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PubMed1989

[Preparation of cerebral ischemia-induced amnesic model in mice and ameliorative effect of several compounds on the model].

A simple and reliable method for the preparation of an ischemia-induced amnesic model was developed in mice and the model animals were employed for screening of the anti-amnesic effect of drugs. Under light thiopental anesthesia the bilateral carotid arteries were exfoliated from the surrounding tissues. Each artery was threaded through a small polyethylene tube, and the incision was sutured, leaving the tip of the tube and both ends of the thread out of the skin. To prevent the tube from falling off, both ends of the thread was ligated at the tip of the tube. Cerebral ischemia was attained by pulling the artery into the tube, and the occlusion was rapidly released by cutting the ligation in the thread and taking off the tube. Twenty-four hours after the surgery, the animals were used for the one trial passive avoidance learning test. In ddY strain mice, the amnesic state was obtained by 5 to 30 min cerebral ischemia, which was applied immediately after the acquisition trial. Mice of the ICR strain were more sensitive to the ischemic treatment and 2 min occlusion of the carotid arteries resulted in a high degree of amnesia. A potent prolyl endopeptidase inhibitor, Z-thiopro-thiazolidine, and 2 novel pyrrolidone derivatives, p-chlorobenzyl-2-pyrrolidone-5-carboxylate and N-(2-pyridylmethyl)-2-pyrrolidone-5-carboxamide, improved the acquisition of the passive avoidance response in the ischemia-induced amnesic models.

Amnesia↗
PubMed2002

Role of adrenoceptor subtypes in memory consolidation.

Noradrenaline release in areas within the forebrain occurs following activation of noradrenergic cells in the locus coeruleus (LoC). Release of noradrenaline by attentional/arousal/vigilance factors appears to be essential for learning and is responsible for the consolidation of memory. Noradrenaline can activate any of nine different adrenoceptor (AR) subtypes in the brain and selectivity of action may be achieved by the spatial location and relative density of the AR subtypes, by different affinities of the different subtypes and by temporal selectivity in terms of when the different ARs are activated in the memory formation process. This review examines the use of selective agonists and antagonists to determine the roles of the AR subtypes in the one-trial discriminated avoidance learning paradigm in the chick. A model is developed that integrates noradrenergic activity in basal ganglia (lobus parolfactorius (LPO)) and association cortex (intermediate medial hyperstriatum ventrale (IMHV)) leading to the consolidation of memory 30 min after training. There is evidence that beta(2)- and beta(3)-ARs are important in the association area but require input from alpha(2)-AR stimulated activity in the basal ganglia for consolidation. On the other hand, alpha(1)-AR activation in the IMHV is inhibitory and prevents consolidation. While there is no role for beta(1)-ARs in memory consolidation, they play a role in short-term memory (STM). The use of the precocial chick has clear advantages in having a temporally discrete learning task which allows for discrimination memory and whose development can be followed at discrete intervals after learning. These studies reveal clear roles for AR subtypes in the formation and consolidation of memory in the chick, which have allowed the development of a model that can now be tested in mammalian systems.

Animals↗
PubMed1989

Age-related changes of the mossy fibre system in rat hippocampus: effect of long term acetyl-L-carnitine treatment.

Age-related changes of the hippocampal mossy fibre system were studied in rats of different ages (4, 12, and 24 months) using the Timm's histochemical technique for the detection of tissue stores of zinc and heavy transitional metals. Quantitative image analysis and microdensitometry techniques were applied for the evaluation of the changes themselves. The area occupied by mossy fibres and the intensity of Timm's staining in field CA3 of hippocampus were greater in adult rats than in young and old animals. These findings are consistent with previous behavioural data indicating that young and old rats exhibited a reduced passive avoidance learning with respect to adult animals. The above techniques were also used in a second session of this study designed to investigate the effect of a 6-months treatment with acetyl-L-carnitine (ALC) on the hippocampal mossy fibre system. ALC was found to increase significantly the area occupied by mossy fibres and the intensity of Timm's staining in the hippocampus of old rats. These findings are in agreement with and support from an anatomical point of view, the data indicating that long-term treatment with ALC improves passive avoidance performance.

Acetylcarnitine↗
PubMed1990

When cognitive exertion does not yield cognitive gain: toward an informational explanation of learned helplessness.

This study tested a new information-processing explanation of learned helplessness that proposes that an uncontrollable situation produces helplessness symptoms because it is a source of inconsistent, self-contradictory task information during problem-solving attempts. The flow of such information makes hypothesis-testing activity futile. Prolonged and inefficient activity of this kind leads in turn to the emergence of a state of cognitive exhaustion, with accompanying performance deficits. In 3 experiments, Ss underwent informational helplessness training (IHT): They were sequentially exposed to inconsistent task information during discrimination problems. As predicted, IHT was associated with subjective symptoms of irreducible uncertainty and resulted in (a) performance deterioration on subsequent avoidance learning, (b) heightened negative mood, and (c) subjective symptoms of cognitive exhaustion.

Achievement↗
PubMed2001

Role of 5-HT6 receptors in memory formation.

Mice lacking the 5-HT(6) receptor presented neither gross anatomical or behavioral abnormalities nor obvious changes in microscopic brain morphology, and their performance in rotarod, open field and novel object testing paradigms revealed no differences compared with wild-type animals. Nevertheless, an association between the 5-HT(6) receptor polymorphism C267T and Alzheimer's disease has been reported. Interestingly, the 5-HT(6) antisense oligonucleotide decreased 5-HT(6) gene expression and enhanced spatial learning acquisition in the water maze. Similarly, injection of the 5-HT(6) receptor antagonist Ro-04-6790 improved learning consolidation in an autoshaping task, while mCPP, scopolamine and dizocilpine decreased performance. The effect induced by scopolamine or dizocilpine, but not that induced by mCPP, was completely or partially reversed by Ro-04-6790. Ro-04-6790 did not modify the 8-OH-DPAT facilitatory effects on learning consolidation. Since Ro-04-6790 facilitatory effect was unaffected by 5-HT(1A), 5-HT(2A/2B/2C), 5-HT(3), 5-HT(4) or 5-HT(7) receptor blockade, the facilitatory effect induced by Ro-04-6790 involved specifically 5-HT6 receptors. Similarly, the 5-HT(6) receptor antagonist SB-271046 improved retention in the water maze and produced a significant performance improvement in aged rats in an operant-delayed alternation task. A series of Ro-04-6790 analogues that penetrate the brain and specifically bind to 5-HT(6) receptors reversed scopolamine-induced retention deficit in a passive avoidance learning test. Collectively, these data provide further support to the notion that 5-HT systems, via 5-HT(6) receptors, also play a significant role in memory formation under normal and dysfunctional memory conditions.

Journal Article↗
PubMed2000

Dopamine deficiency in mice.

Dopamine is the principal neurotransmitter that mediates a wide range of brain functions, including locomotion, emotion, learning, and neuroendocrine modulation. To clarify the role of dopamine during postnatal development, it is useful to have mutant mice genetically deleting dopamine. In this paper, we describe the mice lacking expression of tyrosine hydroxylase (TH), the first and rate-limiting enzyme of catecholamine biosynthetic pathway, in the dopaminergic neuronal type. In these mice, TH expression in noradrenergic and adrenergic cells was restored. Lack of TH expression in dopaminergic neurons resulted in a marked reduction of dopamine accumulation. This led to multiple behavioral abnormalities at the juvenile stage, which were characterized by a reduction in spontaneous locomotor activity, blockade of methamphetamine-induced hyperactivity, cataleptic behavior, and defect in active avoidance learning. In contrast, development of pituitary gland as well as production and secretion of the pituitary peptide hormones dependent on hypothalamic dopaminergic control were normally maintained in spite of the reduced dopamine synthesis. Our findings provide genetic evidence that dopamine is essential for controlling spontaneous and voluntary movement and emotional learning during postnatal development through the nigrostriatal and mesocorticolimbic pathways.

Age Factors↗
PubMed1994

[The sensory and motor components of different forms of learned movement during a change in the activity of the neostriatal cholinergic system].

The role of the neostriatal cholinergic system in the regulation of sensory controlled movements were studied using two behavioral models: 1) maintenance acquired extension of forelimb during proper time (rats) and 2) prolonged conditional flexion of hindlimb (dogs). It was found that injections of carbacholine (Car, 0.03 mkg) into the dorsolateral part of nucleus caudatus (NCd) of rats did not considerable change the movement connected with maintenance of forelimb tonus, while injections of Car (0.05-0.1 mkg) into the same area of the NCd of dogs were accompanied by improved performance of movement connected with maintenance of hindlimb tonus. It is possible to suggest the follows: 1. The neostriatal mechanisms of regulation of fore- and hindlimb tonus maintenance are different. 2. The neostriatal mediator of mechanisms of tonus regulation and regulation of somesthetic control of maintenance of this tonus are probably different too. Bilateral Car microinjections (0.03 mkg) into NCd of rats improved the discriminative active avoidance learning in T-maze. The discrimination of sound signals in dogs were also significantly improved after Car injections (0.05-0.1 mkg) into the NCd. Thus, data obtained at the different behavioral models and different animals suggest that cholinergic system of Neostriatum takes part in the regulation of both motor and sensory components of learned movements realization. The possible mechanisms of this regulation are discussed.

Animals↗
PubMed1981

Effects of bromocriptine in developing rat pups after 6-hydroxydopamine.

The effects of low (0.5 mg/kg) and high (2.0 mg/kg) doses of bromocriptine (BCR) on activity and escape performance were examined during the first month of postnatal life in normal developing rat pups and littermates treated at 5 days of age with a combination of desmethylimipramine and 6-hydroxydopamine (6-OHDA). Such a procedure resulted in significant reductions in brain dopamine to concentrations 10-20% of vehicle controls while norepinephrine was unaffected. BCR increased general motor activity in vehicle pups at 13 and 19 days but had little effect on more mature animals. Pups who had not received BCR exhibited a decline in activity over the hour long observation period (habituation of activity) but this decline was abolished by both low (0.5 mg/kg) and high (2.0 mg/kg) doses of the agent. Stereotyped activity, particularly at 19 days was increased by BCR in 6-OHDA pups but not in vehicle animals, an effect suggesting denervation supersensitivity. Head dips in a hole box at 30 days of age were not influenced by BCR in vehicle pups but significantly reduced by BCR in 6-OHDA pups, suggesting that BCR might be acting to stimulate inhibitory dopaminergic mechanisms. Escape learning in a T-maze at 20 days and shuttle box at 28 days was disrupted by high doses of BCR in vehicle pups and both doses of BCR in 6-OHDA animals. The similarity with the behaviors observed in the clinical syndrome of attention deficit disorder with hyperactivity prompted a number of investigative groups including our own to suggest that the 6-OHDA model might serve as a useful and convenient paradigm to evaluate pharmacological agents that offer potential in the treatment of this most common disorder. From this perspective we would predict that BCR would have little clinical utility since it both failed to attenuate 6-OHDA induced hyperactivity and tended to disrupt performance in an avoidance learning task.

Animals↗
PubMedDate not supplied

Behavioral effects of prenatal methoxy-ethyl-mercury chloride exposure in rat pups.

A number of neurotoxic drugs, when administered prenatally, induce neurobehavioral impairments and cause delay of the development of central nervous functions, without morphological malformations. Experiments were undertaken to clarify the behavioral teratogenicity of the fungicide methoxy-ethyl-mercury chloride (MEMC). CFY rat dams were treated with different doses of MEMC during 7th-15th days of gestation (2.0, 0.62 and 0.02 mg/kg daily), perorally. Development of gait, motor coordination, behavior patterns in an open field test, swimming, and conditioned avoidance learning were tested at different ages of rat pups. MEMC did not cause any mortality of dams, but there was a mild ataxia at the 2.0 mg/kg treatment. While birthweight, number of offspring, ear-eye opening and gait were normal, unexpectedly high mortality occurred perinatally. After weaning, open field behavior was nearly normal, there was a mild decrease of rearing, grooming and ambulation and an initial preference for the periphery of the open field decreased. Ambulation increased significantly in 90-day-old pups. Motor coordination on a rotorod decreased in 23- and 36-day-old pups, but increased in 90-day-old pups at the 2.0 mg/kg dose. There was no difference among groups in amphetamine sensitivity tested in a swim stress test. During avoidance conditioning, pups treated with the two higher doses performed poorly when compared to controls and the latency of the positive conditioned response was lengthened significantly. Our results show a dose-dependent behavioral teratogenicity of this organomercurial fungicide. The so called no effect level--as far as the neurobehavioral impairments due to prenatal exposure are concerned--is 0.02 mg/kg daily.

Aging↗
PubMedDate not supplied

Role of hippocampal signaling pathways in long-term memory formation of a nonassociative learning task in the rat.

Long-term habituation to a novel environment is one of the most elementary forms of nonassociative learning. Here we studied the effect of pre- or posttraining intrahippocampal administration of drugs acting on specific molecular targets on the retention of habituation to a 5-min exposure to an open field measured 24 h later. We also determined whether the exposure to a novel environment resulted in the activation of the same intracellular signaling cascades previously shown to be activated during hippocampal-dependent associative learning. The immediate posttraining bilateral infusion of CNQX (1 microg/side), an AMPA/kainate glutamate receptor antagonist, or of muscimol (0.03 microg/side), a GABA(A) receptor agonist, into the CA1 region of the dorsal hippocampus impaired long-term memory of habituation. The NMDA receptor antagonist AP5 (5 microg/side) impaired habituation when infused 15 min before, but not when infused immediately after, the 5-min training session. In addition, KN-62 (3.6 ng/side), an inhibitor of calcium calmodulin-dependent protein kinase II (CaMKII), was amnesic when infused 15 min before or immediately and 3 h after training. In contrast, the cAMP-dependent protein kinase (PKA) inhibitor Rp-cAMPS, the mitogen-activated protein kinase kinase (MAPKK) inhibitor PD098059, and the protein synthesis inhibitor anisomycin, at doses that fully block memory formation of inhibitory avoidance learning, did not affect habituation to a novel environment. The detection of spatial novelty is associated with a sequential activation of PKA, ERKs (p44 and p42 MAPKs) and CaMKII and the phosphorylation of c-AMP responsive element-binding protein (CREB) in the hippocampus. These findings suggest that memory formation of spatial habituation depends on the functional integrity of NMDA and AMPA/kainate receptors and CaMKII activity in the CA1 region of the hippocampus and that the detection of spatial novelty is accompanied by the activation of at least three different hippocampal protein kinase signaling cascades.

Animals↗
PubMed1993

Muscimol infused into the entorhinal cortex prior to training blocks the involvement of this area in post-training memory processing.

Muscimol infusions into the entorhinal cortex (ERC) have previously been reported to impair the retention of passive avoidance learning, but only when infusions were delayed until 90min after training. In the present study, three experiments were carried out to examine further the effects of muscimol infusions into the ERC prior to training. In Experiment 1, muscimol infusions prior to training had no effect on retention, confirming earlier findings, but blocked the amnestic effect of a second muscimol infusion 90min post-training. In Experiment 2, muscimol infusions prior to training blocked the improvement of retention normally seen following a second training trial 2h after the first. In Experiment 3, the technique of summation of performance across training trials was used to confirm that the direct effects of muscimol infusions lasted less than 2h. The results indicate that the GABA-ergic mechanism in the ERC is normally involved in the formation of memory for passive avoidance, but if the ERC is inactivated at the time of training, memory formation is diverted to other structures, which appear less capable of integrating consecutive memories across time.

Journal Article↗
PubMed1987

A delayed onset of haloperidol effects on learned escape and avoidance behavior.

The effects of 0.3 mg/kg haloperidol (H) on the acquisition and maintenance of footshock escape behavior of rats in a one meter runway was investigated. In the acquisition phase, a group (N = 6) given H before testing (HB) showed severely retarded acquisition and performance of the escape response, as compared with a group (N = 6) given H after testing (HA). When the HB and HA treatments were reversed for the groups behavioral performance was initially unaffected. At first, the HA group switched to the HB condition continued to exhibit rapid escape behavior and the HB group switched to the HA treatment continued to have slow escape behavior. Over the course of 8 days of testing, however, the performances of the two groups gradually reversed. After completion of this testing the HB and HA treatments again were switched and the animals were tested for both avoidance and escape behavior. Again, the performance of the animals initially did not change after the treatment switch, but with repeated testing and treatments, the avoidance and escape behavior of the HB group slowed substantially and that of the HA group accelerated markedly. These findings support previous observations that over learned behaviors are much less sensitive to disruption by haloperidol treatment than behaviors which are undergoing learning. The important contribution of the present study was in demonstrating that this insensitivity is a transitional, transient phenomenon and that with chronic treatment and testing, over learned behaviors can be strongly affected by haloperidol.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Failure to produce taste-aversion learning in rats exposed to static electric fields and air ions.

Taste-aversion (TA) learning was measured to determine whether exposure to high-voltage direct current (HVdc) static electric fields can produce TA learning in male Long Evans rats. Fifty-six rats were randomly distributed into four groups of 14 rats each. All rats were placed on a 20 min/day drinking schedule for 12 consecutive days prior to receiving five conditioning trials. During the conditioning trials, access to 0.1% sodium saccharin-flavored water was given for 20 min, followed 30 min later by one of four treatments. Two groups of 14 rats each were individually exposed to static electric fields and air ions, one group to +75 kV/m (+2 x 10(5) air ions/cm3) and the other group to -75 kV/m (-2 x 10(5) air ions/cm3). Two other groups of 14 rats each served as sham-exposed controls, with the following variation in one of the sham-exposed groups: This group was subdivided into two subsets of seven rats each, so that a positive control group could be included to validate the experimental design. The positive control group (n = 7) was injected with cyclophosphamide 25 mg/kg, i.p., 30 min after access to saccharin-flavored water on conditioning days, whereas the other subset of seven rats was similarly injected with an equivalent volume of saline. Access to saccharin-flavored water on conditioning days was followed by the treatments described above and was alternated daily with water "recovery" sessions in which the rats received access to water for 20 min in the home cage without further treatment. Following the last water-recovery session, a 20 min, two-bottle preference test (between water and saccharin-flavored water) was administered to each group. The positive control group did show TA learning, thus validating the experimental protocol. No saccharin-flavored water was consumed in the two-bottle preference test by the cyclophosphamide-injected, sham-exposed group compared to 74% consumed by the saline-injected sham-exposed controls (P < .0001). Saccharin-preference data for the static field-exposed groups showed no TA learning compared to data for sham-exposed controls. In summary, exposure to intense static electric fields and air ions did not produce TA learning as assessed by this particular design.

Air↗
PubMed2002

The interaction of age and unconditioned stimulus intensity on long-trace conditioned flavor aversion in rats.

To see if the neural representation of the conditioned stimulus (CS) is available to old-age rats beyond the time it is available to young adults, the intensity of the unconditioned stimulus (US) and the length of the CS-US interval were systematically varied in a trace conditioning experiment. Results indicated that increasing US intensity extends the interval over which trace conditioning is evident in old-age rats but not in young adults, suggesting that trace decay occurs more rapidly in young rats. Results were interpreted in terms of age differences in the workings of hypothesized biochemical timing mechanisms that may directly influence the ability to associate stimuli over trace intervals in conditioned taste-aversion procedures.

Aging↗
PubMed2003

Ontogenetic differences in the expression of conditioned visual aversions.

We examined ontogenetic differences in the expression of conditioned visual aversions. Sprague-Dawley-derived rats, 16 or 21 days of age, were conditioned with either an element (brightness) or compound (brightness/odor) CS+ and tested for their aversion to the common element (brightness). Aversions to the brightness cue were assessed by either a traditional test of preference between the CS+ brightness and a contrasting brightness or by assessment of freezing in the presence of either brightness cue. The results indicated that strength of conditioning as well as the expression of overshadowing/potentiation was dependent on the age of the animal and on the technique used to assess conditioning.

Aging↗
PubMed2001

Endogenous opioids and their role in odor preference acquisition and consolidation following odor-shock conditioning in infant rats.

We assessed the neurochemical basis of olfactory learning induced by presentations of odor and moderate shock in infant rats. Paradoxically, shock conditioning produces an odor preference in 8-day-olds, but an odor aversion in 12-day-olds. Studies have demonstrated the importance of opioids in early olfactory learning; their specific role remains undefined. In this study, postnatal Days 8 and 12 pups were systemically injected with naltrexone, a nonspecific opioid antagonist, or saline and received either paired or backward presentations of odor-moderate shock or odor-only presentations. Blocking the opioid system during conditioning disrupted acquisition of the Day 8 odor preference, but not the Day 12 odor aversion. Additional Day 8 pups were given naltrexone posttraining. Naltrexone not only blocked consolidation of an odor preference but also yielded an odor aversion. These results suggest that the opioid system has a critical role in both olfactory learning and consolidation of odor preferences during the sensitive period.

Age Factors↗
PubMed2005

Latent inhibition in the developing rat: an examination of context-specific effects.

Latent inhibition (LI) refers to the reduction in conditioned responding when the conditioned stimulus (CS) is preexposed prior to CS-unconditioned stimulus pairings. Experiment 1a demonstrated that preexposure to an odor CS prior to odor-shock pairings markedly reduced conditioned freezing in 25-day-old rats; however, this LI effect was observed only if odor preexposure and odor-shock pairings occurred in the same context (i.e., LI was context-specific at this age). The results of Experiment 1b showed that 18-day-olds also exhibited LI, but this effect was not context-specific at this age. In Experiment 2, rats were preexposed to the odor at 18 days of age and given odor-shock pairings at 25 days of age. These rats exhibited context-specific latent inhibition, suggesting that 18-day-old rats encoded the preexposure context. In Experiment 3, all parameters were identical to Experiment 2, with the exception that odor-shock pairings were given at approximately PN18 and testing occurred at approximately PN25. These rats exhibited latent inhibition at test, but this effect was not context-specific. The results of this study suggest that (a) PN18 rats can exhibit latent inhibition, and (b) the expression of context-specific latent inhibition depends on the age at which conditioning occurs.

Analysis of Variance↗