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PubMed2003

Mnemonic functions of dorsal striatum and hippocampus in aversive conditioning.

These experiments examined the mnemonic functions of hippocampus and dorsal striatum in Pavlovian aversive conditioning. Rats were trained in a single session by presenting three paired tones and footshocks. Immediately after training, they were given microinjections of D-amphetamine or vehicle into either dorsal hippocampus or dorsal striatum. Twenty-four hours later conditioned freezing (measured as cessation of movement by infrared motion detectors) to the experimental context and to the tone were measured separately. Compared to vehicle injections, amphetamine injections into dorsal hippocampus significantly increased conditioned freezing to the context but not to the tone. Injections into dorsal striatum increased conditioned freezing to both the context and the tone. These results converge with findings from lesion experiments suggesting that hippocampus is involved in aversive conditioning with contextual CSs only, and that dorsal striatum is involved in aversive conditioning with both contextual and discrete cue CSs. The functions of the these two structures in relation to that of the amygdala in the mediation of conditioned freezing are discussed.

Amphetamine↗

PubMed1992

Differential involvement of gustatory insular cortex and amygdala in the acquisition and retrieval of conditioned taste aversion in rats.

Lesion studies of the role of the gustatory insular cortex (GC) and amygdala (Am) in conditioned taste aversion (CTA) are confounded by the irreversibility of the intervention. Functional ablation methods allow more specific influencing of different phases of CTA acquisition and retrieval. Bilateral tetrodotoxin (TTX) blockade of GC (10 ng) or Am (3 ng) before or after saccharin drinking in rats with chronically implanted intracerebral cannulae showed that GC is indispensable for the initial processing of the taste stimulus but not for the association of the gustatory trace with the symptoms of LiCl poisoning. Gustatory signals can by-pass the blocked Am, the inactivation of which, however, impairs the gustatory trace-poisoning association. TTX injection into both GC and Am impairs CTA retrieval more than isolated blockade of either of these structures. It is argued that GC and Am implement processing of gustatory and visceral signals, respectively, but that formation and consolidation of the CTA engram proceeds outside forebrain, probably at the level of the brainstem.

Amygdala↗

PubMed1989

Deficits in conditioned heart rate and taste aversion in area postrema-lesioned rats.

Previous studies have shown that area postrema (AP) lesions cause deficits in conditioned taste aversion in the rat. They also lead to chronically lowered heart rate which can be reversed by the animals' increased appetite for and ingestion of hypertonic saline. Although not previously examined in conditioned taste aversion, changes in autonomic nervous system activity as reflected in heart rate may be an important aspect of conditioning. The present study investigated the effects of AP lesions on heart rate conditioned responses (CRs) and unconditioned responses (UCRs). Two groups of AP lesioned and sham-operated rats, one that did and one that did not drink saline solution to raise heart rate, were studied. Both LiCl and scopolamine, which have opposite effects on heart rate, were the unconditioned stimulus (UCS) agents in two separate studies. In intact rats, LiCl-mediated conditioned taste aversion was associated with decreased conditioned stimulus (CS) intake and decreased heart rate Both effects were blunted by AP lesions, although all rats displayed heart rate UCRs to LiCl. The AP rats that drank saline behaved like intact rats exhibiting both a conditioned taste aversion and conditioned heart rate responses to the CS. Although CS intake decreased, no heart rate CRs developed with scopolamine. Scopolamine-mediated conditioned taste aversion was attenuated in both saline and non-saline drinking AP-lesioned groups. Thus, when conditioned taste aversion was associated with heart rate CRs, the AP lesion-induced deficit was counteracted by saline ingestion. Conversely, when there were no heart rate CRs, conditioned taste aversion was disrupted by the lesion regardless of saline ingestion.

Animals↗

PubMed1989

Dissociation of visual and olfactory conditioning in the neostriatum of rats.

In an experiment designed to demonstrate a double dissociation, the effects of bilateral electrolytic lesions of either the posteroventral or the ventrolateral regions of the neostriatum on the conditioned emotional response (CER) were examined. Posteroventral lesions impaired acquisition of the CER with a visual CS but not with an olfactory CS. Sham-operated posteroventral and ventrolateral lesioned animals acquired the visual CER normally. Ventrolateral lesions impaired acquisition of the CER with the olfactory CS but not with the visual CS. Sham-operated ventrolateral and posteroventral lesioned animals acquired the olfactory CER normally. In a second experiment the effect of post-training unilateral intrastriatal microinjections of (+)-amphetamine on acquisition of the visual and olfactory CERs was studied. Posteroventral injections improved retention of the visual, but not the olfactory CER. Ventrolateral injections improved retention of the olfactory, but not the visual CER. Saline and delayed (+)-amphetamine injection controls demonstrated that the improvement of retention in each case was a retroactive improvement of memory for the recently acquired CERs by (+)-amphetamine. These findings are consistent with previous reports of post-training memory facilitation mediated by dopaminergic function in the neostriatum. The results of both experiments are consistent with a regional functional heterogeneity hypothesis: the idea that anatomically linked areas of cortex and neostriatum process memories involving different stimuli in similar ways and that the integrity of these structures and their connections is necessary to establish and consolidate associative memory.

Amphetamine↗

PubMed1997

Facilitation of memory by peripheral administration of substance P.

This report summarizes a recent series of experiments dealing with the effect of peripheral (i.p.) administration of SP on the learning of avoidance and habituation tasks. In summary, the results from these studies show that peripheral post-training SP administration in rats enhances memory in a dose- and time-dependent way. The effect of substance P on retention was observed across tasks with different response requirements and in the absence of explicit punishment. The memory-enhancing effects are long-lasting, until 21 days post-training, and are mediated, at least in part, via interactions with the endogenous opioid system. The mnemotropic effects of peripherally administered SP are sensitive to the functional integrity of the vagus, suggesting that the vagus nerve may be one pathway by which systemic SP influences memory storage processes in the brain. Furthermore, the data indicated that these effects seemed to be encoded by different SP sequences, the N-terminal SP1-7, but not the C-terminal hepta- and hexapeptide sequences being responsible for the memory-promoting effects. Taken together, these studies strongly suggest that SP may be considered to have memory-promoting effects.

Animals↗

PubMed1985

Interfering with taste aversion learning in rats: the role of associative interference.

Six experiments with rats investigated the conditions under which one flavor interferes with aversion conditioning to a second, familiar flavor. Conditioning to the familiar flavor was weakest when the interference flavor was contiguous to lithium-induced toxicosis, novel, more intense, and strongly associated with toxicosis. In addition, conditioning to the familiar flavor was weakened even if multiple conditioning trials were used. The repeated finding of an inverse relationship between strength of aversion to the target and interference flavors is interpreted as support for an associative competition hypothesis of the interference effect. The possible relevance of the interference effect to the attenuation of taste aversions in cancer patients is discussed.

Animals↗

PubMed1982

Effects of dietary phospholipids and odd-chain fatty acids on the behavioural maturation of mice.

Five groups of female mice were fed from day 14 of pregnancy and throughout lactation on synthetic diets differing only in the lipid component, which constituted 10% of the diet and was derived from (a) the lipid fraction extracted from yeast grown on n-alkanes, (b) commercial soya lecithin, (c) fatty acids isolated from yeast lipids (off-chain fatty acids), (d) lipids extracted from yeast grown on glucose or (e) margarine (8%), corn oil (1%) and the unsaponifiable fraction (1%) from yeast grown on n-alkanes. A control diet (9% margarine and 1% corn oil) was fed to a sixth group of pregnant mice and to the offspring of all the groups from weaning to 60 days after birth. A battery of behavioural tests was performed on the offspring of the six groups between days 1 and 16 after birth (reflex activities), between days 2 and 21 (locomotor activity) and at 60 days of age (avoidance learning). An acceleration of postnatal behavioural maturation was evident in the pups of animals fed lipids from yeast grown on n-alkanes and of those fed soya lecithin, indicating the involvement of phospholipids and odd-chain fatty acids in the aspects of development studied.

Animals↗

PubMed1999

Enhancement by 1-oleoyl-2-docosahexaenoyl phosphatidylcholine of long-term potentiation in the rat hippocampal CA1 region.

We reported previously that administration of 1-oleoyl-2-docosahexaenoyl-sn-glycero-3-phosphorylcholine (ODHPC), a kind of phosphatidylcholine, enhanced discriminatory shock avoidance learning in rats. Since long-term potentiation (LTP) of the hippocampus has been suggested to be a physiological substrate of some forms of memory, we investigated the effects of ODHPC on LTP in the rat hippocampal CA1 region. LTP in the amplitude of population spikes in the CA1 region was induced by tetanic stimulation in anesthetized rats. ODHPC significantly increased magnitudes of LTP in a dose-dependent manner when injected intraperitoneally 20 min before inducing LTP. However, administration of 1,2-dioleoyl-sn-glycero-3-phosphorylcholine, in which only docosahexaenoyl residue of ODHPC was replaced with oleoyl residue, did not affect LTP. These results suggest that ODHPC enhances hippocampal LTP by its specific conformation.

Animals↗

PubMed1998

Increased extracellular dopamine in the nucleus accumbens of the rat during associative learning of neutral stimuli.

Brain microdialysis was used to study changes in dopamine in the nucleus accumbens and the dorsal striatum during associative learning between two neutral stimuli, flashing light and tone, presented on a paired schedule during stage 1 of a sensory preconditioning paradigm. The tone was subsequently paired with mild footshock using standard aversive conditioning procedures and the formation of a conditioned association between the flashing light and the tone in stage 1 was assessed by measuring the ability of the flashing light to elicit the same conditioned response as the tone when presented at test. The first experiment used behavioural monitoring only, to establish stimulus parameters for subsequent microdialysis experiments. Animals receiving paired presentation of the light and tone in stage 1 showed a conditioned suppression of licking to the light as well as to the tone, indicating that associative learning between the flashing light and the tone had occurred during stage 1, whilst in a separate group of animals given the same stimuli over the same time period but on an explicitly non-paired schedule, the conditioned emotional response was seen to the tone, but not to the light, showing that no association had been formed between the two stimuli during stage 1. In dialysis experiments using the same procedure, we measured a two-fold rise in dopamine in the nucleus accumbens during paired presentation of flashing light and tone, but not during non-paired presentation of the two stimuli. On subsequent test presentation of the two stimuli, we saw increases in accumbal dopamine on presentation of the tone in both groups, reflecting the formation of an association with the footshock in both. However the flashing light elicited an increase in dopamine only in the group which had received paired presentation at stage 1. Thus accumbal dopamine release at test is correlated to the ability of the stimulus to evoke a conditioned response measured behaviourally. Hypotheses of the behavioural function of the mesolimbic dopamine system centre on its role in mediating the effects of biological reinforcers, both rewarding and aversive, conditioned and unconditioned. The present results, showing increases in extracellular dopamine in the nucleus accumbens when an association is formed between two stimuli of which neither is a biological reinforcer nor, prior to formation of the association, affects dopamine levels, suggest a role for accumbal dopamine in the modulation of associative learning in general, not only that involving reinforcement.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Lateral parabrachial nucleus lesions in the rat: aversive and appetitive gustatory conditioning.

Previous research involving tests of innate preferences and aversions shows that bilateral ibotenic acid lesions of the visceral neurons located in the lateral parabrachial nucleus of the pons selectively disrupt consumption of those gustatory stimuli whose intake is augmented or restricted by their postoral consequences. The present study examined the performance of the same experimental subjects in learned preference and aversion tasks. The lesioned rats failed to develop a conditioned taste aversion (Experiment 1), a conditioned flavor preference (Experiment 2), and a conditioned aversion to the oral trigeminal stimulus, capsaicin (Experiment 3). The pattern of results from both types of taste-guided behaviors (innate and learned) suggests that excitotoxic lesions of the lateral parabrachial nucleus diminish sensitivity to gastrointestinal feedback which, in the present experiments, precludes aversive and appetitive associative learning.

Alanine↗

PubMed2004

Conditioned taste aversion with lipopolysaccharide and peptidoglycan does not activate cytokine gene expression in the spleen and hypothalamus of mice.

Several reports show that behavioural and physiological components of the acute phase reaction can be conditioned. However, the mechanisms responsible for these effects remain obscure. The underlying assumption that the changes observed in conditioned animals are dependent on a conditioned production of cytokines has never been demonstrated. In the present study, the possibility of conditioning the production of cytokines or molecules implicated in their signalling pathways was tested by submitting mice to conditioned taste aversion with a new saccharin taste paired with intraperitoneal (i.p.) injections of lipopolysaccharide (LPS, 0.83 microg/g) or peptidoglycan (PGN, 20 microg/g). After two conditioning sessions, conditioned mice developed a clear aversion to saccharine that was not associated with activation of genes of the cytokine network either at the periphery, or in the hypothalamus, as demonstrated by a macroarray approach and confirmed by real time RT-PCR. In contrast, there was an activation of the genes coding for nuclear factor kappa B (NFkappaB) and mitogen activated protein kinase (MAPK) signalling pathways in the spleen and to a lesser extent in the hypothalamus. This modulation of the NFkappaB and MAPK signalling pathways is interpreted in terms of a possible conditioned sensitisation of the immune system.

Analysis of Variance↗

PubMed1998

Neuroprotective role of S12024 against neurodegeneration in the rat dentate gyrus.

We assessed the neuroprotective capabilities of S12024 (R,S 1-methyl 8-(2-morpholinylmethoxy)-1,2,3,4-tetrahydroquinoleine methane sulphonate) in a model of neuronal degeneration in the dentate gyrus of the rat hippocampus. Specific degeneration of a large part of neurons in the lateral blade of the gyrus dentatus occurred after small intrahippocampal injections of water with or without amyloid-beta 1-28 fragment. S12024 reduced the number of animals with neuronal loss in the hippocampus, diminished the extent of the lesion, and reversed deficits of passive avoidance learning acquisition in animals with deposits of amyloid-beta 1-28. These results suggest that S12024 has neuroprotective effects on hippocampal cells and that the neurodegeneration by fluid injection combined with deposit of amyloid-beta 1-28 may be used to assay the neuroprotective activity of pharmacological compounds.

Amyloid beta-Peptides↗

PubMed2004

Two different biological configurations for long-term memory.

Long-term memory (LTM) in Hermissenda can be distinguished from consolidated long-term memory (CLTM) by determining how long recall is retained. LTM is retained for approximately 1 day, while CLTM is retained for at least 3 days. During the transition from LTM to CLTM, the extent of retention appears to depend partially on how much consolidation has been completed. Several models are discussed that may be related to the two different manifestations of recall.

Animals↗

PubMed1997

Analysis of the importance of controllable versus uncontrollable stress on subsequent behavioral and physiological functioning.

Original observations of the effects of stress exposure on behavioral, physiological and pathological indices were documented in the mid 1960s [J.B. Overmier, Interference with avoidance behavior: failure to avoid traumatic shock, J. Exp. Psychol. 78 (1968) 340-343 [12]; J.B. Overmier, M.E.P. Seligman, Effects of inescapable shock upon subsequent escape and avoidance learning, J. Comp. Physiol. Psychol. 63 (1967) 28-33 [13]; M.E.P. Seligman, S.F. Maier, Failure to escape traumatic shock, J. Exp. Psychol. 74 (1967) 1-9 [15]; J.M. Weiss, Effects of coping responses on stress, J. Comp. Physiol. Psychol. 65 (1968) 251-260 [18]]. Studies employing the triadic design (e.g. escapable stress, yoked-inescapable stress and no stress) indicated that the deficits following stress exposure were not caused by stress per se, rather the uncontrollability of the stress was the critical determinant. In this paradigm, the first group (escape) receives exposure to an environmental event that it can "control" by performing a behavioral response. Stress control or coping behavior includes the ability to alter the onset, duration, intensity or pattern of an aversive experience [S.F. Maier, M.E.P. Seligman, Learned helplessness: theory and evidence, J. Exp. Psychol.: Gen. 105 (1976) 3-46 [10]]. The second group is "yoked" to its escape partner and receives the identical physical stressor as its escape counterpart, but there is no behavioral response that the yoked subject can make to alter the outcome. The third group (naive) receives no stress exposure and is either restrained in the experimental apparatus or remains in the home cage until subsequent testing. Researchers using this triadic design should be aware of the concerns of certain investigators [R.M. Church, Systematic effect of random error in the yoked control design, Psychol. Bull. 62 (1964) 122-131 [3]; E.A. Wasserman, Response bias in the yoked control procedure, Behav. Brain Sci. 11 (1988) 477-478 [17]] who have raised important issues about the validity of the yoked control design because of the possibility of systematic biases. For example, individual differences in stress reactivity may result in random error in the yoked control group. This point will be addressed further in Section 5. This procedure allows the investigator to analyze the contributions of the importance of psychological dynamics of stress on a variety of dependent measures including: behavioral, pharmacological, neurochemical and immunological indices.

Animals↗

PubMedDate not supplied

Chemical defense in ascidians of the didemnidae family.

Fluorescent analogues (DB1 and TA1) of the secondary metabolites didemnin B (DB) and tamandarin A (TA) were synthesized to investigate the potential chemical defense mechanisms of tunicates in the family Didemnidae. These compounds were found to alter predator-prey relations. Five species of freshwater fish and one marine fish, the damselfish Amphiprion ocellaris, were acclimated to a diet of mosquito larvae. Fish showed an immediate, negative reaction to mosquito larvae treated with >/=5 ng of DB1 or TA1, with consumption of larvae resulting in regurgitation. Both freshwater and marine fish learned to avoid tainted prey by associating species of larvae with "distaste". Distaste for a given organism also arose when depsipeptides DB1 or TA1 were transferred to the fish from the surrounding medium. Fluorescence microscopy in fish indicated that a similar processing and localization followed ingestion and absorption of DB1 or TA1. Fluorescent labeling of DB or TA provided an ideal tool to conduct short-term studies of predator-prey relationships between fish and marine invertebrate larvae.

Animals↗

PubMed1981

Cognition-activating properties of 3-(Aryloxy)pyridines.

A series of 3-(aryloxy)pyridines was found to possess activity in enhancing retention for passive avoidance learning in mice. This test was used to select compounds with potential therapeutic properties for the treatment of cognitive disorders. Reference drugs that gave positive results in this procedure included d-amphetamine, magnesium pemoline, methyl phenidate, picrotoxin, phenytoin, and ethosuximide. All active compounds gave inverted U-shaped dose-response curves. The most active compounds of the 3-(aryloxy)pyridines included 3-phenoxypyridine (1), 3-(2-fluorophenoxy)pyridine (2), 3-(4-fluorophenoxy)pyridine (4), 3,3'-oxybis(pyridine) (23), and 3,3'-oxybis(pyridine) 1-oxide (24). 3-Phenoxypyridine (1) was clearly superior to all of the analogues tested in terms of the level of retention, grammometric potency, and the breadth of its inverted U-shaped dose-response curve. It was given the designation of CI-844 and after a detailed study of its pharmacological profile was submitted for preclinical toxicology.

Animals↗

PubMed2001

Latent inhibition and conditioning in rat strains which show differential prepulse inhibition.

Latent inhibition (LI) is the retardation of associative conditioning resulting from preexposure of the conditioned stimulus (CS) alone prior to conditioning. Schizophrenic patients show deficient prepulse inhibition (PPI) and, at least acutely, deficient LI as well. We recently found that Brown Norway (BN) rats show a PPI deficit compared to Wistar-Kyoto (WKY) rats. If PPI and LI depend on neural processes with common genetic substrates, then LI should be deficient in BN rats as well. Here, LI of a conditioned taste aversion was examined in BN and WKY rats. One group from each strain was preexposed to a saccharin-flavored solution (CS) the day prior to conditioning. For taste aversion conditioning, these two groups again consumed saccharin and were injected with lithium chloride (unconditioned stimulus) 10 min later. A second group from each strain was not preexposed to the CS and was treated identically during conditioning, while a third group was not conditioned (injected with sodium chloride). To test for taste aversion conditioning, saccharin was offered for 20 min/day for 3 days. Nonconditioned BN and WKY rats consumed equal amounts of saccharin on test days. In both strains, conditioned rats showed a saccharin aversion. However, conditioning was less robust in BN than in WKY rats. WKY rats showed good LI of the conditioned taste aversion in that preexposed WKY rats consumed significantly more saccharin on test days than conditioned, nonpreexposed WKY rats. Preexposed BN rats did not consume significantly more saccharin on test days than conditioned, nonpreexposed BN rats. The previously reported deficiency in PPI in the BN rats was confirmed here 1 week after the taste aversion experiment. These results suggest that BN rats show deficient LI as well as PPI and display poor associative learning, a trait also reported in schizophrenia.

Acoustic Stimulation↗

PubMed2004

Biochemical modulation of NMDA receptors: role in conditioned taste aversion.

Glutamate neurotransmission plays a crucial role in a variety of functions in the central nervous system, including learning and memory. However, little is known about the mechanisms underlying this process in mammals because of the scarceness of experimental models that permit correlation of behavioral and biochemical changes occurring during the different stages of learning and the retrieval of the acquired information. One model that has been useful to study these mechanisms is conditioned taste aversion (CTA), a paradigm in which animals learn to avoid new tastes when they are associated with gastrointestinal malaise. Glutamate receptors of the N-methyl-D-aspartate (NMDA) type appear to be necessary in this process, because blockade of this receptor prevents CTA. Phosphorylation of the main subunits of the NMDA receptor is a well-established biochemical mechanism for the modulation of the receptor response. Such modulation seems to be involved in CTA, because inhibitors of protein kinase C (PKC) block CTA acquisition and because the exposure to an unfamiliar taste results in an increased phosphorylation of tyrosine and serine residues of the NR2B subunit of the receptor in the insular cortex, the cerebral region where gustatory and visceral information converge. In this work we review these mechanisms of NMDA receptor modulation in CTA.

Animals↗