes non-optimal effects ISO may have on learning. We demonstrate that CaN inhibition can extend the duration of conditioned olfactory memory and may provide a target for memory prolongation that is superior to even phosphodiesterase inhibition observed in previous studies.

P2-159: Melatonin meliorates calyculin A-induced axonal transport defects and spatial memory retention impairment in rats

We have recently found that melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. In the present study, we are further investigating the in vivo effect of melatonin on spatial memory retention in rats by bilateral injection of calyculin A (CA), a potent and specific inhibitor of protein phosphatase-2A (PP-2A) and protein phosphatase-1 (PP-1) into hippocampus and exploring its underling mechanisms. We examined memory retention of the rats by the Morris Water-Maze Test, analyzed the axonal transport by a time-lapse recording of pEGFP-labeled neurofilament-M (pEGFP-NF-M) subunit in live neuroblastoma N2a cells. In addition, we explored the effect of melatonin on the morphological alteration of the cells during inhibition of the phosphatases by establishing a cell model showing steady outgrowth of axon-like cell processes and employed a stereological system to analyze the retraction of the processes. In the present study,we found that the supplementation of melatonin by intraperitoneal injection for 1 week before injecting CA not only significantly improves CA-induced memory retention deficits of the rats in the Morris Water-Maze Test, but also decreases hyperphosphorylation of neuronal cytoskeletal protein tau and neurofilaments. To further explore the underlying mechanisms by which melatonin exerted the protective effect on spatial memory deficit in rats induced by inhibition of PP-2A and PP-1, we analyzed the axonal transport in live neuroblastoma N2a cells and found that melatonin partially reversed CA-induced impairment of transport of pEGFP-NF-M in the axon-like processes of the cells. In the meantime, we found by western blot that melatonin also decreased CA-induced hyperphosphorylation of cytoskeletal proteins. Furthermore, we found CA-treatment inhibited outgrowth of the cell processes and prolonged treatment with CA caused retraction of the processes and meanwhile, the early neurodegenerative varicosities were also obvious in the CA-treated cells, and the administration of melatonin significantly arrested these pathological alterations. These data suggest that melatonin not only meliorated impaired intracellular transport induced by suppression of PP-2A and PP-1, but also cell degeneration, which may underlie the basis of the effects of protection of melatonin on memory deficits induced by suppression of the phosphatases.

Ca-Stimulated Type 8 Adenylyl Cyclase Is Required for Rapid Acquisition of Novel Spatial Information and for Working/Episodic-Like Memory

Ca-stimulated adenylyl cyclases (ACs) transduce neuronal stimulation-evoked increase in calcium to the production of cAMP, which impinges on the regulation of many aspects of neuronal function. Type 1 and type 8 AC (AC1 and AC8) are the only ACs that are directly stimulated by Ca. Although AC1 function was implicated in regulating reference spatial memory, the function of AC8 in memory formation is not known. Because of the different biochemical properties of AC1 and AC8, these two enzymes may have distinct functions. For example, AC1 activity is regulated by both Ca and G-proteins. In contrast, AC8 is a pure Ca sensor. It is neither stimulated by G(s) nor inhibited by G(i). Recent studies also suggested that AC1 and AC8 were differentially concentrated at different subcellular domains, implicating that Ca-stimulated signaling might be compartmentalized. In this study, we used AC8 knock-out (KO) mice and found behavioral deficits in memory retention for temporal dissociative passive avoidance and object recognition memory. When examined by Morris water maze, AC8 KO mice showed normal reference memory. However, the acquisition of newer spatial information was defective in AC8 KO mice. Furthermore, AC8 KO mice were severely impaired in hippocampus-dependent episodic-like memory when examined by the delayed matching-to-place task. Because AC8 is preferentially localized at the presynaptic active zone, our results suggest a novel role of presynaptic cAMP signaling in memory acquisition and retention, as well as distinct mechanisms underlying reference and working/episodic-like memory.

Carboxyl terminus of heat-shock cognate 70-interacting protein degrades tau regardless its phosphorylation status without affecting the spatial memory of the rats

Accumulation of the hyperphosphorylated tau is a hallmark pathological event for the formation of neurofibrillary tangles in Alzheimer disease (AD). Until now, there is no effective way to antagonize this accumulation. Recently, it has been reported that carboxyl terminus of Hsc70-interacting protein (CHIP) is the specific tau E3 ligase and it mediates tau degradation in vitro. However, the nature of CHIP on in vivo tau degradation is not fully understood. Here, we demonstrated that hippocampal transfection of CHIP plasmid in rats could reach a time-dependent elevated expression of CHIP mRNA and protein in 24 h. Concomitantly, expression of exogenous CHIP could promote the degradation of the hyperphosphorylated tau induced by overactivation of glycogen synthase kinase-3 (GSK-3) or inhibition of protein phosphatase-2A (PP-2A) in the rat brains and N2A cells. CHIP also degraded tau in normal rats regardless the phosphorylation status of tau proteins. Though CHIP overexpression was not able to improve significantly the spatial memory retention deficits induced by overactivation of GSK-3, it did not cause significant damage to the memory function in normal rats. These results suggest that CHIP may degrade tau both in physiological and pathological conditions without affecting the behavior of the rats, implying that overexpression of CHIP may antagonize tau accumulation in the AD brains.

Post-training intrahippocampal infusion of nicotine–bucladesine combination causes a synergistic enhancement effect on spatial memory retention in rats

We previously had shown that bilateral intrahippocampal infusion of 1 μg nicotine (but not 0.5 μg dose) led to an improvement in spatial memory retention in the Morris water maze task in male rats. We also reported that a similar type of bilateral infusion of H89, a protein kinase AII (PKA II) inhibitor, caused a deficit in spatial memory retention. In the present study, we wished to test the hypothesis that intrahippocampal infusion of dibutyryl cyclic AMP (DB-cAMP also called bucladesine), a membrane permeable selective activator of PKA, into the CA1 region can cause an improvement in spatial memory in this maze task. Indeed, bilateral infusion of 10 and 100 μM bucladesine (but not 1 and 5 μM doses) led to a significant reduction in escape latency and travel distance (showing an improvement in spatial memory) compared to the control. Also, bilateral infusion of 0.5 μg nicotine or 1 μM bucladesine alone did not lead to an improvement in spatial memory. However, such bilateral infusion of bucladesine at 1 and 5 μM concentrations infused within minutes after 0.5 μg nicotine infusion improved spatial memory retention. Taken together, our data suggest that intrahippocampal bucladesine infusions improve spatial memory retention in male rats and that bucladesine can interact synergistically with nicotine to improve spatial memory.

Protective Effects of Chronic Lithium Treatment against Spatial Memory Retention Deficits Induced by the Protein Kinase AII Inhibitor H-89 in Rats

We have previously shown that infusion of the PKAII inhibitor H-89 in the CA1 area of the hippocampus impaired spatial memory retention. There is some evidence suggesting the neuroprotective effects of chronic lithium administration including its ability to attenuate a deleterious effect of chronic stress on spatial memory in rats. In the present study, we investigated whether chronic administration of lithium can improve memory as well as influence the inhibitory effect of H-89 on spatial memory retention. Male albino rats were treated systemically with lithium (600 mg/l) for 4 weeks and then trained for 4 days in the Morris water maze. Testing the animals 48 h later showed a significant reduction in escape latency (p < 0.05) and travel distance (p < 0.05) compared to the controls. In separate experiments, the rats were similarly treated with lithium for 4 weeks, followed by similar training for 4 days and then immediately infused bilaterally with vehicle or 5 µmol/l H-89 into the CA1 region of the hippocampus. Animals were then tested 48 h after H-89 infusion in order to assess their spatial memory retention. The lithium treatment caused a significant reduction in escape latency (p < 0.001) and travel distance (p < 0.001) compared to H-89-treated animals. The data suggest that lithium treatment for 4 weeks improved spatial memory retention and that lithium pretreatment prevented or reversed the H-89-induced spatial memory deficits.

Acceleration after-effects on learning and memory in rats: +10 Gz or +6 Gz for 3 min

High sustained positive Gz (+Gz) exposures have been shown to have a pathophysiological impact on the brain in rats. However, the consequence for brain function such as learning and memory remains elusive. In the present study, we investigated locomotor activity, learning ability and memory in rats over 6 days (d) following +6 Gz/3 min and +10 Gz/3 min exposures. In an open field test, rats treated with +10 Gz showed a significant increase in the time spent in the center square immediately and 2d after exposure compared with control rats. In contrast, the number of grid crosses and number of rears of rats decreased significantly immediately after +6 Gz and +10 Gz exposures. In addition, a Y-maze test revealed that +Gz exposures reduced the number of correct responses and increased total reaction time in rats, and the number of correct responses was negatively correlated with the total reaction time in all groups throughout the period of study. Moreover, the passive avoidance test exhibited that the latency increased significantly on 0 d and decreased significantly on 6 d after +Gz exposures compared with control. Thus, +6 Gz/3 min and +10 Gz/3 min exposures may transiently decrease locomotor activity, impair learning, and induce a deficit in memory retention in rats.

Arc/Arg3.1: Linking Gene Expression to Synaptic Plasticity and Memory

Arc/Arg3.1 is an effector immediate-early gene implicated in the consolidation of memories. Although cloned a decade ago, the physiological role of Arc/Arg3.1 in the brain has remained elusive. Four papers in this issue of Neuron address this function. These studies show that Arc/Arg3.1 regulates endophilin 3 and dynamin 2, two components of the endocytosis machinery. Genetic ablation of Arc/Arg3.1 in mice or overexpression in culture suggest that Arc/Arg3.1 regulates AMPA receptor trafficking and synaptic plasticity. Finally, Arc/Arg3.1 knockout mice show memory retention deficits. These recent developments provide new insights into the function of this popular activity-dependent neuronal marker.

P1-192: Activation glycogen synthase kinase 3 inhibits long term potentiation in vivo

Glycogen synthase kinase 3 (GSK–3) plays an important role in the pathogenesis of Alzheimer's disease. Activation GSK–3 by wortmannin induces tau hyperphosphorylation and memory retention deficits in vivo. Long term potentiation (LTP) is a leading candidate for a synaptic mechanism of learning and memory in mammals. To determine the effect of GSK–3 activation on LTP in vivo. LTP was evaluated by the increment in amplitude and slope of population spike (PS), which recorded in hippocampus CA3 region of Wistar rats. 100 μM wortmannin, 100 mM LiCl, 5 μM SB216763 (a specific GSK–3 inhibitor) and related control vehicles were administered during electrophysiological recording. GSK–3 activity was determined by Western blotting, immunohistochemistry with specific antibodies and 32P–labelling assay. Wortmannin can reduce the amplitude and slope of PS rapidly as previously reported, while both LiCl and SB216763 can restore the PS inhibition by wortmannin. Western blotting results showed that no difference in all groups with the antibody of GSK–3 total, only wortmannin administered group decreased the phosphorylation level of Ser9–phospho–GSK–3 significantly. The above phenomena can also be detected by immunohistochemistry in CA3 region of hippocampus. 32P–labelling assay showed that both Lithium and SB216763 can suppress the activity of GSK–3 activated by wortmannin. GSK–3 activation inhibits LTP in vivo, which may play an important role in the memory loss in Alzheimer's disease.

Defective Tumor Necrosis Factor-α-dependent Control of Astrocyte Glutamate Release in a Transgenic Mouse Model of Alzheimer Disease

The cytokine tumor necrosis factor-alpha (TNFalpha) induces Ca2+-dependent glutamate release from astrocytes via the downstream action of prostaglandin (PG) E2. By this process, astrocytes may participate in intercellular communication and neuromodulation. Acute inflammation in vitro, induced by adding reactive microglia to astrocyte cultures, enhances TNFalpha production and amplifies glutamate release, switching the pathway into a neurodamaging cascade (Bezzi, P., Domercq, M., Brambilla, L., Galli, R., Schols, D., De Clercq, E., Vescovi, A., Bagetta, G., Kollias, G., Meldolesi, J., and Volterra, A. (2001) Nat. Neurosci. 4, 702-710). Because glial inflammation is a component of Alzheimer disease (AD) and TNFalpha is overexpressed in AD brains, we investigated possible alterations of the cytokine-dependent pathway in PDAPP mice, a transgenic model of AD. Glutamate release was measured in acute hippocampal and cerebellar slices from mice at early (4-month-old) and late (12-month-old) disease stages in comparison with age-matched controls. Surprisingly, TNFalpha-evoked glutamate release, normal in 4-month-old PDAPP mice, was dramatically reduced in the hippocampus of 12-month-old animals. This defect correlated with the presence of numerous beta-amyloid deposits and hypertrophic astrocytes. In contrast, release was normal in cerebellum, a region devoid of beta-amyloid deposition and astrocytosis. The Ca2+-dependent process by which TNFalpha evokes glutamate release in acute slices is distinct from synaptic release and displays properties identical to those observed in cultured astrocytes, notably PG dependence. However, prostaglandin E2 induced normal glutamate release responses in 12-month-old PDAPP mice, suggesting that the pathology-associated defect involves the TNFalpha-dependent control of secretion rather than the secretory process itself. Reduced expression of DENN/MADD, a mediator of TNFalpha-PG coupling, might account for the defect. Alteration of this neuromodulatory astrocytic pathway is described here for the first time in relation to Alzheimer disease.

Post‐training intrahippocampal infusion of nicotine prevents spatial memory retention deficits induced by the cyclo‐oxygenase‐2‐specific inhibitor celecoxib in rats

Recently, we demonstrated that intrahippocampal infusion of the cyclo-oxygenase (COX)-2-specific inhibitor celecoxib impaired spatial memory retention in the Morris water maze. In the present work, we investigated the effects of nicotine, infused in the rat dorsal hippocampus several minutes after infusion of celecoxib, on memory retention in the Morris water maze. Rats were trained for 3 days; each day included two blocks, and each block contained four trials. Test trials were conducted 48 h after surgery. As expected, bilateral intrahippocampal infusion of celecoxib (19 microg/side; 0.1 m) increased escape latency and travel distance in rats, indicating significant impairment of spatial memory retention. We also examined the effects of bilateral infusion of nicotine (0.5, 1.0 and 2.0 microg/side) on memory retention. Infusion of 1 microg nicotine significantly decreased escape latency and travel distance but not swimming speed, compared with controls, suggesting memory retention enhancement by nicotine at this concentration. In separate experiments, bilateral infusion of nicotine, infused 5 min after 0.1 m (19 microg/side) celecoxib infusion, was associated with escape latency, travel distance and swimming speed profiles very similar to those in control animals. Brain tissue sections from several of these animals were subjected to immunohistochemical staining analysis with anti-COX-2 antibodies. Quantification analysis by optical density measurements showed that the celecoxib infusion reduced the immunoreactivity of COX-2-containing neurons in the CA1 area of the hippocampus compared with controls, although this reduction was not significant. However, infusion of a combination of celecoxib and nicotine significantly increased this immunoreactivity compared with levels in control and celecoxib-infused groups. These results suggest that nicotine prevented or reversed the adverse effects of celecoxib on spatial memory retention and protected or restored the immunostaining pattern of COX-2 neurons in the rat dorsal hippocampus.

Unilateral proximal occlusion of the middle cerebral artery has no effect on acquisition or retention of spatial memory

Stroke is the third most common cause of death and the primary cause of morbidity in the United Kingdom. It can be associated with deterioration in both sensorimotor and cognitive skills. Proximal occlusion of the middle cerebral artery (MCAO) in rodents is a widely used model of experimental cerebral ischaemia, which has been used to investigate the effect of stroke on cognition in spatial learning, such as the watermaze. However, findings to-date have been varied, depending on when testing was started after MCAO and the duration of training and testing, raising doubts about the utility of MCAO in rodents to study memory deficits. The present study was designed to discriminate between sensorimotor and spatial memory to establish whether MCAO has a significant influence on both the acquisition and retention of spatial memory. Female Lister Hooded rats (n=10) underwent MCAO. The artery was electrocoagulated from the origin of the lenticulostriate arteries to the inferior cerebral vein and then transected to ensure complete occlusion. Sham animals (n=9) underwent the same procedure except the artery was not occluded or transected and a group of naive, unoperated animals (n=8) was included. Training in the watermaze commenced 10 days after MCAO with 3 days of training to a visible escape platform of varying positions from different start positions. The animals were then trained to find a hidden escape platform at a fixed location (spatial reference memory). The start position was varied and the first trial every day was a probe trial where no platform was present for the first 60 seconds. For acquisition, animals were trained until they spent at least 50% of the probe trial in the quadrant where the platform was normally placed (target quadrant) for 3 consecutive days. The retention of memory was tested 1, 7 and 28 days after this criterion was reached. MCAO induced a consistent infarct involving both cortex and caudate which by 28 days was represented by ipsilateral tissue loss of 32.1 2.8 % of the contralateral hemisphere (mean S.E.M). The watermaze results revealed no deficit in acquisition or retention of memory in MCAO animals compared to sham and naive animals. There was no difference in the average number of days to reach acquisition criterion (Graph 1), and no difference in the proportion of time spent in the target quadrant during the retention tests (Graph 2). Data are presented as mean S.E.M. In conclusion, this study, designed to differentiate between spatial memory and sensorimotor deficits, revealed no evidence for deficits in memory acquisition or retention following MCAO. (See Figure 1).

Inhibitory avoidance memory retention in the elevated T-maze is impaired after perivascular manipulation of the common carotid arteries

Perivascular manipulation promoted by the positioning of a silicone collar around the common carotid arteries causes local inflammation and has been suggested as an animal model of atherosclerosis. This manipulation induces biochemical and morphological changes that are similar to those observed in the early stage of atherosclerosis in humans. Based on evidences showing that atherosclerosis is associated with cognitive deficits in humans, we presently investigated the temporal consequences of the bilateral positioning of silicone collars around the common carotid arteries (n = 15) on inhibitory avoidance memory retention in male Wistar rats tested in the elevated T-maze. The effects of this procedure were compared to those observed in sham-operated animals (n = 15) and to those observed in animals submitted to permanent bilateral occlusion of the common carotid arteries (n = 16). Additionally we studied the effects of the pretreatment with the non-selective anti-inflammatory drug indomethacin (n = 13) or the selective COX-2 inhibitor celecoxib (n = 12) and compared the effects to those of the pretreatment with vehicle (n = 11). The results showed that the silicone collar implants induced deficits in memory retention when animals were tested 2 and 4, but not 15 or 30, days after surgery. Permanent bilateral occlusion of the common carotid arteries impaired avoidance retention up to 30 days after surgery. Pretreatment with indomethacin (2 mg/kg/day) or celecoxib (5 mg/kg/day) post surgery and up to 3 days thereafter did not prevent memory deficits caused by silicone collar implants. Our data suggest that the prostanoids that participate in the inflammatory process triggered by the placement of the silicone collar do not seem responsible for the deficit in memory retention observed during the first days after collar placement.

The effects of the dopamine D1 receptor antagonist SCH23390 on memory reconsolidation following reminder-activated retrieval in day-old chicks

This series of experiments examined the involvement of the dopamine D1 receptor antagonist, SCH23390, on memory reconsolidation following reminder-activated retrieval. Day-old male New Hampshire × White Leghorn chicks were trained on a single trial passive avoidance task. A dose of 0.5 mg/kg of SCH23390 was administered subcutaneously 5 min before reminder trials, which were presented at 30, 60, and 90 min following training. Memory deficits were observed when reminder trials were presented at 30 and 60 min following training, but not when a reminder was presented at 90 min. No effect on memory retention was observed when reminder trials were not presented, suggesting that reconsolidation mechanisms were both contingent on the presentation of the reminder and independent of the consolidation process. Following a reminder presented at 60 min post-training, deficits in memory retention emerged between 45 and 60 min. The deficit was prolonged, lasting for up until 48 h after reminder presentation. The results indicate an important role for the D1 receptor in reconsolidation processes.

Radiation-induced impairment of hippocampal neurogenesis is associated with cognitive deficits in young mice

Advances in the management of pediatric brain tumors have increased survival rates in children, but their quality of life is impaired due to cognitive deficits that arise from irradiation. The pathogenesis of these deficits remains unknown, but may involve reduced neurogenesis within the hippocampus. To determine the acute radiosensitivity of the dentate subgranular zone (SGZ), 21-day-old C57BL/J6 male mice received whole brain irradiation (2–10 Gy), and 48 h later, tissue was assessed using immunohistochemistry. Proliferating SGZ cells and their progeny, immature neurons, were decreased in a dose-dependent fashion. To determine if acute changes translated into long-term alterations in neurogenesis, mice were given a single dose of 5 Gy, and 1 or 3 months later, proliferating cells were labeled with 5-bromo-2′-deoxyuridine (BrdU). Confocal microscopy was used to determine the percentage of BrdU-labeled cells that showed mature cell phenotypes. X-rays significantly reduced the production of new neurons at both time points, while glial components showed no change or small increases. Measures of activated microglia and infiltrating, peripheral monocytes indicated that reduced neurogenesis was associated with a chronic inflammatory response. Three months after irradiation, changes in neurogenesis were associated with spatial memory retention deficits determined using the Morris water maze. Behavioral training and testing increased the numbers of immature neurons, most prominently in irradiated animals. These data provide evidence that irradiation of young animals induces a long-term impairment of SGZ neurogenesis that is associated with hippocampal-dependent memory deficits.

Role of LRP in TGFβ2‐mediated neuronal uptake of Aβ and effects on memory

AbstractThere is increasing evidence that soluble amyloid‐β peptide (Aβ) uptake into neurons is an early event in the pathogenesis of Alzheimer's disease (AD). Identification of the early events leading to neuronal dysfunction is key to developing therapeutic strategies, but relative roles of receptors and factors modulating uptake are poorly understood. Studies have shown that transforming growth factor β (TGFβ), particularly TGFβ2, can influence the targeting of Aβ to cells in vitro. TGFβ2 can target Aβ to neurons in organotypic hippocampal slice cultures (OHSC). We examine a specific mechanism for TGFβ2‐mediated targeting of Aβ to neurons. The receptor‐associated protein (RAP), a low‐density lipoprotein receptor‐related protein (LRP) antagonist, can attenuate the cellular targeting of Aβ both in vitro and in vivo and prevent Aβ/TGFβ2‐induced memory retention deficits. Using both in vitro and in vivo methods, we identify LRP as playing a role in TGFβ2‐mediated Aβ uptake, neurodegeneration, and spatial memory impairment. © 2004 Wiley‐Liss, Inc.