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PubMed2005

Effects of the rd1 mutation and host strain on hippocampal learning in mice.

Many of the inbred mouse strains commonly used in biomedical research are homozygous for the rd1 mutation of the Pde6b gene, which causes retinal degeneration. To dissociate the behavioural effects of rd1 homozygosity from those of the genetic background of the host strain in the most widely used paradigms for evaluating the cognitive abilities of mice, two rd1 homozygous strains (C3H/HeJ and CBA/J) were compared with two Pde6b wild-type strains, each possessing a genetic background identical (C3A.BLiA-Pde6b+/J) or very similar (CBA/CaJ) to that of its rd1 homozygous relative. In the fear conditioning procedure, the presence of the rd1 mutation had no effect on performance at any stage, as the superior contextual learning of the CBA/J and CBA/CaJ strains could be explained by genetic background effects alone. In the Morris water maze, only the Pde6b wild-type C3A.BLiA-Pde6b+/J and CBA/CaJ strains were able to demonstrate spatial learning. The study thus demonstrates how retinal degeneration and genetic background have different effects in these two tests of hippocampus-dependent learning and memory.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1988

Fetal hippocampal cell suspensions ameliorate behavioral effects of intradentate colchicine in the rat.

Colchicine, a neurotoxin that preferentially destroys dentate gyrus granule cells and mossy fibers, was injected into the hippocampus of adult rats. Three weeks later, the rats were tested for colchicine-induced hypermotility after which they received fetal hippocampal explants. Locomotor activity was retested three weeks later, after which the rats were trained over a period of four weeks on a food-reinforced, spatial, working memory task in an 8-arm radial maze. Fetal hippocampal explants were found to attenuate significantly the colchicine-induced hypermotility and spatial learning deficits. Histological observations showed the presence of surviving hippocampal explants in both the lesioned and the control rat brains, suggesting that the presence of viable implants facilitates the recovery of behavioral function in rats with spatial memory deficits.

Animals↗
PubMed1989

Synaptic plasticity and learning. II: Do different kinds of plasticity underlie different kinds of learning?

This paper discusses certain issues connected with the question of whether synaptic plasticity is involved in information storage by the brain. We begin by contrasting two well documented types of synaptic plasticity--activity-dependent modulation of presynaptic facilitation ("Kandel synapses") and NMDA receptor triggered alterations in excitatory amino acid transmission ("Hebb synapses"). We then propose that, embedded-into appropriate circuitry, these different forms of plasticity might underlie different kinds of learning. In partial support of this idea, we show that, in freely moving rats, intrahippocampal microinfusion of the NMDA-receptor antagonist D,L-AP5 causes a dose-dependent impairment of a type of spatial learning known to be sensitive to disruption by hippocampal lesions (water-maze place-navigation). In a second experiment, the same drug infusion protocol is shown to cause a blockade of hippocampal long-term potentiation in vivo across a comparable dose range. Finally, third, autoradiographic experiments indicate that diffusion of the drug was largely restricted to the hippocampus. Together, these results (1) suggest that blockade of hippocampal NMDA receptors, under conditions which leave baseline synaptic transmission relatively unaffected, blocks a type of learning with which the vertebrate hippocampus has been implicated on the basis of neuropsychological work; and (2) supports Abrams and Kandel's Trends Neurosci. 11 (1988) recent proposal that there may be several logically distinct forms of synaptic plasticity.

Animals↗
PubMed1999

Lesions of the medial or lateral perforant path have different effects on hippocampal contributions to place learning and on fear conditioning to context.

The axons of the neurons in the medial and lateral components of the entorhinal cortex (MEC and LEC) form the medial and lateral perforant paths (MPP and LPP) which represent the major source of cortical input to the hippocampus. Anatomical, physiological, and pharmacological studies have shown that MPP and LPP are distinct. Unfortunately, assessment of the functional significance of damage to either of these pathways has not used tasks known to be sensitive to hippocampal function in the rodent. In this study, we performed dissociated lesions of MPP and LPP using a combined physiological and anatomical method. Rats with lesions of either the MPP or the LPP were tested on place learning in the water task and on a discriminative fear conditioning to context task. The results indicated that the MPP, but not LPP, lesions resulted in impaired place learning. The context discrimination data revealed an amygdala-like, reduced fear effect of MPP lesions and an enhanced discriminative fear conditioning to context effect of LPP lesions. Consistent with a two-stage model of spatial learning proposed by Buzsaki (Buzsaki G. Two-stage model of memory trace formation: a role for 'noisy' brain states. Neuroscience 1989;31(3):551-570), the impairment in the water task can be interpreted as reflecting the higher efficiency of the MPP synapses in activating hippocampal neurons. The context discrimination results can be explained by either a dissociation of sensory information that reaches the MEC and LEC, or alternatively, by a dissociation between the limbic nature of the MEC and the sensory nature of the LEC.

Animals↗
PubMed2005

Spatial navigation impairment in mice lacking cerebellar LTD: a motor adaptation deficit?

L7-PKCI transgenic mice, which lack parallel fiber-Purkinje cell long-term depression (LTD), were tested with two different mazes to dissociate the relative importance of declarative and procedural components of spatial navigation. We show that L7-PKCI mice are deficient in acquisition of an adapted goal-oriented behavior, part of the procedural component of the task. This supports the hypothesis that cerebellar LTD may subserve a general sensorimotor adaptation process shared by motor and spatial learning functions.

Adaptation, Physiological↗
PubMed2006

Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice.

Cholinergic neurons elaborate a hemicholinium-3 (HC-3) sensitive choline transporter (CHT) that mediates presynaptic, high-affinity choline uptake (HACU) in support of acetylcholine (ACh) synthesis and release. Homozygous deletion of CHT (-/-) is lethal shortly after birth (Ferguson et al. 2004), consistent with CHT as an essential component of cholinergic signaling, but precluding functional analyses of CHT contributions in adult animals. In contrast, CHT+/- mice are viable, fertile and display normal levels of synaptosomal HACU, yet demonstrate reduced CHT protein and increased sensitivity to HC-3, suggestive of underlying cholinergic hypofunction. We find that CHT+/- mice are equivalent to CHT+/+ siblings on measures of motor co-ordination (rotarod), general activity (open field), anxiety (elevated plus maze, light/dark paradigms) and spatial learning and memory (Morris water maze). However, CHT+/- mice display impaired performance as a result of physical challenge in the treadmill paradigm, as well as reduced sensitivity to challenge with the muscarinic receptor antagonist scopolamine in the open field paradigm. These behavioral alterations are accompanied by significantly reduced brain ACh levels, elevated choline levels and brain region-specific decreased expression of M1 and M2 muscarinic acetylcholine receptors. Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity.

Acetylcholine↗
PubMed1995

Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice.

BACKGROUND: Cognitive deterioration is a characteristic symptom of Alzheimer's disease. This deterioration is notably associated with structural changes and subsequent cell death which occur, primarily, in acetylcholine-producing neurons, progressively damaging cholinergic neurotransmission. We have reported previously that excess acetylcholinesterase (AChE) alters structural features of neuromuscular junctions in transgenic Xenopus tadpoles. However, the potential of cholinergic imbalance to induce progressive decline of memory and learning in mammals has not been explored. RESULTS: To approach the molecular mechanisms underlying the progressive memory deficiencies associated with impaired cholinergic neurotransmission, we created transgenic mice that express human AChE in brain neurons. With enzyme levels up to two-fold higher than in control mice, transgenic mice displayed an age-independent resistance to the hypothermic effects of the AChE inhibitor, paraoxon. In addition to this improved scavenging capacity for anti-AChEs, however, these transgenic mice also resisted muscarinic, nicotinic and serotonergic agonists, indicating that secondary pharmacological changes had occurred. The transgenic mice also developed progressive learning and memory impairments, although their locomotor activities and open-field behaviour remained similar to those of matched control mice. By six months of age, transgenic mice lost their ability to respond to training in a spatial learning water maze test, whereas they performed normally in this test at the age of four weeks. This animal model is therefore suitable for investigating the transcriptional changes associated with cognitive deterioration and for testing drugs that may attenuate progressive damage. CONCLUSION: We conclude that upsetting cholinergic balance may by itself cause progressive memory decline in mammals, suggesting that congenital and/or acquired changes in this vulnerable balance may contribute to the physiopathology of Alzheimer's disease.

Acetylcholinesterase↗
PubMed1999

Synaptic plasticity and learning and memory: LTP and beyond.

Long-term potentiation (LTP) of synaptic activity is by far the most popular and widely researched model of synaptic plastic changes that might occur during learning. Numerous recent reports, however, have not found a correlation between the inducibility of LTP in the hippocampus and the ability of animals to learn hippocampus-dependent tasks. For example, some experiments with gene deletion (knockout) mice strains have shown that in some strains LTP is not inducible in the dentate gyrus, in area CA3, or CA1, but the animals are still able to learn spatial tasks. This apparent mismatch has rejuvenated the discussion concerning whether LTP is a good model for mechanisms that underlie memory formation in the nervous system. This review analyzes the conditions under which LTP is induced or learning takes place and suggests reasons for the mismatches that can occur and what we can learn from them. High-frequency stimulation protocols and in vitro assays cannot be seen to resemble natural firing patterns or conditions found in the brain. More physiological experimental conditions, especially in vivo recording in awake animals, could lead the way to the development of improved models of learning mechanisms that better correlate with learning abilities of animals.

Animals↗
PubMed2005

Spatial conditional discrimination learning in developing rats.

The present study established an effective procedure for studying spatial conditional discrimination learning in juvenile rats using a T-maze. Wire mesh located on the floor of the maze as well as a second, identical T-maze apparatus served as conditional cues which signaled whether a left or a right response would be rewarded. In Experiment 1, conditional discrimination was evident on Postnatal Day (PND) 30 when mesh+maze or maze-alone were the conditional cues, but not when mesh-alone was the cue. Experiment 2 confirmed that mesh-alone was sufficiently salient to support learning of a simple (nonconditional) discrimination. Its failure to serve as a conditional cue in Experiment 1 does not reflect its general ineffectiveness as a stimulus. Experiment 3 confirmed that the learning shown in Experiment 1 was indeed conditional in nature by comparing performance on conditional versus nonconditional versions of the task. Experiment 4 showed that PND19 and PND23 pups also were capable of performing the task when maze+mesh was the cue; however, the findings indicate that PND19 subjects do not use a conditional strategy to learn this task. The findings suggest postnatal ontogeny of conditional discrimination learning and underscore the importance of conditional cue salience, and of identifying task strategies, in developmental studies of conditional discrimination learning.

Animals↗
PubMed1992

Involvement of glycine site associated with the NMDA receptor in hippocampal long-term potentiation and acquisition of spatial memory in rats.

The effects of 7-chlorokynurenic acid (7-Cl-Kyn), a selective antagonist at the glycine site associated with the N-methyl-D-aspartate (NMDA) receptor, on hippocampal long-term potentiation (LTP) and behavioral performances in a spatial learning task were investigated. Extracellular recordings of evoked potential (population spike) were made in rat hippocampal slices. Perfusion of 7-Cl-Kyn (10(-5) M) inhibited the induction of LTP following a tetanic stimulation (51 or 101 pulses at 100 Hz) both in the Schaffer/commissural-CA1 pyramidal cell synapses and in the perforant path-dentate granule cell synapses. Acquisition of a spatial memory in the Morris water maze was examined using rats chronically cannulated for application of drugs. The intact and vehicle-injected rats learned easily to escape onto a hidden platform with short latencies, while the rats given an injection of 7-Cl-Kyn (10(-8) mol/brain, i.c.v.) prior to every session took a longer time and a longer path to escape even after all 5 sessions of trials. Injection of 7-Cl-Kyn did not affect the swimming speed, an index of swimming ability. This is the first report providing direct evidence that endogenous glycine supports the processes of learning and memory.

Animals↗
PubMed2002

Effects of chronic administration of huperzine A on memory in guinea pigs.

Effects of subchronic administration of huperzine A, a cholinesterase inhibitor, on spatial memory were studied in guinea pig. Spatial memory was appreciated by the Morris water maze test. At a dose of 0.25 microgram/h, inhibiting 36% of blood AChE and 14-20% of central AChE, no effect on spatial learning was found. At a dose of 1 microgram/h, inhibiting 20% of blood AChE and 14-20% of central AChE, no memory impairment was found, on the other hand, a memory enhancing effect, limited to the first day was shown. It thus appears that subchronic administration of huperzine A did not induce deleterious effects on spatial memory.

Acetylcholinesterase↗
PubMed2003

Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.

Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.

Administration, Intranasal↗
PubMed2006

Environmental enrichment enhances neurogranin expression and hippocampal learning and memory but fails to rescue the impairments of neurogranin null mutant mice.

Environmental enrichment is known to enhance hippocampal neurogenesis and cognitive functions. Neurogranin (Ng), a specific substrate of protein kinase C (PKC), is abundantly expressed in brain regions important for cognitive functions. Deletion of Ng in mice causes severe deficits in spatial learning and long-term potentiation (LTP) in the hippocampal CA1 region. These Ng-/- mice, as compared with Ng+/+, respond poorly after treatment of their hippocampal slices with agents that activate signaling molecules important for learning and memory, including Ca2+/calmodulin-dependent protein kinase II (alphaCaMKII), PKC, protein kinase A (PKA), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). In the present study, adult mice were housed in either regular home cages (control group) or more spacious cages with an exercise wheel and change of toys twice per week (enriched group) for at least 3 weeks. Enriched Ng+/+ and Ng+/- mice showed enhanced LTP in the hippocampal CA1 after high-frequency stimulation, but Ng-/- mice were affected only minimally. Behaviorally, the enriched Ng+/+ and Ng+/-, but not Ng-/- mice, performed significantly better than their respective control cohorts in Morris water maze and in step-down fear conditioning. Enriched Ng+/- mice also showed improvement in the radial arm maze. Quantitative immunoblot analyses showed that the enriched groups of all three genotypes exhibited elevated hippocampal levels of alphaCaMKII and CREB, but not ERK. Interestingly, enrichment caused a significant increase in hippocampal Ng levels both in Ng+/+ and Ng+/- mice that seemed to contribute to their improved LTP and behavioral performances. These results suggest that Ng gates the neuronal signaling reactions involved in learning and memory. During environmental enrichment, these Ng-regulated reactions are also critical for the enhancement of synaptic plasticity and cognitive functions.

Animals↗
PubMedDate not supplied

Differential involvement of NMDA and AMPA receptors within the nucleus accumbens in consolidation of information necessary for place navigation and guidance strategy of mice.

Recent evidence now points to a role of glutamate transmission within the nucleus accumbens (Nacc) in spatial learning and memory. Unfortunately, the role of the distinct classes of glutamate receptors within this structure in mediating the different steps of the memorization process is not clear. The aim of this study therefore was to further investigate this issue, trying to assess the involvement of the two classes of glutamate receptors within the Nacc in consolidation of spatial information using an associative spatial task, the water maze. For this purpose, focal injections of the NMDA antagonist, AP-5, and of the AMPA antagonist, DNQX, have been performed immediately after the training phase, and mice have been tested for retention 24 h later. Two different versions of the water-maze task have been used: In the place version, animals could learn the position of the platform using visual distal cues, and in the cue version, the location of the platform was indicated by a single proximal cue. The results demonstrated that posttraining NMDA receptor blockade affects mice response in the place but not in the cue water-maze task. On the contrary, AMPA receptor blockade induced no effect in either version of the task. These data confirm a functional dissociation between glutamate receptors located in the Nacc in modulating spatial memory consolidation and indicate that they are specifically involved in consolidation of information necessary to acquire a place but not to a guidance strategy.

Animals↗
PubMed1996

The memory-modulatory effects of glucocorticoids depend on an intact stria terminalis.

This study examined the effects of stria terminalis (ST) lesions on glucocorticoid-induced modulation of memory formation for inhibitory avoidance training and spatial learning in a water maze. Systemic (s.c.) posttraining injections of the glucocorticoid receptor agonist dexamethasone (0.3 or 1.0 mg/kg) enhanced memory for inhibitory avoidance training in rats with sham ST lesions. Removal of the adrenal glands (adrenalectomy; ADX) significantly impaired spatial memory in a water maze, and immediate posttraining injections of dexamethasone (0.3 mg/kg) attenuated the memory impairment. Bilateral lesions of the ST did not significantly affect retention of these two tasks. However, ST lesions did block the effects of short-term ADX and dexamethasone administration on memory for both tasks. These results are similar to those of previous experiments examining the effects of lesions of the basolateral nucleus of the amygdala on the glucocorticoid-induced modulation of memory for both tasks. These findings suggest that the integrity of the ST, which connects the amygdala with other brain structures, is essential for the modulating effects of glucocorticoids on memory storage.

Adrenalectomy↗
PubMed2004

The effect of reversible inactivation of the supramammillary nucleus on passive avoidance learning in rats.

Previous studies have shown that the presence of hippocampal theta activity is important for learning and memory, and that the medial supramammillary nucleus (mSuM) is involved in the control of the frequency of theta rhythm. It has also been shown that the depression of mSuM activity by chlordiazepoxide causes modest impairment of spatial learning. On the other hand, the lateral supramammillary nucleus (lSum) increases long-term potentiation (LTP) of hippocampal population spikes. However, to our knowledge, no reports exist concerning the role of the supramammillary area (SuM) in passive avoidance (PA) learning. In the present study, rats were chronically implanted with a cannula aimed at SuM and were trained on a step-through PA task. They received intra-SuM injection of lidocaine or saline at the following intervals: 5 min before training, 5, 90, and 360 min after the acquisition trial, or 5 min before the retrieval test. When lidocaine was injected 5 min before training there was no effect on acquisition of PA but retrieval was significantly poorer than the control group injected with saline. Lidocaine injection 5 min after the acquisition trial impaired PA retention, but reversible inactivation of SuM at 90 and 360 min after training and 5 min before the retrieval test showed no significant effect on PA retention. It can be concluded that SuM contributes to PA consolidation at least 5 min after the acquisition trial and that this effect may be accomplished through SuM projections to the septal and/or hippocampal areas participating in the PA memorization processes.

Analysis of Variance↗
PubMed2006

Influence of differential housing on emotional behaviour and neurotrophin levels in mice.

Environmental enrichment condition (EC) induces profound behavioural, neurochemical and neuroanatomical changes. Increasing evidence has shown that the hippocampus, which is implicated in a range of cognitive functions, including learning and memory, is one of the most susceptible brain areas to the effects of enriched rearing. Recent work also suggests that the hippocampus is functionally segregated; lesion studies have shown that the dorsal hippocampus is important for spatial learning, whereas the ventral part is critical in emotional behaviour in rats. We investigated the effects of differential housing environments on anxiety-related behaviour and neurotrophin levels in dorsal and ventral hippocampus, and other brain regions. Ninety-six male and female C57BL/6 mice were reared in EC or standard housing condition (SC) for 4 months after weaning. Thereafter sixty-four animals were tested in the elevated plus-maze, open-field, novel-objects exploration and food neophobia. Thirty-two animals remained as untested. Subsequently, brain nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were analysed in selected brain regions of the tested and non-tested animals. Differential housing influenced anxiety-related behaviour in the plus-maze and brain neurotrophins. Baseline levels of BDNF and NGF protein were differently distributed in dorsal and ventral parts of hippocampus in both male and female mice, with levels in the dorsal hippocampal being consistently higher than those in ventral hippocampus. Exposure to behavioural testing induced complex changes on neurotrophin levels in selected brain regions. This study demonstrates for the first time the differential distribution of normal levels of neurotrophin protein in dorsal and ventral hippocampus in mice, and these levels can be affected by environmental enrichment and have an impact on emotional behaviour.

Analysis of Variance↗
PubMed2006

A vitamin A-free diet results in impairment of the rat hippocampal somatostatinergic system.

Previous studies have revealed the presence of retinoid specific receptors in the hippocampus and have demonstrated that vitamin A deficiency produces a severe deficit in spatial learning and memory which are linked to a proper hippocampal functioning. It is also well known that the tetradecapeptide somatostatin binds to specific receptors in the hippocampus and, when injected into this brain area, facilitates the acquisition of spatial tasks. In addition, depletion of somatostatin by cysteamine impairs acquisition of these tasks. Taken together, these studies support the idea that the hippocampal somatostatinergic system might be regulated by vitamin A. Hence, we evaluated the effects of vitamin A deprivation and subsequent administration of vitamin A on the rat hippocampal somatostatinergic system. Rats fed a vitamin A-free diet exhibited a significant reduction of somatostatin-like immunoreactivity content in the hippocampus whereas the somatostatin mRNA levels were unaltered. Vitamin A deficiency increased the somatostatin receptor density and its dissociation constant. Functional Gi activity as well as the capacity of somatostatin to inhibit basal and forskolin-stimulated adenylyl cyclase activity was decreased in vitamin A deficiency rats as compared with the control animals. All these parameters were fully restored when vitamin A was replaced in the diet. Furthermore, we found that the Gialpha1, Gialpha2 and Gialpha3 protein levels were unaltered in hippocampal membranes from rats fed a vitamin A-free diet whereas subsequent vitamin A administration to these rats caused a significant increase in the levels of Gialpha1 and Gialpha2. Altogether, the present findings suggest that dietary vitamin A levels modulate the somatostatinergic system in the rat hippocampus.

Adenylyl Cyclases↗