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PubMed2005

Enriched environment and spatial learning enhance hippocampal neurogenesis and salvages ischemic penumbra after focal cerebral ischemia.

Enriched environment (EE) has been shown to increase neurogenesis in the adult brain. The aim of this study is to determine the effect of EE and spatial learning on neurogenesis following ischemic stroke. Male adult SD rats were subjected to sham surgery or distal middle cerebral artery occlusion (MCAO). MCAO induced a transient increase followed by a sustained depression of progenitor cell proliferation and neuroblast production below baseline level in both ipsilateral and contralateral DG compared to sham. Increased neuronal differentiation and neurogenesis in the DG were observed in both sham and MCAO rats following 8 weeks in the EE combined with spatial learning, compared to rats housed in the standard environment. EE/Learning also restored the total number of neuroblasts in the DG after MCAO compared to sham. Furthermore, EE/learning enhanced the density of NeuN positive cells in the ischemic penumbra, though no new neurons were detected in this region.

Animals↗
PubMed2007

Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus.

Persistence is the most characteristic attribute of long-term memory (LTM). To understand LTM, we must understand how memory traces persist over time despite the short-lived nature and rapid turnover of their molecular substrates. It is widely accepted that LTM formation is dependent upon hippocampal de novo protein synthesis and Brain-Derived Neurotrophic Factor (BDNF) signaling during or early after acquisition. Here we show that 12 hr after acquisition of a one-trial associative learning task, there is a novel protein synthesis and BDNF-dependent phase in the rat hippocampus that is critical for the persistence of LTM storage. Our findings indicate that a delayed stabilization phase is specifically required for maintenance, but not formation, of the memory trace. We propose that memory formation and memory persistence share some of the same molecular mechanisms and that recurrent rounds of consolidation-like events take place in the hippocampus for maintenance of the memory trace.

Animals↗
PubMed2005

Dissociation of the effect of spatial behaviors on the phosphorylation of cAMP-response element binding protein (CREB) within the nucleus accumbens.

Several studies have reported a role for the nucleus accumbens (NAcc) in learning and synaptic plasticity. Many of them suggest that the NAcc is involved in translating cortico-limbic information to the motor system mediating spatial learning and memory processes. Previous studies from our laboratory have shown that protein kinase C is activated following training in a food search spatial learning task. The present study further characterizes the molecular substrates associated with NAcc-dependent spatial behavior. The cyclic AMP-response element binding protein (CREB), a transcription factor implicated in the formation of long-term memory, was studied in the NAcc following spatial training in a food search spatial learning task. Western blots were performed to detect phosphorylated (activated) and total CREB protein levels. Our results show that CREB is significantly phosphorylated in the NAcc 48 h after habituation and at 5 min and 1 h after the first spatial training session in comparison with the naive animals that remained in their home cages. Since published data show that NAcc plays a role in novelty detection and reactivity, we conducted further experiments in order to dissociate the effect on CREB phosphorylation and expression of spatial novelty (single exposure), exploration, and spatial learning in the food search apparatus. Results show that CREB phosphorylation is significantly increased 48 h after exposure to a novel environment. The present study suggests that CREB phosphorylation observed in the NAcc during habituation and spatial training may be mainly triggered by detection of spatial novelty.

Animals↗
PubMed2005

Learning twice is different from learning once and from learning more.

The rat hippocampus plays a crucial role in the consolidation of a variety of memories, including that for a one trial inhibitory avoidance learning task in which stepping down from a platform is associated with a footshock. Here we show that this is the case regardless of the intensity of the footshock used and hence, of the strength of the learned response. However, additional learning produced by a second training session in this task does not involve the hippocampus but, instead, the striatum. Memory consolidation of the second trial requires glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate, N-methyl-D-aspartate and metabotropic receptors, activation of signaling pathways, gene expression and protein synthesis in the striatum, as are required in the hippocampus during memory consolidation of the first trial.

Animals↗
PubMed2006

Preservation of striatal tissue and behavioral function after neural stem cell transplantation in a rat model of Huntington's disease.

Cell replacement has the potential to become a frontline therapy to remedy behavioral impairments in Huntington's disease. To determine the efficacy of stem cell transplantation, behavioral assessment and in vivo monitoring of the lesion environment are paramount. We here demonstrate that neural stem cells from the MHP36 cell line prevented the development of a deficit on the beam walk test while providing partial recovery of learning in the water maze. However, no beneficial effect on rats' impairment in the staircase test was observed. By quantification of the lesion from serial magnetic resonance images, no effect of neural stem cells on lesion volume was observed. Instead, a preservation of striatal volume over time and its correlation with performance on the beam walk test suggested that sparing of behavioral function was associated with a stagnation of ongoing tissue loss rather than a reduction in lesion size. Serial imaging therefore warrants further implementation in clinical trials of neural grafts to monitor in vivo changes in the damaged brain due to transplantation.

Analysis of Variance↗
PubMed2005

Learning the morphine conditioned cue preference: cue configuration determines effects of lesions.

The morphine conditioned cue preference was investigated using two different apparatus configurations. In one configuration, with a clear Plexiglas partition separating the drug-paired and unpaired compartments, rats could see the cues in both compartments while in either one. In the other configuration, with an opaque wood partition separating the two compartments, rats could see the cues in only one compartment at a time. The experiment had three phases: a session of pre-exposure to the entire apparatus; four 2-day training trials during each of which rats received pairings of 5 mg/Kg morphine sulphate with one compartment and saline with the other (compartments and order counterbalanced), and a test session in which the undrugged rats moved freely between the compartments while the time spent in each was measured. Four groups of rats were trained using the opaque partition in all three phases. Normal rats and rats with amygdala or nucleus accumbens lesions exhibited preferences for their morphine-paired compartments; rats with fimbria-fornix lesions had no preferences. Four additional groups were trained using the clear partition during pre-exposure, the opaque partition during training and the clear partition during testing. Normal rats and rats with fimbria-fornix lesions exhibited preferences, rats with amygdala or nucleus accumbens lesions had no preferences. This interaction between lesioned structures and the apparatus configuration is accounted for by the idea that different types of learning produced the preference for morphine-paired cues in the two apparatus configurations. Each type was learned in a different memory system and so was impaired by different lesions. These findings contribute to understanding the nature of the learning processes that produce the morphine CCP.

Amygdala↗
PubMed2004

Lead (Pb(+2)) impairs long-term memory and blocks learning-induced increases in hippocampal protein kinase C activity.

The long-term storage of information in the brain known as long-term memory (LTM) depends on a variety of intracellular signaling cascades utilizing calcium (Ca2+) and cyclic adenosine monophosphate as second messengers. In particular, Ca(+2)/phospholipid-dependent protein kinase C (PKC) activity has been proposed to be necessary for the transition from short-term memory to LTM. Because the neurobehavioral toxicity of lead (Pb(+2)) has been associated to its interference with normal Ca(+2) signaling in neurons, we studied its effects on spatial learning and memory using a hippocampal-dependent discrimination task. Adult rats received microinfusions of either Na+ or Pb(+2) acetate in the CA1 hippocampal subregion before each one of four training sessions. A retention test was given 7 days later to examine LTM. Results suggest that intrahippocampal Pb(+2) did not affect learning of the task, but significantly impaired retention. The effects of Pb(+2) selectively impaired reference memory measured in the retention test, but had no effect on the general performance because it did not affect the latency to complete the task during the test. Finally, we examined the effects of Pb(+2) on the induction of hippocampal Ca(+2)/phospholipid-dependent PKC activity during acquisition training. The results showed that Pb(+2) interfered with the learning-induced activation of Ca(+2)/phospholipid-dependent PKC on day 3 of acquisition. Overall, our results indicate that Pb(+2) causes cognitive impairments in adult rats and that such effects might be subserved by interference with Ca(+2)-related signaling mechanisms required for normal LTM.

Animals↗
PubMed2003

Association of aortic atherosclerosis with cerebral beta-amyloidosis and learning deficits in a mouse model of Alzheimer's disease.

High fat/high cholesterol diets exacerbate beta-amyloidosis in mouse models of Alzheimer's disease (AD). It has been impossible, however, to study the relationship between atherosclerosis and beta-amyloidosis in those models because such mice were on atherosclerosis-resistant genetic backgrounds. Here we report the establishment of AD model mice, B6Tg2576, that are prone to atherosclerosis. B6Tg2576 mice were produced by back-crossing Tg2576 mice, an AD mouse model overexpressing human amyloid beta-protein precursor with the Swedish double mutation, to C57BL/6 mice, a strain susceptible to diet-induced atherosclerosis. An atherogenic diet induced aortic atherosclerosis and exacerbated cerebral beta-amyloidosis in B6Tg2576 mice. Compared with age-matched non-transgenic littermates, B6Tg2576 mice developed significantly more diet-induced aortic atherosclerosis. Unexpectedly, normal diet-fed B6Tg2576 mice also developed fatty streak lesions (early atherosclerosis) in the aorta. The aortic atherosclerotic lesion area positively correlated with cerebral beta-amyloid deposits in B6Tg2576 mice on both atherogenic and normal diets. Furthermore, behavioral assessments demonstrated that B6Tg2576 mice fed an atherogenic diet had more spatial learning impairment than those fed a normal diet. Our results suggest that synergistic mechanisms may be involved in the pathogenesis of atherosclerosis and AD. These findings may have important implications in the prevention and treatment of cardiovascular diseases as well as AD.

Aging↗
PubMed2001

Serum cleaved Tau protein and neurobehavioral battery of tests as markers of brain injury in experimental bacterial meningitis.

Brain injury due to bacterial meningitis affects multiple areas of the brain with a heterogeneous distribution generating a challenge to assess severity. Tau proteins are microtubular binding proteins localized in the axonal compartment of neurons. Brain injury releases cleaved Tau proteins (C-tau) into the extracellular space where they are transported to the cerebral spinal fluid. We hypothesized that C-tau crosses the blood-brain barrier during inflammation and that it can be detected in serum. The correlation between serum C-tau levels and the extent of the meningitic insult was examined. Furthermore, we studied whether the use of a subset of neurobehavioral tasks can assess the extent of brain injury after meningitis. The tests were chosen primarily for their ability to detect deficits in the acoustic system, low brain, reflexive responding, as well as for impaired motor coordination and the higher brain functions of learning and memory. A rat model of group B streptococcal meningitis with variable severity was utilized. At five days after bacterial inoculation followed by antibiotic therapy neurobehavioral tests were performed and serum C-tau and histologic samples of the brain were obtained. Our study shows that during meningitis C-tau appears in serum and reflects the extent of neurologic damage. Neurobehavioral performance was altered after bacterial meningitis and could be correlated with histologic and biochemical markers of neurologic sequelae. We conclude that serum C-tau and a composite of neurobehavioral tests could become useful markers for assessing the severity of neurological damage in experimental bacterial meningitis.

Animals↗
PubMed2002

Hippocampal lesions, contextual retrieval, and autoshaping in pigeons.

Both pigeons and rats with damage to the hippocampus are slow to acquire an autoshaped response and emit fewer overall responses than control animals. Experiment 1 explored the possibility that the autoshaping deficit was due to an impairment in contextual retrieval. Pigeons were trained for 14 days on an autoshaping task in which a red stimulus was followed by reinforcement in context A, and a green stimulus was followed by reinforcement in context B. On day 15, the subjects were given a context test in which the red and green stimuli were presented simultaneously in context A and then later in context B. Both control and hippocampal animals showed context specificity, that is, they responded more to the red stimulus in context A and to the green stimulus in context B. In Experiment 2 we video-recorded the control and hippocampal animals performing the autoshaping task. Hippocampal animals tended to miss-peck the key more often than control animals. In addition, the number of missed pecks increased across days for hippocampal animals but not for control animals, suggesting that while the control animals increased their pecking accuracy, the hippocampal animals actually decreased their pecking accuracy. Our findings suggest that impairments in moving through space may underlie the hippocampal autoshaping deficit.

Animals↗
PubMed1998

Impaired spatial navigation learning in transgenic mice over-expressing heme oxygenase-1.

Transgenic mice expressing heme oxygenase-1 (HO-1) using the neuron-specific enolase promoter were impaired in learning the Morris water maze compared to nontransgenic littermates. The memory of the HO-1 mice for the location of the platform was similarly impaired when tested using a probe trial after 7 training blocks, but performance on visible platform trials was similar for both groups of mice. Importantly, both HO-1 and nontransgenic mice had normal sensorimotor function, and performed the same on a Y-maze alternation task, highlighting the specificity of memory deficit in the spatial navigation task. These results suggest that carbon monoxide, one product of HO-1 activity, interferes in the development of spatial navigation memory, and may play a role in normal memory function.

Animals↗
PubMed1998

Declarative and procedural learning in Parkinson's disease patients having tremor or bradykinesia as the predominant symptom.

The distinction between procedural and declarative memory is widely accepted in the memory literature. Converging evidence makes a strong case that the medial aspects of the temporal lobes and the diencephalon subserve the declarative memory system. However, the neuroanatomy of procedural memory is much less clear. In animal studies, damage to the basal ganglia has been found to affect procedural memory, but studies of patients suffering from degenerative diseases of the basal ganglia (e.g., Parkinson's and Huntington's disease) are less conclusive. Two groups of Parkinson's disease subtypes, with tremor (PDt) and bradykinesia (PDb) as the predominant motor symptom, were compared to controls on declarative and procedural memory tasks. The two patient groups did not differ from each other on the declarative tasks. However, in the procedural learning tasks, the PDb but not the PDt group, was significantly impaired compared to the control group. The results are discussed in terms of the differential involvement of discrete neuroanatomic loops connecting the basal ganglia and the prefrontal cortex.

Acoustic Stimulation↗
PubMed2000

Huperzine A improves cognitive deficits caused by chronic cerebral hypoperfusion in rats.

The effects of (-)-huperzine A, a promising therapeutic agent for Alzheimer's disease, on learning behavior and on alterations of the cholinergic system, the oxygen free radicals and energy metabolites induced by permanent bilateral ligation of the common carotid arteries were investigated in rats. Daily oral administration of huperzine A produced a significant improvement of the deficit in the learning of the water maze task, beginning 28 days after ischemia, correlating to about 33-40% inhibition of acetylcholinesterase activity in cortex and hippocampus. Huperzine A significantly restored the decrease in choline acetyltransferase activity in hippocampus and significantly reduced the increases in superoxide dismutase, lipid peroxide, lactate and glucose to their normal levels. The present findings demonstrate that the improvement by huperzine A of the cognitive dysfunction in the late phase in chronically hypoperfused rats is due to its effects, not only on the cholinergic system, but also on the oxygen free radical system and energy metabolism. Our results strongly suggest that huperzine A has therapeutic potential for the treatment of dementia caused by cholinergic dysfunction and/or decrease of cerebral blood flow.

Acetylcholinesterase↗
PubMed2003

Effects of the synthetic cannabinoid nabilone on spatial learning and hippocampal neurotransmission.

Cannabinoids, the active components of marijuana, affect memory and hippocampal neurotransmission. It has been claimed that nabilone, a synthetic cannabinoid endowed with antiemetic properties, has a peculiar profile of actions. We studied the effects of the drug on spatial learning and in vitro hippocampal CA1 electrophysiology in the rat. Nabilone (0.1, 0.5, and 1.0 mg/kg ip) does not impair place learning in a water maze task, whereas Delta(8)-tetrahydrocannabinol (Delta(8)-THC) disrupts this function. At concentrations ranging from 1 nM to 10 microM nabilone does not influence basal glutamatergic neurotransmission, which is decreased by Delta(8)-THC. Although cannabinoids have been consistently reported to affect synaptic plasticity, nabilone 1 microM does not change paired-pulse facilitation, long-term potentiation and the magnitude of long-term depression. However, the time course of the latter phenomenon is significantly changed by the drug, the depression being lower than in control experiments from 7 to 35 min postinduction. Altogether, our data indicate that there might be differences in the effects of agonists for central cannabinoid receptors, which could help to understand the pharmacology of this class of molecules. The results also suggest that amnesia induced by cannabinoids be possibly related to their effects on hippocampal neurotransmission. The study supports the use of nabilone in conditions the course of which is complicated by cognitive impairment.

Animals↗
PubMed2002

A spatial memory task appropriate for electrophysiological recordings.

We developed a novel method for assessing spatial learning that is compatible with the requirements of electrophysiological recording of multiple single neurons. The behavioral task utilized a rectangular track with 8 reward boxes of which a subset contained available food (bait). Errors were scored whenever the rat investigated a non-baited box location (commission), failed to investigate a baited box location (omission), or hesitated in front of a non-baited box location (hesitation). Several controls encouraged the animal to solve the task through allocentric cues rather than through procedural strategies or simple local cue pairing. The learning curve for this task (3-5 d to criterion) was comparable to that of other spatial learning tasks when adequately motivated. The types of errors varied as the animal learned the task. Unlike other spatial learning tasks, the multi-box track allows many repeated samples of the same spatial coordinates within a short period of time to allow, for example, reliable determination of place fields while recording from hippocampal cells. Multiple trials per session also allow for high intensity training important for many learning assessments such as the timing and type of sleep involved in learning and memory.

Analysis of Variance↗
PubMed2001

Timing of cognitive deficits following neonatal seizures: relationship to histological changes in the hippocampus.

Neonatal seizures are frequently associated with cognitive impairment and reduced seizure threshold. Previous studies in our laboratory have demonstrated that rats with recurrent neonatal seizures have impaired learning, lower seizure thresholds, and sprouting of mossy fibers in CA3 and the supragranular region of the dentate gyrus in the hippocampus when studied as adults. The goal of this study was to determine the age of onset of cognitive dysfunction and alterations in seizure susceptibility in rats subjected to recurrent neonatal seizures and the relation of this cognitive impairment to mossy fiber sprouting and expression of glutamate receptors. Starting at postnatal day (P) 0, rats were exposed to 45 flurothyl-induced seizures over a 9-day period of time. Visual-spatial learning in the water maze and seizure susceptibility were assessed in subsets of the rats at P20 or P35. Brains were evaluated for cell loss, mossy fiber distribution, and AMPA (GluR1) and NMDA (NMDAR1) subreceptor expression at these same time points. Rats with neonatal seizures showed significant impairment in the performance of the water maze and increased seizure susceptibility at both P20 and P35. Sprouting of mossy fibers into the CA3 and supragranular region of the dentate gyrus was seen at both P20 and P35. GluR1 expression was increased in CA3 at P20 and NMDAR1 was increased in expression in CA3 and the supragranular region of the dentate gyrus at P35. Our findings indicate that altered seizure susceptibility and cognitive impairment occurs prior to weaning following a series of neonatal seizures. Furthermore, these alterations in cognition and seizure susceptibility are paralleled by sprouting of mossy fibers and increased expression of glutamate receptors. To be effective, our results suggest that strategies to alter the adverse outcome following neonatal seizures will have to be initiated during, or shortly following, the seizures.

Animals↗
PubMedDate not supplied

Effect of aging on the basal expression of c-Fos, c-Jun, and Egr-1 proteins in the hippocampus.

In the present study the effect of aging on the basal expression of three different immediate early genes (IEGs) was investigated. The protein products of c-fos, c-jun, and egr-1 genes were visualized immunohistochemically in the rat hippocampus of young adult (4-month-old) and old rats (20-month-old). Astrocytes were quantified by GFAp immunostaining to determine whether changes in the expression of IEGs were correlated with modifications in this marker of degenerative changes. In the young adult rat brain, basal levels of c-Jun and Egr-1 but not c-Fos were detected within the hippocampal formation. Whereas very high basal levels of c-Jun were found in the dentate granule cells and in the pyramidal cells of the ventral hippocampus, Egr-1 was highly expressed in the CA1 pyramidal cells of the dorsal hippocampus. Aging was accompanied by a decrease in Egr-1 expression, by a decrease in total cell density, as well as by a loss of astrocytes in CA1 subfields. In contrast, basal expression of c-Fos and c-Jun as well as astrocyte density within the dentate gyrus were not affected by aging. No difference in these markers was observed in aged rats with or without impairment in spatial learning in a water maze. It was concluded that although these changes may reflect senescence-induced decline of brain function, they do not constitute the defect underlying the age-associated reduction in mnesic capability.

Aging↗