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PubMed1995

Effects of prenatal ultrasound exposure on adult offspring behavior in the Wistar rat.

An ultrasound exposure tank was specifically designed for experimental bioeffects studies. Thirty-six pregnant rats were anesthetized, immersed to the axilla in a water tank, and exposed on Day 15, 17, and 19 of gestation. Twelve rats were exposed to 5.0 MHz pulsed ultrasound of effective pulse duration equal to approximately 0.170 microseconds, pulse repetition rate (PRF) 1 kHz, and a spatial peak, temporal peak intensity (lsptp) of 500 W/cm2, representing a clinically appropriate exposure level. The spatial peak pulse average (lsppa), spatial peak temporal average (lspta), and instantaneous maximum (lm) intensities were determined to be 100 W/cm2, 24 mW/cm2, and 230 W/cm2, respectively. The maximum rarefraction pressure, pr, was measured as 12.5 x 10(5) Pa, and the total power was 2.5 mW. Twelve other rats were exposed to 1500 W/cm2, lsptp, and 12 were sham insonified. Since the focal area was about 0.05 cm2, computer controlled stepper motors moved the rats through the ultrasound field to ensure uniform exposure of the abdominal/pelvic region. Total exposure time was 35 min. A miniature thermocouple was implanted in a few rats to verify that no significant temperature increase took place due to exposure. A total of 278 offspring were maintained until postnatal Day 60 when they were subjected to two of four behavioral tests in random order within sexes. The results indicate no consistently observed dose-related alterations in adult behavior due to prenatal fetal exposure to 5.0 MHz ultrasound below an intensity (lsptp) of 1500 W/cm2.

Animals↗
PubMed1992

Total amount learned versus learning rate of verbal and nonverbal information, in differentiating left-from right-brain injured patients.

Twenty Left-Brain Damaged (LBD), 20 Right-Brain Damaged (RBD), and 20 control subjects were compared on three different learning tasks: (a) verbal, the Paired Associate Learning subtest of the Wechsler Memory Scale; (b) figural, the Gollin Incomplete Figures task, which can be easily verbalized, and (c) spatial, the Stylus Maze. When learning ability was measured, by assessing the total amount learned (sum of items learned in all trials), the results showed that, on all three tasks, the control group's performance significantly surpassed that of the patient groups. The RBD group performed better than the LBD group on the verbal learning task, while LBD subjects performed better than their RBD counterparts on the spatial learning task. No significant difference between the two patient groups was detected on the figural task, suggesting that a task using visually and verbally codable stimuli is not useful in differentiating between LBD and RBD groups. When the learning rate was measured, similar results were obtained in the verbal and figural task. However, in the spatial task, the learning rates of the three groups did not significantly differ, probably because the specific task used required procedural learning, which is normally preserved in amnesics.

Journal Article↗
PubMed1997

MK-801 administration during ethanol withdrawal in neonatal rat pups attenuates ethanol-induced behavioral deficits.

Alcohol exposure during development can produce central nervous system dysfunction, resulting in a wide range of behavioral alterations. The various mechanisms by which alcohol causes these behavioral changes, however, remain unknown. One mechanism that has been suggested is NMDA receptor-mediated excitotoxic cell death produced by ethanol withdrawal. The present study examined whether MK-801, an antagonist of the NMDA receptor that has been shown to protect against NMDA receptor-mediated excitotoxicity, could block alcohol's adverse effects on behavior. Sprague-Dawley rat pups were exposed to alcohol (6.0 g/kg) in a binge-like manner on postnatal day 6 using an artificial rearing procedure. Subjects then received an injection of MK-801 (0.1 mg/kg) or vehicle during withdrawal, 21 hr after ethanol exposure. At postnatal day 40, all subjects were tested on a serial spatial discrimination reversal task. Ethanol-exposed subjects were impaired in both discrimination and reversal learning, and committed a significantly greater number of perseverative-type errors, compared with controls. MK-801 administration during ethanol withdrawal significantly attenuated ethanol-induced deficits in reversal learning and increases in perseverative-type errors, whereas MK-801 exposure by itself had no significant effect on performance. Thus, exposure to MK-801 during ethanol withdrawal partially protected against alcohol-related disruptions in spatial reversal learning. These results support the suggestion that NMDA receptor-mediated excitotoxicity may be one mechanism by which alcohol induces behavioral teratogenicity.

Alcohol Withdrawal Delirium↗
PubMed1998

Characterization of perforant path lesions in rodent models of memory and attention.

Early stage Alzheimer's disease (AD) pathology is associated with neurodegeneration of systems within the temporal cortex, e.g. the entorhinal cortex, perforant pathway and hippocampus. The perforant pathway provides the major neuronal input to the hippocampus from the entorhinal cortex and thus relays multimodal sensory information derived from cortical zones into the hippocampus. The earliest symptoms of AD include cognitive impairments, e.g. deficits in short-term memory and attention. Consequently, we have investigated the effect of bilateral knife cut lesions to the perforant path on cognition in rats using models measuring primarily short-term memory (operant delayed match to position task), attention (serial five-choice reaction time task) and spatial learning (Morris water maze). Rats receiving bilateral perforant path lesions showed normal neurological function and a mild hyperactivity. The lesion produced little effect on attention assessed using the five-choice task. In contrast, animals with equivalent lesions showed a robust delay-dependent deficit in the delayed match to position task. Spatial learning in the water maze task was also severely impaired. The delay-dependent deficit in the match to position task was not reversed by tacrine (3 mg/kg) pretreatment. The present data support a selective impairment of cognitive function following perforant path lesions that was confined to mnemonic rather than attentional processing. These findings complement primate and human studies identifying a critical role of the perforant pathway and associated temporal lobe structures in declarative memory. Degeneration of the perforant pathway is likely to contribute to the mnemonic deficits characteristic of early AD. The failure of tacrine to ameliorate these deficits may be relevant to an emerging clinical literature suggesting that cholinomimetic therapies improve attentional rather than mnemonic function in AD.

Animals↗
PubMed2006

Ginkgo biloba extract improves spatial memory in rats mainly but not exclusively via a histaminergic mechanism.

In order to clarify the mechanism of Ginkgo biloba extract (GBE) on learning and memory, we studied the effect of GBE on spatial memory deficits induced by diphenhydramine, pyrilamine and scopolamine using the eight-arm radial maze performance of rats, in comparison with donepezil. Total error (TE), reference memory error (RME) and working memory error (WME) were used as indices of spatial memory deficits. Both GBE and donepezil caused a potent antagonistic effect on the increase in TE, RME and WME induced by diphenhydramine. GBE and donepezil also antagonized scopolamine-induced spatial memory deficits. Although the antagonistic effect of GBE on pyrilamine-induced spatial memory deficits was weak, a significant difference was observed with TE and WME. However, donepezil caused no antagonistic effect on pyrilamine-induced memory deficits. From these findings, we concluded that the effects of GBE are mainly contributable to cholinergic activity and perhaps partly due to a histaminergic mechanism.

Acetylcholine↗
PubMed2005

Effects of harmaline on anxiety-related behavior in mice.

Harmaline (HA) is a beta-carboline commonly known to provoke motor alterations through activation of cells in the inferior olive. In addition, this pharmacological agent also induces cognitive disturbances such as motor and spatial learning impairments. In order to complete and extend these data, we examined the effects of this drug on state anxiety in mice, employing elevated plus maze test. We report here that lower doses of harmaline (5-10 mg/kg) have anxiogenic since higher doses (20 mg/kg) have anxiolytic-like properties. Overall pattern of our behavioral results provides evidence that harmaline also acts on emotional reactivity in mice by influencing their decision making when placed in an anxiogenic situation.

Analysis of Variance↗
PubMed2001

A role for the angiotensin AT4 receptor subtype in overcoming scopolamine-induced spatial memory deficits.

There is increasing interest in the role of the brain angiotensin AT4 receptor subtype in cognitive processing. This receptor subtype is activated by angiotensin IV (AngIV), is heavily distributed in the mammalian hippocampus, neocortex, and cerebellum, and has been linked with a learning and memory function. The present investigation utilized intracerebroventricular (i.c.v.)-infused scopolamine hydrobromide (scop), a muscarinic receptor antagonist, to disrupt acquisition of the circular water maze task of spatial memory. All animals received 2 days of training trials (five trials/day) using a visible platform in an effort to preclude subsequent confounding by scopolamine-induced sensory and/or motor impairments. In the first experiment, i.c.v.-infused scopolamine (70 nmol) was followed by 0, 10, 100, or 1000 pmol i.c.v. doses of Nle(1)-AngIV in separate groups of rats. Results indicated that each dose of Nle(1)-AngIV improved the poor acquisition of this task induced by scopolamine treatment. However, the 100- and 1000-pmol doses were most effective with respect to latency and distance to find the submerged pedestal. A second experiment demonstrated that treatment with a specific AT4 receptor antagonist, Nle(1), Leual(3)-AngIV (1000 pmol), blocked the ability of Nle(1)-AngIV (100 pmol) to improve the performance of scopolamine-compromised rats. These results support the notion that hippocampal AT4 receptors are involved in spatial memory processing, and that activation of these binding sites can overcome the disruption of spatial memory accompanying treatment with a muscarinic receptor antagonist.

Analysis of Variance↗
PubMed1995

Spatial learning with a minislab in the dorsal hippocampus.

We have determined the volume and location of hippocampal tissue required for normal acquisition of a spatial memory task. Ibotenic acid was used to make bilateral symmetric lesions of 20-100% of hippocampal volume. Even a small transverse block (minislab) of the hippocampus (down to 26% of the total) could support spatial learning in a water maze, provided it was at the septal (dorsal) pole of the hippocampus. Lesions of the septal pole, leaving 60% of the hippocampi intact, caused a learning deficit, although normal electrophysiological responses, synaptic plasticity, and preserved acetylcholinesterase staining argue for adequate function of the remaining tissue. Thus, with an otherwise normal brain, hippocampal-dependent spatial learning only requires a minislab of dorsal hippocampal tissue.

Acetylcholinesterase↗
PubMed2002

Spatial learning is unimpaired in mice containing a deletion of the alpha-synuclein locus.

Alpha-synuclein belongs to a family of structurally related proteins expressed highly in the brain and is the major component of filamentous deposits present in a range of neurodegenerative diseases (synucleinopathies). It has been implicated in learning and memory, yet the physiological role of this protein is still unclear. It was recently found that a subpopulation of C57BL/6J mice carries a chromosomal deletion of the alpha-synuclein locus, often unknown to the experimenter. As genetically engineered mice are often backcrossed with C57BL/6J animals for learning and memory experiments, we studied the importance of alpha-synuclein in spatial learning tasks by examining the performance of alpha-synuclein-/- mice in the hidden platform reference memory version of the watermaze. Our data show that alpha-synuclein-/- mice had no significant impairment in performance during training or probe trials, compared with wild-type littermates. Therefore, we conclude that alpha-synuclein is not essential for this type of spatial learning.

Animals↗
PubMed2004

Systemic administration of MK-801, a non-competitive NMDA-receptor antagonist, elicits a behavioural deficit of rats in the Active Allothetic Place Avoidance (AAPA) task irrespectively of their intact spatial pretraining.

Spatial orientation is considered to be an animal model of human cognitive functions. Efficient navigation is believed to require a brain representation of the environment. The role of NMDA-receptor-dependent neurotransmission in encoding spatial representations has been intensively studied; however, its involvement in organizing spatial information into neural representations is poorly understood. We tested the effect of NMDA-receptor blockade on the performance of rats in Active Allothetic Place Avoidance (AAPA), a cognitive task which requires rats to separate two conflicting spatial reference frames (room and arena frames), when only the room frame is relevant for solution of the task. The NMDA-receptor blockade was achieved by systemic administration of either 0.15 mg/kg or 0.2 mg/kg of dizocilpine (MK-801), a non-competitive NMDA-receptor antagonist. Two distinct AAPA setups located in different rooms were used. The rooms had different layouts of robust extramaze landmarks. Intact rats were trained in the upstairs arena and, subsequently, they received saline or MK-801 and their performance was tested (reinforced retention). Re-acquisition of AAPA task in the downstairs room was then tested under saline or MK-801. MK-801 at the dose of 0.2 mg/kg was found to disrupt the reinforced retention of the AAPA. Re-acquisition of AAPA in the novel environment was impaired by both doses of MK-801. Taken together, administration of MK-801 causes an orientation deficit in the AAPA task irrespectively of the rats' prior intact pretraining. These results support the hypothesis that NMDA-receptors play a pivotal role in cognitive processes.

Analysis of Variance↗
PubMed2005

Neuropsychological disorders indicative of postresuscitation encephalopaty in rats.

The aim of this research was to study the effect of 12-minute clinical death on innate and acquired behavior, biogenic amine concentration, and the composition and quantity of neural populations in specific brain regions of white rats. The study shows that in animals during the postresuscitation period with formal restoration of neurological status, there are changes in emotional reactivity, orientation-exploration reactions, impairment of learning and memory, decrease in exercise tolerance and pain sensitivity. These processes are accompanied by alterations in serotonin and norepinephrine levels in the frontal cerebral cortex, dopamine and serotonin levels in the striatum, certain biochemical indices in blood plasma and neural loss in the CA1 sector of the hippocampus and lateral portions of the cerebellum.

Animals↗
PubMed2000

Recovery of emotional behaviour in neural cell adhesion molecule (NCAM) null mutant mice through transgenic expression of NCAM180.

In the present study we further investigate functions of the neural cell adhesion molecule (NCAM) in the mature central nervous system and its implications for animal behaviour. To this end we generated transgenic mice expressing the major NCAM isoform with the largest cytoplasmic domain, NCAM180, under control of a promoter for the small form neurofilament gene. Transgenic mice were also bred with mice deficient in endogenous NCAM (Ncam-/- mice) so that effects of NCAM180 could be analysed in the presence and absence of endogenous NCAM. While overexpression of transgenic NCAM180 was without apparent behavioural or morphological effect, its expression in Ncam-/- mice counteracted NCAM ablation-induced aggressive, anxiety-like and antidepressant-like behaviour. It furthermore prevented a hypersensitivity of Ncam-/- mice to the anxiolytic serotonin1A (5-HT1A) receptor agonist buspirone. Such recovery of emotional behaviour and behavioural 5-HT1A response occurred in spite of misdevelopment of the olfactory bulb and hippocampus that is characteristic of Ncam-/- mice, and without an apparent change in the expression of 5-HT1A binding sites in the brain. Hippocampus- and amygdala-dependent learning, though disturbed in Ncam-/- mice, remained unaffected by the transgenic NCAM180. We suggest an involvement of NCAM180-mediated cell recognition processes in the serotonergic modulation of emotional behaviour in adult mice.

Aggression↗
PubMed2001

Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior.

The ability to selectively lesion mouse basal forebrain cholinergic neurons would permit experimental examination of interactions between cholinergic functional loss and genetic factors associated with neurodegenerative disease. We developed a selective toxin for mouse basal forebrain cholinergic neurons by conjugating saporin (SAP), a ribosome-inactivating protein, to a rat monoclonal antibody against the mouse p75 nerve growth factor (NGF) receptor (anti-murine-p75). The toxin proved effective and selective in vitro and in vivo. Intracerebroventricular injections of anti-murine-p75-SAP produced a dose-dependent loss of choline acetyltransferase (ChAT) activity in the hippocampus and neocortex without affecting glutamic acid decarboxylase (GAD) activity. Hippocampal ChAT depletions induced by the immunotoxin were consistently greater than neocortical depletions. Immunohistochemical analysis revealed a dose-dependent loss of cholinergic neurons in the medial septum (MS) but no marked loss of cholinergic neurons in the nucleus basalis magnocellularis after intracerebroventricular injection of the toxin. No loss of noncholinergic neurons in the MS was apparent, nor could we detect loss of noncholinergic cerebellar Purkinje cells, which also express p75. Behavioral analysis suggested a spatial learning deficit in anti-murine-p75-SAP-lesioned mice, based on a correlation between a loss of hippocampal ChAT activity and impairment in Morris water maze performance. Our results indicate that we have developed a specific cholinergic immunotoxin for mice. They also suggest possible functional differences in the mouse and rat cholinergic systems, which may be of particular significance in attempts to develop animal models of human diseases, such as Alzheimer's disease, which are associated with impaired cholinergic function.

Animals↗
PubMed2005

[Dependence of long-lasting effects of the ACTH(4-10) analogue semax on the time of its neonatal administration].

Long-lasting behavioural effects of chronic administration of synthetic ACT(4-10) analogue Semax (MEHFPGP) during early neonatal life were studied. The peptide was injected daily intraperitoneally in dose 0.05 mg/kg during the first, second or second-third weeks of postnatal development. It was shown that the peptide injections during the first week lead to a decrease and during second or second-third weeks--to an increase of exploratory activity in 4-8-week aged rats. Furthermore, the peptide adminictration at all times diminished anxiety and improved learning ability of adult rats. The data obtained show that Semax neonatal administration during the first three weeks of life modulates development of brain structures involved in regulation of exploration, anxiety and learning.

Adrenocorticotropic Hormone↗
PubMed1994

Selective reduction of hippocampal dentate frequency potentiation in aged rats with impaired place learning.

Induction of posttetanic potentiation (PTP) and long-term potentiation (LTP) was analyzed in hippocampal slices obtained from a) young 6-month-old Sprague-Dawley (SD) rats, all of them performing well in the Morris Maze, and b) aged SD 20-month-old and Fischer 344 24-month-old rats showing different degrees of ability in the same test. After the application of an electrical tetanus 1 s, 100 Hz, 50 microA in the stratum radiatum, no significant differences were found in the percent of induction of both PTP and LTP in the CA1 area of hippocampal slices obtained from rats of different strains and ages. After the application of an electrical tetanus 1 s, 100 Hz, 50 microA in the stratum moleculare, a significant difference was found in the percent of dentate PTP induction in hippocampal slices obtained from rats of different ages. Specifically, dentate PTP induction was significantly (p < 0.01) higher in slices obtained from young SD rats, and from old SD rats with a better performance in the Morris maze, escape latency less than 10 s and 150 cm, than in slices obtained from old SD or Fischer 344 rats that had shown poor performance in the Morris Maze. On the contrary, no significant differences were found in the percent of dentate LTP in hippocampal slices obtained from rats of different strains and ages. The data demonstrate that the induction of hippocampal dentate high-frequency PTP is selectively reduced in old rats with impaired Morris Maze performance.

Aging↗
PubMedDate not supplied

Effects of prenatal exposure to N-methylpyrrolidone on postnatal development and behavior in rats.

Pregnant rats (Mol:WIST) were exposed to 150 ppm N-methylpyrrolidone for 6 hours per day on gestation days 7-20. The dose level was selected so as not to induce maternal toxicity or decrease viability of offspring. In the preweaning period, the exposed offspring had a lower body weight and their physical development was delayed. Neurobehavioral evaluation of the male pups revealed no effects on basal functions of the central nervous system. The animals appeared normal and motor function (rotarod), activity level (open field), and performance in learning tasks with a low grade of complexity were similar in the two groups. However, in more difficult tasks such as the reversal procedure in Morris water maze and operant delayed spatial alternation (Skinner boxes), performance was impaired in exposed offspring.

Animals↗
PubMed2004

Ginkgo biloba promotes short-term retention of spatial memory in rats.

This study examines possible interactions between exposure to Ginkgo biloba extract and enriched environments on the acquisition and retention of spatial learning following massed and spaced trials. After 4 weeks of exposure to either ginkgo or vehicle, 8-week-old rats were tested using a Morris Water Maze in either massed or spaced trials. While ginkgo did not have an effect on maze acquisition or long-term retention, it did promote short-term retention of spatial memory. Following reversal training, ginkgo promoted short-term retention for two groups but impaired retention for a third. These results suggest that ginkgo has powerful effects on short-term retention that vary with training conditions.

Animals↗
PubMed2001

Relationship between three intensity levels of Toxocara canis larvae in the brain and effects on exploration, anxiety, learning and memory in the murine host.

Outbred LACA mice were administered low (100 ova), medium (1000 ova), high (3000 ova) and trickle (4x250 ova) doses of Toxocara canis ova and the effect of infection was examined with respect to the number of larvae recovered from the brain and their behaviour. Recovery of larvae from the brain was generally low with the % recovery expressed in terms of the total dose administered being highest for the 3000 dose (6.1%) and 1000 dose (6%), followed by the 100 (4.4%) and trickle (3.5%) doses. The variation in larval recoveries was large between individual mice receiving similar doses. The level of infection in the brain was lower in mice receiving a multiple as opposed to an equivalent single dose of ova. Mice were then divided into three larval intensity groupings based upon the number of larvae recovered from their brain. The ranges for the groups were as follows: low intensity group, 0-15 larvae; moderate intensity group, 27-55 larvae; high intensity group, 66-557 larvae. Three behavioural tests were carried out on control and infected mice. Exploration and response to novelty was examined using a 'T' maze and learning was investigated by means of a water-finding task. Anxiety was measured using an elevated plus maze apparatus. Infected mice were less explorative and less responsive to novelty in the 'T' maze and this was particularly pronounced for the heavily infected mice. In the elevated plus maze, infected mice displayed reduced levels of anxiety to aversive and exposed areas of the maze, particularly in the case of the moderate and high intensity mice. There was evidence for impaired learning ability in the water task apparatus for moderate and high intensity mice. In general, the effects of infection on behaviour were more pronounced in the moderate and high intensity groups compared to the low intensity group.

Animals↗