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Hippocampal 72-kDa heat shock protein expression varies according to mice learning performance independently from chronic exposure to stress.

The possibility that the inducible 72-kDa heat shock protein (hsp72) is involved in learning-related plasticity mechanisms was investigated in two inbred strains of mice that show spontaneous differences in spatial learning performance as well as an opposite reactivity to stress. Induction of hsp72 after radial maze training was measured by immunoblotting in the hippocampus of C57BL/6 (C57) and DBA/2 (DBA) inbred mice exposed or nonexposed to chronic acoustic stress. In agreement with previous studies, inter-strain differences in radial maze performance were found in nonstressed mice with C57 mice showing the higher scores. Chronic acoustic stress, however, impaired performance in the high-learner C57 strain and improved performance in the low-learner DBA strain. Western blot analysis revealed that post-training expression of hsp72 was low in the condition each strain was showing the higher-performance (nonstressed C57 and stressed DBA) and high in the condition each strain was showing the lower performance (stressed C57 and nonstressed DBA). These findings indicate that expression of hsp72 in the hippocampus varies as a function of the learning performance independently from exposure to chronic acoustic stress.

Acoustic Stimulation↗

Reduced hippocampal in vitro CA1 long-term potentiation in rat offsprings with increased circulating corticosterone during neonatal life.

A moderate increase in plasma level of corticosterone was induced in dams by adding the hormone (200 micrograms/ml) to the drinking water from the day after delivery to weaning. This procedure produces a parallel increase in plasma levels of the hormone in the pups (from 0.7 +/- 0.1 to 1.2 +/- 0.2 micrograms/100 ml) at 10 days of lactation. A significant (P < 0.01) reduction in the magnitude of the long-term potentiation (LTP) of the CA1 population spike occurred in hippocampal slices obtained from 30-45 day old male corticosterone-nursed rats with respect to controls, while no significant difference occurred in the magnitude of the basal CA1 evoked extracellular somatic field potentials with respect to controls. The results demonstrate that a moderate increase in plasma corticosterone during neonatal life, obtained through maternal milk, has long-lasting effects on the hippocampal CA1 synaptic plasticity. In addition, these results together with our previous findings [Catalani, A. et al., Brain Res., 624 (1993) 209-215], demonstrating that 30 day old corticosterone-nursed offsprings perform better than controls in the place learning version of the Morris water maze, show no relationships between in vitro CA1 LTP induction and spatial learning in agreement with literature data.

Animals↗

The distribution of nitric oxide synthase-I and NADPH-diaphorase containing neurons in the cerebral cortex of different strains of mice and its association with learning and memory.

We investigated the distribution of nitric oxide synthase-I (NOS-I) containing neurons within the neocortex of inbred mice belonging to the Balb/c, NMRI and DBA/2 strains which differ in learning and memory performance. The NOS-I positive neurons were detected immunohistochemically with antibodies against NOS-I and enzyme histochemically using their NADPH-diaphorase (NADPH-d) activity. The qualitative and quantitative evaluation of cortical NADPH-d and NOS-I containing neurons revealed that more than 95% of these cells contained both enzymes. Therefore, we combined the NADPH-d with the WFA-staining to evaluate and parcellate at one section. The specific differences in learning and memory tasks of the three mouse strains have been tested in previous studies. Our investigation test the hypothesis that differences in various aspects of eight-arm radial maze learning are associated with differences in the density of NOS-I positive neurons in cytoarchitectonically and functionally identified cortical areas. We found an increased density of NADPH-d neurons within the whole neocortex in the DBA/2 strain, which reached a lower learning score than the Balb/c and NMRI strains. Significantly higher densities of NADPH-d neurons appeared in the areas of the gustatory cortex, the piriform cortex, the entorhinal cortex and in area 1 of the temporal cortex in DBA/2 mice. A negative correlation exists between the learning scores and the number of NADPH-d positive neurons. If NOS-I activity influences spatial learning as determined in the eight-arm radial maze, the areas with strongly elevated NADPH-d positive neurons may demarcate task-related cortical areas affected in mice with a reduced learning capacity.

Animals↗

Testing the importance of the caudal retrosplenial cortex for spatial memory in rats.

Although there is evidence to suggest that the retrosplenial cortex is involved in spatial learning and memory, many lesion studies have left the more caudal part of this region intact so leaving its role untested. In the first experiment, rats with neurotoxic lesions of the caudal half of the retrosplenial cortex (RspC1) were tested on a reference memory task in the water-maze. The RspC1 animals were impaired on initial acquisition although they performed normally on a subsequent probe test. The second experiment looked at working memory in the radial-arm maze and water-maze. Animals with caudal retrosplenial lesions (RspC2) were unimpaired on the acquisition stage of the radial-arm maze task but were impaired when the task involved maze rotation to control for the possible use of intramaze cues. The RspC2 animals also took longer to learn the platform position on a delayed matching-to-place task in the water-maze. These results show a subtle impairment in spatial memory performance that is not as severe as that seen when more complete lesions of the retrosplenial cortex are made.

Animals↗

Metabotropic glutamate receptors in spatial and nonspatial learning in rats studied by means of agonist and antagonist application.

We examined the effects of both the metabotropic glutamate receptor (mGluR) antagonist MCPG and the agonist tADA in two behavioral paradigms in rats: (1) brightness discrimination and (2) spatial alternation. Compounds were applied intracerebroventricularly at different times, either 30 min prior to training or immediately after training, and rats were tested for retention 24 hr later in the same paradigms. Both MCPG and tADA caused amnesia in the spatial alternation test, when applied pretraining, but no effect was obtained in the brightness discrimination paradigm. Drug-induced amnesia was shown not to be attributable to state-dependent effects of MCPG or tADA. Moreover, the memory inhibiting effect of MCPG was dose dependent, with a low dose (20 mM/5 ml) having no effect on learning and memory and a 10 times higher concentration (200 mM/5 ml) causing complete amnesia. Application of both saline and MCPG immediately post-training prevented memory formation, which may be attributable to an interference by the injection procedure with the process of memory formation. The mGluR agonist tADA, however, facilitated memory formation in the spatial alternation task, when injected immediately after training. Post-training application of the compounds had no effect on retention in the brightness discrimination task. On the basis of these data we conclude that (1) mGluRs are of particular importance for spatial learning and play no role in visual discrimination; (2) both the block and the activation of mGluRs inhibit spatial learning, suggesting that saturated activation prevents further modulation of mGluRs, which may be required during learning or memory formation; and (3) mGluR agonist tADA may be memory facilitating when applied after training, thus enhancing the establishment of the memory trace.

Animals↗

Learning deficits in congenitally hydrocephalic rats and prevention by early shunt treatment.

Shunt surgery is the usual treatment for infantile hydrocephalus; however, the extent to which it avoids subsequent neurological deficits is uncertain. The effect of early-onset hydrocephalus was tested in H-Tx rats using the Morris water maze. Spatial learning was assessed at 21 days after birth in control (n = 18), hydrocephalic (n = 18) and hydrocephalic rats shunt-treated at 4-5 (n = 7) or at 10-12 days of life (n = 13). The time taken to find a hidden platform was measured in five trials on 2 consecutive days and the data analyzed by one- and two-way ANOVA and t-tests. The latencies of the control rats decreased significantly between the first and second trial on the 1st day, and learning was retained until the 2nd day. The hydrocephalic group had longer latencies than controls on both days, with no significant decrease between any trials. Performance was not significantly different between the two shunt groups. Overall, the shunted rats had latencies which were not significantly different from controls but were significantly lower than hydrocephalics. Despite this, the shunted rats did not perform as well as the controls. It is concluded that, although shunt treatment improved learning, some effects of early-onset hydrocephalus may not be reversible and/or a longer recovery time is required.

Animals↗

The seasonal pattern of cell proliferation and neuron number in the dentate gyrus of wild adult eastern grey squirrels.

The dentate gyrus is one of two areas in the mammalian brain that produces neurons in adulthood. Neurogenesis (proliferation, survival, and differentiation of new neurons) is regulated by experience, and increased neurogenesis appears to be correlated with improved spatial learning in mammals and birds. We tested the hypothesis that in long-lived mammals that scatter-hoard food, seasonal variations in spatial memory processing (i.e. increased processing during caching season in the autumn) might correlate with changes in neurogenesis and neuron number in the granule cell layer of the dentate gyrus (gcl DG). We investigated the rate of cell proliferation and the total number of neurons in the granule cell layer of wild adult eastern grey squirrels (Sciurus carolinensis) at three different times of the year (October, January and June). We found no seasonal differences in cell proliferation rate or in total neuron number in the granule cell layer. Our findings are in agreement with those of previous studies in laboratory mice and rats, and in free-ranging, food-caching, black-capped chickadees, as well as with current hypotheses regarding the relationship between neurogenesis and learning. Our results, however, are also in agreement with the hypothesis that neurogenesis in the dentate gyrus represents a maintenance system that may be regulated by environmental factors, and that changes in total neuron number previously reported in rodents represent developmental changes rather than adult plasticity. The patterns observed in mature wild rodents, such as free-ranging squirrels, may represent more accurately the extent of hippocampal plasticity in adult mammals.

Animals↗

Impairment of olfactory, auditory, and spatial serial reversal learning in rats recovered from pyrithiamine-induced thiamine deficiency.

Rats that had recovered from pyrithiamine-induced thiamine deficiency (PTD) were compared with controls for spatial, auditory, and olfactory serial reversal learning (SRL); spatial matching to sample (MTS); auditory go-no-go discrimination; and open-field exploration. PTD rats made more errors reaching criterion for SRL in all modalities but showed normal transfer effects between problems. PTD rats were also impaired in learning the go-no-go and MTS tasks and showed consistent alterations in exploratory activity. It is argued that the PTD rat, like human Korsakoff patients, have impairments of learning and memory (but spared capacity for reference memory) that extend across sensory modalities. Postmortem analyses showed normal indices of cortical cholinergic, noradrenergic, dopaminergic, and serotonergic function and consistent bilateral lesions of the thalamus, which were centered on the internal medullary lamina, and the medial mammillary nucleus.

Animals↗

Norepinephrine and neural plasticity: the effects of xylamine on experience-induced changes in brain weight, memory, and behavior.

The hypothesis that norepinephrine (NE) is critically involved in neural plasticity was tested by administering xylamine, (N-2-chloroethyl-2-methylbenzylamine, 50 mg/kg ip) a noradrenergic neurotoxin, to young rats prior to maze training or environmentally enriched housing. In saline-treated rats, exposure to enriched conditions significantly increased the weight of occipital, dorsal, and ventral cortices and the remaining brain compared to individually housed rats. In xylamine-treated rats, only the weight of dorsal cortex increased with exposure to enriched conditions. Maze training increased the weight of dorsal and ventral cortices of saline-treated animals compared to rats without training. However, maze training did not increase brain weights of xylamine-treated rats compared to those of xylamine-treated controls. Xylamine treatment did not reduce brain weights of individually housed animals. Behavior was assessed with spatial learning on a holeboard maze and with investigatory measures of locomotion and hole investigation in a multicompartmented arena. Spatial working memory on the holeboard maze was not impaired by xylamine treatment. Arena measures were affected mainly by the housing condition, testing condition, and strain of rat (Long-Evans vs Wistar), with only subtle changes in behavior induced by NE depletion. Thus, an intact NE projection was required for environmentally dependent changes in cortical morphology. In contrast, measures of memory and investigatory behavior were not dependent on an intact noradrenergic projection. These results support the hypothesis that NE facilitates selective neuronal changes, and that the impairment in cortical weight gain does not results from a general impairment of growth or a secondary response to reduced exploration and activity.

Animals↗

Behavioral effects of non-NMDA glutamate receptor antagonists.

Non-NMDA receptor antagonists decrease motor activity in some situations, alter the sleep-wake cycle, possess anticonvulsant and neuroprotectant actions, and appear to impair some learning tasks but not others. NMDA receptor antagonists affect these same functions but often in different and even opposite ways. NMDA receptor antagonists impair many different spatial learning tasks, including the Morris water maze, the Olton radial maze, and the hole-board task. Non-NMDA receptor antagonists are either ineffective in these spatial tasks or have not yet been evaluated. However, non-NMDA receptor antagonists may impair associative processes required in a bar-press response and in discrimination learning. Further research is needed in the context of comparing NMDA as opposed to non-NMDA receptor antagonists within the same paradigm.

Animals↗

Positron emission tomographic scan investigations of Huntington's disease: cerebral metabolic correlates of cognitive function.

Fifteen drug-free patients with early to mid-stage Huntington's disease (HD) were evaluated with positron emission tomographic (PET) scans of 18F-2-fluoro-2-deoxy-D-glucose uptake and quantitative measures of neurological function, learning, memory, and general intelligence. In comparison with a group of normal volunteers, the HD patients showed lower metabolism in both caudate (p less than 0.001) and putamen (p less than 0.001) on PET scans. A significant and positive relationship was found between neuropsychological measures of verbal learning and memory and caudate metabolism in the patient group but not in the normal group. Visual-spatial learning did not reflect a similar pattern, but performance intelligence quotient was positively related to both caudate and putamen metabolism in the HD group. Vocabulary level was unrelated to either brain structure. Discussion focuses on these and other observed brain-behavior relationships and on the implications of these findings for general behaviors such as those involved in coping and adaptation.

Adult↗

Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis.

Transgenic mice expressing mutant forms of both amyloid-beta (Abeta) precursor protein (APP) and presenilin (PS) 2 develop severe brain amyloidosis and cognitive deficits, two pathological hallmarks of Alzheimer's disease (AD). One-year-old APP/PS2 mice with high brain levels of Abeta and abundant Abeta plaques show disturbances in spatial learning and memory. Treatment of these deteriorated mice with a systemic slow-release formulation of insulin-like growth factor I (IGF-I) significantly ameliorated AD-like disturbances. Thus, IGF-I enhanced cognitive performance, decreased brain Abeta load, increased the levels of synaptic proteins, and reduced astrogliosis associated to Abeta plaques. The beneficial effects of IGF-I were associated to a significant increase in brain Abeta complexed to protein carriers such as albumin, apolipoprotein J or transthyretin. Since levels of APP were not modified after IGF-I therapy, and in vitro data showed that IGF-I increases the transport of Abeta/carrier protein complexes through the choroid plexus barrier, it seems that IGF-I favors elimination of Abeta from the brain, supporting a therapeutic use of this growth factor in AD.

Amyloid beta-Peptides↗

An animal model of generalized nonconvulsive status epilepticus: immediate characteristics and long-term effects.

Absence seizures are traditionally believed to have no significant long-term neurological consequences, but few basic scientific studies have examined the effects of absence seizures on neuronal function, especially regarding absence status epilepticus. We developed a model of generalized nonconvulsive status epilepticus (GNCSE) in rats to study behavioral, functional, and histological effects of GNCSE. Using repetitive timed injections of low-dose pentylenetetrazol (PTZ), a state of prolonged behavioral arrest and immobility associated with frequent generalized spike-wave discharges on EEG could be induced for hours, consistent with GNCSE. GNCSE occurred reproducibly in adult rats, but surprisingly not in juvenile rats or adult mice. There was no evidence of pathological damage following GNCSE using Fluoro-Jade B and Cresyl Violet histological methods. Although a transient, subtle deficit in place learning occurred in PTZ-treated rats, there were no long-term behavioral effects of GNCSE on spatial learning or sensorimotor function. However, 1 week after a single episode of GNCSE, there was an increase in absence seizures in response to a repeat dose of PTZ compared to controls. These results indicate that an animal model of GNCSE can be generated and that even in the absence of overt neuronal damage, GNCSE may produce functional changes in neurons that alter electrical excitability of neural circuits.

Age Factors↗

Repeated treatment with cholecystokinin octapeptide improves maze performance in aged Fischer 344 rats.

Previous studies have shown that sulfated cholecystokinin octapeptide (CCK-8S) can improve learning in adult rodents when administered systemically or into the central nucleus of amygdala. Here we analyzed the effect of repeated intraperitoneal (i.p.) injection of CCK-8S on the performance of 26-month-old Fischer 344 rats in different versions of the Morris water maze and in a rota-rod test of motor coordination. Old rats were injected daily with different doses of CCK-8S (0.32 to 8.0 microg/kg; IP) 10 min before the behavioral tests. Control groups included vehicle-injected old and adult (3-month-old) F 344 rats. To control for a possible development of tolerance to the behavioral effects of repeated CCK-8S administration, groups of aged rats were included which were subjected to an acute rather than a repeated CCK injection schedule. The repeated administration of CCK-8S did not influence the performance of the old rats in the hidden-platform version of the maze. In addition, the acute treatment with CCK-8S failed to modify navigation performance in this task, suggesting that drug-tolerance may not account for the lack of behavioral effects seen after repeated CCK-8S injection. During the "probe trial", the percentage of animals per group, which swam exactly across the former platform site, was markedly increased in aged rats treated repeatedly with 1.6 microg/kg CCK-8S. This might be indicative of improved retention of the prior platform location and/or a higher resistance of the learned escape response to extinction. The specificity of the effect of CCK-8S on processes related to spatial learning and memory is supported by the lack of effect on motor performance.

Age Factors↗

Sex and seasonal differences in the rate of cell proliferation in the dentate gyrus of adult wild meadow voles.

In order to study the neurobiological basis of seasonal changes in hippocampal structure and function, the rate of cell proliferation was examined in male and female wild meadow voles captured during different seasons. We found that the number of [3H]thymidine-labeled cells varied across the seasons and across sex in the meadow vole. Non-breeding female meadow voles had a higher rate of cell proliferation and cell death than males captured during either season or breeding females. These seasonal changes in the female meadow vole were associated with both fluctuating levels of adrenal steroids and gonadal steroids. Estradiol level was highly correlated with both the number of [3H]thymidine-labeled cells and the number of pyknotic cells in female meadow voles, with high levels of estradiol being associated with low levels of cell proliferation and cell death. Corticosterone level was associated with the number of [3H]thymidine-labeled cells in the hilus of female meadow voles. This seasonal change in the number of [3H]thymidine-labeled cells was also related to the overall volume of the hippocampus. At variance with past literature, there was no statistically significant sex difference favoring males in hippocampal volume, although the means were in the predicted direction. In male meadow voles, the number of pyknotic cells was related to testosterone level, with high levels of testosterone being associated with greater levels of cell death in the granular cell layer. There was also a suggestion that the number of [3H]thymidine-labeled cells in the hilus varied seasonally in males, with higher rates of cell proliferation during the breeding season than during the non-breeding season. In summary, we found that there were large fluctuations across the season in the rate of cell proliferation in the dentate gyrus of adult female meadow voles. Females captured during the non-breeding season had higher rates of cell proliferation in the granule cell layer than females captured during the breeding season. This seasonal fluctuation was related to hormone levels, with high levels of corticosterone and estradiol being related to lower levels of cell proliferation. These seasonal changes in cell proliferation may be related to known changes in spatial learning in the meadow vole and provide insights into changes in the hippocampus that occur in other species, including primates.

Animals↗

Neonatal binge ethanol exposure using intubation: timing and dose effects on place learning.

Neonatal rats were given ethanol using an acute intubation procedure that resulted in daily binge-like exposure with minimal effects on somatic growth. Acquisition of place learning in the Morris water maze was evaluated on postnatal days (PD) 26-31. In Experiment 1, a total of 5.25 g/kg/day of ethanol was administered in two daily intubations on PD 4-6, PD 7-9, or PD 4-9, producing mean peak BACs of 265 mg/dL. Place learning acquisition deficits in a 114-cm-diameter tank were found for the PD 4-9 and PD 7-9 groups, but not the PD 4-6 group. In Experiment 2, either 4.5 or 5.25 g/kg/day of ethanol was administered on PD 7-9 and place learning was tested in a 171-cm-diameter tank. Significant acquisition deficits resulted from the higher dose, and probe trial search patterns for both ethanol groups were significantly less localized than controls. In Experiment 3, no significant effects of either PD 7-9 dose were found on a visible platform task. These findings reveal selective place learning deficits in this intubation model of neonatal binge exposure, and confirm a temporal window of vulnerability to spatial learning deficits during the second neonatal week.

Animals↗

Deficient plasticity in the primary visual cortex of alpha-calcium/calmodulin-dependent protein kinase II mutant mice.

The recent characterization of plasticity in the mouse visual cortex permits the use of mutant mice to investigate the cellular mechanisms underlying activity-dependent development. As calcium-dependent signaling pathways have been implicated in neuronal plasticity, we examined visual cortical plasticity in mice lacking the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha CaMKII). In wild-type mice, brief occlusion of vision in one eye during a critical period reduces responses in the visual cortex. In half of the alpha CaMKII-deficient mice, visual cortical responses developed normally, but visual cortical plasticity was greatly diminished. After intensive training, spatial learning in the Morris water maze was severely impaired in a similar fraction of mutant animals. These data indicate that loss of alpha CaMKII results in a severe but variable defect in neuronal plasticity.

Animals↗

Spatial memory deficits in patients with chronic bilateral vestibular failure.

The role of the vestibular system for navigation and spatial memory has been demonstrated in animals but not in humans. Vestibular signals are necessary for location-specific "place cell" activity in the hippocampus which provides a putative neural substrate for the spatial representation involved in navigation. To investigate the spatial memory in patients with bilateral vestibular failure due to NF2 with bilateral neurectomy, a virtual variant (on a PC) of the Morris water task adapted to humans was used. Significant spatial learning and memory deficits were shown in 12 patients as compared to 10 healthy controls. These data suggest that functional hippocampal deficits manifest due to a chronic lack of vestibular input in these patients. These deficits can even be demonstrated with the subjects stationary, i.e., without any actual vestibular or somatosensory stimulation.

Adult↗