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PubMed2005

Both early and delayed treatment with melanocortin 4 receptor-stimulating melanocortins produces neuroprotection in cerebral ischemia.

Ischemic stroke is one of the main causes of death and disability. We investigated whether melanocortin peptides, which have protective effects in severe hypoxic conditions, also produce neuroprotection in a gerbil model of ischemic stroke. A 10-min period of global cerebral ischemia, induced by occluding both common carotid arteries, caused impairment in spatial learning and memory that was associated with activation of inflammatory and apoptotic pathways, including severe DNA damage and delayed neuronal death, in the hippocampus. Treatment with nanomolar doses of the melanocortin analog [Nle4, D-Phe7] alpha-MSH [which activates the melanocortin receptor subtypes (MC) mainly expressed in central nervous system, namely MC3 and MC4] modulated the inflammatory and apoptotic cascades and reduced hippocampus injuries even when delayed up to 9 h after ischemia, with consequent dose-dependent improvement in subsequent functional recovery. The selective MC3 receptor agonist gamma2-MSH had no protective effects. Pharmacological blockade of MC4 receptors prevented the neuroprotective effects of [Nle4, D-Phe7] alpha-MSH and worsened some ischemia outcomes. Together, our findings suggest that MC4 receptor-stimulating melanocortins might provide potential to develop a class of drugs with a broad treatment window for a novel approach to neuroprotection in ischemic stroke.

Animals↗
PubMed1999

Cognitive deficits in a genetic mouse model of the most common biochemical cause of human mental retardation.

Phenylalanine hydroxylase (Pah)-deficient "PKU mice" have a mutation in the Pah gene that causes phenylketonuria (PKU) in humans. PKU produces cognitive deficits in humans if it is untreated. We report here the first evidence that the genetic mouse model of PKU (Pah(enu2)) also produces cognitive impairments. PKU mice were impaired on both odor discrimination reversal and latent learning compared with heterozygote littermates and with wild-type mice of the same BTBR strain. A small container of cinnamon-scented sand was presented on the right or left, and nutmeg-scented sand was presented on the other side; left-right location varied over trials. Digging in sand of the correct scent was rewarded by finding phenylalanine-free chocolate. To prevent scent cuing, new containers were used on every trial, and both containers always contained chocolate. Digging in the incorrect choice was stopped before the chocolate was uncovered. Once criterion was reached, the other scent was rewarded. PKU mice were impaired on reversals 2, 3, and 4. They were also impaired in latent learning. On day 1, half the mice were allowed to explore a maze and discover the location of water. On day 2, all mice were water-deprived and were placed in the maze. Whereas pre-exposed wild-type and heterozygous mice showed evidence that they remembered the location of the water and hence could find the water faster on day 2, pre-exposed PKU mice showed no significant benefit from their pre-exposure on day 1.

Animals↗
PubMed2001

Retrograde amnesia for spatial memory induced by NMDA receptor-mediated long-term potentiation.

If information is stored as distributed patterns of synaptic weights in the hippocampal formation, retention should be vulnerable to electrically induced long-term potentiation (LTP) of hippocampal synapses after learning. This prediction was tested by training animals in a spatial water maze task and then delivering bursts of high-frequency (HF) or control stimulation to the perforant path in the angular bundle. High-frequency stimulation induced LTP in the dentate gyrus and probably also at other hippocampal termination sites. Retention in a later probe test was disrupted. When the competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) was administered before the high-frequency stimulation, water maze retention was unimpaired. CPP administration blocked the induction of LTP. Thus, high-frequency stimulation of hippocampal afferents disrupts memory retention only when it induces a change in the spatial pattern of synaptic weights. The NMDA receptor dependency of this retrograde amnesia is consistent with the synaptic plasticity and memory hypothesis.

Afferent Pathways↗
PubMed2002

Extensive cytotoxic lesions of the rat retrosplenial cortex reveal consistent deficits on tasks that tax allocentric spatial memory.

Despite the connections of the retrosplenial cortex strongly suggesting a role in spatial memory, the lesion data to date have been equivocal. Whether subjects are impaired after retrosplenial lesions seems to depend on whether the lesions were aspirative or excitotoxic, with the latter failing to produce an impairment. A shortcoming of previous excitotoxic lesion studies is that they spared the most caudal part of the retrosplenial cortex. The present study thus used rats with extensive neurotoxic lesions of the retrosplenial cortex that encompassed the entire rostrocaudal extent of this region. These rats were consistently impaired on several tests that tax allocentric memory. In contrast, they were unimpaired on an egocentric discrimination task. Although the lesions did not appear to affect object recognition, clear deficits were found for an object-in-place discrimination. The present study not only demonstrates a role for the retrosplenial cortex in allocentric spatial memory, but also explains why previous excitotoxic lesions have failed to detect any deficits.

Animals↗
PubMed2003

Cognitive strategy-specific increases in phosphorylated cAMP response element-binding protein and c-Fos in the hippocampus and dorsal striatum.

Extensive research has shown that the hippocampus and striatum have dissociable roles in memory and are necessary for "place" and "response" learning, respectively. In the present study, rats were trained on a cross maze task that could be solved by either a place or a response strategy, and the strategy used was determined by a probe trial. Phosphorylated cAMP response element-binding protein (pCREB) and c-Fos immunoreactivity (IR) were measured in the hippocampus and striatum either immediately or 1 hr after cross maze training. Immediately after training, pCREB-IR and c-Fos-IR were significantly higher in the hippocampus and striatum of trained rats than in control rats matched for motor activity, but the increase was independent of the strategy revealed at probe. One hour after training, however, pCREB-IR and c-Fos-IR were sustained in the hippocampal pyramidal and granule cell layers of place learners but returned to basal levels among response learners. In addition, pCREB-IR was sustained in the dorsomedial and dorsolateral striatum of response learners but returned to basal levels among place learners. There were no differences between place and response learners in c-Fos-IR in the striatum at either time point. The present results indicate that cross maze training causes an initial activation of transcription factors in both the hippocampus and striatum. Formation of memory for a place strategy, however, is related to sustained phosphorylation of CREB and expression of c-Fos for at least 1 hr in the hippocampus, whereas formation of memory for a response strategy is related to phosphorylation of CREB in the striatum.

Analysis of Variance↗
PubMed1998

The effects of gestational cocaine exposure on pregnancy outcome, postnatal development, cognition and locomotion in rats.

Pregnant female Sprague-Dawley rats were injected with either 40 mg/kg (-)cocaine hydrochloride or an equivalent volume of 0.9% saline, subcutaneously (s.c.), once daily from gestational day 12 (GD 12) to GD 21. Gestational cocaine exposure had no effect on maternal weight gain, length of gestation, birthweight, fetal mortality, postnatal weight gain or locomotive activity in offspring. There was an unusual reduction in the male/female offspring ratio in the treated group (1:0.65) verses controls (1:1.04) (p < 0.01). Male offspring scored significantly lower on memory and learning tasks on postnatal day 30 (PND30) as determined by the water maze test (p < 0.01). Exposure to cocaine in utero had no effect on postnatal female sexual maturation or cognitive function. The present study indicated that gestational cocaine exposure can lead to cognitive impairment selectively in male offspring, without any apparent postnatal physical abnormalities or adverse effects on maternal health status.

Animals↗
PubMed2006

Estrogen modulates learning in female rats by acting directly at distinct memory systems.

Physiologically high levels of circulating estradiol enhance the use of place learning and impair the use of response learning to find food on a land maze. These two types of learning are impaired by lesions of distinct neuronal structures, i.e. the hippocampus and striatum, respectively. Moreover, it has been shown in male rats that compromising hippocampal function can promote the use of response learning, while compromising striatal function can promote place learning. These findings suggest an ongoing competition between the hippocampus and striatum during cognition, such that intact functioning of one structure somehow obstructs the relative participation of the other. The goal of this study was to determine if estrogen's opposing effects on place and response learning in female rats are due to direct actions, either independent or interacting, at the hippocampus and striatum. We infused 0.5 microM 17beta-estradiol 3-sulfate sodium or vehicle bilaterally into the dorsal hippocampus or dorsolateral striatum of ovariectomized young adult female rats, 48, 24 and 2 h before training. Rats were tested on one of three appetitive tasks in a Y-maze: place learning, response learning, or response learning with reduced visual cues (cue-poor condition). Intrahippocampal estradiol infusions enhanced place learning, reversing a cannula-induced impairment, whereas intrastriatal infusions had no effects on place learning. Estradiol infusions into neither structure significantly affected response learning when extramaze cues were visible. However, in the response task, cue-poor condition, intrastriatal but not intrahippocampal infusions impaired learning. These data demonstrate that estrogen modulates place and response learning at the hippocampus and striatum respectively, most likely through independent actions at these two structures.

Animals↗
PubMed2006

Orientation in the cuttlefish Sepia officinalis: response versus place learning.

Several studies have demonstrated that mammals, birds and fish use comparable spatial learning strategies. Unfortunately, except in insects, few studies have investigated spatial learning mechanisms in invertebrates. Our study aimed to identify the strategies used by cuttlefish (Sepia officinalis) to solve a spatial task commonly used with vertebrates. A new spatial learning procedure using a T-maze was designed. In this maze, the cuttlefish learned how to enter a dark and sandy compartment. A preliminary test confirmed that individual cuttlefish showed an untrained side-turning preference (preference for turning right or left) in the T-maze. This preference could be reliably detected in a single probe trial. In the following two experiments, each individual was trained to enter the compartment opposite to its side-turning preference. In Experiment 1, distal visual cues were provided around the maze. In Experiment 2, the T-maze was surrounded by curtains and two proximal visual cues were provided above the apparatus. In both experiments, after acquisition, strategies used by cuttlefish to orient in the T-maze were tested by creating a conflict between the formerly rewarded algorithmic behaviour (turn, response learning) and the visual cues identifying the goal (place learning). Most cuttlefish relied on response learning in Experiment 1; the two strategies were used equally often in Experiment 2. In these experiments, the salience of cues provided during the experiment determined whether cuttlefish used response or place learning to solve this spatial task. Our study demonstrates for the first time the presence of multiple spatial strategies in cuttlefish that appear to closely parallel those described in vertebrates.

Animals↗
PubMed1995

Gonadal hormone levels and spatial learning performance in the Morris water maze in male and female meadow voles, Microtus pennsylvanicus.

The present study examined the relationships between spatial learning and circulating levels of plasma estradiol and testosterone in adult male and female meadow vole, Microtus pennsylvanicus. Meadow voles are induced ovulators and most females that are housed with females or in isolation are in constant diestrus, whereas most females that are housed with males are in constant behavioral estrus. In this study sexually mature, adult male and female meadow voles housed with either females (constant diestrus) or males (constant behavioral estrus) were required to learn the spatial position of a hidden, submerged platform in the Morris water maze. Individual voles were tested using two blocks of four trials twice a day for 3 days for a total of six blocks. Task retention was examined with a probe trial 1 day after the last acquisition trial. Females were divided into two groups based on the median level of plasma estradiol [High Estradiol (15.79 +/- 1.20 pg/ml) and Low Estradiol (6.22 +/- 2.79 pg/ml) Females]. Males were similarly divided on the basis of median plasma testosterone levels [High (2.53 +/- 0.96 ng/ml) and Low Testosterone (0.45 +/- 0.08 ng/ml) Males]. High Estradiol females exhibited significantly longer latencies to reach the hidden platform, indicating poorer acquisition, than did either males (P = 0.025) or Low Estradiol females (for Blocks, 2, 3, 4, and 6, P = 0.037). Male superiority in spatial learning performance was evident only when High Estradiol females were compared to males. There were no significant performance differences between High and Low Testosterone males. There were also no group differences in retention, with all voles displaying significant retention of the spatial task. There was, however, a significant correlation between plasma estradiol levels in females and retention, with higher estradiol levels being associated with poorer retention. These results suggest that levels of estradiol in adult female meadow voles are significantly related to spatial learning, with low levels of estradiol being associated with better spatial learning. There was no evidence that levels of testosterone were related to spatial performance in adult male meadow voles. The results suggest that estradiol may have activational effects on spatial learning in the adult meadow vole and that sex differences in spatial learning are evident only when High Estradiol females are compared to adult males.

Animals↗
PubMedDate not supplied

Exposure to 3,4-methylenedioxymethamphetamine (MDMA) on postnatal days 11-20 induces reference but not working memory deficits in the Morris water maze in rats: implications of prior learning.

3,4-methylenedioxymethamphetamine (MDMA) in previous experiments has been shown to induce long-term spatial and sequential learning and memory deficits in adult offspring after exposure to the drug on postnatal (P) days 11-20, but not after exposure on P1-10. Herein we further tested for the effects of MDMA (0, 5, 10 or 20 mg/kg x 2/day) after exposure on P11-20 on reference and working memory in the Morris water maze (MWM), on reference memory in the Barnes maze, and on cued learning in the visible platform version of the MWM. The MWM and Barnes mazes were counterbalanced such that half the litters received the MWM-first and the other half received the Barnes maze first. Effects on MWM performance as a function of test order were observed. For animals that received the Barnes maze first, spatial MWM learning and memory trends were seen but they were not significantly different between MDMA groups and saline controls. For those receiving the MWM-first, there are consistent impairments on all measures in the MDMA groups compared to controls on MWM performance (latency, path length, and cumulative distance from the goal). On probe trials, MDMA animals receiving the MWM-first showed increased distance from the target site compared to controls. There were no MDMA effects seen on cued trials in the MWM or on straight channel swimming trials regardless of test order, indicating that MDMA had no effects on swimming ability or on the skills needed to learn the MWM. Similarly, there were no effects of MDMA on MWM working memory regardless of test order. No MDMA effects on the Barnes maze were found regardless of test order, however, the interpretation of this finding was compromised by the poor performance of the animals on this task.

Age Factors↗
PubMed1995

Ameliorating effects of histidine on scopolamine-induced learning deficits using an elevated plus-maze test in mice.

We investigated the effects of histidine on scopolamine-induced learning deficits in the elevated plus-maze test in mice. In this test, transfer latency (TL), the time mice took to move from the open arm to the enclosed arm, was used as an index of learning and memory. Intraperitoneal administration of scopolamine (0.5 mg/kg) prolonged the TL on day 2 compared with that in the saline-treated group. Histidine loading (500, 800 and 1600 mg/kg) reversed the prolongation of the TL induced by scopolamine. This ameliorating effect of histidine was abolished by alpha-fluoromethylhistidine, an inhibitor of histidine decarboxylase, suggesting that histidine itself has no such ameliorating effect. Moreover, the ameliorating effect of histidine was antagonized by a histamine H1 receptor antagonist, pyrilamine. However, zolantidine, a histamine H2 receptor antagonist, showed no antagonism of the effect of histidine. Thus, histamine, a decarboxylated product of histidine, elicited an ameliorating effect on scopolamine-induced learning deficit via histamine H1 receptors in mice. These findings clearly indicated that there is a close relationship between histaminergic and cholinergic systems in the brain, and that histamine may play certain important roles in learning and memory.

Animals↗
PubMed2004

Obstructive jaundice in rats: cause of spatial memory deficits with recovery after biliary decompression.

Children with end-stage liver disease have been found to have cognitive deficits. The aim of this study was to examine whether cholestatic jaundice causes spatial deficits in rats and if these cognitive deficits are reversed by biliary drainage. Rats were randomly divided into three groups. In the first group, the bile duct was ligated for 3 weeks (BDL group); in the second group, the proximal bile duct was ligated with a Broviac CV catheter for 2 weeks followed by a tube bilioduodenostomy (TBD group); in the third group, a sham operation was performed (SHAM group). All the surviving rats were assessed for spatial learning and memory (a major cognitive function in rats) by the Morris water maze task about 3 weeks after the first operation. Blood was aspirated by cardiocentesis and assayed for total bilirubin, albumin, ammonia, and hemoglobin levels on the day following the water maze task. During the four consecutive acquisition trial days of the Morris water maze, jaundiced rats (BDL group) had a significant longer latency to escape than the SHAM group ( p < 0.05). Rats that underwent biliary decompression for 1 week (TBD group) showed improved status of the spatial deficit, as they required less time to reach the escape platform, approaching the performance of the SHAM group. The BDL group had a significantly higher serum ammonia level, higher bilirubin level, and lower hemoglobin level than the other two groups. After biliary decompression for 1 week, the serum albumin concentration in the TBD group still did not return to the level of the SHAM group. The results of this study suggest that long-term cholestasis results in spatial memory deficits in rats that correlate with anemia and hyperbilirubinemia encephalopathy. Early biliary decompression of obstructive jaundice improves spatial memory deficits, possibly related to the recovery of the serum ammonia and hemoglobin levels.

Analysis of Variance↗
PubMedDate not supplied

Working memory deficits in BXSB mice with neocortical ectopias.

Approximately 40-60% of BXSB/MpJ-Yaa mice exhibit neocortical ectopias, which are misplaced clusters of neurons in layer I of cortex. These ectopias are usually located in the prefrontal and/or motor region of cortex in BXSB mice, and are similar in appearance to those found in postmortem analyses of the brains of dyslexic humans. Several within-strain learning differences between mice with ectopias and those without have been reported. In particular, ectopic BXSB mice exhibited superior reference memory learning, but inferior working memory learning in several studies from our laboratory. This study used the Morris water maze delayed matching-to sample task and the water radial-arm maze to asses working memory in female BXSB mice with and without ectopias. In the delayed matching-to sample task, a hidden escape platform remained in a constant position for each four-trial session, but changed position between sessions. Trial 2 was the measure of working memory, i.e., how well did the mouse remember where the platform was located for that session. In the water version of the eight-arm radial maze, hidden escape platforms were located in four of the eight arms, and each platform was removed from the maze once found. This enabled us to assess working and reference memory simultaneously. Ectopic mice demonstrated working memory deficits during the first part of the delayed matching-to sample task compared to nonectopics. Similarly, ectopics made more working memory errors during the latter half of radial-arm maze testing, while not differing from nonectopics in reference memory performance. Additionally, there were significant correlations between measures of working memory in the radial-arm maze and working memory in a delayed matching-to-sample task. These findings are in agreement with other studies demonstrating working memory deficits in ectopic BXSB mice.

Animals↗
PubMed2002

Cognitive deficit and development of motor impairment in a mouse model of Niemann-Pick type C disease.

Niemann-Pick disease type C (NPC) is a fatal, autosomal recessive lipidosis characterized by a unique error in cellular trafficking of cholesterol. In the disease, unesterified cholesterol as well as sphingolipids accumulate in the late endosomes/lysosomes due to mutations in either of two recently isolated genes, NPC1 or NPC2. A metabolic and neurological disorder reminiscent of human NPC disease has been described in Balb/C mice, and it was recently shown that the mutation in the NPC mice resides in the orthologous murine Npc1 gene. Here we have followed the growth rate and applied behavioural methods in order to establish the onset and development of the major symptoms in the NPC mouse model. Wild type and NPC mice were studied during 28-59 days of age. Both male and female NPC mice displayed retarded growth at the age between 25 and 35 days. At the age of 35-45 days the weight was similar to controls and thereafter very rapidly decreased. The battery of coordination tests (vertical screen, beam balancing, coat hanger and rotating rod) established motor impairment of the NPC mice already at the age of 28-42 days, well before the onset of visually detectable ataxia. Decreased exploratory activity and lack of habituation was revealed in the NPC mice by open field test. The diseased mice were unable to learn and remember the location of the hidden escape platform in spatial water maze task suggesting cognitive impairment. In several tests the male NPC mice were more affected than the females. The present study represents the first behavioural analysis of the NPC mice. The battery of behavioural tests employed here should be valuable in the assessment of effective approaches to treat NPC, for which no preventive or curative measures have so far been established.

Animals↗
PubMed2003

Spatial pre-training attenuates hippocampal impairments in rats exposed to intermittent hypoxia.

Intermittent hypoxia (IH), such as occurs in sleep apnea, is associated with increased apoptosis and neurobehavioral impairments in rats. To determine whether pre-training (P) modifies the effect of IH on spatial learning, adult male rats were trained in a spatial version of the water maze, exposed to IH or room air (RA) for 14 days, and then trained in a novel spatial task. P-RA had lower initial pathlengths than naive RA (N-RA), which were similar in P-IH and N-IH, indicating an adverse effect of IH on retention of behavioral strategies to solve the maze. However, P-IH acquired the later spatial task faster than N-IH. Pre-training was associated with increased phosphorylation of the cAMP-response element binding protein (CREB) in the hippocampus. Further, IH-induced decreases in CREB phosphorylation were attenuated by pre-training. We conclude that prior exposure to the water maze behavioral requirements attenuates the behavioral deficits occurring after IH exposure.

Animals↗
PubMed2002

Vaccinia virus complement control protein enhances functional recovery after traumatic brain injury.

Inflammation is a major contributor to the neuropathological consequences of traumatic brain injury (TBI). Previous studies have shown that proinflammatory complement activation fragments are present in the injured brain within the first 24 h after trauma. To investigate whether complement activation within the injured brain leads to the neuropathology and subsequent functional impairment associated with TBI, we examined what effect administration of a complement inhibitor, the vaccinia virus complement control protein (VCP), would have on spatial learning and memory in brain injured rats, as measured using the Morris Water Maze (MWM) procedure. Animals were subjected to a lateral fluid percussion brain injury of moderate severity and, 15 min later, received a 10-microL injection of either full-length VCP, a truncated version of VCP (VCPt), which lacks the complement inhibitory activity but retains the heparin binding activity of VCP, or saline directly into the cortex. Results of such intervention indicated that, at 2 weeks postinjury, both VCP and VCPt treatment attenuated impairments in spatial memory, but not neuropathological damage, as compared to the saline treated controls. These results were surprising and suggest that the neuroprotective effects following administration of VCP after acute brain injury are mediated by mechanisms other than complement inhibition. Potential mechanisms are discussed.

Animals↗
PubMed2004

Effects of raloxifene and estradiol on hippocampal acetylcholine release and spatial learning in the rat.

The effects of raloxifene on acquisition of a delayed matching to position (DMP) T-maze task and on hippocampal acetylcholine release were evaluated and compared with estradiol, to determine whether raloxifene has estrogenic effects on cognitive performance and hippocampal cholinergic activity. Ovariectomized rats received continuous treatment with raloxifene (one of two doses), estradiol, or vehicle for 30 days, followed by behavioral training, and then in vivo microdialysis assessment of basal and potassium-stimulated acetylcholine release. The data show that estradiol significantly enhanced DMP acquisition, whereas raloxifene did not. In contrast, both estradiol and the higher dose of raloxifene significantly increased potassium-stimulated acetylcholine release in the hippocampus. These data suggest that, despite increasing evidence for estrogenic effects of raloxifene in brain, raloxifene does not mimic the effects of estrogen on cognitive performance as assessed by acquisition of a simple spatial memory task in ovariectomized rats.

Acetylcholine↗