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PubMed2005

Cocaine-conditioned activity persists for a longer time than cocaine-sensitized activity in mice: implications for the theories using Pavlovian excitatory conditioning to explain the context-specificity of sensitization.

The present study was aimed at testing the prediction of the Pavlovian excitatory conditioning explanation of context-specific sensitization that the sensitized effect (SE) should persist as long as the post-sensitization conditioned activity (CR). C57BL/6J mice were tested for the expression of cocaine-induced conditioned and sensitized locomotion on several intervals after the establishment of a sensitization in an unchanging context. A group of mice received 10 once-daily injections of 10 mg/kg cocaine (s.c.) in a short time prior to being tested in activity-meters for 60 min sessions (cocaine-pretreated group), mice from a control group receiving saline in the same manner (saline-pretreated group). On the test sessions, taking place 1, 8 and 28 days after cocaine pretreatment, half of the animals of each pretreatment group (n=8) received a challenge test with saline and the other half with 10 mg/kg cocaine in the pretreatment context room (for CR and SE tests, respectively). The CR was significantly expressed on the three successive saline-challenge tests, albeit the activity levels were markedly decreased on the 28-day retention test. In contrast, the SE was significantly expressed only during the first half of the 1-day test session and the first 10 min of the 8-day test session, no SE effect being expressed on the 28-day retention test. The results, suggesting a functional uncoupling of the CR from the SE, disprove the theories of context-specificity of sensitization based completely or partially on Pavlovian excitatory conditioning mechanisms.

Analysis of Variance↗
PubMed2005

Chronic stress impairs acoustic conditioning more than visual conditioning in rats: morphological and behavioural evidence.

Chronic stress affects brain areas involved in learning and emotional responses. These alterations have been related with the development of cognitive deficits in major depression. The aim of this study was to determine the effect of chronic immobilization stress on the auditory and visual mesencephalic regions in the rat brain. We analyzed in Golgi preparations whether stress impairs the neuronal morphology of the inferior (auditory processing) and superior colliculi (visual processing). Afterward, we examined the effect of stress on acoustic and visual conditioning using an avoidance conditioning test. We found that stress induced dendritic atrophy in inferior colliculus neurons and did not affect neuronal morphology in the superior colliculus. Furthermore, stressed rats showed a stronger impairment in acoustic conditioning than in visual conditioning. Fifteen days post-stress the inferior colliculus neurons completely restored their dendritic structure, showing a high level of neural plasticity that is correlated with an improvement in acoustic learning. These results suggest that chronic stress has more deleterious effects in the subcortical auditory system than in the visual system and may affect the aversive system and fear-like behaviors. Our study opens a new approach to understand the pathophysiology of stress and stress-related disorders such as major depression.

Acoustic Stimulation↗
PubMed2004

Ethanol-conditioned flavor preferences compared with sugar- and fat-conditioned preferences in rats.

Rats can learn to prefer flavors paired with ethanol and various nutrients. The present study examined the relative strengths of flavor preferences conditioned by 5% ethanol and isocaloric solutions of 7.18% sucrose, 7.18% fructose, or 3.26% corn oil. In three experiments, nondeprived rats were trained with different flavored solutions (conditioned stimuli, CS) paired with intragastric (IG) infusions: a CS+E flavor paired with ethanol infusion, a second CS+ paired with a nutrient infusion, and a CS- paired with water infusion. In two-bottle tests, rats strongly preferred a sucrose-paired CS+S over the CS- and over the CS+E. The preference for the CS+E over CS- was weaker. These effects occurred when the rats drank substantially more CS+S than CS+E in training and when training intakes were matched. Similar results were obtained when the nutrient infusion was fructose or corn oil, except that preferences for the CS+F or CS+O over the CS+E were less pronounced than with CS+S. Consistent with the IG results, rats trained to drink flavored sucrose and ethanol solutions preferred the CS+S to CS+E in a flavored water test. These results confirm prior reports of ethanol-conditioned preferences but show that ethanol is less effective than other nutrients at isocaloric concentrations. The marked individual differences in ethanol-conditioned preferences may be related to the impact of the sugar or fat infusions on the reward evaluation of the ethanol-paired flavor.

Animals↗
PubMed2001

The nature of the conditioned response mediating olfactory conditioned ejaculatory preference in the male rat.

We have developed a model to study the influence of conditioning on sexual partner preference in the rat. In this model, pairing a neutral odor (almond) with copulation to ejaculation produces a subsequent preference to ejaculate with females bearing that odor. We refer to this phenomenon as a conditioned ejaculatory preference (CEP). The present study investigates the nature of the conditioned response that mediates CEP. Given equal mount and intromission distributions, but an unequal ejaculation distribution, we hypothesized that two mechanisms could account for CEP: facilitated ejaculation or selective ejaculation. To test these hypotheses, we examined the effect of omitting the olfactory conditioned stimulus (CS) or applying it to a nonreceptive female. Males trained with the CS paired with copulation (paired-trained males) failed to display evidence of delayed ejaculation when copulating with unscented females. Conversely, paired-trained males displayed CS-elicited copulatory behavior with CS-bearing nonreceptive females. In addition, we re-analyzed the data from the copulatory preference tests of previous experiments for CEP-displaying males. Again, we failed to find evidence of facilitated ejaculation with the scented female. However, the time between the last mount or intromission and ejaculation was increased if either occurred with the scented female. Furthermore, more mounts were directed towards the scented female near the end, but not at other points, of an ejaculatory series. These findings suggest that the paired-trained males attend to the scented female near the point of ejaculation, and are consistent with the hypothesis that CEP is mediated by selective ejaculation.

Animals↗
PubMed1999

Effects of conditioned stimulus presentation on diminution of the unconditioned response in aversive classical conditioning.

The purpose of this experiment was to study whether conditioned diminution of the unconditioned response (UR) is a phenomenon with an associative basis. Discriminative electrodermal conditioning was used with an interval between the conditioned stimulus (CS) and unconditioned stimulus (US; aversive white-noise) of 8 s. Fifty-nine volunteer subjects received discrimination training in which one CS was reinforced (CS+ /US) and a second CS was non-reinforced (CS-). After this discriminative training phase, participants were tested using intermixed trials in which a US was preceded by either a CS+, a CS-, or a neutral stimulus (NS). The results indicated that the skin conductance response amplitude of the UR was lower when the US was preceded by the CS+ than when the US was preceded by the CS- or the NS. However, NS/US presentations elicited URs of greater amplitude than those of the CS- /US presentations. The results can be explained in terms of orienting reflex reinstatement. In addition, it is argued that conditioned diminution has an associative basis.

Adult↗
PubMed1998

Both medial prefrontal and amygdala central nucleus lesions abolish heart rate classical conditioning, but only prefrontal lesions impair reversal of eyeblink differential conditioning.

Rabbits with lesions of either medial prefrontal cortex (mPFC) or amygdala central nucleus (ACN) were compared with sham-lesioned animals during differential and reversal classical conditioning of the eyeblink (EB) and heart rate (HR) response. Lesions of the mPFC, but not ACN, produced a severe impairment in EB reversal conditioning, but neither lesion affected original discrimination. However, both mPFC and ACN lesions produced a severe attenuation of accompanying HR decelerations during both initial differentiation and reversal. These results suggest that mPFC processing of Pavlovian conditioning contingencies affects not only the autonomic component of learning but preservative somatomotor conditioning as well, whereas ACN processing affects only the autonomic component.

Amygdala↗
PubMed1991

Aversive conditioning in the rat: effects of a benzodiazepine and of an opioid agonist and antagonist on conditioned hypoalgesia and fear.

Hypoalgesia and fear co-occurred in rats trained on a heated floor and tested for their latencies to paw lick on that floor and to step down onto a nonheated floor. These responses were extinguished, suggesting a mediation by aversive conditioning processes. A benzodiazepine impaired the acquisition of aversive conditioning, but it did not attenuate the expression of conditioned hypoalgesia. The opioid agonist morphine also impaired acquisition across a range of drug doses and variations in hypoalgesic tolerance, whereas the opioid antagonist naloxone facilitated acquisition. The results are discussed in terms of the perceptual-defensive-recuperative (Fanselow, 1986) and working memory (Grau, 1987) models of the mechanisms for the co-occurrence of conditioned hypoalgesia and fear.

Animals↗
PubMed1998

Modulation of the acquisition of the rabbit eyeblink conditioned response by conditioned contextual stimuli.

Three experiments were conducted to ask if conditioned emotional responses (CERs) controlled by contextual cues modulate the acquisition of eyelid conditioned responses (CRs) to discrete conditioned stimuli (CSs). Experiment 1 showed that 30-s auditory stimuli that were paired with aversive shocks to one paraorbital region or the other controlled discriminated CERs, as measured by potentiation of a startle response. In Experiments 2 and 3, similarly trained 30-s stimuli served as contexts in which 1.050-ms CSs were paired with a paraorbital unconditioned stimulus (US). Reinforced contexts both impaired (Experiments 2A and 2B) and facilitated (Experiment 3B) acquisition of the eyeblink CR, depending on the locus of the USs involved. The data are consistent with the interpretation that CERs controlled by contextual cues facilitate CR acquisition, but do so in the face of blocking effects of CR tendencies also conditioned to the contextual cues.

Animals↗
PubMed2000

Mechanisms of second-order conditioning with a backward conditioned stimulus.

Five conditioned suppression experiments with rats examined the conditions under which backward pairings endow a first-order conditioned stimulus (CS1) with the ability to serve as a secondary reinforcer. Experiments 2-5B found evidence for excitatory second-order conditioning (SOC) if, during first-order pairings, the US-CS1 interval was 0 s rather than 3 s. Levels of SOC were comparable after forward and backward pairings (Experiments 1-3), and were unaffected by extinction of CS1 after SOC (Experiment 3). These results suggest that forward and backward CS1s support SOC for the same reason, and they call into question the need to invoke any special mechanism such as memory integration.

Analysis of Variance↗
PubMed2000

Conditioning across the duration of a backward conditioned stimulus.

Five conditioned suppression experiments examined the extent to which an appetitively motivated lever-press response can be punished by different components of a backward conditioned stimulus (CS). Using a 0-s unconditioned stimulus (US)-CS interval, Experiments 1 and 2 showed that the initial 3 s of a normally 30-s backward CS served as a more effective punisher than the CS as a whole. Experiment 3 found no such effect if the US-CS interval were 3 s rather than 0 s. Experiments 4A and 4B found that if the US-CS interval were 0 s, the initial part of the backward CS acquired excitatory properties although the CS as a whole passed a summation test for conditioned inhibition. By contrast, the 3-s US-CS interval supported inhibitory conditioning across the whole duration of the backward CS. Taken together, these findings support a modified version of Wagner's sometimes opponent process model, which suggests that different components of a backward CS become either excitatory or inhibitory depending on the components' temporal proximity to the US.

Animals↗
PubMed1989

Conditional stimulus probability and activity of hippocampal, cingulate cortical, and limbic thalamic neurons during avoidance conditioning in rabbits.

Past studies of the neuronal correlates of avoidance conditioning in rabbits have led to a model of information flow among structures of the limbic system. A hypothesis of the model is that unexpected stimuli activate certain hippocampal and cingulate cortical neurons. This activity in turn suppresses or "limits" the firing of limbic thalamic neurons. This hypothesis is tested in relation to stimuli classified as unexpected or expected on the basis of their incidence or "probability." Multi-unit and field potential responses in the anterior and posterior cingulate cortices (AC and PC), the dentate gyrus (DG), and the anterior ventral (AV) and medial dorsal (MD) thalamic nuclei were recorded during the acquisition and performance of a locomotor conditioned response (CR). The CR, stepping in an activity wheel in response to a 0.5-s tone (CS+), prevented the occurrence of a shock US scheduled 5 s after CS+ onset. The rabbits also learned to ignore a different tone (CS-), not predictive of the US. Training was given daily (120 trials, 60 with each CS in an irregular sequence) until behavioral discrimination reached criterion. After criterion, asymmetric probability (AP) sessions were given, in which the CS+/CS- proportions were .2/.8 or .8/.2. The AP sessions were the same as conditioning sessions except for the probability manipulation. A significant discriminative response, i.e., a greater neuronal discharge to the CS+ than to the CS-, developed in all regions during behavioral acquisition. The unit response in the AP sessions was enhanced in all areas by rare presentation of the CS-, compared with the equal and frequent CS- conditions. Rare presentation of the CS+ enhanced the unit response in the cortical areas (AC, PC, and DG), but it suppressed the firing of limbic thalamic (AV and MD) neurons. These results were supportive of the model. Rare CS+ presentations did not alter AV and PC neuronal activity in rabbits with subicular lesions, a result suggesting that an intact hippocampus is essential for normal neuronal responses to stimulus probability in the cingulate cortex and limbic thalamus.

Animals↗
PubMed1992

Pairings of a drug or place conditioned stimulus with lithium chloride produce conditioned sickness, not antisickness.

In different experiments, pairings of a drug (pentobarbital or morphine) or place as the conditioned stimulus (CS) with lithium-induced sickness as the unconditioned stimulus (US) were given to rats to produce Pavlovian conditioning. Control rats received unpaired exposures. In the test, each rat was exposed to the CS, injected with lithium, and then offered food. If such pairings produce conditioning of antisickness (i.e., a compensatory response that opposes lithium sickness), then the experimental rats should eat more than the controls. The reverse occurred. Thus, pairings of a drug or place CS with a lithium US resulted in conditioned sickness rather than antisickness.

Animals↗
PubMed1992

Place conditioning in a three- or four-choice apparatus: role of stimulus novelty in drug-induced place conditioning.

A series of 4 experiments examined the suggestion (Scoles & Siegel, 1986) that drug-induced place preference conditioning may be due to interference with habituation. In each experiment, rats had the opportunity to select among a drug-paired chamber, a saline-paired chamber, and a novel (or relatively novel) chamber. The drugs included the positively reinforcing drugs amphetamine, apomorphine, morphine, and nicotine and the aversive drug lithium chloride. The rats preferred chambers that were paired with amphetamine, apomorphine, and morphine more than chambers that were novel; however, they also consistently preferred novel chambers to familiar saline-paired chambers. There was no evidence of place conditioning with nicotine. The drug-induced place preference, but not the novelty preference, occurred after a single conditioning trial in a 3-choice apparatus but not a 4-choice apparatus. Lithium chloride established a place aversion after 1-3 conditioning trials. Measures of activity revealed that the rats were least active while in their most preferred chamber and most active while in their least preferred chamber.

Animals↗
PubMed1993

Contextual conditioning and auditory cue conditioning dissociate during development.

Following a single shock presentation, fear conditioning to an auditory cue and to the experimental context was assessed by measuring the rat's tendency to freeze. On the conditioning day 18-day-old rats showed as much freezing to the auditory cue as older rats. However, 18-day-old pups displayed much less freezing to the training context than pups 21- to 27-days old. The developmental dissociation between contextual and auditory cue conditioning parallels the dissociation produced by damage to the adult rat's hippocampal system (Kim & Fanselow, 1992; Phillips & LeDoux, 1992). The dissociation is also consistent with the developmental hypothesis that the configural association system develops late in comparison with the elemental association system (Rudy, 1991, 1992). The implications of the findings for the maturation of the neural components of the fear-conditioning circuit also are discussed.

Acoustic Stimulation↗
PubMed1998

Classical conditioning to hypoxia using odors as conditioned stimuli in rats.

The authors performed a differential conditioning experiment in 30 rats, using 2 odors as the conditioned stimuli (CS+ and CS-) and hypoxia (8% O2) as the unconditioned stimulus. Vanillin was the CS+ and rose the CS- in half of the rats, and vice versa in the other half. Fifteen paired CS+/hypoxia trials and 15 CS- only trials were performed in random order, followed by 3 CS+ only and 3 CS- only trials to test for conditioning. The increase in ventilation from prestimulus levels averaged 116 +/- 85% in response to CS+ versus 55 +/- 36% in response to CS-. This effect was supported by the significant Pre-Post Stimulus x CS Type interaction for this variable (p < .003). The data confirm the sensitivity of breathing to conditioning processes and also indirectly support the hypothesis that feedforward responses may complement feedback reflex pathways in respiratory homeostasis.

Animals↗
PubMed1999

Conditioned stimulus control in the rat circadian system depends on clock resetting during conditioning.

The authors examined the ability of a conditioned stimulus (CS; mild air disturbance) previously paired with an entraining light pulse to reset the circadian pacemaker in rats. Rats were entrained to a single 30-min light stimulus delivered every 25 hr or 24 hr (T cycle). Each daily light presentation was paired with the CS. After at least 20 days of stable entrainment to each of the T cycles, the rats were allowed to free run and were then presented with the CS at circadian time 15. CS-induced phase shifts in wheel-running activity rhythms were taken as evidence for conditioning. For the most part, conditioning occurred after CS-light pairings on the 25-hr but not 24-hr T cycle. The results suggest that CS control of the circadian clock phase depends on the effect that the entraining light pulse has on the clock during conditioning.

Animals↗
PubMed2004

Associative change in the representations acquired during conditional discriminations: further analysis of the nature of conditional learning.

Three experiments with rats investigated how the associative strengths of the representations that underlie conditional learning change when they are conditioned in compound. The results of each experiment suggest that the representation whose associative strength is most discrepant from the asymptote supported by the outcome of the trial undergoes the greatest change in associative strength. These results parallel those from simple Pavlovian conditioning (e.g., R. A. Rescorla, 2000). are inconsistent with unique-cue and configural accounts of conditional learning, and support a connectionist analysis of learning in which a "winner-takes-all" rule applies to the hidden units that can be activated and acquire associative strength at a given point in time.

Analysis of Variance↗
PubMed1999

Primary CA1 and conditionally immortal MHP36 cell grafts restore conditional discrimination learning and recall in marmosets after excitotoxic lesions of the hippocampal CA1 field.

Common marmosets (Callithrix jacchus, n = 18) were trained to discriminate between rewarded and non-rewarded objects (simple discriminations, SDs) and to make conditional discriminations (CDs) when presented sequentially with two different pairs of identical objects signifying reward either in the right or left food well of the Wisconsin General Test Apparatus. After bilateral N-methyl-D-aspartate (0.12 M) lesions through the cornu ammonis-1 (CA1) field (7 microl in five sites), marmosets showed profound impairment in recall of CDs but not SDs, and were assigned to lesion only, lesion plus CA1 grafts and lesion plus Maudsley hippocampal cell line, clone 36 (MHP36) grafts groups matched for lesion-induced impairment. Cell suspension grafts (4 microl, 15-25 000 cells/microl) of cells dissected from the CA1 region of foetal brain at embryonic day 94-96, or of conditionally immortalized MHP36 cells, derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium and labelled with [3H]thymidine, were infused at the lesion sites. The lesion plus MHP36 grafts group was injected five times per week with cyclosporin A (10 mg/kg) throughout testing. Lesion, grafted and intact control marmosets (n = 4-5/group) were tested on recall of SDs and CDs learned before lesioning and on acquisition of four new CDs over a 6-month period. Lesioned animals were highly impaired in recall and acquisition of CD tasks, but recall of SDs was not significantly disrupted. Both grafted groups of marmosets showed improvement to control level in recall of CDs. They were significantly slower in learning the first new CD task, but mastered the remaining tasks as efficiently as controls and were substantially superior to the lesion-only group. Visualized by Nissl staining, foetal grafts formed clumps of pyramidal-like cells within the denervated CA1 field, or jutted into the lateral ventricles. MHP36 cells, identified by beta-galactosidase staining and autoradiography, showed neuronal and astrocytic morphology, and were distributed evenly throughout the CA1 region. The results indicate that MHP36 cell grafts are as functionally effective as foetal grafts and appear to integrate into the host brain in a structurally appropriate manner, showing the capacity to differentiate into both mature neurons and glia, and to develop morphologies appropriate to the site of migration. These findings, which parallel the facilitative effects of foetal and MHP36 grafts in rats with ischaemic CA1 damage, offer encouragement for the development of conditionally immortal neuroepithelial stem cell lines for grafting in conditions of severe amnesia and hippocampal damage following recovery from cardiac arrest or other global ischaemic episodes.

Animals↗