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The cerebellum and learning processes in animals.

In theories of motor learning, the cerebellum is assumed to be the storage site of the engram. Recent evidence is presented that the cerebellum, in addition to its mediation of learning of simple motor responses, has a role in cognitive behaviors. For this type of learning, it is possible that the storage site is not the cerebellum, but cerebellar target areas. The possible role of the cerebellum in spatial learning and discrimination learning is emphasized. Ascending cerebellar afferents to fronto-parietal association cortex, the limbic system and the superior colliculus and feedback loops from these areas may be the anatomical basis underlying cerebellar modulation of spatial learning. In regard to discrimination learning, the possible significance of pathways arising from the visual cortex to pontine nuclei projecting to the cerebellar hemispheres must be evaluated. Although much remains to be resolved, the cerebellum seems to contribute to various emotions such as fear, the neural basis of which being cerebellar contributions to the reticular activating system, the limbic system and two-way hypothalamo-cerebellar connections.

Animals↗

Differential effects of haloperidol, clozapine and olanzapine on learning and memory functions in mice.

Many schizophrenic patients exhibit impairments in neurocognitive functions. Typical antipsychotic drugs such as haloperidol, have limited or even detrimental influence on cognitive functions. In contrast, atypical antipsychotic drugs, such as clozapine and olanzapine, may improve memory function in schizophrenics. However, only a few studies have been conducted to directly compare the effects of olanzapine, clozapine and haloperidol on memory functions in animal models. Thus, their effects on this issue were investigated in the present studies by using one-way step-through passive avoidance task and Morris water maze as models of learning and memory. The results showed that olanzapine did not affect acquisition, consolidation or retrieval process in step-through test. Moreover, it improved spatial learning function in mice in Morris water maze task. Clozapine and haloperidol appeared to impair acquisition process and consolidation process, respectively, in step-through test. Both drugs impaired spatial learning function in mice in Morris water maze task. The results suggested a positive implication for the clinical medication of olanzapine in schizophrenic treatment.

Animals↗

Pentyl-4-yn-valproic acid reverses age-associated memory impairment in the Wistar rat.

Pentyl-4-yn-valproic acid (VPA), a cognition-enhancing agent whose mode of action has been attributed to cell adhesion molecule-mediated neuritogenesis, has been shown to enhance hippocampus-dependent spatial learning. Here, we investigated its potential to reverse age-related memory impairment that relates mainly to declarative memory. Aged spatial learning deficits in the water maze paradigm were demonstrated by swim angle analysis, the angle between axes of start-to-platform and start-to-animal position, and latency to reach a submerged platform. Chronic pentyl-4-yn-VPA administration mediated a significant improvement in both search strategy and latency to find the submerged platform in aged animals. Pentyl-4-yn-VPA also facilitated task recall in aged animals as evidenced by increased time in the target quadrant during a probe trial 3 days following the final training session. The action of pentyl-4-yn-VPA on platform latency, search strategy and task recall suggests that this agent may have great benefit in the treatment of age-dependent cognitive decline.

Aging↗

Concurrent muscarinic and beta-adrenergic blockade in rats impairs place-learning in a water maze and retention of inhibitory avoidance.

These experiments examined the effects of separate and concurrent muscarinic cholinergic and beta-adrenergic blockade on inhibitory (passive) avoidance performance and spatial learning in the Morris water maze. Pretraining systemic administration of either scopolamine (0.3 or 1.0 mg/kg) or propranolol (3.0 or 10.0 mg/kg) had no significant effect on one-day retention of step-through inhibitory avoidance training. Similarly, pretraining administration of either 0.3 mg/kg scopolamine or 10 mg/kg propranolol did not affect spatial learning in the Morris water maze. However, combined administration of scopolamine and 10.0 mg/kg of propranolol impaired performance on these tasks. These findings further support a role for interactions between norepinephrine and acetylcholine in the modulation of learning and memory and implicate the participation of beta-adrenergic mechanisms in this interaction. Because cholinergic and noradrenergic deterioration is found in aging and Alzheimer's disease, these results also have implications regarding the role of age-related noradrenergic and cholinergic dysfunction in cognitive decline.

Animals↗

First reproductive experience persistently affects spatial reference and working memory in the mother and these effects are not due to pregnancy or 'mothering' alone.

Pregnancy and motherhood are life-altering events that result in a number of hormonal, neural and behavioral changes in the mother. Motherhood has been shown to influence spatial learning and memory performance of the mother. In turn new research has shown that reproductive experience (number of times pregnant and mothered) plays a significant role on spatial learning and memory performance. How long these changes persist after weaning and the role of pregnancy and/or mothering on these changes have yet to be fully investigated. The present study aimed to determine whether enhanced spatial working and/or reference memory in the mother is evident long after weaning and whether these effects are due, in part, to pregnancy or 'mothering' alone. Five groups of age-matched rats: multiparous, primiparous, nulliparous, pregnant-only and sensitized rats were tested approximately 1 month after weaning/pup-exposure, or 55 days after birth, on the spatial working/reference version of the radial arm maze. Results show that regardless of error type (reference or working memory errors), primiparous rats make fewer errors compared to multi- and nulli-parous rats, with a trend to enhanced memory compared to sensitized rats. In addition, pregnant-only rats completed the task on significantly fewer days than primiparous, multiparous, nulliparous and sensitized rats. Clearly the combination of first pregnancy and first mothering experience has a significant impact on hippocampus-dependent learning and memory performance in the mother.

Analysis of Variance↗

Memory-specific temporal profiles of gene expression in the hippocampus.

Many experiments in the past have demonstrated the requirement of de novo gene expression during the long-term retention of learning and memory. Although previous studies implicated individual genes or genetic pathways in learning and memory, they did not uncover the collective behaviors or patterns of the genes. We have used genome-scale screening to analyze gene expression during spatial learning of rats in the Morris water maze. Our results show distinct temporal gene expression profiles associated with learning and memory. Exogenous administration of one peptide whose sustained increase during memory retention was implicated by microarray analysis, fibroblast growth factor (FGF)-18, improved spatial learning behavior, suggesting that pharmacological modulation of pathways and targets identified may allow new therapeutic approaches for improving learning and memory. Results of this study also suggest that while learning and physical activity involve common groups of genes, the behavior of learning and memory emerges from unique patterns of gene expression across time.

Animals↗

Multidimensional measures of person knowledge and spatial associative learning: can these be applied to the differentiation of Alzheimer's disease from frontotemporal and vascular dementia?

Patients with early stage Alzheimer's disease (AD) show deficits in person knowledge and spatial associative memory. The current investigation examined the ability of impairment in these domains to differentiate AD from other overlapping conditions. In experiment 1, 14 AD patients, 21 vascular dementia (VaD) patients, 11 frontal variant frontotemporal dementia (fvFTD) patients and 41 controls were administered a graded faces test. VaD patients demonstrated a level of impairment comparable to the AD group on both the naming and person identification elements of the task. A mild naming deficit was revealed in the fvFTD group. In experiment 2, 22 AD patients, 23 patients with mild cognitive impairment (MCI), 11 fvFTD patients, 13 semantic dementia (SD) patients, and 23 elderly controls were administered the face-place test, a newly developed task that combines naming of famous faces, item recognition and spatial location. The naming component of the face-place test clearly differentiated SD patients from all dementia groups. All patient groups, except those with fvFTD, showed substantial deficits in the item recognition and spatial components. Consistency analyses indicated a fairly robust association between the two episodic components (item recognition and placing), but not between semantic and episodic elements of the FPT. Person knowledge deficits are, therefore, not specific to AD and the employment of face stimuli may influence the performance of SD patients on tasks of episodic memory.

Aged↗

Variable alternative spliced exon (VASE)-containing and VASE-lacking neural cell adhesion molecule in the dorsal and ventral hippocampus of SAMP8 mice.

The neural cell adhesion molecule (NCAM) is involved in the development and synaptic plasticity of the brain. Differential splicing of the variable alternative spliced exon (VASE) in the fourth immunoglobulin domain can dramatically change the functional properties of NCAM. This paper discusses our analysis of the levels of different expression of VASE-containing NCAM (NCAM-VASE(+)) and VASE-lacking NCAM (NCAM-VASE(-)) mRNAs in the dorsal and ventral hippocampus of senescence-accelerated mice (SAM). We further investigated the individual level of NCAM-VASE(+) and NCAM-VASE(-) in relation to the capacity for spatial learning and memory as assessed by a Morris water maze task. The results showed that the levels of both NCAM-VASE(+) and NCAM-VASE(-) were increased significantly in dorsal but not ventral hippocampus in aged SAMP8 mice. The mean latencies to find the hidden platform of the learning task on the last day were positively correlated with the levels of NCAM-VASE(+) in the dorsal hippocampus of SAMP8, which reveals that the mice with high levels of NCAM-VASE(+) have poor learning performances. These results suggest that the up-regulation of NCAM-VASE(+) could be involved in the impairments of spatial learning and memory.

Aging↗

Effects of six weeks of chronic ethanol administration on the behavioral outcome of rats after lateral fluid percussion brain injury.

This study examined the effects of 6 weeks of chronic ethanol administration on the behavioral outcome in rats after lateral fluid percussion (FP) brain injury. Rats were given either an ethanol liquid diet (ethanol diet-groups) or a pair-fed isocaloric sucrose control diet (control diet groups) for 6 weeks. After 6 weeks, the ethanol diet was discontinued for the ethanol diet rats and they were then given the control sucrose diet for 2 days. During those 2 days, the rats were trained to perform a beam-walking task and subjected to either lateral FP brain injury of low to moderate severity (1.8 atm) or to sham operation. In both the control diet and the ethanol diet groups, lateral FP brain injury caused beam-walking impairment on days 1 and 2 and spatial learning disability on days 7 and 8 after brain injury. There were no significant differences in beam-walking performance and spatial learning disability between brain injured animals from the control and ethanol diet groups. However, a trend towards greater behavioral deficits was observed in brain injured animals in the ethanol diet group. Histologic analysis of both diet groups after behavioral assessment revealed comparable ipsilateral cortical damage and observable CA3 neuronal loss in the ipsilateral hippocampus. These results only suggest that chronic ethanol administration, longer than six weeks of administration, may worsen behavioral outcome following lateral FP brain injury. For more significant behavioral and/or morphological change to occur, we would suggest that the duration of chronic ethanol administration must be increased.

Animals↗

Colostrinin, a polypeptide isolated from early milk, facilitates learning and memory in rats.

Initial observations in humans indicated that colostrinin, a complex of polypeptides derived from the colostrum of sheep, facilitates cognitive functioning in patients with Alzheimer's disease. Its effect on learning and memory in more controlled settings as well as the specificity of these effects were, however, unknown. The present experiments evaluated the effects of colostrinin on spatial learning (Morris water maze) and incidental memory (habituation test) in male Wistar rats of two age groups. Colostrinin, at a dose of 4 microg/rat IP, facilitated acquisition of spatial learning of 13- (aged) but not 3-month-old (young) rats. At the same dose, it improved incidental learning in aged rats, while the dose of 20 microg/rat attenuated it. Colostrinin did not change locomotor activity of rats. Taken together, the present findings indicate that colostrinin may have some beneficial effects on cognitive functioning, particularly in aged subjects. Given the fact that colostrum is the first nutritive agent of neonates, it might be speculated that its peptides may facilitate the early postnatal development of the cerebral neurons and their plasticity.

Aging↗

Learning impairment produced in rats by the cannabinoid agonist HU 210 in a water-maze task.

To ascertain whether the cannabinoid agonist HU 210 (25, 50, or 100 microg/kg, IP) influences rat spatial learning, water-maze performance was examined in the place (hidden platform)--and cue (visible platform)--versions of the Morris water maze. In addition, other unlearned behaviors were examined, namely, vocalization and wall hugging during the place task, and motor abilities during a motor test battery. The results obtained show that HU 210 at 50 or 100 microg/kg (once daily for 4 days, 60 min before a daily session) impaired learning in the place version but not in the cue one; wall hugging and enhanced vocalization were also displayed by the animals in the fourth session. Motor activity was compromised by the same treatment schedule. When the drug was discontinued, the effects produced by HU 210 at 50 microg/kg reversed in 3 days, while disruption of acquisition and vocalization caused by HU 210 at 100 microg/kg remained after 7 days' abstinence. Discussion centers on the possible specific cognitive mechanisms affected by the drug and on aspecific factors (i.e., anxiety-like state), which may contribute to the impairment of spatial learning.

Animals↗

Behavioral effects of MK-801 in the rat.

Several experiments were conducted to study the effects of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801, on learning and memory in the rat. Rats displayed impaired performance on several sensorimotor tests and appeared grossly intoxicated when treated IP with 0.2 mg/kg MK-801, but not when treated with lower doses (0.05 or 0.1 mg/kg). Postacquisition performance on two spatial learning tasks involving working memory protocols (reinforced alternation and radial arm maze) was impaired by MK-801 at intoxicating doses (greater than or equal to 0.2 mg/kg) but not at lower doses (0.05 or 0.1 mg/kg). Using a position habit reversal task, we found that rats could learn to reverse a position habit while under the influence of a nonintoxicating dose of MK-801 (0.1 mg/kg), but when tested on the following day performed as if they did not recall what they had learned. Thus, acute administration of a nonintoxicating dose of MK-801 disrupts the retention of new information learned under the influence of the drug but does not interfere with the performance of tasks that are well learned before the drug is administered. Whether the performance deficits on the spatial learning tasks observed only following intoxicating doses of MK-801 reflect an effect on memory is not clear.

Animals↗

Alpha7 nicotinic receptor subunits are not necessary for hippocampal-dependent learning or sensorimotor gating: a behavioral characterization of Acra7-deficient mice.

The alpha7 nicotinic acetylcholine receptor (nAChR) subunit is abundantly expressed in the hippocampus and contributes to hippocampal cholinergic synaptic transmission suggesting that it may contribute to learning and memory. There is also evidence for an association between levels of alpha7 nAChR and in sensorimotor gating impairments. To examine the role of alpha7 nAChRs in learning and memory and sensorimotor gating, Acra7 homozygous mutant mice and their wild-type littermates were tested in a Pavlovian conditioned fear test, for spatial learning in the Morris water task, and in the prepulse inhibition paradigm. Exploratory activity, motor coordination, and startle habituation were also evaluated. Acra7 mutant mice displayed the same levels of contextual and auditory-cue condition fear as wild-type mice. Similarly, there were no differences in spatial learning performance between mutant and wild-type mice. Finally, Acra7 mutant and wild-type mice displayed similar levels of prepulse inhibition. Other behavioral responses in Acra7 mutant mice were also normal, except for an anxiety-related behavior in the open-field test. The results of this study show that the absence of alpha7 nAChRs has little impact on normal, base-line behavioral responses. Future studies will examine the contribution of alpha7 nAChR to the enhancement of learning and sensorimotor gating following nicotine treatments.

Animals↗

Effects of sex on object recognition and spatial navigation in humans.

Human tests designed to mirror rodent tests of object recognition and spatial navigation were administered to adult cognitively healthy humans. Facial recognition was also assessed. There was no sex difference in facial recognition, consistent with earlier studies. In the object recognition test, the test-retest NINL total scores during the same visit were highly correlated, comparable to the test-retest correlations obtained in the established facial recognition test. There were no effects of sex on object recognition. However, in the spatial navigation test, there were effects of sex on spatial learning and memory during the session with the hidden, but not visible, target. These tests might be useful to compare assessments of object recognition and spatial learning and memory in humans and animal models.

Adult↗

Selection for body weight induces differences in exploratory behavior and learning in mice.

Mice that were selected for over 108 generations for body weight at the postnatal (PN) day 21 were examined in the open field (OF) test and in the Lashley maze (LM) for their exploratory behavior and spatial learning. Light (L), heavy (C) and control (K) lines of mice in three age groups: PN-21, PN-56 and PN-90, were tested once in the OF and three times in the LM. During the session in the OF the L mice displayed a steady increase of behavioral activity (sum of locomotion and rearing, climbing, sniffing, and grooming acts), whereas mice C and K habituated in the last stage. During entire session in the OF activity of the L mice was lower than that of the C and K mice. The L mice displayed high defecation/urination scores. In the learning task the L mice performed worse than the C and K mice. In conclusion, behavior of the L line was different from that of the two other lines: they showed higher anxiety and poorer spatial learning.

Age Factors↗

Embryonic and postnatal injections of bromodeoxyuridine produce age-dependent morphological and behavioral abnormalities.

The mitotic marker 5-bromodeoxyuridine (BrdU) was injected twice daily (60 mg/kg) into pregnant hooded rats on one of embryonic days (E) 11, 12, 13, 15, 17, or 21, or into rat pups on postnatal day (P) 10. The principal findings were the following: (1) BrdU exposure on E11 produces profound effects on body morphology, and animals must be fed a special diet because of chronic tooth abnormalities; (2) BrdU exposure at E17 or earlier produces a change in coat spotting pattern, the precise pattern varying with age; (3) BrdU exposure on E15 or earlier produces a reduction in both brain and body weight; (4) BrdU exposure on E17 or earlier reduces cortical thickness; (5) BrdU exposure on E11-E13 and at P10 reduces cerebellar size relative to cerebral size; (6) spatial learning is significantly affected after injections of BrdU at E11-E17, but the largest effect is on E17; (7) the deficit in spatial learning may be related in part to a reduction in visual acuity; and (8) skilled forelimb ability is most disrupted after BrdU exposure at E15 but is also impaired after injections on E13 or earlier. BrdU thus has teratological effects on body, brain, and behavior that vary with the developmental age of the fetus or infant.

Abnormalities, Drug-Induced↗

Effects of tianeptine on spontaneous alternation, simple and concurrent spatial discrimination learning and on alcohol-induced alternation deficits in mice.

The effects of systemic administration of tianeptine, a new psychotropic agent with antidepressant properties, were investigated on spontaneous alternation behavior, and on simple and concurrent spatial discrimination, in normal mice of the BALB/c strain. Tianeptine increased rates of spontaneous T-maze alternation, facilitated retention of a T-maze left-right discrimination, and speeded up acquisition of concurrent discrimination in a radial maze. These effects were consistent across successive experiments with a dose of 10mg/kg; lower doses (2.5 and 5.0mg/kg) had less or no effect depending on the task. These results, together with theoretical considerations, led us to investigate the effect of tianeptine on the sequential-specific alternation deficit induced by long-term ethanol administration in the same strain of mice. Results showed that, at the dose of 10mg/kg, the drug completely alleviated the alcohol-induced deficit. Unlike tianeptine, fluoxetine impaired discrimination performance in the radial maze. These data are discussed in light of the effects of tianeptine on serotonergic transmission and of the role of serotonin and acetylcholine in learning and memory processes.

Journal Article↗

Neonatal hippocampal damage in rats: long-term spatial memory deficits and associations with magnitude of hippocampal damage.

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20-25, PN50-55, or PN90-95, separate groups of rats were tested in a Morris water maze on a visible "cue" condition (visible platform in a fixed location of the maze), a spatial "place" condition (submerged platform in a fixed location), or a no-contingency "random" condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20-25) or as adults (PN50-55 and PN90-95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm.

Age Factors↗