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PubMed2000

Dehydroevodiamine.HCl prevents impairment of learning and memory and neuronal loss in rat models of cognitive disturbance.

We previously reported that dehydroevodiamine.HCl (DHED) has anticholinesterase and antiamnesic activities. To verify the effects of DHED on cognitive deficits further, we tested it on the scopolamine-induced amnesia model of the rat using the passive avoidance and eight-arm radial maze tests. A single (20 mg/kg p.o.) and repeated (10 mg/kg p.o.) administrations of DHED could significantly reverse the latency time shortened by scopolamine (1 mg/kg i.p.) to control level. The impaired spatial working memory induced by scopolamine (1 mg/kg i.p.) was also improved significantly by a single injection (6.25 mg/kg i.p.) and repeated administrations of DHED (10 mg/kg p.o.) in the eight-arm radial maze test. In addition, we examined the effects of DHED on the memory impairment and the histological changes of the brain after unilateral electrolytic lesion of the entorhinal cortex (EC) and middle cerebral artery occlusion in rats. The cognitive deficits caused by EC lesion and middle cerebral artery occlusion were improved significantly by repeated administrations of DHED (6.25 mg/kg i.p.) after EC lesion or ischemic insult once a day for 7 days in the passive avoidance test. Histological analysis showed that the neuronal loss in the DHED-treated group was notably reduced in the hippocampal area (CA1) of ischemic rats and in the dentate gyrus and hippocampal area (CA1 and CA3) of EC-lesioned rats compared with the nontreated group. The infarction area was decreased significantly by a single administration of DHED (6.25 mg/kg i.p.) 30 min before ischemic insult for 6 h. These results suggest that DHED might be an effective drug for not only the Alzheimer's disease type, but also the vascular type of dementia.

Alkaloids↗
PubMed1999

Mild impairment of learning and memory in mice overexpressing the mSim2 gene located on chromosome 16: an animal model of Down's syndrome.

Human Sim2 is a product of one of the genes located on human chromosome 21q22 and is a homolog of Drosophila single-minded ( sim ) which is a critical player in midline development of the central nervous system of the fly. Since Sim2 mRNA is expressed in facial, skull, palate and vertebra primordia in human and rodent embryos, features that are associated with phenotypes of Down's syndrome (DS), its trisomic state is suspected to contribute to the symptoms of DS. Here we describe that mSim2 mRNA is expressed in hippocampus and amygdala of adult mice, and that while mice overexpressing mSim2 under the control of the beta-actin promoter are viable and fertile and have superficially normal skeletal, brain and heart structures, they exhibit a moderate defect in context-dependent fear conditioning and a mild defect in the Morris water maze test. Taken together, our data show that overdosage of Sim2 may be important for the pathogenesis of Down's syndrome, especially mental retardation.

Animals↗
PubMed2002

Behavioural and physiological characterization of inbred mouse strains: prospects for elucidating the molecular mechanisms of mammalian learning and memory.

With the advent of recombinant DNA methodology, it has become possible to dissect the molecular mechanisms of complex traits, including brain function and behaviour. The increasing amount of available information on the genomes of mammalian organisms, including our own, has facilitated this research. The present review focuses on a somewhat neglected area of genetics, one that involves the study of inbred mouse strains. It is argued that the use of inbred mice is complementary to transgenic approaches in the analysis of molecular mechanisms of complex traits. Whereas transgenic technology allows one to manipulate a single gene and investigate the in vivo effects of highly specific, artificially induced mutations, the study of inbred mouse strains should shed light on the roles of naturally occurring allelic variants in brain function and behaviour. Systematic characterization of the behavioural, electrophysiological, neurochemical, and neuroanatomical properties of a large number of inbred strains is required to elucidate mechanisms of mammalian brain function and behaviour. In essence, a 'mouse phenome' project is needed, entailing the construction of databases to investigate possible causal relationships amongst the phenotypical characteristics. This review focuses on electrophysiological and behavioural characterization of mouse strains. Nevertheless, it is emphasized that the full potential of the analysis of inbred mouse strains may be attained if techniques of numerous disciplines, including gene expression profiling, biochemical analysis, and quantitative trait loci (QTL) mapping, to name but a few, are also included.

Animals↗
PubMed2005

[Learning and memory amelioration of transplantation of the neural stem cells modified with human brain-derived neurotrophic factor gene on Alzheimer disease model rat].

OBJECTIVE: To investigate the memory amelioration of the Alzheimer disease (AD) model rat after being transplanted the single neural stem cells (NSC) and NSC modified with human brain-derived neurotrophic factor (hBDNF) gene. METHODS: Forty SD rats were divided evenly into 4 groups randomly. The AD model rats were made by cutting unilaterally the fibria-fornix of male rats. Ten to twelve days after surgery, the genetically modified and unmodified NSC were implanted into the lateral cerebral ventricle of group III and group IV respectively. Two weeks after transplantation, the amelioration of memory impairment of the rats was detected by Morris water maze. RESULTS: The average escaping latency of the group III and group IV (41.84 +/- 21.76 s, 25.23 +/- 17.06 s respectively) was shorter than that of the group II (70.91 +/- 23.67 s) (P<0.01). The percentage of swimming distance in the platform quadrant in group III (36.9%) and in group IV (42.0%) was higher than that in the group II (26.0%) (P<0.01). More marginal and random strategies were used in group II. The percentage of swimming distance in the platform quadrant in group IV was also greater than that in group III (P<0.05). There were no significant differences in the average escaping latency, the percentage of swimming distance in the platform quadrant and the probe strategy between group IV and group I (P>0.05). More lineal and oriented strategies were used in group IV. CONCLUSION: The behavioral amelioration of AD model rat was obtained by transplanting single NSC and hBDNF-gene-modified NSC. The effect of the NSC group modified with hBDNF gene is better than that of the group III.

Alzheimer Disease↗
PubMed1983

Digoxin-related impairment of learning and memory in cardiac patients.

The relationship between the plasma level of the cardiac glycoside digoxin and performance on a range of cognitive tasks was investigated in a group of cardiac outpatients on maintenance therapy. The cognitive functions assessed were speed of decision-making and recognition memory of nonverbal and verbal material, competitive audio-visual attention performance, visuo-motor-choice reaction time and auditory verbal learning (AVL). Multiple regression analysis of the data revealed a strong relationship between plasma digoxin level at the time of testing and the number of trials to criterion in the AVL task (plasma digoxin level 0.7-1.8 nmol/l). Further data analysis indicated that this association was unlikely to be due to age, education or severity of cardiac disorder. The results strongly suggest that an increasing plasma level of digoxin may produce a progressive deterioration in auditory verbal learning and short-term memory.

Adult↗
PubMed1995

Role of nitric oxide in learning and memory and in monoamine metabolism in the rat brain.

1. We investigated the effects of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthase, on the performance of rats in a radial arm maze and in habituation tasks, and on monoamine metabolism in the brain. 2. Daily administration of L-NAME (10-60 mg kg-1) resulted in a dose-dependent impairment of performance during the acquisition of the radial arm maze task, while it failed to affect performance in those rats that had previously acquired the task. 3. The rate of decrease in locomotor activity in the habituation task in the L-NAME-treated rats was significantly less than that in control rats. 4. NG-nitro-D-arginine methyl ester (D-NAME, a less active inhibitor of NO synthase) showed no effects in the above behavioural tasks. 5. NO synthase activity was significantly decreased in both the L-NAME and D-NAME-treated rats, with the magnitude of inhibition being greater in the L-NAME-treated animals. 6. The content of 5-hydroxyindoleacetic acid (5-HIAA) in the hippocampus and the 5-HIAA/5-hydroxytryptamine ratio in the hippocampus and cortex were significantly decreased in the L-NAME (60 mg kg-1)-treated rats compared with these values in the controls. 7. Striatal 3,4-dihydroxyphenylacetic acid (DOPAC) content was significantly increased in the L-NAME (60 mg kg-1)-treated rats compared with the values in the controls, while the DOPAC/dopamine ratio was not changed. 8. These results suggest that: (i) NO may play an important role in performance during the acquisition,but not retention, of the radial arm maze task, and (ii) that endogenous NO may be involved in the regulation of monoamine metabolism.

Animals↗
PubMed1987

Development of learning and memory in Aplysia. I. Functional assembly of gill and siphon withdrawal.

The marine mollusc Aplysia californica provides an excellent preparation with which to examine the development of the neuronal control of behavior for 2 reasons: first, adult Aplysia exhibit a variety of behaviors that are well understood in cellular terms; and second, the development of Aplysia from embryo to adult has been studied in considerable detail. Among the best understood behaviors in Aplysia are the withdrawal responses of the mantle organs (the gill, siphon, and mantle shelf), which exhibit 2 different kinds of behaviors: "spontaneous" contractions that are part of a fixed action pattern, a respiratory pumping sequence of the mantle organs, and reflex contractions in response to tactile stimuli. We have examined the development of both of these withdrawal behaviors in juvenile stages 9-12 and found that they are functionally assembled according to different ontogenetic timetables. Spontaneous contractions. As soon as the siphon and gill emerge, in stages 9 and 10, respectively, they each show a high rate of spontaneous contraction that gradually diminishes throughout subsequent stages until it reaches the low rate typical of adults (stage 13). Since the siphon emerges first, it already exhibits a significant decline in its spontaneous activity (e.g., in stage 11) when the gill's spontaneous activity is at its highest. In addition to a developmental trend in the rate of contractions, there was also a clear developmental progression in the degree of cocontraction of the siphon and gill during spontaneous contractions. In adults, the siphon and gill show a very high degree of cocontraction during spontaneous pumping. However, in juvenile animals, there was a very low degree. Thus, it appears that the siphon and gill withdrawal components of the fixed action pattern become progressively more functionally coupled during juvenile development. Reflex contractions. As soon as the siphon and gill emerge in their respective developmental stages, they exhibit a brisk withdrawal reflex to tactile stimulation of the siphon. Moreover, at each developmental stage, reflex siphon contractions were graded as a function of stimulus intensity, as they are in the adult. Finally, throughout development tactile stimulation of the siphon invariably evoked coincident contractions of both the siphon and the gill, which is characteristic of the adult reflex. Thus, unlike the fixed action pattern that takes several weeks to mature, the defensive withdrawal reflex closely resembles the adult form as soon as the effector organs emerge during juvenile development.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

NMDA receptors mediate olfactory learning and memory in Drosophila.

BACKGROUND: Molecular and electrophysiological properties of NMDARs suggest that they may be the Hebbian "coincidence detectors" hypothesized to underlie associative learning. Because of the nonspecificity of drugs that modulate NMDAR function or the relatively chronic genetic manipulations of various NMDAR subunits from mammalian studies, conclusive evidence for such an acute role for NMDARs in adult behavioral plasticity, however, is lacking. Moreover, a role for NMDARs in memory consolidation remains controversial. RESULTS: The Drosophila genome encodes two NMDAR homologs, dNR1 and dNR2. When coexpressed in Xenopus oocytes or Drosophila S2 cells, dNR1 and dNR2 form functional NMDARs with several of the distinguishing molecular properties observed for vertebrate NMDARs, including voltage/Mg(2+)-dependent activation by glutamate. Both proteins are weakly expressed throughout the entire brain but show preferential expression in several neurons surrounding the dendritic region of the mushroom bodies. Hypomorphic mutations of the essential dNR1 gene disrupt olfactory learning, and this learning defect is rescued with wild-type transgenes. Importantly, we show that Pavlovian learning is disrupted in adults within 15 hr after transient induction of a dNR1 antisense RNA transgene. Extended training is sufficient to overcome this initial learning defect, but long-term memory (LTM) specifically is abolished under these training conditions. CONCLUSIONS: Our study uses a combination of molecular-genetic tools to (1) generate genomic mutations of the dNR1 gene, (2) rescue the accompanying learning deficit with a dNR1+ transgene, and (3) rapidly and transiently knockdown dNR1+ expression in adults, thereby demonstrating an evolutionarily conserved role for the acute involvement of NMDARs in associative learning and memory.

Amino Acid Sequence↗
PubMed2005

Ca2+/calmodulin protein kinase II and memory: learning-related changes in a localized region of the domestic chick brain.

The role of calcium/calmodulin-dependent protein kinase II (CaMKII) in the recognition memory of visual imprinting was investigated. Domestic chicks were exposed to a training stimulus and learning strength measured. Trained chicks, together with untrained chicks, were killed either 1 h or 24 h after training. The intermediate and medial hyperstriatum ventrale/mesopallium (IMHV/IMM), a forebrain memory storage site, was removed together with a control brain region, the posterior pole of the neostriatum/nidopallium (PPN). Amounts of membrane total alphaCaMKII (tCaMKII) and Thr286-autophosphorylated alphaCaMKII (apCAMKII) were measured. For the IMHV/IMM 1 h group, apCaMKII amount and apCAMKII/tCaMKII increased as chicks learned. The magnitude of the molecular changes were positively correlated with learning strength. No learning-related effects were observed in PPN, or in either region at 24 h. These results suggest that CaMKII is involved in the formation of memory but not in its maintenance.

Animals↗
PubMed1991

[Involvement of the olfactory system in learning and memory: a close correlation between the olfactory deficit and the course of Alzheimer's disease?].

Alzheimer's disease is characterized pathologically by the development of numerous neuritic plaques (NP) and neurofibrillary tangles (NFT) within the brain. Recent studies of Alzheimer's disease patients have uniformly shown marked impairment on odor recognition. In Alzheimer's disease, brain structures closely related to the olfactory bulb (OB) or the olfactory system demonstrate significantly histopathological changes. Anatomically, the olfactory bulbs project through the lateral olfactory tracts to the olfactory tubercules, the pyriform cortex, the cortical amygdala nucleus, and the ventrolateral entorhinal area. In addition, the olfactory system is particularly rich in acetylcholine and other neurotransmitters, many of which are deficient in Alzheimer's disease. Furthermore, increased numbers of NP and NFT in the OB and anterior olfactory nucleus have been demonstrated in patients with Alzheimer's disease. These findings suggest that there is a close correlation between the impairment of olfactory processes and the course of Alzheimer's disease. In animal study, many investigators have become interested in the role that olfactory cues play in learning/memory. Bilateral olfactory bulbectomy in rats impairs passive avoidance and radial-maze task in acquisition. In both working and reference memory tasks using a 3-panel runway apparatus, OB-lesioned rats showed a marked increase of errors (pushes made on the two incorrect panels of the 3-panel gates located at 4 choice points). Furthermore, in 3-lever operant task using a delayed matching-to-lever location procedure, OB lesions decreased significantly the correct response in test trials without affecting that in training trials. These findings indicate that olfactory bulbectomy leads to severe impairment of memory in rats. Interestingly, the appearance of memory impairment is delayed following OB lesions. Earlier studies also had shown that the rats do not require olfactory cues for efficient performance in some learning task. Judging from these findings, the impairment of memory do not attribute solely to olfactory deficit. Therefore, it seems likely that the impairment of memory following the bulbectomy might be due to secondary degeneration in several areas projected from the OB rather than to the olfactory deficit. Unfortunately, investigation of the mechanism underlying the development of Alzheimer's disease has been hampered by the lack of an animal model. In this context, as reviewed here, since OB-lesioned rats show severe impairment of memory with some emotional changes, the olfactory bulbectomy syndrome may be a useful model of Alzheimer's disease. Such a review inevitably raises more questions than its answers, but it is hoped that it may stimulate further investigation in this new field.

Alzheimer Disease↗
PubMed2002

Visuospatial memory and learning in first-episode schizophreniform psychosis and established schizophrenia: a functional correlate of hippocampal pathology?

BACKGROUND: Despite a number of studies that have indicated impaired memory function in patients with schizophrenia, there have been few that have used a sensitive measure of right medial temporal lobe pathology. Given the reported findings of reduced hippocampal volume in schizophrenia, we used a theoretically sensitive test of the right medial temporal lobe to determine the nature of the visuospatial memory deficit in the disorder. METHODS: Seventy-six patients (37 with a first-episode schizophreniform psychosis, and 39 with established schizophrenia) were compared with 41 comparison subjects on a number of tests of visuospatial memory. These included spatial working memory, spatial and pattern recognition memory and a pattern-location associative learning test. RESULTS: Both patient groups displayed recognition memory deficits when compared to the comparison group. However, only those patients with established schizophrenia (of 9 years duration on average) were impaired on the associative learning test. CONCLUSIONS: The results indicate either a progressive decline in visuospatial associative learning ability over the course of the disorder, or that poor visuospatial associative learning is a marker for poor prognosis. In addition, these results have implications for our understanding of the role of the right medial temporal lobe in the pathophysiology of schizophrenia.

Adolescent↗
PubMed2006

Disruption of primary motor cortex before learning impairs memory of movement dynamics.

Although multiple lines of evidence implicate the primary motor cortex (M1) in motor learning, the precise role of M1 in the adaptation to novel movement dynamics and in the subsequent consolidation of a memory of those dynamics remains unclear. Here we used repetitive transcranial magnetic stimulation (rTMS) to dissociate the contribution of M1 to these distinct aspects of motor learning. Subjects performed reaching movements in velocity-dependent force fields over three epochs: a null-field baseline epoch, a clockwise-field learning epoch (15 min after the baseline epoch), and a clockwise-field retest epoch (24 h after the learning epoch). Half of the subjects received 15 min of 1 Hz rTMS to M1 between the baseline and learning epochs. Subjects given rTMS performed identically to control subjects during the learning epoch. However, control subjects performed with significantly less error than rTMS subjects in the retest epoch on the following day. These results suggest that M1 is not critical to the network supporting motor adaptation per se but that, within this network, M1 may be important for initiating the development of long-term motor memories.

Adaptation, Physiological↗
PubMed1992

Blood ethanol concentration from early postnatal exposure: effects on memory-based learning and hippocampal neuroanatomy in infant and adult rats.

Early postnatal exposure to ethanol (EtOH) that results in daily high-peak blood ethanol concentration (BEC) retarded the acquisition of single-patterned alteration (PA), a kind of memory-based discrimination learning, and was related to reduced brain weight, hippocampal cell number, and CA1 area in infant rats. These behavioral and neuroanatomical effects survived into young adulthood. On the PA discrimination, in both pups and young adults, postnatal exposure to high-peak EtOH condition, in relation to low-peak and control conditions, impaired the acquisition of PA at 60-s but not at 30-s intertrial intervals. These results provide further evidence of hippocampal involvement in intermediate-term memory and indicate that early postnatal EtOH is a behavioral and neuroanatomical teratogen, particularly when the BEC is relatively high.

Alcohol Drinking↗
PubMed2002

Learning and memory is preserved after induced asanguineous hyperkalemic hypothermic arrest in a swine model of traumatic exsanguination.

BACKGROUND: Induced asanguineous hypothermic metabolic arrest (suspended animation) could provide valuable time to repair major vascular injuries if safely induced in patients with trauma. We report a novel method of doing this in a swine model of uncontrolled lethal hemorrhage (ULH) that resulted in preservation of learning ability and memory. METHODS: Yorkshire swine (100 to 125 lb) underwent ULH before rapid intra-aortic infusion of a hypothermic (4 degrees C), hyperkalemic (70 mEq/L) organ preservation solution by a left thoracotomy. Cooling continued until core temperature reached 10 degrees C, and this was maintained for 60 minutes using low-flow cardiopulmonary bypass. Vascular injuries were repaired during this state of suspended animation, which was then reversed, and the animals were observed for 6 weeks. Cognitive functions were tested by training animals to retrieve food from color-coded boxes. Postoperatively, the ability to remember this task and a 75-point objective neurologic scale were used to test neurologic function. In experiment I, ULH was caused by lacerating thoracic aorta (n = 9). Five preoperatively untrained animals were trained to perform the task and compared with control animals (n = 15), and 4 preoperatively trained animals were tested for memory retention postoperatively. In experiment II, ULH was induced by creating an iliac artery and vein injury (n = 15). Animals were kept in shock for 15, 30, and 60 minutes before the induction of hypothermia. RESULTS: In experiment I, surviving animals (7/9) were neurologically intact, and their capacity to learn new skills was no different than for control animals. All pretrained animals demonstrated complete memory retention. In experiment II, survival with 15, 30, and 60 minutes of shock were 80%, 60%, and 80%, respectively. All animals (except 1) in the 60-minute group were neurologically intact and displayed normal learning capacity. CONCLUSIONS: Induction of hypothermic metabolic arrest (by thoracotomy) for repair of complex traumatic injuries is feasible with preservation of normal neurologic function, even after extended periods of shock from an intra-abdominal source of uncontrolled hemorrhage.

Animals↗