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PubMed1990

Odor memory and odor learning in rats with lesions of the lateral olfactory tract and mediodorsal thalamic nucleus.

Rats with posterior transection of the lateral olfactory tract (LOT), lesions of the mediodorsal thalamic nucleus (MD), or with combined lesions of these structures were tested for retention of a preoperatively learned multiple odor discrimination task, acquisition of 3 simple 2-odor discrimination problems, and reversal of the last problem of the series. Compared to controls, rats with transection of the LOT had no deficits in any task. Those with MD lesions had no deficits in retention but moderate deficits in acquisition of novel odor discriminations and a severe deficit in reversal learning. Rats with combined LOT and MD lesions had no retention of the preoperatively learned task but their performance on the remaining problems was similar to that of rats with only MD lesions. These results suggest that neither the olfactory thalamocortical projections nor those to the periamygdaloid or entorhinal cortex are essential for storage and/or recall of an olfactory procedural memory task. Performance on the postoperative acquisition tests indicate that the thalamocortical but not the limbic olfactory projections play an important role in olfactory discrimination learning.

Animals↗
PubMed2006

Estrogen modulates learning in female rats by acting directly at distinct memory systems.

Physiologically high levels of circulating estradiol enhance the use of place learning and impair the use of response learning to find food on a land maze. These two types of learning are impaired by lesions of distinct neuronal structures, i.e. the hippocampus and striatum, respectively. Moreover, it has been shown in male rats that compromising hippocampal function can promote the use of response learning, while compromising striatal function can promote place learning. These findings suggest an ongoing competition between the hippocampus and striatum during cognition, such that intact functioning of one structure somehow obstructs the relative participation of the other. The goal of this study was to determine if estrogen's opposing effects on place and response learning in female rats are due to direct actions, either independent or interacting, at the hippocampus and striatum. We infused 0.5 microM 17beta-estradiol 3-sulfate sodium or vehicle bilaterally into the dorsal hippocampus or dorsolateral striatum of ovariectomized young adult female rats, 48, 24 and 2 h before training. Rats were tested on one of three appetitive tasks in a Y-maze: place learning, response learning, or response learning with reduced visual cues (cue-poor condition). Intrahippocampal estradiol infusions enhanced place learning, reversing a cannula-induced impairment, whereas intrastriatal infusions had no effects on place learning. Estradiol infusions into neither structure significantly affected response learning when extramaze cues were visible. However, in the response task, cue-poor condition, intrastriatal but not intrahippocampal infusions impaired learning. These data demonstrate that estrogen modulates place and response learning at the hippocampus and striatum respectively, most likely through independent actions at these two structures.

Animals↗
PubMed2000

Strain and sex differences on olfactory discrimination learning in C57BL/6J and DBA/2J inbred mice (Mus musculus).

In this study, the authors explored potential strain and sex differences in nonspatial cognitive ability. Beginning around 90 days of age, male and female C57BL/6J (C57) and DBA/2J (DBA) inbred mice (Mus musculus) were tested on a task of simple odor discrimination learning with 3 repeated reversals. Males learned the task more readily than females, and DBA mice learned the task more readily than C57 mice. All differences became evident after repeated testing. Similarity of perseveration measures indicated the differences were not due to inhibitory deficits. Instead, a phase analysis localized differences to a transitional period of reversal learning. Females increased transitional errors that more likely indicated adaptive sampling strategies than memory failures. C57 females used this strategy indiscriminately, but DBA females sampled as a function of environmental uncertainty.

Animals↗
PubMed2000

Behavioural evaluation of long-term neurotoxic effects of NMDA receptor antagonists.

High doses of NMDA antagonists e.g. (+)MK-801 evoke neurodegeneration in retrosplenial cortex in rodents. To assess functional consequences of such treatment, three paradigms of two-way active avoidance learning (with visual or auditory conditioned stimuli) and additionally a spatial learning paradigm - radial maze - were used. Female rats were treated i.p. with 5 mg/kg of (+)MK-801. Recumbence, severe hypothermia and loss of body weight were observed for 3-7 days. Despite that, there were no statistically significant differences in performance of avoidance reaction between saline and (+)MK-801 treated animals trained 10-40 days after the drug administration. However, in the radial maze test (+)MK-801 impaired reference (but not working) memory in the experiment that started 8 days after the treatment. Similar effect was observed on reversal learning. The clinically used NMDA receptor antagonist memantine at the doses of 20 and 40 mg/kg had also no such long term negative effect on working memory during training (even positive effect was seen at 20 mg/kg) but at 40 mg/kg impaired learning on the first day of reversal. This indicates that (+)MK-801 neurotoxicity in the retrosplenial cortex is connected with subtle alterations in the learning performance that may be seen in some tests only. Moreover, memantine doses greatly exceeding therapeutically relevant range produce minimal functional alteration. An additional experiment revealed that the same dose of memantine results in two fold higher serum levels of the antagonist in female than male rats. Hence, considering that profiling studies are done in male rats, a safety factor of over 16 fold can be calculated for memantine.

Journal Article↗
PubMed2002

Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome.

Estrogen maintains normal function of basal forebrain (BF) cholinergic neurons and estrogen replacement therapy (ERT) has therefore been proposed as a therapy for Alzheimer's disease (AD). We provide evidence to support this hypothesis in an animal model of Down syndrome (DS), a chromosome 16 segmental trisomy (Ts65Dn) mouse. These mice develop cholinergic degeneration similar to young adults with DS and AD patients. ERT has not been tested in women with DS, even though they are more likely than normosomic women to develop early menopause and AD. Female Ts65Dn and normosomic mice (11-15 months) received a subcutaneous estrogen pellet or a sham operation. After 60 days, estrogen treatment improved learning of a T-maze task and normalized behavior in the Ts65Dn mice in reversal learning of the task, a measure of cognitive flexibility. Stereological evaluation of choline acetyltransferase (ChAT) immunopositive BF neurons showed that estrogen increased cell size and total number of cholinergic neurons in the medial septum of Ts65Dn mice. In addition, estrogen increased NGF protein levels in the BF of trisomic mice. These findings support the emerging hypothesis that estrogen may play a protective role during neurodegeneration and cognitive decline, particularly in cholinergic BF neuronal systems underlying cognition. The findings also indicate that estrogen may act, at least partially, via endogenous growth factors. Collectively, the data suggest that ERT may be a viable therapeutic approach for women with DS coupled with dementia.

Animals↗
PubMed1999

Characterization of learning and memory deficits in C57BL/6 mice infected with LP-BM5, a murine model of AIDS.

Mice infected with an immunosuppressive murine leukemia virus mixture, LP-BM5 show a profound immunosuppression described as murine acquired immune deficiency syndrome (AIDS). In the present study, we characterized learning and memory deficits in C57BL/6 mice infected with LP-BM5. Spontaneous alternation behavior in a Y-maze and latent learning (spatial attention) in a water-finding test, as well as spatial reference and reversal learning in a water maze test, were significantly impaired in the mice infected with LP-BM5. These deficits appeared in the absence of any motoric and visual impairment as assessed by open-field, rotarod and visual water maze tests. These results suggest that cognitive functions are impaired in the mice infected with LP-BM5. Furthermore, LP-BM5-infected mice may be useful as a model for the AIDS dementia complex.

AIDS Dementia Complex↗
PubMedDate not supplied

Periadolescent rats (P41-50) exhibit increased susceptibility to D-methamphetamine-induced long-term spatial and sequential learning deficits compared to juvenile (P21-30 or P31-40) or adult rats (P51-60).

We have previously shown that P11-20 treatment with d-methamphetamine (MA) induces impaired spatial navigation in the Morris water maze (MWM), whereas P1-10 treatment does not. Little is known about the long-term behavioral consequences of MA during juvenile, adolescent, and early adult brain development. In dose-response experiments, we tested successive 10-day intervals of exposure to MA in rats (P21-30, P31-40, P41-50, and P51-60; four doses per day). MA dosing prior to P21 produces little or no toxicity; however, we observed an increased toxicity with advancing age. Across-age comparisons revealed no MWM acquisition or Cincinnati water maze (CWM) effects after MA treatment on P21-30 (2.5-10 mg/kg/dose), P31-40 (1.25-7.5 mg/kg/dose), or P51-60 (1.25-5.0 mg/kg/dose); however, significantly impaired MWM acquisition was observed after P41-50 MA treatment at the highest dose (6.25 mg/kg/dose). Learning in the CWM was also impaired in this group. No effects were seen at 1.25, 2.5, or 5 mg/kg/dose following P41-50 MA treatment. MWM reversal learning trials after P41-50 treatment showed a trend towards longer latency in all MA dose groups, but no effect on double-reversal trials. Reversal and double-reversal also showed no effects at the other exposure ages. No differences in straight channel swimming or cued learning in the MWM were seen after MA treatment at any exposure age. P41-50 is the periadolescent stage of brain development in rodents. The effects observed at this age may suggest a previously unrecognized period of susceptibility for MA-induced cognitive deficits.

Age Factors↗
PubMed2001

Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down's syndrome.

Down's syndrome (DS) is a major cause of mental retardation, hypotonia and delayed development. Murine models of DS carrying large murine or human genomic fragments show motor alterations and memory deficits. The specific genes responsible for these phenotypic alterations have not yet been defined. DYRK1A, the human homolog of the Drosophila minibrain gene, maps to the DS critical region of human chromosome 21 and is overexpressed in DS fetal brain. DYRK1A encodes a serine-threonine kinase, probably involved in neuroblast proliferation. Mutant Drosophila minibrain flies have a reduction in both optic lobes and central brain, showing learning deficits and hypoactivity. We have generated transgenic mice (TgDyrk1A) overexpressing the full-length cDNA of Dyrk1A. TgDyrk1A mice exhibit delayed cranio-caudal maturation with functional consequences in neuromotor development. TgDyrk1A mice also show altered motor skill acquisition and hyperactivity, which is maintained to adulthood. In the Morris water maze, TgDyrk1A mice show a significant impairment in spatial learning and cognitive flexibility, indicative of hippocampal and prefrontal cortex dysfunction. In the more complex repeated reversal learning paradigm, this defect turned out to be specifically related to reference memory, whereas working memory was almost unimpaired. These alterations are comparable with those found in the partial trisomy chromosome 16 murine models of DS and suggest a causative role of DYRK1A in mental retardation and in motor anomalies of DS.

Animals↗
PubMed1996

A comparison of the effects of frontal cortical and thalamic lesions on measures of spatial learning and memory in the rat.

Two experiments were conducted to compare the effects of radiofrequency lesions of thalamus and frontal cortex on three measures of spatial learning and memory: delayed non-matching to sample (DNMTS), radial arm maze with imposed delays, and serial reversal learning. Thalamic lesions were aimed at the lateral internal medullary lamina (L-IML) and cortical lesions at the projection areas of the mediodorsal nucleus along the medial wall (MW) and dorsal to the rhinal sulcus (RS) in frontal cortex. In Experiment 1 rats were trained on DNMTS prior to surgery. After recovery, rats with MW lesions showed persistent deficits on DNMTS that were significantly greater than for RS lesions. The deficits observed in MW lesioned animals were comparable to the effects of L-IML lesions on this task that have been described in previous studies. In Experiment 2 animals were trained to perform the radial arm maze task prior to treatment. After recovery, animals with L-IML lesions were impaired on the radial arm maze and on subsequent acquisition of the serial reversal task. Rats with RS and MW lesions showed transient impairments on the radial arm maze task, but otherwise performed as well as controls on both these tasks.

Animals↗
PubMed2001

Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695.

We have created early-onset transgenic (Tg) models by exploiting the synergistic effects of familial Alzheimer's disease mutations on amyloid beta-peptide (Abeta) biogenesis. TgCRND8 mice encode a double mutant form of amyloid precursor protein 695 (KM670/671NL+V717F) under the control of the PrP gene promoter. Thioflavine S-positive Abeta amyloid deposits are present at 3 months, with dense-cored plaques and neuritic pathology evident from 5 months of age. TgCRND8 mice exhibit 3,200-4,600 pmol of Abeta42 per g brain at age 6 months, with an excess of Abeta42 over Abeta40. High level production of the pathogenic Abeta42 form of Abeta peptide was associated with an early impairment in TgCRND8 mice in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months of age. Notably, learning impairment in young mice was offset by immunization against Abeta42 (Janus, C., Pearson, J., McLaurin, J., Mathews, P. M., Jiang, Y., Schmidt, S. D., Chishti, M. A., Horne, P., Heslin, D., French, J., Mount, H. T. J., Nixon, R. A., Mercken, M., Bergeron, C., Fraser, P. E., St. George-Hyslop, P., and Westaway, D. (2000) Nature 408, 979-982). Amyloid deposition in TgCRND8 mice was enhanced by the expression of presenilin 1 transgenes including familial Alzheimer's disease mutations; for mice also expressing a M146L+L286V presenilin 1 transgene, amyloid deposits were apparent by 1 month of age. The Tg mice described here suggest a potential to investigate aspects of Alzheimer's disease pathogenesis, prophylaxis, and therapy within short time frames.

Aging↗
PubMed2005

Downregulation of endocannabinoid signaling in the hippocampus following chronic unpredictable stress.

Deficits in cognitive functioning and flexibility are seen following both chronic stress and modulation of endogenous cannabinoid (eCB) signaling. Here, we investigated whether alterations in eCB signaling might contribute to the cognitive impairments induced by chronic stress. Chronic stress impaired reversal learning and induced perseveratory behavior in the Morris water maze without significant effect on task acquisition. These cognitive impairments were reversed by exogenous cannabinoid administration, suggesting deficient eCB signaling underlies these phenomena. In line with this hypothesis, chronic stress downregulated CB1 receptor expression and significantly reduced the content of the endocannabinoid 2-arachidonylglycerol within the hippocampus. CB1 receptor density and 2-arachidonylglycerol content were unaffected in the limbic forebrain. These data suggest that stress-induced downregulation of hippocampal eCB signaling contributes to problems in behavioral flexibility and could play a role in the development of perseveratory and ruminatory behaviors in stress-related neuropsychiatric disorders.

Animals↗
PubMed2000

Spatial learning, contextual fear conditioning and conditioned emotional response in Fmr1 knockout mice.

Fmr1 knockout mice are an animal model for fragile X syndrome, the most common form of heritable mental retardation in humans. Fmr1 knockout mice exhibit macro-orchidism and cognitive and behavioural deficits reminiscent of the human phenotype. In the present study additional behavioural and cognitive testing was performed. Knockouts and control littermates were subjected to a spatial learning test using a plus-shaped water maze. Animals had to learn the position of a hidden escape platform during training trials. The position of this platform was changed during subsequent reversal trials. Previously reported deficits in reversal learning were replicated, but we also observed significant differences during the acquisition trials. A plus-shaped water maze experiment with daily changing platform positions failed to provide clear evidence for a working memory impairment, putatively underlying the spatial learning deficits. Two different test settings were used to examine the reported deficit of Fmr1 knockout mice in fear conditioning. Conditioned fear responses were observed in a contextual fear test, and the ability to acquire an emotional response was tested by means of response suppression in a conditioned emotional response procedure. Neither protocol revealed significant differences between controls and knockouts.

Acoustic Stimulation↗
PubMedDate not supplied

Learning impairment caused by a toxin produced by Pfiesteria piscicida infused into the hippocampus of rats.

Pfiesteria piscicida, an estuarine dinoflagellate, which has been shown to kill fish, has also been associated with neurocognitive deficits in humans. With a rat model, we have demonstrated the cause-and-effect relationship between Pfiesteria exposure and learning impairment. In several studies, we have replicated the finding in Sprague-Dawley rats that exposure to fixed acute doses of Pfiesteria cells or filtrates caused radial-arm maze learning impairment. Recently, this finding of Pfiesteria-induced learning impairment in rats has been independently replicated in another laboratory as well. We have demonstrated significant Pfiesteria-induced learning impairment in both the win-shift and repeated-acquisition tasks in the radial-arm maze and in reversal learning in a visual operant signal detection task. These learning impairments have been seen as long as 10 weeks after a single acute exposure to Pfiesteria. In the current study, we used a hydrophilic toxin isolated from clonal P. piscicida cultures (PfTx) and tested its effect when applied locally to the ventral hippocampus on repeated acquisition of rats in the radial-arm maze. Toxin exposure impaired choice accuracy in the radial-arm maze repeated acquisition procedure. The PfTx-induced impairment was seen at the beginning of the session and the early learning deficit was persistent across 6 weeks of testing after a single administration of the toxin. Eventually, with enough practice, in each session, the PfTx-exposed rats did learn that session's problem as did control rats. This model has demonstrated the cause-and-effect relationship between exposure to a hydrophilic toxin produced by P. piscicida and learning impairment, and specifically that the ventral hippocampus was critically involved.

Animals↗
PubMed1998

The profile of sabcomeline (SB-202026), a functionally selective M1 receptor partial agonist, in the marmoset.

1. Sabcomeline (SB-202026, 0.03 mg kg(-1), p.o.), a potent and functionally selective M1 receptor partial agonist, caused a statistically significant improvement in the performance of a visual object discrimination task by marmosets. No such improvement was seen after RS86 (0.1 mg kg(-1), p.o.). 2. Initial learning, which only required an association of object with reward and an appropriate response to be made, was not significantly affected. Reversal learning, which required both the extinction of the previously learned response and the acquisition of a new response strategy, was significantly improved after administration of sabcomeline (0.03 mg kg(-1), p.o.). 3. Sabcomeline (0.03 and 0.1 mg kg(-1), p.o.) had no significant effect on mean blood pressure measured for 2 h after administration in the conscious marmoset. 4. Sabcomeline (0.03 mg kg(-1), p.o.) caused none of the overt effects such as emesis or behaviours often seen after the administration of muscarinic agonists, e.g. face rubbing and licking. 5. This is the first study to demonstrate cognitive enhancement by a functionally selective M1 receptor partial agonist in a normal (i.e. non-cognitively impaired) non-human primate and this effect was seen at a dose which did not cause side effects. 6. Perseverative behaviour and deficient acquisition of new information are seen in patients with Alzheimer's disease (AD). Therefore the data suggest that sabcomeline might be of therapeutic benefit in the treatment of AD.

Alzheimer Disease↗
PubMed1980

[Effect of neuropeptide fragments of adrenocorticotropic hormone and vasopressin on the behavioral activity of rats].

The effects of vasopressin and those of fragments of adrenocorticotropin ACTH5-10; ACTH4-7; l-phenilalanin, and ACTH4-7 d-phenilalanin on the learning of rats in U-shaped labyrinth were studied. The consolidation of skills in long-term memory ability for reversal learning were checked. The results suggest that effect of all these oligopeptides on the higher nervous activity is significant and specific, vasopressin improving the long-term memory, ACTH4-7-l-phenilalanin improving the learning, ACTH4-7-d-phenilalanin making learning next to impossible.

Adrenocorticotropic Hormone↗
PubMed2004

A novel cognitive palatability assessment protocol for dogs.

Assessment of canine palatability is important for both the pet food and pharmaceutical industries; however, the current palatability assessment protocols are limited in their utility. The most common technique, the two-pan test, does not control for the satiating effects of food and may not be useful for long-term palatability analysis because nutritional or caloric characteristics of the diets may interfere with the results. Furthermore, the large quantities of foods consumed may be detrimental to the health of animals that do not self-limit their food intake. The purpose of this study was to determine whether a cognitive protocol could be used to determine food palatability in dogs. Five beagle dogs were trained on a three-choice object-discrimination learning task. After establishing object preferences, the preferred object was associated with no reward, a second object was associated with the dog's normal laboratory diet (Purina Agribrands Canine Lab Chow No. 5006; Agribrands Purina Canada, Inc., Woodstock, ON, Canada), and the third object was associated with a commercial (Hill's P/D; Hill's Pet Nutrition Inc., Topeka, KS) diet. In the discrimination-training phase, dogs were trained until they learned to avoid the no-reward object. They were subsequently given an additional 20 test sessions, which were used to determine food preference. In the reversal phase, which involved reversal learning, the object-food associations were modified, such that the object that was previously associated with Hill's P/D diet was now associated with the normal laboratory diet and vice versa. Once the dogs learned to avoid the no-reward object, they were tested for an additional 20 sessions. All subjects learned to avoid the no-reward object during the initial learning, and the number of choices to the object associated with the Hill's P/D diet was greater than the number of choices to the objects associated with the dry laboratory diet (P < 0.05) and no reward (P < 0.05), indicating a strong preference for the Hill's P/D diet. The object preferences were reversed in only three of five dogs when the food-choice associations were reversed, although the two phases did not differ significantly from one another. The protocol in the present study provides a robust measure of food palatability and circumvents many of the limitations associated with other palatability assessment techniques. The present protocol should be useful as a replacement or adjunct to other tests of palatability, but requires further validation by comparing the assessment of more similar and novel foods directly with other palatability tests.

Animal Feed↗
PubMed2003

Protein tyrosine phosphatase alpha (PTP alpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety.

Receptor PTPalpha is a widely expressed transmembrane enzyme enriched in brain. PTPalpha knockout (PTPalpha(-/-)) mice are viable and display no gross abnormalities. Brain and embryo derived fibroblast src and fyn activity is reduced to <50% in PTPalpha(-/-) mice. These protein kinases are implicated in multiple aspects of neuronal development and function. However, the effect of the loss of function of the PTPalpha gene on behavior has yet to be investigated. PTPalpha(-/-) and WT mice were tested for anxiety, swimming ability, spatial learning, cued learning, locomotor activity, and novel object recognition (NOR). PTPalpha(-/-) mice were indistinguishable from WT in swimming ability, cued learning and novel object recognition. Knockout mice showed decreased anxiety without an increase in head dips and stretch-attend movements. During Morris water maze (MWM) learning, PTPalpha(-/-) mice had increased latencies to reach the goal compared to WT on acquisition, but no memory deficit on probe trials. On reversal learning, knockout mice showed no significant effects. PTPalpha(-/-) mice showed decreased exploratory locomotor activity, but responded normally to a challenge dose of D-methamphetamine. The data suggest that PTPalpha serves a regulatory function in learning and other forms of neuroplasticity.

Animals↗
PubMed1995

Neuropsychological changes in a prospectively followed cohort of homosexual and bisexual men with and without HIV infection.

We evaluated neuropsychological test performance of 168 homosexual and bisexual men with and without human immunodeficiency virus (HIV) infection (113 HIV+ subjects and 55 HIV- controls) over 4.5 years of semiannual follow-up. Analyses of the longitudinal data were performed by applying generalized estimating equations (GEEs) to regression analyses with repeated measures. Compared with the HIV- men, the HIV+ subjects performed more poorly on memory testing. Performance on all tests tended to improve over time, but this improvement was attenuated or eliminated in the HIV+ group for tests of language and attention. Within the HIV+ subjects, improvement over time in tests of memory, executive function, language, and attention was attenuated or eliminated in patients with lower CD4 levels; more advanced HIV disease was associated with poorer memory and executive function and with attenuated or reduced learning effects for memory, motor speed, and language tests. Clinically significant neurologic findings were associated with worse memory and orientation and with attenuated or reversed learning effects for memory, language, and attention tests. There were 33 deaths in the HIV+ group. In the men who died, there was more rapid decline in executive, language, and attentional test performance. These observations remained significant after controlling for HIV disease severity. We conclude that HIV infecting the CNS results in progressive cognitive change that is closely associated with neurologic findings. In addition, our findings suggest a relation between more rapid cognitive progression and death.

Adult↗