Conditioned Taste Aversion Is Enhanced When the Unconditioned Stimulus Is Presented in a Different Context

ERIC Educational Resources Information Center

Ishii, Kiyoshi; Iguchi, Yoshio; Fukumoto, Kazuya; Nakayasu, Tomohiro

2008-01-01

Using a conditioned taste aversion procedure with rats as the subjects, two experiments examined the effect of presenting a conditioned stimulus (CS saccharin solution) in one context followed by an unconditioned stimulus (US LiCl) in a different context. Experiment 1 showed that animals which received the above-mentioned procedure (Group D)…

β1-Adrenoceptor in the Central Amygdala Is Required for Unconditioned Stimulus-Induced Drug Memory Reconsolidation

PubMed Central

Zhu, Huiwen; Zhou, Yiming; Liu, Zhiyuan; Chen, Xi; Li, Yanqing; Liu, Xing; Ma, Lan

2018-01-01

Abstract Background Drug memories become labile and reconsolidated after retrieval by presentation of environmental cues (conditioned stimulus) or drugs (unconditioned stimulus). Whether conditioned stimulus and unconditioned stimulus retrieval trigger different memory reconsolidation processes is not clear. Methods Protein synthesis inhibitor or β-adrenergic receptor (β-AR) antagonist was systemically administrated or intra-central amygdala infused immediately after cocaine reexposure in cocaine-conditioned place preference or self-administration mice models. β-ARs were selectively knocked out in the central amygdala to further confirm the role of β-adrenergic receptor in cocaine reexposure-induced memory reconsolidation of cocaine-conditioned place preference. Results Cocaine reexposure triggered de novo protein synthesis dependent memory reconsolidation of cocaine-conditioned place preference. Cocaine-priming-induced reinstatement was also impaired with post cocaine retrieval manipulation, in contrast to the relapse behavior with post context retrieval manipulation. Cocaine retrieval, but not context retrieval, induced central amygdala activation. Protein synthesis inhibitor or β1-adrenergic receptor antagonist infused in the central amygdala after cocaine retrieval, but not context retrieval, inhibited memory reconsolidation and reinstatement. β1-adrenergic receptor knockout in the central amygdala suppressed cocaine retrieval-triggered memory reconsolidation and reinstatement of cocaine conditioned place preference. β1-adrenergic receptor antagonism after cocaine retrieval also impaired reconsolidation and reinstatement of cocaine self-administration. Conclusions Cocaine reward memory triggered by unconditioned stimulus retrieval is distinct from conditioned stimulus retrieval. Unconditioned stimulus retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala. Post unconditioned stimulus retrieval manipulation can prevent drug memory reconsolidation and relapse to cocaine, thus providing a potential strategy for the prevention of substance addiction. Significance Statement It is well known that drug memories become labile and reconsolidated upon retrieval by the presentation of conditioned stimulus (CS) or unconditioned stimulus (US). Whether CS and US retrieval trigger different memory reconsolidation processes is unknown. In this study, we found that US retrieval, but not CS retrieval, triggered memory reconsolidation of cocaine-conditioned place preference dependent on β1-AR and de novo protein synthesis in the central amygdala. Furthermore, cocaine priming-induced reinstatement was impaired with post US retrieval manipulation in contrast to the relapse behavior with post CS retrieval manipulation. In cocaine self-administration, β1-AR antagonism after US retrieval also impaired reconsolidation and reinstatement. Our study indicates that reconsolidation of cocaine reward memory triggered by US retrieval is distinct from CS retrieval. US retrieval induced reconsolidation of cocaine reward memory depends on β1-adrenergic signaling in the central amygdala. PMID:29216351

The role of conditioning on heterosexual and homosexual partner preferences in rats.

PubMed

Coria-Avila, Genaro A

2012-01-01

Partner preferences are expressed by many social species, including humans. They are commonly observed as selective contacts with an individual, more time spent together, and directed courtship behavior that leads to selective copulation. This review discusses the effect of conditioning on the development of heterosexual and homosexual partner preferences in rodents. Learned preferences may develop when a conditioned stimulus (CS) is associated in contingency with an unconditioned stimulus (UCS) that functions as a reinforcer. Consequently, an individual may display preference for a partner that bears a CS. Some UCS may be more or less reinforcing, depending on when they are experienced, and may be different for males and females. For example, it could be that, only during periods of early development, that stimuli associated with nurture and juvenile play become conditioned. In adulthood, other stimuli such as sexual reward, cohabitation, mild stress, or even pharmacological manipulations may function as reinforcers to condition partner preferences. Evolutionary biologists and psychologists must take into consideration the idea that an individual's experience with reward (i.e. sexual and pharmacological) can override presumably 'innate' mate choices (e.g. assortativeness and orientation) or mate strategies (e.g. monogamy or polygamy) by means of Pavlovian and operant contingencies. In fact, it is likely as innate to learn about the environment in ways that maximize reward and minimize aversive outcomes, making so-called 'proximate' causes (e.g. pleasure) ultimately more powerful predictors of social behavior and choice than so-called 'ultimate' causes (e.g. genetic or reproductive fitness).

Alleviation of response suppression to conditioned aversive stimuli by lesions of the dorsal noradrenergic bundle.

PubMed

Tsaltas, E; Gray, J A; Fillenz, M

1984-08-01

Rats with neurotoxic lesions of the dorsal ascending noradrenergic bundle (DB) were compared with sham-operated (SH) controls on the acquisition, steady state and extinction of response suppression maintained by a classical (conditioned suppression) or an instrumental (discriminated punishment) contingency. DB lesions interfered neither with the acquisition of the reference response of sucrose-rewarded barpressing nor with unconditioned responding to the overhead flashing light subsequently used as a signal of shock. The acquisition of discriminated response suppression was also unaffected by the lesion under both types of contingency. However, once discriminated suppression had stabilized, both the conditioned and the discriminative stimulus used were significantly less effective in maintaining suppression in DB animals than in SH controls provided that low intensity footshock (0.2 mA) was used as the unconditioned stimulus (UCS). Upon increase of UCS intensity (to 0.5 mA) normal suppression was observed in the DB group under both contingencies. Extinction of the classical contingency reinstated the difference between DB and SH performance: DB lesion resulted in significantly faster extinction of fear. In contrast, extinction of the discriminated punishment contingency was unaffected by the lesion, although generalized response suppression dissipated faster in the DB than in the SH animals trained under this condition. Our results offer no support for the reinforcement hypothesis of DB function (normal acquisition of barpressing and of discriminated suppression of barpressing); mixed support (greater initial generalization of suppression in DB animals) and contradiction (more rapid extinction of conditioned suppression in DB animals) for the attentional hypothesis; and weak support (reduced suppression and more rapid extinction of suppression in DB animals, but only within limited experimental parameters) for the anxiety hypothesis of DB function. Hence none of the extant theories of DB function offer a ready explanation of the pattern of results presented here. A simple interpretation which conforms with the sparsity of positive behavioural findings in the literature on DB lesions is that forebrain noradrenaline contributes to the detection and utilization of conditioned stimuli; but that this contribution is critical only for the detection of stimuli with low associative strength.

Taste-dependent sociophobia: when food and company do not mix.

PubMed

Guitton, Matthieu J; Klin, Yael; Dudai, Yadin

2008-08-22

Using a combination of the paradigm of conditioned taste aversion (CTA) and of the paradigm of social interactions, we report here that in the rat, eating while anxious may result in long-term alterations in social behavior. In the conventional CTA, the subject learns to associate a tastant (the conditioned stimulus, CS) with delayed toxicosis (an unconditioned stimulus, UCS) to yield taste aversion (the conditioned response, CR). However, the association of taste with delayed negative internal states that could generate CRs that are different from taste aversion should not be neglected. Such associations may contribute to the ontogenesis, reinforcement and symptoms of some types of taste- and food-related disorders. We have recently reported that a delayed anxiety-like state, induced by the anxiogenic drug meta-chlorophenylpiperazine (mCPP), can specifically associate with taste to produce CTA. We now show that a similar protocol results in a marked lingering impairment in social interactions in response to the conditioned taste. This is hence a learned situation in which food and company do not mix well.

Classical conditioning of proboscis extension in harnessed Africanized honey bee queens (Apis mellifera L.).

PubMed

Aquino, Italo S; Abramson, Charles I; Soares, Ademilson E E; Fernandes, Andrea Cardoso; Benbassat, Danny

2004-06-01

Experiments are reported on learning in virgin Africanized honey bee queens (Apis mellifera L.). Queens restrained in a "Pavlovian harness" received a pairing of hexanal odor with a 1.8-M feeding of sucrose solution. Compared to explicitly unpaired controls, acquisition was rapid in reaching about 90%. Acquisition was also rapid in queens receiving an unconditioned stimulus of "bee candy" or an unconditioned stimulus administered by worker bees. During extinction the conditioned response declines. The steepest decline was observed in queens receiving an unconditioned stimulus of bee candy. These findings extend previous work on learning of Afrianized honey bee workers to a population of queen bees.

Initial uncertainty in Pavlovian reward prediction persistently elevates incentive salience and extends sign-tracking to normally unattractive cues.

PubMed

Robinson, Mike J F; Anselme, Patrick; Fischer, Adam M; Berridge, Kent C

2014-06-01

Uncertainty is a component of many gambling games and may play a role in incentive motivation and cue attraction. Uncertainty can increase the attractiveness for predictors of reward in the Pavlovian procedure of autoshaping, visible as enhanced sign-tracking (or approach and nibbles) by rats of a metal lever whose sudden appearance acts as a conditioned stimulus (CS+) to predict sucrose pellets as an unconditioned stimulus (UCS). Here we examined how reward uncertainty might enhance incentive salience as sign-tracking both in intensity and by broadening the range of attractive CS+s. We also examined whether initially induced uncertainty enhancements of CS+ attraction can endure beyond uncertainty itself, and persist even when Pavlovian prediction becomes 100% certain. Our results show that uncertainty can broaden incentive salience attribution to make CS cues attractive that would otherwise not be (either because they are too distal from reward or too risky to normally attract sign-tracking). In addition, uncertainty enhancement of CS+ incentive salience, once induced by initial exposure, persisted even when Pavlovian CS-UCS correlations later rose toward 100% certainty in prediction. Persistence suggests an enduring incentive motivation enhancement potentially relevant to gambling, which in some ways resembles incentive-sensitization. Higher motivation to uncertain CS+s leads to more potent attraction to these cues when they predict the delivery of uncertain rewards. In humans, those cues might possibly include the sights and sounds associated with gambling, which contribute a major component of the play immersion experienced by problematic gamblers. Copyright © 2014 Elsevier B.V. All rights reserved.

The role of conditioning on heterosexual and homosexual partner preferences in rats

PubMed Central

Coria-Avila, Genaro A.

2012-01-01

Partner preferences are expressed by many social species, including humans. They are commonly observed as selective contacts with an individual, more time spent together, and directed courtship behavior that leads to selective copulation. This review discusses the effect of conditioning on the development of heterosexual and homosexual partner preferences in rodents. Learned preferences may develop when a conditioned stimulus (CS) is associated in contingency with an unconditioned stimulus (UCS) that functions as a reinforcer. Consequently, an individual may display preference for a partner that bears a CS. Some UCS may be more or less reinforcing, depending on when they are experienced, and may be different for males and females. For example, it could be that, only during periods of early development, that stimuli associated with nurture and juvenile play become conditioned. In adulthood, other stimuli such as sexual reward, cohabitation, mild stress, or even pharmacological manipulations may function as reinforcers to condition partner preferences. Evolutionary biologists and psychologists must take into consideration the idea that an individual’s experience with reward (i.e. sexual and pharmacological) can override presumably ‘innate’ mate choices (e.g. assortativeness and orientation) or mate strategies (e.g. monogamy or polygamy) by means of Pavlovian and operant contingencies. In fact, it is likely as innate to learn about the environment in ways that maximize reward and minimize aversive outcomes, making so-called ‘proximate’ causes (e.g. pleasure) ultimately more powerful predictors of social behavior and choice than so-called ‘ultimate’ causes (e.g. genetic or reproductive fitness). PMID:24693350

Initial uncertainty in Pavlovian reward prediction persistently elevates incentive salience and extends sign-tracking to normally unattractive cues

PubMed Central

Robinson, Mike J. F.; Anselme, Patrick; Fischer, Adam M.; Berridge, Kent C.

2014-01-01

Uncertainty is a component of many gambling games and may play a role in incentive motivation and cue attraction. Uncertainty can increase the attractiveness for predictors of reward in the Pavlovian procedure of autoshaping, visible as enhanced sign-tracking (or approach and nibbles) by rats of a metal lever whose sudden appearance acts as a conditioned stimulus (CS+) to predict sucrose pellets as an unconditioned stimulus (UCS). Here we examined how reward uncertainty might enhance incentive salience as sign-tracking both in intensity and by broadening the range of attractive CS+s. We also examined whether initially-induced uncertainty enhancements of CS+ attraction can endure beyond uncertainty itself, and persist even when Pavlovian prediction becomes 100% certain. Our results show that uncertainty can broaden incentive salience attribution to make CS cues attractive that would otherwise not be (either because they are too distal from reward or too risky to normally attract sign-tracking). In addition, uncertainty enhancement of CS+ incentive salience, once induced by initial exposure, persisted even when Pavlovian CS-UCS correlations later rose toward 100% certainty in prediction. Persistence suggests an enduring incentive motivation enhancement potentially relevant to gambling, which in some ways resembles incentive-sensitization. Higher motivation to uncertain CS+s leads to more potent attraction to these cues when they predict the delivery of uncertain rewards. In humans, those cues might possibly include the sights and sounds associated with gambling, which contribute a major component of the play immersion experienced by problematic gamblers. PMID:24631397

Pre-exposure to wheel running disrupts taste aversion conditioning.

PubMed

Salvy, Sarah-Jeanne; Pierce, W David; Heth, Donald C; Russell, James C

2002-05-01

When rats are given access to a running wheel after drinking a flavored solution, they subsequently drink less of that flavor solution. It has been suggested that running produces a conditioned taste aversion (CTA). This study explored whether CTA is eliminated by prior exposure to wheel running [i.e., unconditioned stimulus (UCS) pre-exposure effect]. The rats in the experimental group (UW) were allowed to wheel run for 1 h daily for seven consecutive days of pre-exposure. Rats in the two other groups had either access to locked wheels (LW group) or were maintained in their home cages (HC group) during the pre-exposure days. All rats were then exposed to four paired and four unpaired trials using a "ABBAABBA" design. Conditioning trials were composed of one flavored liquid followed by 60-min access to wheel running. For the unpaired trials, rats received a different flavor not followed by the opportunity to run. All rats were then initially tested for water consumption followed by tests of the two flavors (paired or unpaired) in a counterbalanced design. Rats in the UW group show no CTA to the liquid paired with wheel running, whereas LW and HC groups developed CTA. These results indicate that pre-exposure to wheel running (i.e., the UCS), eliminates subsequent CTA.

Evoking Blinks with Natural Stimulation and Detecting Them with a Noninvasive Optical Device: A Simple, Inexpensive Method for Use with Freely Moving Animals

PubMed Central

Weiss, Craig; Disterhoft, John F.

2008-01-01

Many laboratories studying eyeblinks in unanesthetized rodents use a periorbital shock to evoke the blink. The stimulus is typically delivered via a tether and usually obliterates detection of a full unconditioned response with electromyographic (EMG) recording. Here we describe the adapter we have used successfully for several years to deliver puffs of air to the cornea of freely moving rats during our studies of eyeblink conditioning. The stimulus evokes an unconditioned response that can be recorded without affecting the EMG signal. This allows a complete analysis of the unconditioned response which is important for studies examining reflex modification or the effect of drugs, genetic manipulations, or aging on the unconditioned blink reflex. We also describe an infrared reflective sensor that can be added to the tether to minimize the number of wires that need to be implanted around the eye, and which is relatively immune to electrical artifacts associated with a periorbital shock stimulus or other devices powered by alternating current. The responses recorded simultaneously by EMG wires and the optical sensor appear highly correlated and demonstrate that the optical sensor can measure responses that might otherwise be lost due to electrical interference from a shock stimulus. PMID:18598716

Norepinephrine and Learning-Induced Plasticity in Infant Rat Olfactory System

PubMed Central

Sullivan, Regina M.; Wilson, Donald A.; Leon, Michael

2007-01-01

Postnatal olfactory learning produces both a conditioned behavioral response and a modified olfactory bulb neural response to the learned odor. The present report describes the role of norepinephrine (NE) on both of these learned responses in neonatal rat pups. Pups received olfactory classical conditioning training from postnatal days (PN) 1-18. Training consisted of 18 trials with an intertrial interval of 24 hr. For the experimental group, a trial consisted of a pairing of unconditioned stimulus (UCS, stroking/tactile stimulation) and the conditioned stimulus (CS, odor). Control groups received either only the CS (Odor only) or only the UCS (Stroke only). Within each training condition, pups were injected with either the NE β-receptor agonist isoproterenol (1, 20, or 4 mg/kg), the NE β-receptor antagonist propranolol (10, 20, 40 mg/kg), or saline 30 min prior to training. On day 20, pups received one of the following tests: (1) behavioral conditioned responding, (2) injection with 14C-2-deoxyglucase (2-DG) and exposed to the CS odor, or (3) tested for olfactory bulb mitral/tufted cell single-unit responses to the CS odor. The results indicated that training with either: (1) Odor-Stroke-Saline, (2) Odor-Stroke-lsoproterenol-Propranolol, or (3) Odor only-lsoproterenol (2 mg/kg) was sufficient to produce a learned behavioral odor preference, enhanced uptake of 14C-2-DG in the odor-specific foci within the bulb, and a modified output signal from the bulb as measured by single-cell recordings of mitral/tufted cells. Moreover, propranolol injected prior to Odor-Stroke training blocked the acquisition of both the learned behavior and olfactory bulb responses. PMID:2585063

On the respective contributions of awareness of unconditioned stimulus valence and unconditioned stimulus identity in attitude formation through evaluative conditioning.

PubMed

Stahl, Christoph; Unkelbach, Christian; Corneille, Olivier

2009-09-01

Evaluative conditioning (EC) is a central mechanism for both classic and current theories of attitude formation. In contrast to Pavlovian conditioning, it is often conceptualized as a form of evaluative learning that occurs without awareness of the conditioned stimulus-unconditioned stimulus (CS-US) contingencies. In the present research, the authors directly address this point by assessing the respective roles of US valence awareness and US identity awareness in attitude formation through EC. Across 4 experiments, EC was assessed with evaluative ratings as well as evaluative priming measures, and the impact of valence and identity awareness on EC was evaluated. EC effects on priming and rating measures occurred only for CSs for which participants could report the associated US valence, and US identity awareness did not further contribute to EC. This finding was obtained both for semantically meaningless (i.e., nonword letter sequences) and meaningful (i.e., consumer products) CSs. These results provide further support for the critical role of contingency awareness in EC, albeit valence awareness, not identity awareness. (c) 2009 APA, all rights reserved).

Repeated administration of LiCl produces an unconditioned stimulus preexposure effect in backward excitatory CTA but not habituation of the unconditioned increment in neophobia.

PubMed

De Brugada, Isabel; González, Felisa; Cándido, Antonio

2003-01-31

In one experiment using conditioned taste aversion and the unconditioned stimulus (US) preexposure procedure, one group of rats was given LiCl exposure for 3 days, whereas two other groups received saline. Following this phase, all groups were given a novel flavour (saccharine) to drink following either LiCl (group preexposed and one of the control groups) or saline injections (the remaining control group) and the consumption of the flavour was assessed. After this neophobia test, the acquired saccharine aversion was evaluated. The results show that three LiCl injections are enough to produce a US preexposure effect on backward excitatory taste aversion conditioning, whereas this number of injections procedure does not produce habituation of the increment in neophobia, an unconditioned response to the LiCl. The results are discussed taking into account different mechanisms involved in US preexposure effect.

Biologically-inspired adaptive obstacle negotiation behavior of hexapod robots

PubMed Central

Goldschmidt, Dennis; Wörgötter, Florentin; Manoonpong, Poramate

2014-01-01

Neurobiological studies have shown that insects are able to adapt leg movements and posture for obstacle negotiation in changing environments. Moreover, the distance to an obstacle where an insect begins to climb is found to be a major parameter for successful obstacle negotiation. Inspired by these findings, we present an adaptive neural control mechanism for obstacle negotiation behavior in hexapod robots. It combines locomotion control, backbone joint control, local leg reflexes, and neural learning. While the first three components generate locomotion including walking and climbing, the neural learning mechanism allows the robot to adapt its behavior for obstacle negotiation with respect to changing conditions, e.g., variable obstacle heights and different walking gaits. By successfully learning the association of an early, predictive signal (conditioned stimulus, CS) and a late, reflex signal (unconditioned stimulus, UCS), both provided by ultrasonic sensors at the front of the robot, the robot can autonomously find an appropriate distance from an obstacle to initiate climbing. The adaptive neural control was developed and tested first on a physical robot simulation, and was then successfully transferred to a real hexapod robot, called AMOS II. The results show that the robot can efficiently negotiate obstacles with a height up to 85% of the robot's leg length in simulation and 75% in a real environment. PMID:24523694

Evaluative Conditioning in Humans: A Meta-Analysis

ERIC Educational Resources Information Center

Hofmann, Wilhelm; De Houwer, Jan; Perugini, Marco; Baeyens, Frank; Crombez, Geert

2010-01-01

This article presents a meta-analysis of research on "evaluative conditioning" (EC), defined as a change in the liking of a stimulus (conditioned stimulus; CS) that results from pairing that stimulus with other positive or negative stimuli (unconditioned stimulus; US). Across a total of 214 studies included in the main sample, the mean…

Forward and Backward Second-Order Pavlovian Conditioning in Honeybees

ERIC Educational Resources Information Center

Hussaini, Syed Abid; Komischke, Bernhard; Menzel, Randolf; Lachnit, Harald

2007-01-01

Second-order conditioning (SOC) is the association of a neutral stimulus with another stimulus that had previously been combined with an unconditioned stimulus (US). We used classical conditioning of the proboscis extension response (PER) in honeybees ("Apis mellifera") with odors (CS) and sugar (US). Previous SOC experiments in bees were…

Central Cannabinoid Receptors Modulate Acquisition of Eyeblink Conditioning

ERIC Educational Resources Information Center

Steinmetz, Adam B.; Freeman, John H.

2010-01-01

Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light, and an unconditioned stimulus (US) that elicits the blink reflex. Conditioned stimulus information is projected from the basilar pontine nuclei to the cerebellar interpositus nucleus and cortex. The cerebellar cortex,…

Extinction of the soleus H reflex induced by conditioning stimulus given after test stimulus.

PubMed

Hiraoka, Koichi

2002-02-01

To quantify the extinction of the soleus H reflex induced by a conditioning stimulus above the motor threshold to the post-tibial nerve applied 10-12 ms after a test stimulus (S2 method). Ten healthy subjects participated. The sizes of extinction induced by a test stimulus above the motor threshold (conventional method) and by the S2 method were measured. The size of the conditioned H reflex decreased as the intensity of the S2 conditioning stimulus increased. The decrease was less than that induced by the conventional method. The difference between the two methods correlated highly with the amount of orthodromically activated recurrent inhibition. When the S2 conditioning stimulus evoked an M wave that was roughly half of the maximum M wave, the decrease in the size of the conditioned H reflex depended on the size of the unconditioned H reflex. The S2 method allows us to observe extinction without changing the intensity of the test stimulus. The amount of the extinction depends partially on the size of the unconditioned H reflex. The difference in the sizes of extinction between the S2 and conventional methods should relate to recurrent inhibition.

What is learned from repeated pairings? On the scope and generalizability of evaluative conditioning.

PubMed

Hütter, Mandy; Kutzner, Florian; Fiedler, Klaus

2014-04-01

The investigation of evaluative conditioning (EC) has been mainly concerned with the conditioning of individual stimuli. Namely, a specific conditioned stimulus (CS) is paired with a positive or negative unconditioned stimulus and consequently acquires the valence of the unconditioned stimulus. In the present article, we expand the notion of EC to CS cues (e.g., gender) as distinguished from CS objects (e.g., an individual). We developed a conditioning paradigm that allows for the simultaneous investigation of both types of EC effects, evaluative identity conditioning and evaluative cue conditioning. The experiments demonstrate that EC has the potential to change attitudes not only toward CS individuals but also toward CS cues. We applied this twofold approach to both impoverished and more complex learning environments, demonstrating that evaluative identity conditioning is dependent on stimulus complexity while evaluative cue conditioning depends on the complexity of the stimulus context. The findings have distinct implications for the generalization of EC effects as well as for the investigation of EC.

Short- and Long-Term Memories Formed upon Backward Conditioning in Honeybees ("Apis Mellifera")

ERIC Educational Resources Information Center

Felsenberg, Johannes; Plath, Jenny Aino; Lorang, Steven; Morgenstern, Laura; Eisenhardt, Dorothea

2014-01-01

In classical conditioning, the temporal sequence of stimulus presentations is critical for the association between the conditioned stimulus (CS) and the unconditioned stimulus (US). In forward conditioning, the CS precedes the US and is learned as a predictor for the US. Thus it acquires properties to elicit a behavioral response, defined as…

Is the devil in the detail? Evidence for S-S learning after unconditional stimulus revaluation in human evaluative conditioning under a broader set of experimental conditions.

PubMed

Jensen-Fielding, Hannah; Luck, Camilla C; Lipp, Ottmar V

2017-11-28

Whether valence change during evaluative conditioning is mediated by a link between the conditional stimulus (CS) and the unconditional stimulus (US; S-S learning) or between the CS and the unconditional response (S-R learning) is a matter of continued debate. Changing the valence of the US after conditioning, known as US revaluation, can be used to dissociate these accounts. Changes in CS valence after US revaluation provide evidence for S-S learning but if CS valence does not change, evidence for S-R learning is found. Support for S-S learning has been provided by most past revaluation studies, but typically the CS and US have been from the same stimulus category, the task instructions have suggested that judgements of the CS should be based on the US, and USs have been mildly valenced stimuli. These factors may bias the results in favour of S-S learning. We examined whether S-R learning would be evident when CSs and USs were taken from different categories, the task instructions were removed, and more salient USs were used. US revaluation was found to influence explicit US evaluations and explicit and implicit CS evaluations, supporting an S-S learning account and suggesting that past results are stable across procedural changes.

Consolidation of an extinction memory depends on the unconditioned stimulus magnitude previously experienced during training.

PubMed

Stollhoff, Nicola; Eisenhardt, Dorothea

2009-07-29

Here, we examine the role of the magnitude of the unconditioned stimulus (US) during classical conditioning in consolidation processes after memory retrieval. We varied the US durations during training and we test the impact of these variations on consolidation after memory retrieval with one or two conditioned stimulus-only trials. We found that the consolidation of an extinction memory depends on US duration during training and ruled out the possibility that this effect is attributable to differences in satiation after conditioning. We conclude that consolidation of an extinction memory is triggered only when the duration of the US reaches a critical threshold. This demonstrates that memory consolidation cannot be regarded as an isolated process depending solely on training conditions. Instead, it depends on the animal's previous experience as well.

The Influence of Prior Handling on the Effective CS-US Interval in Long-Trace Taste-Aversion Conditioning in Rats

ERIC Educational Resources Information Center

Hinderliter, Charles F.; Andrews, Amy; Misanin, James R.

2012-01-01

In conditioned taste aversion (CTA), a taste, the conditioned stimulus (CS), is paired with an illness-inducing stimulus, the unconditioned stimulus (US), to produce CS-US associations at very long (hours) intervals, a result that appears to violate the law of contiguity. The specific length of the maximum effective trace interval that has been…

Color Modulates Olfactory Learning in Honeybees by an Occasion-Setting Mechanism

ERIC Educational Resources Information Center

Mota, Theo; Giurfa, Martin; Sandoz, Jean-Christophe

2011-01-01

A sophisticated form of nonelemental learning is provided by occasion setting. In this paradigm, animals learn to disambiguate an uncertain conditioned stimulus using alternative stimuli that do not enter into direct association with the unconditioned stimulus. For instance, animals may learn to discriminate odor rewarded from odor nonrewarded…

Reinstatement in Honeybees Is Context-Dependent

ERIC Educational Resources Information Center

Plath, Jenny Aino; Felsenberg, Johannes; Eisenhardt, Dorothea

2012-01-01

During extinction animals experience that the previously learned association between a conditioned stimulus (CS) and an unconditioned stimulus (US) no longer holds true. Accordingly, the conditioned response (CR) to the CS decreases. This decrease of the CR can be reversed by presentation of the US alone following extinction, a phenomenon termed…

Unpaired Shocks during Extinction Weaken the Contextual Renewal of a Conditioned Discrimination

ERIC Educational Resources Information Center

Vervliet, Bram; Vansteenwegen, Deb; Hermans, Dirk

2010-01-01

Extinction is generally more fragile than conditioning, as illustrated by the contextual renewal effect. The traditional extinction procedure entails isolated presentations of the conditioned stimulus. Extinction may be boosted by adding isolated presentations of the unconditioned stimulus, as this should augment breaking the contingency between…

Classical Conditioning of Eyelid and Mystacial Vibrissae Responses in Conscious Mice

ERIC Educational Resources Information Center

Delgado-Garcia, Jose Maria; Troncoso, Julieta; Munera, Alejandro

2004-01-01

The murine vibrissae sensorimotor system has been scrutinized as a target of motor learning through trace classical conditioning. Conditioned eyelid responses were acquired by using weak electrical whisker-pad stimulation as conditioned stimulus (CS) and strong electrical periorbital stimulation as unconditioned stimulus (US). In addition,…

Appetitive but Not Aversive Olfactory Conditioning Modifies Antennal Movements in Honeybees

ERIC Educational Resources Information Center

Cholé, Hanna; Junca, Pierre; Sandoz, Jean-Christophe

2015-01-01

In honeybees, two olfactory conditioning protocols allow the study of appetitive and aversive Pavlovian associations. Appetitive conditioning of the proboscis extension response (PER) involves associating an odor, the conditioned stimulus (CS) with a sucrose solution, the unconditioned stimulus (US). Conversely, aversive conditioning of the sting…

Proboscis Conditioning Experiments with Honeybees, Apis Mellifera Caucasica, with Butyric Acid and DEET Mixture as Conditioned and Unconditioned Stimuli

PubMed Central

Abramson, Charles I.; Giray, Tugrul; Mixson, T. Andrew; Nolf, Sondra L.; Wells, Harrington; Kence, Aykut; Kence, Meral

2010-01-01

Three experiments are described investigating whether olfactory repellents DEET and butyric acid can support the classical conditioning of proboscis extension in the honeybee, Apis mellifera caucasica (Hymenoptera: Apidae). In the first experiment DEET and butyric acid readily led to standard acquisition and extinction effects, which are comparable to the use of cinnamon as a conditioned stimulus. These results demonstrate that the odor of DEET or butyric acid is not intrinsically repellent to honey bees. In a second experiment, with DEET and butyric acid mixed with sucrose as an unconditioned stimulus, proboscis conditioning was not established. After several trials, few animals responded to the unconditioned stimulus. These results demonstrate that these chemicals are gustatory repellents when in direct contact. In the last experiment a conditioned suppression paradigm was used. Exposing animals to butyric acid or DEET when the proboscis was extended by direct sucrose stimulation or by learning revealed that retraction of the proboscis was similar to another novel odor, lavender, and in all cases greatest when the animal was not permitted to feed. These results again demonstrate that DEET or butyric acid are not olfactory repellents, and in addition, conditioned suppression is influenced by feeding state of the bee. PMID:20879917

Proboscis conditioning experiments with honeybees, Apis mellifera caucasica, with butyric acid and DEET mixture as conditioned and unconditioned stimuli.

PubMed

Abramson, Charles I; Giray, Tugrul; Mixson, T Andrew; Nolf, Sondra L; Wells, Harrington; Kence, Aykut; Kence, Meral

2010-01-01

Three experiments are described investigating whether olfactory repellents DEET and butyric acid can support the classical conditioning of proboscis extension in the honeybee, Apis mellifera caucasica (Hymenoptera: Apidae). In the first experiment DEET and butyric acid readily led to standard acquisition and extinction effects, which are comparable to the use of cinnamon as a conditioned stimulus. These results demonstrate that the odor of DEET or butyric acid is not intrinsically repellent to honey bees. In a second experiment, with DEET and butyric acid mixed with sucrose as an unconditioned stimulus, proboscis conditioning was not established. After several trials, few animals responded to the unconditioned stimulus. These results demonstrate that these chemicals are gustatory repellents when in direct contact. In the last experiment a conditioned suppression paradigm was used. Exposing animals to butyric acid or DEET when the proboscis was extended by direct sucrose stimulation or by learning revealed that retraction of the proboscis was similar to another novel odor, lavender, and in all cases greatest when the animal was not permitted to feed. These results again demonstrate that DEET or butyric acid are not olfactory repellents, and in addition, conditioned suppression is influenced by feeding state of the bee.

On the Intentional Control of Conditioned Evaluative Responses

ERIC Educational Resources Information Center

Balas, Robert; Gawronski, Bertram

2012-01-01

The evaluative conditioning (EC) effect is defined as a change in the evaluation of a conditioned stimulus (CS) due to its pairing with a valenced unconditioned stimulus (US). The current research investigated the controllability of EC effects by asking participants to either promote or prevent the influence of CS-US pairings before they provided…

When Two Paradigms Meet: Does Evaluative Learning Extinguish in Differential Fear Conditioning?

ERIC Educational Resources Information Center

Blechert, Jens; Michael, Tanja; Williams, S. Lloyd; Purkis, Helena M.; Wilhelm, Frank H.

2008-01-01

Contemporary theories of Pavlovian conditioning propose a distinction between signal learning (SL), in which a conditioned stimulus (CS) becomes a predictor for a biologically significant unconditioned stimulus (US), and evaluative learning (EL), in which the valence of the US is transferred to the CS. This distinction is based largely on the…

Overexpectation: Response Loss during Sustained Stimulus Compounding in the Rabbit Nictitating Membrane Preparation

ERIC Educational Resources Information Center

Kehoe, E. James; White, Natasha E.

2004-01-01

Rabbits were given reinforced training of the nictitating membrane (NM) response using separate conditioned stimuli (CSs), which were a tone, light, and/or tactile vibration. Then, two CSs were compounded and given further pairings with the unconditioned stimulus (US). Evidence of both overexpectation and summation effects appeared. That is,…

Learned Together, Extinguished Apart: Reducing Fear to Complex Stimuli

ERIC Educational Resources Information Center

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie-H.

2013-01-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window…

Neural Correlates of Appetitive-Aversive Interactions in Pavlovian Fear Conditioning

ERIC Educational Resources Information Center

Nasser, Helen M.; McNally, Gavan P.

2013-01-01

We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of…

Enhancement of antibody response by one-trial conditioning: contrasting results using different antigens.

PubMed

Espinosa, Enrique; Calderas, Tania; Flores-Muciño, Oscar; Pérez-García, Georgina; Vázquez-Camacho, Ana C; Bermúdez-Rattoni, Federico

2004-01-01

New research in conditioned enhancement of antibody response requires a general paradigm effective with different antigens. In this experiment series we applied a one-trial protocol using keyhole limpet hemocyanin immunization as an unconditioned stimulus. Several different conditions were tested. Two different times between conditioning and test trial, two relevant antigen doses and the use of an antigen booster during test trial were investigated. We did not find a conditioned effect in any of the conditions used. In contrast, we found a reliable albeit modest conditioned effect using hen egg lysozyme as unconditioned stimulus. By comparing these and other findings we conclude that the number of conditioning trials is a possible requirement for a more reliable conditioning of antibody response.

Prefrontal/accumbal catecholamine system processes high motivational salience

PubMed Central

Puglisi-Allegra, Stefano; Ventura, Rossella

2012-01-01

Motivational salience regulates the strength of goal seeking, the amount of risk taken, and the energy invested from mild to extreme. Highly motivational experiences promote highly persistent memories. Although this phenomenon is adaptive in normal conditions, experiences with extremely high levels of motivational salience can promote development of memories that can be re-experienced intrusively for long time resulting in maladaptive outcomes. Neural mechanisms mediating motivational salience attribution are, therefore, very important for individual and species survival and for well-being. However, these neural mechanisms could be implicated in attribution of abnormal motivational salience to different stimuli leading to maladaptive compulsive seeking or avoidance. We have offered the first evidence that prefrontal cortical norepinephrine (NE) transmission is a necessary condition for motivational salience attribution to highly salient stimuli, through modulation of dopamine (DA) in the nucleus accumbens (NAc), a brain area involved in all motivated behaviors. Moreover, we have shown that prefrontal-accumbal catecholamine (CA) system determines approach or avoidance responses to both reward- and aversion-related stimuli only when the salience of the unconditioned stimulus (UCS) is high enough to induce sustained CA activation, thus affirming that this system processes motivational salience attribution selectively to highly salient events. PMID:22754514

At the Crossroads: Attention, Contingency Awareness, and Evaluative Conditioning

ERIC Educational Resources Information Center

Blask, Katarina; Walther, Eva; Halbeisen, Georg; Weil, Rebecca

2012-01-01

Evaluative conditioning (EC) refers to changes in the evaluation of a conditioned stimulus (CS) due to its repeated pairing with an unconditioned stimulus (US). One of the most debated topics in EC research is whether or not EC is dependent on contingency awareness. In this study, we go beyond this debate by examining whether contingency awareness…

Context-Dependent Olfactory Learning in an Insect

ERIC Educational Resources Information Center

Matsumoto, Yukihisa; Mizunami, Makoto

2004-01-01

We studied the capability of the cricket "Gryllus bimaculatus" to select one of a pair of odors and to avoid the other in one context and to do the opposite in another context. One group of crickets was trained to associate one of a pair of odors (conditioned stimulus, CS1) with water reward (appetitive unconditioned stimulus, US+) and another…

Cash for Comment: Participation Money as a Mechanism for Measurement, Reward, and Formative Feedback in Active Class Participation

ERIC Educational Resources Information Center

Chylinski, Mathew

2010-01-01

An unconditioned stimulus in the form of "participation money" serves to keep track of students' comments during class discussions and extrinsically to reinforce their class participation behaviors. Using a longitudinal experiment to investigate the effect of the participation money stimulus on several education outcomes, the author finds that the…

A Different Recruitment of the Lateral and Basolateral Amygdala Promotes Contextual or Elemental Conditioned Association in Pavlovian Fear Conditioning

ERIC Educational Resources Information Center

Calandreau, Ludovic; Desmedt, Aline; Decorte, Laurence; Jaffard, Robert

2005-01-01

Convergent data suggest dissociated roles for the lateral (LA) and basolateral (BLA) amygdaloid nuclei in fear conditioning, depending on whether a discrete conditioned stimulus (CS)-unconditional stimulus (US) or context-US association is considered. Here, we show that pretraining inactivation of the BLA selectively impaired conditioning to…

Roles of octopaminergic and dopaminergic neurons in appetitive and aversive memory recall in an insect.

PubMed

Mizunami, Makoto; Unoki, Sae; Mori, Yasuhiro; Hirashima, Daisuke; Hatano, Ai; Matsumoto, Yukihisa

2009-08-04

In insect classical conditioning, octopamine (the invertebrate counterpart of noradrenaline) or dopamine has been suggested to mediate reinforcing properties of appetitive or aversive unconditioned stimulus, respectively. However, the roles of octopaminergic and dopaminergic neurons in memory recall have remained unclear. We studied the roles of octopaminergic and dopaminergic neurons in appetitive and aversive memory recall in olfactory and visual conditioning in crickets. We found that pharmacological blockade of octopamine and dopamine receptors impaired aversive memory recall and appetitive memory recall, respectively, thereby suggesting that activation of octopaminergic and dopaminergic neurons and the resulting release of octopamine and dopamine are needed for appetitive and aversive memory recall, respectively. On the basis of this finding, we propose a new model in which it is assumed that two types of synaptic connections are formed by conditioning and are activated during memory recall, one type being connections from neurons representing conditioned stimulus to neurons inducing conditioned response and the other being connections from neurons representing conditioned stimulus to octopaminergic or dopaminergic neurons representing appetitive or aversive unconditioned stimulus, respectively. The former is called 'stimulus-response connection' and the latter is called 'stimulus-stimulus connection' by theorists studying classical conditioning in higher vertebrates. Our model predicts that pharmacological blockade of octopamine or dopamine receptors during the first stage of second-order conditioning does not impair second-order conditioning, because it impairs the formation of the stimulus-response connection but not the stimulus-stimulus connection. The results of our study with a cross-modal second-order conditioning were in full accordance with this prediction. We suggest that insect classical conditioning involves the formation of two kinds of memory traces, which match to stimulus-stimulus connection and stimulus-response connection. This is the first study to suggest that classical conditioning in insects involves, as does classical conditioning in higher vertebrates, the formation of stimulus-stimulus connection and its activation for memory recall, which are often called cognitive processes.

Human fear conditioning and extinction: Timing is everything . . . or is it?

PubMed Central

Prenoveau, Jason M.; Craske, Michelle G.; Liao, Betty; Ornitz, Edward M.

2012-01-01

A differential fear conditioning paradigm was used with 107 healthy undergraduate participants to evaluate the effect of conditioned stimulus (CS) temporal properties on fear acquisition and extinction. Two minute duration CSs were used for Day 1 fear acquisition. Participants were randomized to receive either 1, 2, or 4 minute CS durations during Day 2 extinction. Extinction re-test was examined on Day 3 using the original acquisition CS duration (2 minutes). Findings indicated that participants who were aware of the CS+/unconditioned stimulus (US) contingency (n=52) develop a temporal expectation about when the unconditioned stimulus will be delivered. Although the shorter duration CS resulted in greater fear reduction during extinction, cessation of fear responding at re-test was the same for CS extinction durations ranging from half the CS acquisition duration to twice the CS acquisition duration. Thus, extinction performance did not predict extinction at re-test, which could have important implications for optimizing exposure therapy for anxiety disorders. PMID:22349998

N-methyl-D-aspartate receptor antagonist MK-801 impairs learning but not memory fixation or expression of classical fear conditioning in goldfish (Carassius auratus).

PubMed

Xu, X; Davis, R E

1992-04-01

The amnestic effects of the noncompetitive antagonist MK-801 on visually mediated, classic fear conditioning in goldfish (Carassius auratus) was examined in 5 experiments. MK-801 was administered 30 min before the training session on Day 1 to look for anterograde amnestic effects, immediately after training to look for retrograde amnestic effects, and before the training or test session, or both, to look for state-dependence effects. The results showed that MK-801 produced anterograde amnesia at doses that did not produce retrograde amnesia or state dependency and did not impair the expression of conditioned or unconditioned branchial suppression responses (BSRs) to the conditioned stimulus. The results indicate that MK-801 disrupts the mechanism of learning of the conditioned stimulus-unconditioned stimulus relation. Evidence is also presented that the learning processes that are disrupted by MK-801 occur during the initial stage of BSR conditioning.

Species-specific response-topography of chickens' and pigeons' water-induced autoshaped responding.

PubMed

Ploog, Bertram O

2014-07-01

Four pigeons and eight chickens received autoshaping training where a keylight (conditioned stimulus) signaled response-independent deliveries of water (unconditioned stimulus). Pigeons drink while keeping their beaks submerged in water and moving their beaks to create suction ("mumbling"), whereas chickens drink by trapping a small amount of water in their mouths and then lifting their heads so the water trickles down. This experiment tested whether these and other species-specific differences in drinking and related behaviors of pigeons and chickens would be reflected in the form of conditioned (autoshaped) responding. Touchscreens and videotapes were used for data recording. Results showed that chickens moved their heads more than pigeons when drinking (unconditioned response). The birds also differed in conditioned responding in the presence of the keylight: Pigeons produced more keyswitch closures and mumbled at the keylight more than chickens whereas chickens scratched more than pigeons. In conclusion, with this unique comparative method that employed identical contingencies and comparable deprivation levels, species-specific differences in unconditioned responses and, more importantly, differences in their corresponding conditioned responses were observed. Copyright © 2014 Elsevier B.V. All rights reserved.

Duration of the unconditioned stimulus in appetitive conditioning of honeybees differentially impacts learning, long-term memory strength, and the underlying protein synthesis

PubMed Central

Marter, Kathrin; Grauel, M. Katharina; Lewa, Carmen; Morgenstern, Laura; Buckemüller, Christina; Heufelder, Karin; Ganz, Marion

2014-01-01

This study examines the role of stimulus duration in learning and memory formation of honeybees (Apis mellifera). In classical appetitive conditioning honeybees learn the association between an initially neutral, conditioned stimulus (CS) and the occurrence of a meaningful stimulus, the unconditioned stimulus (US). Thereby the CS becomes a predictor for the US eliciting a conditioned response (CR). Here we study the role of US duration in classical conditioning by examining honeybees conditioned with different US durations. We quantify the CR during acquisition, memory retention, and extinction of the early long-term memory (eLTM), and examine the molecular mechanisms of eLTM by interfering with protein synthesis. We find that the US duration affects neither the probability nor the strength of the CR during acquisition, eLTM retention, and extinction 24 h after conditioning. However, we find that the resistance to extinction 24 h after conditioning is susceptible to protein synthesis inhibition depending on the US duration. We conclude that the US duration does not affect the predictability of the US but modulates the protein synthesis underlying the eLTM's strength. Thus, the US duration differentially impacts learning, eLTM strength, and its underlying protein synthesis. PMID:25403456

Occasion Setting Is Specific to the CS-US Association

ERIC Educational Resources Information Center

Bonardi, Charlotte

2007-01-01

In Experiment 1, rats were trained on a discrimination in which one occasion setter, A, signaled that one cue (conditioned stimulus, CS), x, would be followed by one outcome, p (unconditioned stimulus, US), and a second CS, y, by a different outcome, q (x [right arrow] p and y [right arrow] q); a second occasion setter, B signalled the reverse…

The Resistance of Renewal to Instructions that Devalue the Role of Contextual Cues in a Conditioned Suppression Task with Humans

ERIC Educational Resources Information Center

Neumann, David L.

2007-01-01

The renewal of extinguished conditioned behaviour appears to reflect context-dependent learning. The present research used a conditioned suppression task with humans to examine whether instructions concerning the context could influence renewal. Pairings of a conditional stimulus (CS) and unconditional stimulus (US) were made in one context,…

Eye-Blink Conditioning Is Associated with Changes in Synaptic Ultrastructure in the Rabbit Interpositus Nuclei

ERIC Educational Resources Information Center

Weeks, Andrew C. W.; Connor, Steve; Hinchcliff, Richard; LeBoutillier, Janelle C.; Thompson, Richard F.; Petit, Ted L.

2007-01-01

Eye-blink conditioning involves the pairing of a conditioned stimulus (usually a tone) to an unconditioned stimulus (air puff), and it is well established that an intact cerebellum and interpositus nucleus, in particular, are required for this form of classical conditioning. Changes in synaptic number or structure have long been proposed as a…

When orienting and anticipation dissociate--a case for scoring electrodermal responses in multiple latency windows in studies of human fear conditioning.

PubMed

Luck, Camilla C; Lipp, Ottmar V

2016-02-01

Electrodermal activity in studies of human fear conditioning is often scored by distinguishing two electrodermal responses occurring during the conditional stimulus-unconditional stimulus interval. These responses, known as first interval responding (FIR) and second interval responding (SIR), are reported to be differentially sensitive to the effects of orienting and anticipation. Recently, the FIR/SIR scoring convention has been questioned, with some arguing in favor of scoring a single response within the entire conditional stimulus-unconditional stimulus interval (entire interval responding, EIR). EIR can be advantageous in practical terms but may fail to capture experimental effects when manipulations produce dissociations between orienting and anticipation. As an illustration, we rescored the data reported by Luck and Lipp (2015b) using both FIR/SIR and EIR scoring techniques and provide evidence that the EIR scoring technique fails to detect the effects of instructed extinction, an experimental manipulation which produces a dissociation between orienting and anticipation. Thus, using a technique that scores electrodermal response indices of fear conditioning in multiple latency windows is recommended. Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of Multiple Contexts and Context Similarity on the Renewal of Extinguished Conditioned Behaviour in an ABA Design with Humans

ERIC Educational Resources Information Center

Balooch, Siavash Bandarian; Neumann, David L.

2011-01-01

The ABA renewal procedure involves pairing a conditional stimulus (CS) and an unconditional stimulus (US) in one context (A), presenting extinction trials of the CS alone in a second context (B), and nonreinforced test trials of the CS in the acquisition context (A). The renewal of extinguished conditioned behaviour is observed during test. The…

Sensory Responsiveness and the Effects of Equal Subjective Rewards on Tactile Learning and Memory of Honeybees

ERIC Educational Resources Information Center

Scheiner, Ricarda; Kuritz-Kaiser, Anthea; Menzel, Randolf; Erber, Joachim

2005-01-01

In tactile learning, sucrose is the unconditioned stimulus and reward, which is usually applied to the antenna to elicit proboscis extension and which the bee can drink when it is subsequently applied to the extended proboscis. The conditioned stimulus is a tactile object that the bee can scan with its antennae. In this paper we describe the…

Autoshaping the pigeon's gape response: acquisition and topography as a function of reinforcer type and magnitude.

PubMed Central

Allan, R W; Zeigler, H P

1994-01-01

The pigeon's key-pecking response is experimentally dissociable into transport (head movement) and gape (jaw movement) components. During conditioning of the key-pecking response, both components come under the control of the conditioned stimulus. To study the acquisition of gape conditioned responses and to clarify the contribution of unconditioned stimulus (reinforcer) variables to the form of the response, gape and key-contact responses were recorded during an autoshaping procedure and reinforcer properties were systematically varied. One group of 8 pigeons was food deprived and subgroups of 2 birds each were exposed to four different pellet sizes as reinforcers, each reinforcer signaled by a keylight conditioned stimulus. A second group was water deprived and received water reinforcers paired with the conditioned stimulus. Water- or food-deprived control groups received appropriate water or food reinforcers that were randomly delivered with respect to the keylight stimulus. Acquisition of the conditioned gape response frequently preceded key-contact responses, and gape conditioned responses were generally elicited at higher rates than were key contacts. The form of the conditioned gape was similar to, but not identical with, the form of the unconditioned gape. The gape component is a critical topographical feature of the conditioned key peck, a sensitive measure of conditioning during autoshaping, and an important source of the observed similarities in the form of conditioned and consummatory responses. PMID:7964365

S-R associations, their extinction, and recovery in an animal model of anxiety: a new associative account of phobias without recall of original trauma.

PubMed

Laborda, Mario A; Miller, Ralph R

2011-06-01

Associative accounts of the etiology of phobias have been criticized because of numerous cases of phobias in which the client does not remember a relevant traumatic event (i.e., Pavlovian conditioning trial), instructions, or vicarious experience with the phobic object. In three lick suppression experiments with rats as subjects, we modeled an associative account of such fears. Experiment 1 assessed stimulus-response (S-R) associations in first-order fear conditioning. After behaviorally complete devaluation of the unconditioned stimulus, the target stimulus still produced strong conditioned responses, suggesting that an S-R association had been formed and that this association was not significantly affected when the outcome was devalued through unsignaled presentations of the unconditioned stimulus. Experiments 2 and 3 examined extinction and recovery of S-R associations. Experiment 2 showed that extinguished S-R associations returned when testing occurred outside of the extinction context (i.e., renewal) and Experiment 3 found that a long delay between extinction and testing also produced a return of the extinguished S-R associations (i.e., spontaneous recovery). These experiments suggest that fears for which people cannot recall a cause are explicable in an associative framework, and indicate that those fears are susceptible to relapse after extinction treatment just like stimulus-outcome (S-O) associations. Copyright © 2010. Published by Elsevier Ltd.

Autoshaping the pigeon's gape response: acquisition and topography as a function of reinforcer type and magnitude.

PubMed

Allan, R W; Zeigler, H P

1994-09-01

The pigeon's key-pecking response is experimentally dissociable into transport (head movement) and gape (jaw movement) components. During conditioning of the key-pecking response, both components come under the control of the conditioned stimulus. To study the acquisition of gape conditioned responses and to clarify the contribution of unconditioned stimulus (reinforcer) variables to the form of the response, gape and key-contact responses were recorded during an autoshaping procedure and reinforcer properties were systematically varied. One group of 8 pigeons was food deprived and subgroups of 2 birds each were exposed to four different pellet sizes as reinforcers, each reinforcer signaled by a keylight conditioned stimulus. A second group was water deprived and received water reinforcers paired with the conditioned stimulus. Water- or food-deprived control groups received appropriate water or food reinforcers that were randomly delivered with respect to the keylight stimulus. Acquisition of the conditioned gape response frequently preceded key-contact responses, and gape conditioned responses were generally elicited at higher rates than were key contacts. The form of the conditioned gape was similar to, but not identical with, the form of the unconditioned gape. The gape component is a critical topographical feature of the conditioned key peck, a sensitive measure of conditioning during autoshaping, and an important source of the observed similarities in the form of conditioned and consummatory responses.

Effect of Selective Inhibition of Reactivated Nicotine-Associated Memories With Propranolol on Nicotine Craving.

PubMed

Xue, Yan-Xue; Deng, Jia-Hui; Chen, Ya-Yun; Zhang, Li-Bo; Wu, Ping; Huang, Geng-Di; Luo, Yi-Xiao; Bao, Yan-Ping; Wang, Yu-Mei; Shaham, Yavin; Shi, Jie; Lu, Lin

2017-03-01

A relapse into nicotine addiction during abstinence often occurs after the reactivation of nicotine reward memories, either by acute exposure to nicotine (a smoking episode) or by smoking-associated conditioned stimuli (CS). Preclinical studies suggest that drug reward memories can undergo memory reconsolidation after being reactivated, during which they can be weakened or erased by pharmacological or behavioral manipulations. However, translational clinical studies using CS-induced memory retrieval-reconsolidation procedures to decrease drug craving reported inconsistent results. To develop and test an unconditioned stimulus (UCS)-induced retrieval-reconsolidation procedure to decrease nicotine craving among people who smoke. A translational rat study and human study in an academic outpatient medical center among 96 male smokers (aged 18- 45 years) to determine the association of propranolol administration within the time window of memory reconsolidation (after retrieval of the nicotine-associated memories by nicotine UCS exposure) with relapse to nicotine-conditioned place preference (CPP) and operant nicotine seeking in rats, and measures of preference to nicotine-associated CS and nicotine craving among people who smoke. The study rats were injected noncontingently with the UCS (nicotine 0.15 mg/kg, subcutaneous) in their home cage, and the human study participants administered a dose of propranolol (40 mg, per os; Zhongnuo Pharma). Nicotine CPP and operant nicotine seeking in rats, and preference and craving ratings for newly learned and preexisting real-life nicotine-associated CS among people who smoke. Sixty-nine male smokers completed the experiment and were included for statistical analysis: 24 in the group that received placebo plus 1 hour plus UCS, 23 who received propranolol plus 1 hour plus UCS, and 22 who received UCS plus 6 hours plus propranolol. In rat relapse models, propranolol injections administered immediately after nicotine UCS-induced memory retrieval inhibited subsequent nicotine CPP and operant nicotine seeking after short (CPP, d = 1.72, 95% CI, 0.63-2.77; operant seeking, d = 1.61, 95% CI, 0.59-2.60) or prolonged abstinence (CPP, d = 1.46, 95% CI, 0.42-2.47; operant seeking: d = 1.69, 95% CI, 0.66-2.69), as well as nicotine priming-induced reinstatement of nicotine CPP (d = 1.28, 95% CI, 0.27-2.26) and operant nicotine seeking (d = 1.61, 95% CI, 0.59-2.60) after extinction. Among the smokers, oral propranolol administered prior to nicotine UCS-induced memory retrieval decreased subsequent nicotine preference induced by newly learned nicotine CS (CS1, Cohen d = 0.61, 95% CI, 0.02-1.19 and CS2, d = 0.69, 95% CI, 0.10-1.28, respectively), preexisting nicotine CS (d = 0.57, 95% CI, -0.02 to 1.15), and nicotine priming (CS1, d = 0.82, 95% CI, 0.22-1.41 and CS2, d = 0.78, 95% CI, 0.18-1.37, respectively; preexisting nicotine CS, d = 0.92, 95% CI, 0.31-1.52), as well as nicotine craving induced by the preexisting nicotine CS (d = 0.64, 95% CI, 0.05-1.22), and nicotine priming (d = 1.15, 95% CI, 0.52-1.76). In rat-to-human translational study, a novel UCS-induced memory retrieval-reconsolidation interference procedure inhibited nicotine craving induced by exposure to diverse nicotine-associated CS and nicotine itself. This procedure should be studied further in clinical trials.

Latent Inhibition as a Function of US Intensity in a Two-Stage CER Procedure

ERIC Educational Resources Information Center

Rodriguez, Gabriel; Alonso, Gumersinda

2004-01-01

An experiment is reported in which the effect of unconditioned stimulus (US) intensity on latent inhibition (LI) was examined, using a two-stage conditioned emotional response (CER) procedure in rats. A tone was used as the pre-exposed and conditioned stimulus (CS), and a foot-shock of either a low (0.3 mA) or high (0.7 mA) intensity was used as…

Extended lowered body temperature increases the effective CS-US interval in conditioned taste aversion for adult rats.

PubMed

Hinderliter, Charles F; Goodhart, Mark; Anderson, Matthew J; Misanin, James R

2002-06-01

Assuming body temperature correlates with metabolic activities, rate of body temperature recovery was manipulated to assess effects on long-trace conditioning in a conditioned taste-aversion paradigm. Following 10 min. access to a .1% saccharin solution and then 10 min. immersion in 0-0.5 degrees C water, two groups of 16 Wistar-derived, 81-113 day-old, male albino rats received either saline or lithium chloride injections 3 hr. later. These two groups were subdivided on basis of warming rate during the 3-hr. interval. Half of the rats recovered at room temperature (20 degrees to 21 degrees C), and half recovered in an incubator maintained at 30 degrees C. Maintaining a lowered body temperature between the conditioned stimulus and unconditioned stimulus allowed an association to be made at 3 hr., an interval that normally does not support conditioning. In contrast, lowering body temperature and then inducing a fast warming rate did not produce evidence of an aversion. It is suggested that maintaining a low body temperature over the interval between the presentation of the conditioned stimulus and unconditioned stimulus slows a metabolic clock that extends the measured interval at which associations can be made using conditioned taste-aversion procedures.

Explicit Disassociation of a Conditioned Stimulus and Unconditioned Stimulus during Extinction Training Reduces Both Time to Asymptotic Extinction and Spontaneous Recovery of a Conditioned Taste Aversion

ERIC Educational Resources Information Center

Mickley, G. Andrew; DiSorbo, Anthony; Wilson, Gina N.; Huffman, Jennifer; Bacik, Stephanie; Hoxha, Zana; Biada, Jaclyn M.; Kim, Ye-Hyun

2009-01-01

Conditioned taste aversions (CTAs) may be acquired when an animal consumes a novel taste (CS) and then experiences the symptoms of poisoning (US). This aversion may be extinguished by repeated exposure to the CS alone. However, following a latency period in which the CS is not presented, the CTA will spontaneously recover (SR). In the current…

Effects of inferior olive lesion on fear-conditioned bradycardia

PubMed Central

Kotajima, Hiroko; Sakai, Kazuhisa; Hashikawa, Tsutomu

2014-01-01

The inferior olive (IO) sends excitatory inputs to the cerebellar cortex and cerebellar nuclei through the climbing fibers. In eyeblink conditioning, a model of motor learning, the inactivation of or a lesion in the IO impairs the acquisition or expression of conditioned eyeblink responses. Additionally, climbing fibers originating from the IO are believed to transmit the unconditioned stimulus to the cerebellum in eyeblink conditioning. Studies using fear-conditioned bradycardia showed that the cerebellum is associated with adaptive control of heart rate. However, the role of inputs from the IO to the cerebellum in fear-conditioned bradycardia has not yet been investigated. To examine this possible role, we tested fear-conditioned bradycardia in mice by selective disruption of the IO using 3-acetylpyridine. In a rotarod test, mice with an IO lesion were unable to remain on the rod. The number of neurons of IO nuclei in these mice was decreased to ∼40% compared with control mice. Mice with an IO lesion did not show changes in the mean heart rate or in heart rate responses to a conditioned stimulus, or in their responses to a painful stimulus in a tail-flick test. However, they did show impairment of the acquisition/expression of conditioned bradycardia and attenuation of heart rate responses to a pain stimulus used as an unconditioned stimulus. These results indicate that the IO inputs to the cerebellum play a key role in the acquisition/expression of conditioned bradycardia. PMID:24784584

Conditioned [corrected] stimulus informativeness governs conditioned stimulus-unconditioned stimulus associability.

PubMed

Ward, Ryan D; Gallistel, C R; Jensen, Greg; Richards, Vanessa L; Fairhurst, Stephen; Balsam, Peter D

2012-07-01

In a conditioning protocol, the onset of the conditioned stimulus ([CS]) provides information about when to expect reinforcement (unconditioned stimulus [US]). There are two sources of information from the CS in a delay conditioning paradigm in which the CS-US interval is fixed. The first depends on the informativeness, the degree to which CS onset reduces the average expected time to onset of the next US. The second depends only on how precisely a subject can represent a fixed-duration interval (the temporal Weber fraction). In three experiments with mice, we tested the differential impact of these two sources of information on rate of acquisition of conditioned responding (CS-US associability). In Experiment 1, we showed that associability (the inverse of trials to acquisition) increased in proportion to informativeness. In Experiment 2, we showed that fixing the duration of the US-US interval or the CS-US interval or both had no effect on associability. In Experiment 3, we equated the increase in information produced by varying the C/T ratio with the increase produced by fixing the duration of the CS-US interval. Associability increased with increased informativeness, but, as in Experiment 2, fixing the CS-US duration had no effect on associability. These results are consistent with the view that CS-US associability depends on the increased rate of reward signaled by CS onset. The results also provide further evidence that conditioned responding is temporally controlled when it emerges.

Differential Expression of Phosphorylated Mitogen-Activated Protein Kinase (pMAPK) in the Lateral Amygdala of Mice Selectively Bred for High and Low Fear

DTIC Science & Technology

2013-07-02

amygdala induced by hippocampal formation stimulation in vivo. The Journal of neuroscience: the official journal of the Society for Neuroscience 15...6 Figure 1.3. Schematic model of the neural circuitry of Pavlovian auditory fear conditioning. Model shows how an auditory conditioned...stimulus and a nociceptive unconditioned foot shock stimulus converge in the lateral amygdala (LA) via auditory thalamus and cortex and somatosensory

Olfactory memory formation and the influence of reward pathway during appetitive learning by honey bees.

PubMed

Wright, Geraldine A; Mustard, Julie A; Kottcamp, Sonya M; Smith, Brian H

2007-11-01

Animals possess the ability to assess food quality via taste and via changes in state that occur after ingestion. Here, we investigate the extent to which a honey bee's ability to assess food quality affected the formation of association with an odor stimulus and the retention of olfactory memories associated with reward. We used three different conditioning protocols in which the unconditioned stimulus (food) was delivered as sucrose stimulation to the proboscis (mouthparts), the antennae or to both proboscis and antennae. All means of delivery of the unconditioned stimulus produced robust associative conditioning with an odor. However, the memory of a conditioned odor decayed at a significantly greater rate for subjects experiencing antennal-only stimulation after either multiple- or single-trial conditioning. Finally, to test whether the act of feeding on a reward containing sucrose during conditioning affected olfactory memory formation, we conditioned honey bees to associate an odor with antennal stimulation with sucrose followed by feeding on a water droplet. We observed that a honey bee's ability to recall the conditioned odor was not significantly different from that of subjects conditioned with an antennal-only sucrose stimulus. Our results show that stimulation of the sensory receptors on the proboscis and/or ingestion of the sucrose reward during appetitive olfactory conditioning are necessary for long-term memory formation.

Evaluative conditioning may incur attentional costs.

PubMed

Pleyers, Gordy; Corneille, Olivier; Yzerbyt, Vincent; Luminet, Olivier

2009-04-01

Evaluative conditioning (EC) refers to changes in the liking of an affectively neutral stimulus (conditioned stimulus, or CS) after pairing this stimulus with an affect-laden stimulus (unconditioned stimulus, or US). Several authors proposed that EC incurs little or no attentional cost. Using a rigorous design, we provide evidence that a reduction in attentional resources may have a negative impact on EC. Additional analyses also revealed that participants correctly encoded fewer CS-US pairings when their attentional resources were depleted. Replicating Pleyers, Corneille, Luminet, and Yzerbyt's (2007) findings, EC was also obtained only for CSs that could be correctly linked to their associated US in the context of an identification task. This research clarifies the role of higher order processes in EC and has significant practical implications. Copyright (c) 2009 APA, all rights reserved.

The development and present status of the SOP model of associative learning.

PubMed

Vogel, Edgar H; Ponce, Fernando P; Wagner, Allan R

2018-05-01

The Sometimes Opponent Processes (SOP) model in its original form was especially calculated to address how expected unconditioned stimulus (US) and conditioned stimulus (CS) are rendered less effective than their novel counterparts in Pavlovian conditioning. Its several elaborations embracing the essential notion have extended the scope of the model to integrate a much greater number of phenomena of Pavlovian conditioning. Here, we trace the development of the model and add further thoughts about its extension and refinement.

Polymorphism of inflammatory genes and arsenic methylation capacity are associated with urothelial carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Chia-Chang; Department of Urology, Taipei Medical University—Shuang Ho Hospital, Taipei, Taiwan; Huang, Yung-Kai

2013-10-01

Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). TNF-α, IL-6 and IL-8 have been shown to be involved in the development and progression of various cancers, including bladder cancer. This study aimed to investigate the joint effect of the polymorphism of TNF-α − 308 G/A, IL-6 − 174 G/C, IL-8 − 251 T/A and urinary arsenic profiles on urothelial carcinoma (UC) risk. This study evaluated 300 pathologically-confirmed cases of UC and 594 cancer-free controls. Urinary arsenic species were detected using high-performance liquidmore » chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphism of TNF-α − 308 G/A, IL-6 − 174 G/C and IL-8 − 251 T/A was determined using polymerase chain reaction-restriction fragment length polymorphism. The joint effects on UC risk were estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. We found that the TNF-α − 308 A/A and IL-8 − 251 T/T polymorphisms were significantly associated with UC. Moreover, significant dose–response joint effect of TNF-α − 308 A/A or IL-8 − 251 T/T genotypes and arsenic methylation indices were seen to affect UC risk. The present results also showed a significant increase in UC risk in subjects with the IL-8 − 251 T/T genotype for each SD increase in urinary total arsenic and MMA%. In contrast, a significant decrease in UC risk was found in subjects who carried the IL-8 − 251 T/T genotype for each SD increase in DMA%. - Highlights: • Joint effect of the TNF-α -308 A/A genotype and urinary total arsenic affected UC. • Joint effect of the IL-8 -251 T/T genotype and urinary total arsenic affected UC. • Urinary total arsenic level, TNF-α -308 A/A and IL-8 -251 T/T genotype affected UC.« less

A Neutral Odor May Become a Sexual Incentive through Classical Conditioning in Male Rats

ERIC Educational Resources Information Center

Kvitvik, Inger-Line; Berg, Kristine Marit; Agmo, Anders

2010-01-01

A neutral olfactory stimulus was employed as CS in a series of experiments with a sexually receptive female as UCS and the execution of an intromission as the UCR. Each experimental session lasted until the male ejaculated. The time the experimental subject spent in a zone adjacent to the source of the olfactory stimulus during the 10 s of CS…

Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus.

PubMed

Connor, David A; Kutlu, Munir G; Gould, Thomas J

2017-07-01

Learned safety, a learning process in which a cue becomes associated with the absence of threat, is disrupted in individuals with post-traumatic stress disorder (PTSD). A bi-directional relationship exists between smoking and PTSD and one potential explanation is that nicotine-associated changes in cognition facilitate PTSD emotional dysregulation by disrupting safety associations. Therefore, we investigated whether nicotine would disrupt learned safety by enhancing fear associated with a safety cue. In the present study, C57BL/6 mice were administered acute or chronic nicotine and trained over three days in a differential backward trace conditioning paradigm consisting of five trials of a forward conditioned stimulus (CS)+ (Light) co-terminating with a footshock unconditioned stimulus followed by a backward CS- (Tone) presented 20 s after cessation of the unconditioned stimulus. Summation testing found that acute nicotine disrupted learned safety, but chronic nicotine had no effect. Another group of animals administered acute nicotine showed fear when presented with the backward CS (Light) alone, indicating the formation of a maladaptive fear association with the backward CS. Finally, we investigated the brain regions involved by administering nicotine directly into the dorsal hippocampus, ventral hippocampus, and prelimbic cortex. Infusion of nicotine into the dorsal hippocampus disrupted safety learning.

A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking.

PubMed

Luo, Yi-xiao; Xue, Yan-xue; Liu, Jian-feng; Shi, Hai-shui; Jian, Min; Han, Ying; Zhu, Wei-li; Bao, Yan-ping; Wu, Ping; Ding, Zeng-bo; Shen, Hao-wei; Shi, Jie; Shaham, Yavin; Lu, Lin

2015-07-14

We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts.

A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking

PubMed Central

Luo, Yi-xiao; Xue, Yan-xue; Liu, Jian-feng; Shi, Hai-shui; Jian, Min; Han, Ying; Zhu, Wei-li; Bao, Yan-ping; Wu, Ping; Ding, Zeng-bo; Shen, Hao-wei; Shi, Jie; Shaham, Yavin; Lu, Lin

2015-01-01

We recently reported that a conditioned stimulus (CS) memory retrieval-extinction procedure decreases reinstatement of cocaine and heroin seeking in rats and heroin craving in humans. Here we show that non-contingent cocaine or methylphenidate injections (UCS retrieval) 1 h before the extinction sessions decreases cocaine-priming-induced reinstatement, spontaneous recovery, and renewal of cocaine seeking in rats. Unlike the CS-based memory retrieval-extinction procedure, the UCS memory retrieval manipulation decreases renewal and reinstatement of cocaine seeking in the presence of cocaine cues that were not present during extinction training and also decreases cocaine seeking when the procedure commences after 28 days of abstinence. The inhibitory effect of the UCS retrieval manipulation on cocaine-priming-induced reinstatement is mediated by regulation of AMPA-receptor endocytosis in the basolateral amygdala. The UCS memory retrieval-extinction procedure has superior relapse prevention characteristics than the CS memory retrieval-extinction procedure and could be a promising method for decreasing relapse in human addicts. PMID:26169171

Central Localization of Plasticity Involved in Appetitive Conditioning in "Lymnaea"

ERIC Educational Resources Information Center

Straub, Volko A.; Styles, Benjamin J.; Ireland, Julie S.; O'Shea, Michael; Benjamin, Paul R.

2004-01-01

Learning to associate a conditioned (CS) and unconditioned stimulus (US) results in changes in the processing of CS information. Here, we address directly the question whether chemical appetitive conditioning of "Lymnaea" feeding behavior involves changes in the peripheral and/or central processing of the CS by using extracellular recording…

Pavlovian Incubation of US Signal Value

ERIC Educational Resources Information Center

Goddard, Murray J.

2013-01-01

Four experiments with rats examined Pavlovian incubation, in which responding increases when Pavlovian conditioning is followed by a testing delay. In a within-subjects design, Experiment 1 first showed that when a single food pellet unconditioned stimulus (US) signaled the delivery of three additional pellets, responding after the single US was…

A Classical Conditioning Procedure for the Hearing Assessment of Multiply Handicapped Persons.

ERIC Educational Resources Information Center

Lancioni, Giulio E.; And Others

1989-01-01

Hearing assessments of multiply handicapped children/adolescents were conducted using classical conditioning (with an air puff as unconditioned stimulus) and operant conditioning (with a modified visual reinforcement audiometry procedure or edible reinforcement). Findings indicate that classical conditioning was successful with 21 of the 23…

Unconditioned stimulus pathways to the amygdala: effects of lesions of the posterior intralaminar thalamus on foot-shock-induced c-Fos expression in the subdivisions of the lateral amygdala.

PubMed

Lanuza, E; Moncho-Bogani, J; Ledoux, J E

2008-08-26

The lateral nucleus of the amygdala (LA) is a site of convergence for auditory (conditioned stimulus) and foot-shock (unconditioned stimulus) inputs during fear conditioning. The auditory pathways to LA are well characterized, but less is known about the pathways through which foot shock is transmitted. Anatomical tracing and physiological recording studies suggest that the posterior intralaminar thalamic nucleus, which projects to LA, receives both auditory and somatosensory inputs. In the present study we examined the expression of the immediate-early gene c-fos in the LA in rats in response to foot-shock stimulation. We then determined the effects of posterior intralaminar thalamic lesions on foot-shock-induced c-Fos expression in the LA. Foot-shock stimulation led to an increase in the density of c-Fos-positive cells in all LA subnuclei in comparison to controls exposed to the conditioning box but not shocked. However, some differences among the dorsolateral, ventrolateral and ventromedial subnuclei were observed. The ventrolateral subnucleus showed a homogeneous activation throughout its antero-posterior extension. In contrast, only the rostral aspect of the ventromedial subnucleus and the central aspect of the dorsolateral subnucleus showed a significant increment in c-Fos expression. The density of c-Fos-labeled cells in all LA subnuclei was also increased in animals placed in the box in comparison to untreated animals. Unilateral electrolytic lesions of the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body reduced foot-shock-induced c-Fos activation in the LA ipsilateral to the lesion. The number of c-Fos labeled cells on the lesioned side was reduced to the levels observed in the animals exposed only to the box. These results indicate that the LA is involved in processing information about the foot-shock unconditioned stimulus and receives this kind of somatosensory information from the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body.

Reward uncertainty enhances incentive salience attribution as sign-tracking

PubMed Central

Anselme, Patrick; Robinson, Mike J. F.; Berridge, Kent C.

2014-01-01

Conditioned stimuli (CSs) come to act as motivational magnets following repeated association with unconditioned stimuli (UCSs) such as sucrose rewards. By traditional views, the more reliably predictive a Pavlovian CS-UCS association, the more the CS becomes attractive. However, in some cases, less predictability might equal more motivation. Here we examined the effect of introducing uncertainty in CS-UCS association on CS strength as an attractive motivation magnet. In the present study, Experiment 1 assessed the effects of Pavlovian predictability versus uncertainty about reward probability and/or reward magnitude on the acquisition and expression of sign-tracking (ST) and goal-tracking (GT) responses in an autoshaping procedure. Results suggested that uncertainty produced strongest incentive salience expressed as sign-tracking. Experiment 2 examined whether a within-individual temporal shift from certainty to uncertainty conditions could produce a stronger CS motivational magnet when uncertainty began, and found that sign-tracking still increased after the shift. Overall, our results support earlier reports that ST responses become more pronounced in the presence of uncertainty regarding CS-UCS associations, especially when uncertainty combines both probability and magnitude. These results suggest that Pavlovian uncertainty, although diluting predictability, is still able to enhance the incentive motivational power of particular CSs. PMID:23078951

Pavlovian drug-sickness pairings result in the conditioning of an antisickness response.

PubMed

Lett, B T

1983-10-01

After a drug conditioned stimulus (CS) has been injected prior to lithium chloride as the unconditioned stimulus (US) on five occasions, the drug CS becomes able to evoke a conditioned antisickness response (CAR). This CAR is implied by the finding that the CS drug mitigates the conditioned saccharin aversion produced by lithium when it is administered in the interval between saccharin consumption and lithium injection. The following drugs were tested and are listed in approximate order of their effectiveness in producing a conditioned antisickness effect: pentobarbital, ethanol, morphine, amphetamine, and chlordiazepoxide.

Perceptual learning transfer in an appetitive Pavlovian task.

PubMed

Artigas, Antonio A; Prados, Jose

2017-06-01

In two experiments, rats were given intermixed or blocked preexposure to two similar compound stimuli, AX and BX. Following preexposure, conditioning trials took place in which AX (Experiment 1) or a novel compound stimulus NX (Experiment 2) was paired with a food-unconditioned stimulus in an appetitive Pavlovian preparation. Animals that were given alternated preexposure showed lower generalization from AX to BX (Experiment 1) and from NX to a new compound, ZX (Experiment 2), than animals that were given blocked preexposure, a perceptual learning and a perceptual learning transfer effect, respectively.

Pavlovian conditioning in the rabbit during inactivation of the interpositus nucleus.

PubMed Central

Welsh, J P; Harvey, J A

1991-01-01

1. We have examined the role of the anterior interpositus nucleus (AIP) of the cerebellum in Pavlovian conditioning of the nictitating membrane response (NMR) of the rabbit with the use of reversible brain lesions produced by the local anaesthetic lidocaine. Previous experiments have demonstrated that destructive lesions of the AIP prevent the performance of conditioned NMRs (CRs). Microinjections of lidocaine into the AIP were used in the present experiment to determine whether the deficit in the performance of CRs resulted from a deficit in learning or memory. 2. A 3-phase procedure was employed to determine whether associative learning required the function of the AIP. In phase 1, rabbits were trained to make CRs to a flashing-light conditioned stimulus (CS) that was paired with an air-puff unconditioned stimulus (UCS) directed at the cornea. In phase 2, the AIP was anaesthetized during a session of conditioning in which a tone CS was paired with the UCS. Presentations of the light CS were interpolated throughout the tone conditioning in order to monitor the degree to which CRs were impaired by lidocaine. Phase 3 occurred after the effects of the lidocaine had dissipated and consisted of a test of retention to determine whether learning occurred during phase 2 but could not be expressed because of a performance deficit resulting from the inactivation of the AIP. 3. Infusion of lidocaine into the AIP abolished CRs to the light CS and prevented the performance of CRs to the tone CS in phase 2. The effect of the infusion was specifically due to a conduction block of neurons and/or fibres in the lateral aspect of the AIP. The infusion of lidocaine into regions surrounding the AIP did not affect CRs elicited by the light CS or prevent acquisition of CRs to the tone. Infusions of saline directly into the AIP did not impair the performance of CRs to either the tone or light CS. Quantitative analysis of diffusion revealed that the abolition of CRs was accompanied by anaesthetization of the AIP. 4. The retention test in phase 3 indicated that learning occurred normally during phase 2 when the AIP was inactivated and performance was abolished. When the function of the AIP was restored and performance had recovered, the subjects demonstrated a frequency of CRs to the tone CS that was indistinguishable from control subjects whose performance had never been impaired. 5. The CRs observed during the retention test provided an unequivocal measure of associative learning.(ABSTRACT TRUNCATED AT 400 WORDS) Images Fig. 8 Fig. 9 PMID:1822558

The Amygdala Is Not Necessary for Unconditioned Stimulus Inflation after Pavlovian Fear Conditioning in Rats

ERIC Educational Resources Information Center

Rabinak, Christine A.; Orsini, Caitlin A.; Zimmerman, Joshua M.; Maren, Stephen

2009-01-01

The basolateral complex (BLA) and central nucleus (CEA) of the amygdala play critical roles in associative learning, including Pavlovian conditioning. However, the precise role for these structures in Pavlovian conditioning is not clear. Recent work in appetitive conditioning paradigms suggests that the amygdala, particularly the BLA, has an…

Neurobiology of anxiety disorders and implications for treatment.

PubMed

Garakani, Amir; Mathew, Sanjay J; Charney, Dennis S

2006-11-01

The neurobiology of the anxiety disorders, which include panic disorder, post-traumatic stress disorder (PTSD), and specific phobias, among others, has been clarified by advances in the field of classical or Pavlovian conditioning, and in our understanding of basic mechanisms of memory and learning. Fear conditioning occurs when a neutral conditioned stimulus (such as a tone) is paired with an aversive, or unconditioned stimulus (such as a footshock), and then in the absence of the unconditioned stimulus, causes a conditioned fear response. Preclinical studies have shown that the amygdala plays a key role in fear circuitry, and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Drugs such as glutamate N-methyl-D-aspartate (NMDA) antagonists, and blockers of voltage-gated calcium channels, in the amygdala, may block these effects. There is also preliminary evidence for the use of centrally acting beta-adrenergic antagonists, like propranolol, to inhibit consolidation of traumatic memories in PTSD. Finally, fear extinction, which entails new learning of fear inhibition, is central to the mechanism of effective anti-anxiety treatments. Several pharmacological manipulations, such as D-cycloserine, a partial NMDA agonist, have been found to facilitate extinction. Combining these medication approaches with psychotherapies that promote extinction, such as cognitive behavioral therapy (CBT), may offer patients with anxiety disorders a rapid and robust treatment with good durability of effect.

Sex and the stimulus-movement effect: Differences in acquisition of autoshaped responding in cynomolgus monkeys.

PubMed

Rice, Nathaniel C; Makar, Jennifer R; Myers, Todd M

2017-03-15

The stimulus-movement effect refers to the phenomenon in which stimulus discrimination or acquisition of a response is facilitated by moving stimuli as opposed to stationary stimuli. The effect has been found in monkeys, rats, and humans, but the experiments conducted did not provide adequate female representation to investigate potential sex differences. The current experiment analyzed acquisition of stimulus touching in a progressive series of classical conditioning procedures in cynomolgus monkeys (Macaca fascicularis) as a function of sex and stimulus movement. Classical conditioning tasks arrange two or more stimuli in relation to each other with different temporal and predictive relations. Autoshaping procedures overlay operant contingencies onto a classical-conditioning stimulus arrangement. In the present case, a neutral stimulus (a small gray square displayed on a touchscreen) functioned as the conditional stimulus and a food pellet functioned as the unconditional stimulus. Although touching is not required to produce food, with repeated stimulus pairings subjects eventually touch the stimulus. Across conditions of increasing stimulus correlation and temporal contiguity, male monkeys acquired the response faster with a moving stimulus. In contrast, females acquired the response faster with a stationary stimulus. These results demonstrate that the stimulus-movement effect may be differentially affected by sex and indicate that additional experiments with females are needed to determine how sex interacts with behavioral phenomena discovered and elaborated almost exclusively using males. Published by Elsevier Inc.

A New Tool for Assessing Context Conditioning Induced by US-Unpredictability in Humans: The Martians Task Restyled

ERIC Educational Resources Information Center

Meulders, Ann; Vervliet, Bram; Vansteenwegen, Debora; Hermans, Dirk; Baeyens, Frank

2011-01-01

Unpredictability of an unconditioned stimulus (US) typically produces context conditioning in animals and humans. We modified the Martians task--a computer game measuring learning of Pavlovian associations through conditioned suppression--for assessing context conditioning in humans. One between-subjects and one within-subjects study are reported.…

The Effects of Context Extinction on US Signal Value

ERIC Educational Resources Information Center

Goddard Murray J.

2007-01-01

Two experiments with rats examined the effects of context extinction on responding to the signal value of an unconditioned stimulus (US). In Experiment 1, US signal value was first trained when a single food pellet signaled the delivery of three additional pellets. After training, rats received either context extinction (CE) or home cage (HC)…

The Etymology of Basic Concepts in the Experimental Analysis of Behavior

ERIC Educational Resources Information Center

Dinsmoor, James A.

2004-01-01

The origins of many of the basic concepts used in the experimental analysis of behavior can be traced to Pavlov's (1927/1960) discussion of unconditional and conditional reflexes in the dog, but often with substantial changes in meaning (e.g., stimulus, response, and reinforcement). Other terms were added by Skinner (1938/1991) to describe his…

The role of nucleus accumbens shell in learning about neutral versus excitatory stimuli during Pavlovian fear conditioning.

PubMed

Bradfield, Laura A; McNally, Gavan P

2010-07-01

We studied the role of nucleus accumbens shell (AcbSh) in Pavlovian fear conditioning. Rats were trained to fear conditioned stimulus A (CSA) in Stage I, which was then presented in compound with a neutral stimulus and paired with shock in Stage II. AcbSh lesions had no effect on fear-learning to CSA in Stage I, but selectively prevented learning about the neutral conditioned stimulus (CS) in Stage II. These results add to a growing body of evidence indicating an important role for the ventral striatum in fear-learning. They suggest that the ventral striatum and AcbSh, in particular, directs learning toward or away from a CS as a consequence of how well that CS predicts the shock unconditioned stimulus (US). AcbSh is required to reduce the processing of established predictors, thereby permitting neutral or less predictive stimuli to be learned about.

Inhibition of long-term memory formation by anti-ependymin antisera after active shock-avoidance learning in goldfish.

PubMed

Piront, M L; Schmidt, R

1988-02-23

Ependymins are acidic glycoprotein constituents of goldfish brain cytoplasm and extracellular fluid which are known to participate in biochemical reactions of long-term memory formation. In earlier experiments, anti-ependymin antisera were found to cause amnesia when injected into goldfish brain ventricles after the acquisition of a vestibulomotoric training task. To investigate whether they also inhibit memory consolidation after other learning events the anti-ependymin antisera were injected after an active shock-avoidance learning paradigm, as follows: goldfish were trained in a shuttle-box to cross a barrier in order to avoid electric shocks (unconditioned stimulus) applied shortly after a light signal (conditioned stimulus). Anti-ependymin antisera blocked retention of the learned avoidance when injected 0.5, 4.5 or 24 h after acquisition of the new behavior. They had no effect, however, when injected 72 h after learning. Apparently, long-term memory was already consolidated at this point. Antisera injected 0.5 or 72 h prior to training, also did not influence learning or memory. Thirteen percent of the goldfish fled the light stimulus spontaneously. These fish therefore did not experience the unconditioned stimulus and thus were unable to learn the task. When they were treated with the anti-ependymin antisera and tested 3 days later, the spontaneous escape reaction was not affected (active control group). The ability of anti-ependymin antisera to inhibit memory consolidation and their efficacy after administration at specific time intervals are very similar for the active shock-avoidance learning and for the vestibulomotoric training. We conclude that ependymins are not task-specific, but serve a general function in biochemical reactions essential for long-term memory formation.

Short-term total sleep deprivation alters delay-conditioned memory in the rat.

PubMed

Tripathi, Shweta; Jha, Sushil K

2016-06-01

Short-term sleep deprivation soon after training may impair memory consolidation. Also, a particular sleep stage or its components increase after learning some tasks, such as negative and positive reinforcement tasks, avoidance tasks, and spatial learning tasks, and so forth. It suggests that discrete memory types may require specific sleep stage or its components for their optimal processing. The classical conditioning paradigms are widely used to study learning and memory but the role of sleep in a complex conditioned learning is unclear. Here, we have investigated the effects of short-term sleep deprivation on the consolidation of delay-conditioned memory and the changes in sleep architecture after conditioning. Rats were trained for the delay-conditioned task (for conditioning, house-light [conditioned stimulus] was paired with fruit juice [unconditioned stimulus]). Animals were divided into 3 groups: (a) sleep deprived (SD); (b) nonsleep deprived (NSD); and (c) stress control (SC) groups. Two-way ANOVA revealed a significant interaction between groups and days (training and testing) during the conditioned stimulus-unconditioned stimulus presentation. Further, Tukey post hoc comparison revealed that the NSD and SC animals exhibited significant increase in performances during testing. The SD animals, however, performed significantly less during testing. Further, we observed that wakefulness and NREM sleep did not change after training and testing. Interestingly, REM sleep increased significantly on both days compared to baseline more specifically during the initial 4-hr time window after conditioning. Our results suggest that the consolidation of delay-conditioned memory is sleep-dependent and requires augmented REM sleep during an explicit time window soon after training. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Dorsal periaqueductal gray-amygdala pathway conveys both innate and learned fear responses in rats

PubMed Central

Kim, Eun Joo; Horovitz, Omer; Pellman, Blake A.; Tan, Lancy Mimi; Li, Qiuling; Richter-Levin, Gal; Kim, Jeansok J.

2013-01-01

The periaqueductal gray (PAG) and amygdala are known to be important for defensive responses, and many contemporary fear-conditioning models present the PAG as downstream of the amygdala, directing the appropriate behavior (i.e., freezing or fleeing). However, empirical studies of this circuitry are inconsistent and warrant further examination. Hence, the present study investigated the functional relationship between the PAG and amygdala in two different settings, fear conditioning and naturalistic foraging, in rats. In fear conditioning, electrical stimulation of the dorsal PAG (dPAG) produced unconditional responses (URs) composed of brief activity bursts followed by freezing and 22-kHz ultrasonic vocalization. In contrast, stimulation of ventral PAG and the basolateral amygdalar complex (BLA) evoked freezing and/or ultrasonic vocalization. Whereas dPAG stimulation served as an effective unconditional stimulus for fear conditioning to tone and context conditional stimuli, neither ventral PAG nor BLA stimulation supported fear conditioning. The conditioning effect of dPAG, however, was abolished by inactivation of the BLA. In a foraging task, dPAG and BLA stimulation evoked only fleeing toward the nest. Amygdalar lesion/inactivation blocked the UR of dPAG stimulation, but dPAG lesions did not block the UR of BLA stimulation. Furthermore, in vivo recordings demonstrated that electrical priming of the dPAG can modulate plasticity of subiculum–BLA synapses, providing additional evidence that the amygdala is downstream of the dPAG. These results suggest that the dPAG conveys unconditional stimulus information to the BLA, which directs both innate and learned fear responses, and that brain stimulation-evoked behaviors are modulated by context. PMID:23959880

Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit.

PubMed

Tracy, Jo Anne; Thompson, Judith K; Krupa, David J; Thompson, Richard F

2013-10-01

Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated. Pontine projection patterns to the cerebellum were confirmed with retrograde labeling techniques. These results add to the body of literature suggesting that the pons relays CS information to the cerebellum and provide further evidence of synaptic plasticity in the cerebellar network. 2013 APA, all rights reserved

Behavioral conditioning of immunosuppression is possible in humans.

PubMed

Goebel, Marion U; Trebst, Almuth E; Steiner, Jan; Xie, Yu F; Exton, Michael S; Frede, Stilla; Canbay, Ali E; Michel, Martin C; Heemann, Uwe; Schedlowski, Manfred

2002-12-01

Behavioral conditioned immunosuppression has been described in rodents as the most impressive demonstration of brain-to-immune system interaction. To analyze whether behavioral conditioned immunosuppression is possible in humans, healthy subjects in this double-blind, placebo-controlled study were conditioned in four sessions over 3 consecutive days, receiving the immunosuppressive drug cyclosporin A as an unconditioned stimulus paired with a distinctively flavored drink (conditioned stimulus) each 12 h. In the next week, re-exposure to the conditioned stimulus (drink), but now paired with placebo capsules, induced a suppression of immune functions as analyzed by the IL-2 and IFN-gamma mRNA expression, intracellular production, and in vitro release of IL-2 and IFN-gamma, as well as lymphocyte proliferation. These data demonstrate for the first time that immunosuppression can be behaviorally conditioned in humans.

Human umbilical cord mesenchymal stem cells hUC-MSCs exert immunosuppressive activities through a PGE2-dependent mechanism.

PubMed

Chen, Ke; Wang, Ding; Du, Wei Ting; Han, Zhi-Bo; Ren, He; Chi, Ying; Yang, Shao Guang; Zhu, Delin; Bayard, Francis; Han, Zhong Chao

2010-06-01

Human umbilical-cord-derived mesenchymal stem cells (hUC-MSCs) constitute an attractive alternative to bone-marrow-derived MSCs for potential clinical applications because of easy preparation and lower risk of viral contamination. In this study, both proliferation of human peripheral blood mononuclear cells (hPBMCs) and their IFN-gamma production in response to mitogenic or allogeneic stimulus were effectively inhibited by hUC-MSCs. Co-culture experiments in transwell systems indicated that the suppression was largely mediated by soluble factor(s). Blocking experiments identified prostaglandin E(2) (PGE(2)) as the major factor, because inhibition of PGE(2) synthesis almost completely mitigated the immunosuppressive effects, whereas neutralization of TGF-beta, IDO, and NO activities had little effects. Moreover, the inflammatory cytokines, IFN-gamma and IL-1beta, produced by hPBMCs upon activation notably upregulated the expression of cyclooxygenase-2 (COX-2) and the production of PGE(2) by hUC-MSCs. In conclusion, our data have demonstrated for the first time the PGE(2)-mediated mechanism by which hUC-MSCs exert their immunomodulatory effects. Copyright 2010 Elsevier Inc. All rights reserved.

Reinforcement in an in Vitro Analog of Appetitive Classical Conditioning of Feeding Behavior in "Aplysia": Blockade by a Dopamine Antagonist

ERIC Educational Resources Information Center

Reyes, Fredy D.; Mozzachiodi, Riccardo; Baxter, Douglas A.; Byrne, John H.

2005-01-01

In a recently developed in vitro analog of appetitive classical conditioning of feeding in "Aplysia," the unconditioned stimulus (US) was electrical stimulation of the esophageal nerve (En). This nerve is rich in dopamine (DA)-containing processes, which suggests that DA mediates reinforcement during appetitive conditioning. To test this…

Spermidine-Induced Improvement of Reconsolidation of Memory Involves Calcium-Dependent Protein Kinase in Rats

ERIC Educational Resources Information Center

Girardi, Bruna Amanda; Ribeiro, Daniela Aymone; Signor, Cristiane; Muller, Michele; Gais, Mayara Ana; Mello, Carlos Fernando; Rubin, Maribel Antonello

2016-01-01

In this study, we determined whether the calcium-dependent protein kinase (PKC) signaling pathway is involved in the improvement of fear memory reconsolidation induced by the intrahippocampal administration of spermidine in rats. Male Wistar rats were trained in a fear conditioning apparatus using a 0.4-mA footshock as an unconditioned stimulus.…

Subliminal influence on preferences? A test of evaluative conditioning for brief visual conditioned stimuli using auditory unconditioned stimuli

PubMed Central

2017-01-01

In the field of evaluative conditioning (EC), two opposing theories—propositional single-process theory versus dual-process theory—are currently being discussed in the literature. The present set of experiments test a crucial prediction to adjudicate between these two theories: Dual-process theory postulates that evaluative conditioning can occur without awareness of the contingency between conditioned stimulus (CS) and unconditioned stimulus (US); in contrast, single-process propositional theory postulates that EC requires CS-US contingency awareness. In a set of three studies, we experimentally manipulate contingency awareness by presenting the CSs very briefly, thereby rendering it unlikely to be processed consciously. We address potential issues with previous studies on EC with subliminal or near-threshold CSs that limited their interpretation. Across two experiments, we consistently found an EC effect for CSs presented for 1000 ms and consistently failed to find an EC effect for briefly presented CSs. In a third pre-registered experiment, we again found evidence for an EC effect with CSs presented for 1000 ms, and we found some indication for an EC effect for CSs presented for 20 ms. PMID:28989730

Subliminal influence on preferences? A test of evaluative conditioning for brief visual conditioned stimuli using auditory unconditioned stimuli.

PubMed

Heycke, Tobias; Aust, Frederik; Stahl, Christoph

2017-09-01

In the field of evaluative conditioning (EC), two opposing theories-propositional single-process theory versus dual-process theory-are currently being discussed in the literature. The present set of experiments test a crucial prediction to adjudicate between these two theories: Dual-process theory postulates that evaluative conditioning can occur without awareness of the contingency between conditioned stimulus (CS) and unconditioned stimulus (US); in contrast, single-process propositional theory postulates that EC requires CS-US contingency awareness. In a set of three studies, we experimentally manipulate contingency awareness by presenting the CSs very briefly, thereby rendering it unlikely to be processed consciously. We address potential issues with previous studies on EC with subliminal or near-threshold CSs that limited their interpretation. Across two experiments, we consistently found an EC effect for CSs presented for 1000 ms and consistently failed to find an EC effect for briefly presented CSs. In a third pre-registered experiment, we again found evidence for an EC effect with CSs presented for 1000 ms, and we found some indication for an EC effect for CSs presented for 20 ms.

It’s The Information!

PubMed Central

Ward, Ryan D.; Gallistel, C.R.; Balsam, Peter D

2013-01-01

Learning in conditioning protocols has long been thought to depend on temporal contiguity between the conditioned stimulus and the unconditioned stimulus. This conceptualization has led to a preponderance of associative models of conditioning. We suggest that trial-based associative models that posit contiguity as the primary principle underlying learning are flawed, and provide a brief review of an alternative, information theoretic approach to conditioning. The information that a CS conveys about the timing of the next US can be derived from the temporal parameters of a conditioning protocol. According to this view, a CS will support conditioned responding if, and only if, it reduces uncertainty about the timing of the next US. PMID:23384660

Pavlovian contingencies and temporal information.

PubMed

Balsam, Peter D; Fairhurst, Stephen; Gallistel, Charles R

2006-07-01

The effects of altering the contingency between the conditioned stimulus (CS) and the unconditioned stimulus (US) on the acquisition of autoshaped responding was investigated by changing the frequency of unsignaled USs during the intertrial interval. The addition of the unsignaled USs had an effect on acquisition speed comparable with that of massing trials. The effects of these manipulations can be understood in terms of their effect on the amount of information (number of bits) that the average CS conveys to the subject about the timing of the next US. The number of reinforced CSs prior to acquisition is inversely related to the information content of the CS.

Cornering the fear engram: long-term synaptic changes in the lateral nucleus of the amygdala after fear conditioning.

PubMed

Kwon, Jeong-Tae; Choi, June-Seek

2009-08-05

Use-dependent synaptic modifications in the lateral nucleus of the amygdala (LA) have been suggested to be the cellular analog of memory trace after pavlovian fear conditioning. However, whether neurophysiological changes in the LA are produced as a direct consequence of associative learning awaits additional proof. Using microstimulation of the medial geniculate nucleus of the thalamus as the conditioned stimulus (CS), we demonstrated that contingent pairings of the brain-stimulation CS and a footshock unconditioned stimulus lead to enhanced synaptic efficacy in the thalamic input to the LA, supporting the hypothesis that localized synaptic alterations underlie fear memory formation.

Stimulus properties of inhaled substances

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wood, R.W.

1978-10-01

Inhaled substances can modify behavior by their toxic action, or because they are discriminable events, or because they can support or suppress behavior. They can be used as discriminative stimuli at concentrations above the olfactory threshold. Inhalants can elicit unconditioned reflexes. As aversive stimuli, they can be studied in respondent conditioning experiments (e.g. conditioned suppression), in punishment paradigms, or as negative reinforcers in escape paradigms. Inhalants can also be positive reinforcers; their intoxication properties have engendered patterns of chronic self-administration (solvent abuse). Such stimulus properties should be considered in industrial hygiene and environmental quality decisions. Laboratory techniques to study suchmore » properties abound.« less

Stimulus properties of inhaled substances

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wood, R.W.

1978-01-01

Inhaled substances can modify behavior by their toxic action, or because they are discriminable events, or because they can support or suppress behavior. They can be used as discriminative stimuli at concentrations above the olfactory threshold. Inhalants can elicit unconditioned reflexes. As aversive stimuli, they can be studied in respondent conditioning experiments (e.g. conditioned suppression), in punishment paradigms, or as negative reinforcers in escape paradigms. Inhalants can also be positive reinforcers; their intoxicating properties have engendered patterns of chronic self-administration (solvent abuse). Such stimulus properties should be considered in industrial hygiene and environmental quality decisions. Laboratory techniques to study suchmore » properties abound.« less

Attenuation and cross-attenuation in taste-aversion learning in the rat: Studies with ionizing radiation, lithium chloride, and ethanol. Scientific report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabin, B.M.; Hunt, W.A.; Lee, J.

1989-01-01

The pre-exposure paradigm was utilized to evaluate the similarity of ionizing radiation, lithium chloride, and ethanol as unconditioned stimuli for the acquisition of a conditioned taste aversion. Three unpaired pre-exposures to lithium chloride blocked the acquisition of a taste aversion when a novel sucrose solution was paired with either the injection of the same dose of lithium chloride or exposure to ionizing radiation (100 rad). Similar pretreatment with radiation blocked the acquisition of a radiation-induced aversion, but had no effect on taste aversions produced by lithium aversion, but not radiation- or lithium chloride-induced aversions. In contrast, preexposure to either radiationmore » or lithium chloride attenuated an ethanol-induced taste aversion in intact rats, but not in rats with lesions of the area postrema. The results are discussed in terms of relationships between these three unconditioned stimuli and in terms of implications of these results for understanding the nature of the proximal unconditioned stimulus in taste aversion learning.« less

Taste Aversions Conditioned by the Aversiveness of Insulin and Formalin: Role of CS Specificity

ERIC Educational Resources Information Center

Domjan, Michael; Levy, Carolyn J.

1977-01-01

Experimenters in the past have reported that when insulin is used as the unconditioned stimulus (US), rats will learn an aversion to a sodium chloride but not a sucrose solution, whereas with formalin as the US, they will learn an aversion to a sucrose but not a saline solution. The present experiments failed to confirm these findings. (Editor)

Role of benzodiazepine and serotonergic mechanisms in conditioned freezing and antinociception using electrical stimulation of the dorsal periaqueductal gray as unconditioned stimulus in rats.

PubMed

Castilho, V M; Macedo, C E; Brandão, M L

2002-12-01

The dorsal periaqueductal gray matter (dPAG) has been implicated in the modulation of defensive behavior. Electrical stimulation of this structure can be used as an unconditioned stimulus to produce a conditioned fear reaction expressed by freezing, antinociception, and autonomic responses. This study investigated the influence of benzodiazepine, serotonergic, and opioid mechanisms on these conditioned responses. Animals implanted with an electrode and a guide cannula into the dPAG were submitted to two conditioning sessions. Each session consisted of ten pairings of the light in a distinctive chamber (CS) with the electrical stimulation of this structure at the escape threshold. On the next day, each animal was exposed only to the CS (testing) and the duration of freezing, number of rearing and grooming episodes were recorded for 5 min. Before and after the testing session, animals were submitted to the tail-flick test. Fifteen minutes before the exposure to the CS, animals received injections into the dPAG of midazolam (a positive modulator of benzodiazepine sites), alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT; an agonist of 5-HT(2) receptors), naltrexone (an opioid antagonist), or vehicle. Conditioning with dPAG electrical stimulation caused significant increases in the time of freezing and conditioned antinociception. Injections of midazolam into the dPAG significantly inhibited freezing behavior and antinociception due to conditioning. Injections of alpha-Me-5-HT inhibited the effects of conditioning on freezing without affecting conditioned antinociception. Injections of naltrexone (13 nmol/0.2 micro l) did not change any of the conditioned responses studied. (1) Conditioned freezing and antinociception are modulated by benzodiazepine mechanisms into dPAG. (2) 5-HT(2) receptors seem to regulate conditioned freezing behavior. However, conditioned antinociception was not affected by 13 nmol naltrexone. (3) Opioid mechanisms do not seem to be involved in the conditioned responses using electrical stimulation of the dPAG as unconditioned stimulus. Further studies with other opioid and 5-HT(2) receptor antagonists are still needed to confirm the conclusions drawn from the present work.

Responses of the circadian system of rats to conditioned and unconditioned stimuli.

PubMed

de Groot, M H; Rusak, B

2000-08-01

The circadian systems of rodents respond to light pulses presented during the subjective night with phase shifts and altered cellular activity in the suprachiasmatic nuclei (SCN), including expression of immediate-early genes (IEGs) such as c-fos. A recent study showed that a nonphotic stimulus (an air disturbance generated by a fan) that does not normally induce the expression of c-fos-like immunoreactivity in the SCN of rats can be made to do so after being paired repeatedly with a light pulse in a Pavlovian conditioning paradigm. Furthermore, after conditioning (but not after noncontingent exposure to these stimuli), the fan also induced phase shifts in activity and body temperature rhythms comparable to those produced by light. The authors performed three experiments designed to replicate and extend these findings in rats. In experiment 1, rats were tested for conditioning effects of repeated pairings of a light pulse with a neutral air disturbance under a full photoperiod. In experiment 2, a modified conditioning paradigm was used in which a skeleton photoperiod served as both the entraining zeitgeber and the unconditioned stimulus. Animals in the paired and unpaired training conditions were exposed to both the light pulse and the air disturbance, but the air disturbance signaled the onset of light in the paired condition only. Phase shifts of wheel-running activity rhythms and gene expression in the SCN, intergeniculate leaflet, and paraventricular nucleus of the thalamus were assessed in animals following either of the training conditions or the control procedures. Experiment 3 assessed whether the air disturbance could entrain the circadian activity rhythms of rats with or without previous pairing with light in a classical conditioning paradigm. No evidence for classical conditioning, nor for unconditioned effects of the air disturbance on the circadian system, was found in these studies.

Intra-articular administration of xenogeneic neonatal Mesenchymal Stromal Cells early after meniscal injury down-regulates metalloproteinase gene expression in synovium and prevents cartilage degradation in a rabbit model of osteoarthritis.

PubMed

Saulnier, N; Viguier, E; Perrier-Groult, E; Chenu, C; Pillet, E; Roger, T; Maddens, S; Boulocher, C

2015-01-01

The anti-inflammatory and anti-catabolic effects of neonatal Mesenchymal Stromal Cell (MSC) were investigated in a xenogeneic model of mild osteoarthritis (OA). The paracrine properties of MSC on synoviocytes were further investigated in vitro. OA was induced by medial meniscal release (MMR) in 30 rabbit knees. A single early (day 3) or delayed (day 15) intra-articular (IA) injection of MSC isolated from equine Umbilical Cord Wharton's jelly (UC-MSC) was performed. Rabbits were euthanized on days 15 or 56. OA grading was performed and gene expression of inflammatory cytokines and metalloproteinases was measured in synovial tissue. Paracrine effects of UC-MSC were investigated using UC-conditioned vs control medium on rabbit primary synoviocytes stimulated with interleukin 1 beta in vitro. No adverse local or systemic responses were observed clinically after xenogeneic UC-MSC injection. At study end point, cartilage fibrillation was lower in early treatment than in delayed treatment group. Cellular infiltrate was observed in the synovium of both UC-MSC groups. OA synovium exhibited a reduced expression of metalloproteinases-1, -3, -13 in the early cell-treated group at d56. In vitro, UC-conditioned medium exerted anti-inflammatory and anti-catabolic effects on synoviocytes exposed to pro-inflammatory stimulus. Early IA injection of equine UC-MSC was effective in preventing OA signs in rabbit knees following MMR. UC-MSC target the synovium and modulate the gene expression pattern of synoviocytes to promote an anti-catabolic environment. This confirms the synovium is a major target and mediator of MSC therapy, modulating the expression of matrix-degrading enzymes. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model

PubMed Central

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-01-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction. PMID:27617747

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model.

PubMed

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-09-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction.

An unconditioned stimulus retrieval extinction procedure to prevent the return of fear memory.

PubMed

Liu, Jianfeng; Zhao, Liyan; Xue, Yanxue; Shi, Jie; Suo, Lin; Luo, Yixiao; Chai, Baisheng; Yang, Chang; Fang, Qin; Zhang, Yan; Bao, Yanping; Pickens, Charles L; Lu, Lin

2014-12-01

Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. We introduced a technique to target all diverse cues associated with an aversive event that causes fear. In human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as that used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Presentation of a lower intensity US before extinction disrupted the associations between the different CS and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. These findings demonstrate that a modified US retrieval extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Evaluation of the Risk of Relapse in Ulcerative Colitis According to the Degree of Mucosal Healing (Mayo 0 vs 1): A Longitudinal Cohort Study.

PubMed

Barreiro-de Acosta, Manuel; Vallejo, Nicolau; de la Iglesia, Daniel; Uribarri, Laura; Bastón, Iria; Ferreiro-Iglesias, Rocío; Lorenzo, Aurelio; Domínguez-Muñoz, J Enrique

2016-01-01

Mucosal healing in ulcerative colitis (UC) has become a common endpoint in most clinical trials and a relevant therapeutic goal in clinical practice. Despite important differences between endoscopic Mayo scores 0 and 1, both scores are considered as mucosal healing in most important trials. The aim of the present study was to evaluate the risk of relapse in UC patients according to the degree of mucosal healing (endoscopic Mayo scores of 0 and 1). A prospective longitudinal cohort study was designed. All UC patients who presented with mucosal healing at colonoscopy were consecutively included. Mucosal healing was defined as an endoscopic Mayo score of 0 or 1. Clinical relapse was defined as the need for therapy to induce remission, any treatment escalation, hospitalization or colectomy. All clinical relapses were evaluated at months 6 and 12 after study entry. Results were subjected to unconditional stepwise logistic and Kaplan-Meier regression analysis. One hundred and eighty-seven consecutive UC patients (126 [67.3%] with Mayo score 0 and 61 [32.7%] with Mayo score 1) were included. Of patients with Mayo scores 0 and 1, 9.4 and 36.6% respectively presented a relapse during the first 6 months of follow-up (p < 0.001). The only factor independently associated with UC relapses in the multivariate analysis was an endoscopic Mayo score of 1 (odds ratio 6.27, 95% confidence interval 2.73-14.40, p < 0.001). Patients with an endoscopic Mayo score of 1 have a higher risk of relapse than those with a score of 0. The concept of mucosal healing should be limited to patients with an endoscopic Mayo score of 0. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

A train of electrical pulses applied to the primary auditory cortex evokes a conditioned response in guinea pigs.

PubMed

Okuda, Yuji; Shikata, Hiroshi; Song, Wen-Jie

2011-09-01

As a step to develop auditory prosthesis by cortical stimulation, we tested whether a single train of pulses applied to the primary auditory cortex could elicit classically conditioned behavior in guinea pigs. Animals were trained using a tone as the conditioned stimulus and an electrical shock to the right eyelid as the unconditioned stimulus. After conditioning, a train of 11 pulses applied to the left AI induced the conditioned eye-blink response. Cortical stimulation induced no response after extinction. Our results support the feasibility of auditory prosthesis by electrical stimulation of the cortex. Copyright © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

It's the information!

PubMed

Ward, Ryan D; Gallistel, C R; Balsam, Peter D

2013-05-01

Learning in conditioning protocols has long been thought to depend on temporal contiguity between the conditioned stimulus and the unconditioned stimulus. This conceptualization has led to a preponderance of associative models of conditioning. We suggest that trial-based associative models that posit contiguity as the primary principle underlying learning are flawed, and provide a brief review of an alternative, information theoretic approach to conditioning. The information that a CS conveys about the timing of the next US can be derived from the temporal parameters of a conditioning protocol. According to this view, a CS will support conditioned responding if, and only if, it reduces uncertainty about the timing of the next US. Copyright © 2013 Elsevier B.V. All rights reserved.

Temporal specificity of extinction in autoshaping.

PubMed

Drew, Michael R; Yang, Cynthia; Ohyama, Tatsuya; Balsam, Peter D

2004-07-01

Three experiments investigated the effects of varying the conditioned stimulus (CS) duration between training and extinction. Ring doves (Streptopelia risoria) were autoshaped on a fixed CS-unconditioned stimulus (US) interval and extinguished with CS presentations that were longer, shorter, or the same as the training duration. During a subsequent test session, the training CS duration was reintroduced. Results suggest that the cessation of responding during an extinction session is controlled by generalization of excitation between the training and extinction CSs and by the number of nonreinforced CS presentations. Transfer of extinction to the training CS is controlled by the similarity between the extinction and training CSs. Extinction learning is temporally specific. (c) 2004 APA, all rights reserved

Memories of Reward and Nonreward Regulate the Extinction and Reacquisition of both Excitatory and Inhibitory Associations

ERIC Educational Resources Information Center

Capaldi, E. J.; Martins, Ana P. G.; Altman, Meaghan

2009-01-01

arrow]US associations also survived The memories of the unconditioned stimulus (US) and its absence (No US), symbolized as S[superscript R] and S[superscript N], respectively, may be retrieved on US or No US trials giving rise to four types of associations, S[superscript R][right arrow]US, S[superscript R][right arrow]No US, S[superscript N][right…

Autoshaping in the rat: conditioned licking response to a stimulus that signals sucrose reinforcement.

PubMed

Reilly, Steve; Grutzmacher, Richard P.

2002-07-31

The present experiments were designed to determine if repeated presentations of an empty sipper tube (the conditioned stimulus or CS) with the response-independent delivery of a sucrose solution (the unconditioned stimulus or US) from a second spout results in the development of Pavlovian conditioned responding. In Experiment 1, rats in the experimental condition received paired CS-US presentations whereas subjects in the control condition were exposed to random presentations of CS and US. In Experiment 2, an additional control condition (CS alone) was included and, to encourage generalized responding between the US and CS, the CS tube was filled with water for all groups. The results of both experiments indicate that the CS-directed responding in the paired CS-US condition was Pavlovian in nature. Thus, the present procedure serves as an autoshaping task in which conditioned licking is generated.

Lever conditioned stimulus-directed autoshaping induced by saccharin-ethanol unconditioned stimulus solution: effects of ethanol concentration and trial spacing.

PubMed

Tomie, Arthur; Festa, Eugene D; Sparta, Dennis R; Pohorecky, Larissa A

2003-05-01

Two experiments were designed to evaluate whether brief access to a saccharin-ethanol solution would function as an effective unconditioned stimulus (US) in Pavlovian-autoshaping procedures. In these experiments, the insertion of a lever conditioned stimulus (CS) was followed by the brief presentation of a sipper tube containing saccharin-ethanol US solution. Experience with this Pavlovian-autoshaping procedure engendered lever CS-directed autoshaping conditioned responses (CRs) in all rats. In Experiment 1, the concentration of ethanol [0%, 2%, 4%, 6%, or 8% (vol./vol.)] in 0.1% saccharin was systematically increased within subjects across autoshaping sessions to evaluate the relation between a rat's drinking and lever pressing. In Experiment 2, the mean intertrial interval (ITI) duration (60, 90, 120 s) was systematically increased within subjects across autoshaping sessions to evaluate the effect of ITI duration on drinking and lever pressing. A pseudoconditioning control group received lever CS randomly with respect to the saccharin-ethanol US solution. In Experiment 1, lever-press autoshaping CRs developed in all rats, and the tendency of a rat to drink an ethanol concentration was predictive of the performance of lever-press autoshaping CRs. In Experiment 2, longer ITIs induced more lever CS-directed responding, and CS-US paired procedures yielded more lever CS-directed responding than that observed in CS-US random procedures. Saccharin-ethanol is an effective US in Pavlovian-autoshaping procedures, inducing more CS-directed responding than in pseudoconditioning controls receiving CS-US random procedures. More lever CS-directed responding was observed when there was more drinking of the saccharin-ethanol US solution (Experiment 1); when the CS and US were paired, rather than random (Experiment 2); and with longer mean ITI durations (Experiment 2). This pattern of results is consistent with the hypothesis that lever CS-directed responding reflects performance of Pavlovian-autoshaping CRs.

Attenuation and cross-attenuation in taste aversion learning in the rat: Studies with ionizing radiation, lithium chloride and ethanol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabin, B.M.; Hunt, W.A.; Lee, J.

1988-12-01

The preexposure paradigm was utilized to evaluate the similarity of ionizing radiation, lithium chloride and ethanol as unconditioned stimuli for the acquisition of a conditioned taste aversion. Three unpaired preexposures to lithium chloride (3.0 mEq/kg, IP) blocked the acquisition of a taste aversion when a novel sucrose solution was paired with either the injection of the same dose of lithium chloride or exposure to ionizing radiation (100 rad). Similar pretreatment with radiation blocked the acquisition of a radiation-induced aversion, but had no effect on taste aversions produced by lithium chloride (3.0 or 1.5 mEq/kg). Preexposure to ethanol (4 g/kg, PO)more » disrupted the acquisition of an ethanol-induced taste aversion, but not radiation- or lithium chloride-induced aversions. In contrast, preexposure to either radiation or lithium chloride attenuated an ethanol-induced taste aversion in intact rats, but not in rats with lesions of the area postrema. The results are discussed in terms of relationships between these three unconditioned stimuli and in terms of implications of these results for understanding the nature of the proximal unconditioned stimulus in taste aversion learning.« less

Attenuation and cross-attenuation in taste aversion learning in the rat: studies with ionizing radiation, lithium chloride and ethanol.

PubMed

Rabin, B M; Hunt, W A; Lee, J

1988-12-01

The preexposure paradigm was utilized to evaluate the similarity of ionizing radiation, lithium chloride and ethanol as unconditioned stimuli for the acquisition of a conditioned taste aversion. Three unpaired preexposures to lithium chloride (3.0 mEq/kg, IP) blocked the acquisition of a taste aversion when a novel sucrose solution was paired with either the injection of the same dose of lithium chloride or exposure to ionizing radiation (100 rad). Similar pretreatment with radiation blocked the acquisition of a radiation-induced aversion, but had no effect on taste aversions produced by lithium chloride (3.0 or 1.5 mEq/kg). Preexposure to ethanol (4 g/kg, PO) disrupted the acquisition of an ethanol-induced taste aversion, but not radiation- or lithium chloride-induced aversions. In contrast, preexposure to either radiation or lithium chloride attenuated an ethanol-induced taste aversion in intact rats, but not in rats with lesions of the area postrema. The results are discussed in terms of relationships between these three unconditioned stimuli and in terms of implications of these results for understanding the nature of the proximal unconditioned stimulus in taste aversion learning.

The central amygdala controls learning in the lateral amygdala

PubMed Central

Yu, Kai; Ahrens, Sandra; Zhang, Xian; Schiff, Hillary; Ramakrishnan, Charu; Fenno, Lief; Deisseroth, Karl; Zhao, Fei; Luo, Min-Hua; Gong, Ling; He, Miao; Zhou, Pengcheng; Paninski, Liam; Li, Bo

2018-01-01

Experience-driven synaptic plasticity in the lateral amygdala (LA) is thought to underlie the formation of associations between sensory stimuli and an ensuing threat. However, how the central amygdala (CeA) participates in such learning process remains unclear. Here we show that PKC-δ-expressing CeA neurons are essential for the synaptic plasticity underlying learning in the LA, as they convey information about unconditioned stimulus to LA neurons during fear conditioning. PMID:29184202

Maternal Pre-Gravid Obesity Changes Gene Expression Profiles Towards Greater Inflammation and Reduced Insulin Sensitivity in Umbilical Cord

PubMed Central

Thakali, Keshari M.; Saben, Jessica; Faske, Jennifer B.; Lindsey, Forrest; Gomez-Acevedo, Horacio; Lowery, Curtis L.; Badger, Thomas M.; Andres, Aline; Shankar, Kartik

2014-01-01

Background Maternal obesity is associated with unfavorable outcomes, which may be reflected in the as yet undiscovered gene expression profiles of the umbilical cord (UC). Methods UCs from 12 lean (pre-gravid BMI < 24.9) and 10 overweight/obese (OW/OB, pre-gravid BMI ≥25) women without gestational diabetes were collected for gene expression analysis using Human Primeview microarrays (Affymetrix). Metabolic parameters were assayed in mother’s plasma and cord blood. Results Although offspring birth weight and adiposity (at 2-wk) did not differ between groups, expression of 232 transcripts was affected in UC from OW/OB compared to those of lean mothers. GSEA analysis revealed an up-regulation of genes related to metabolism, stimulus and defense response and inhibitory to insulin signaling in the OW/OB group. We confirmed that EGR1, periostin, and FOSB mRNA expression was induced in UCs from OW/OB moms, while endothelin receptor B, KFL10, PEG3 and EGLN3 expression was decreased. Messenger RNA expression of EGR1, FOSB, MEST and SOCS1 were positively correlated (p<0.05) with mother’s first trimester body fat mass (%). Conclusions Our data suggest a positive association between maternal obesity and changes in UC gene expression profiles favoring inflammation and insulin resistance, potentially predisposing infants to develop metabolic dysfunction later on in life. PMID:24819376

Extinction of likes and dislikes: effects of feature-specific attention allocation.

PubMed

Vanaelst, Jolien; Spruyt, Adriaan; Everaert, Tom; De Houwer, Jan

2017-12-01

The evaluative conditioning (EC) effect refers to the change in the liking of a neutral stimulus (conditioned stimulus, CS) due to its pairing with another stimulus (unconditioned stimulus, US). We examined whether the extinction rate of the EC effect is moderated by feature-specific attention allocation. In two experiments, CSs were abstract Gabor patches varying along two orthogonal, perceptual dimensions (i.e. spatial frequency and orientation). During the acquisition phase, one of these dimensions was predictive of the valence of the USs. During the extinction phase, CSs were presented alone and participants were asked to categorise the CSs either according to their valence, the perceptual dimension that was task-relevant during the acquisition phase, or a perceptual dimension that was task-irrelevant during the acquisition phase. As predicted, explicit valence measures revealed a linear increase in the extinction rate of the EC effect as participants were encouraged to assign attention to non-evaluative stimulus information during the extinction phase. In Experiment 1, Affect Misattribution Paradigm (AMP) data mimicked this pattern of results, although the effect just missed conventional levels of significance. In Experiment 2, the AMP data revealed an increase of the EC effect if attention was focused on evaluative stimulus information. Potential mechanisms to explain these findings are discussed.

Associative learning of odor with food- or blood-meal by Culex quinquefasciatus Say (Diptera: Culicidae)

NASA Astrophysics Data System (ADS)

Tomberlin, Jeffery K.; Rains, Glen C.; Allan, Sandy A.; Sanford, Michelle R.; Lewis, W. Joe

2006-11-01

The ability of many insects to learn has been documented. However, a limited number of studies examining associative learning in medically important arthropods has been published. Investigations into the associative learning capabilities of Culex quinquefasciatus Say were conducted by adapting methods commonly used in experiments involving Hymenoptera. Male and female mosquitoes were able to learn a conditioned stimulus that consisted of an odor not normally encountered in nature (synthetic strawberry or vanilla extracts) in association with an unconditioned stimulus consisting of either a sugar (males and females) or blood (females) meal. Such information could lead to a better understanding of the ability of mosquitoes to locate and select host and food resources in nature.

Interoceptive fear conditioning and panic disorder: the role of conditioned stimulus-unconditioned stimulus predictability.

PubMed

Acheson, Dean T; Forsyth, John P; Moses, Erica

2012-03-01

Interoceptive fear conditioning is at the core of contemporary behavioral accounts of panic disorder. Yet, to date only one study has attempted to evaluate interoceptive fear conditioning in humans (see Acheson, Forsyth, Prenoveau, & Bouton, 2007). That study used brief (physiologically inert) and longer-duration (panicogenic) inhalations of 20% CO(2)-enriched air as an interoceptive conditioned (CS) and unconditioned (US) stimulus and evaluated fear learning in three conditions: CS only, CS-US paired, and CS-US unpaired. Results showed fear conditioning in the paired condition, and fearful responding and resistance to extinction in an unpaired condition. The authors speculated that such effects may be due to difficulty discriminating between the CS and the US. The aims of the present study are to (a) replicate and expand this line of work using an improved methodology, and (b) clarify the role of CS-US discrimination difficulties in either potentiating or depotentiating fear learning. Healthy participants (N=104) were randomly assigned to one of four conditions: (a) CS only, (b) contingent CS-US pairings, (c) unpaired CS and US presentations, or (d) an unpaired "discrimination" contingency, which included an exteroceptive discrimination cue concurrently with CS onset. Electrodermal and self-report ratings served as indices of conditioned responding. Consistent with expectation, the paired contingency and unpaired contingencies yielded elevated fearful responding to the CS alone. Moreover, adding a discrimination cue to the unpaired contingency effectively attenuated fearful responding. Overall, findings are consistent with modern learning theory accounts of panic and highlight the role of interoceptive conditioning and unpredictability in the etiology of panic disorder. Copyright © 2011. Published by Elsevier Ltd.

Training-Dependent Associative Learning Induced Neocortical Structural Plasticity: A Trace Eyeblink Conditioning Analysis

PubMed Central

Chau, Lily S.; Prakapenka, Alesia V.; Zendeli, Liridon; Davis, Ashley S.; Galvez, Roberto

2014-01-01

Studies utilizing general learning and memory tasks have suggested the importance of neocortical structural plasticity for memory consolidation. However, these learning tasks typically result in learning of multiple different tasks over several days of training, making it difficult to determine the synaptic time course mediating each learning event. The current study used trace-eyeblink conditioning to determine the time course for neocortical spine modification during learning. With eyeblink conditioning, subjects are presented with a neutral, conditioned stimulus (CS) paired with a salient, unconditioned stimulus (US) to elicit an unconditioned response (UR). With multiple CS-US pairings, subjects learn to associate the CS with the US and exhibit a conditioned response (CR) when presented with the CS. Trace conditioning is when there is a stimulus free interval between the CS and the US. Utilizing trace-eyeblink conditioning with whisker stimulation as the CS (whisker-trace-eyeblink: WTEB), previous findings have shown that primary somatosensory (barrel) cortex is required for both acquisition and retention of the trace-association. Additionally, prior findings demonstrated that WTEB acquisition results in an expansion of the cytochrome oxidase whisker representation and synaptic modification in layer IV of barrel cortex. To further explore these findings and determine the time course for neocortical learning-induced spine modification, the present study utilized WTEB conditioning to examine Golgi-Cox stained neurons in layer IV of barrel cortex. Findings from this study demonstrated a training-dependent spine proliferation in layer IV of barrel cortex during trace associative learning. Furthermore, findings from this study showing that filopodia-like spines exhibited a similar pattern to the overall spine density further suggests that reorganization of synaptic contacts set the foundation for learning-induced neocortical modifications through the different neocortical layers. PMID:24760074

When congruence breeds preference: the influence of selective attention processes on evaluative conditioning.

PubMed

Blask, Katarina; Walther, Eva; Frings, Christian

2017-09-01

We investigated in two experiments whether selective attention processes modulate evaluative conditioning (EC). Based on the fact that the typical stimuli in an EC paradigm involve an affect-laden unconditioned stimulus (US) and a neutral conditioned stimulus (CS), we started from the assumption that learning might depend in part upon selective attention to the US. Attention to the US was manipulated by including a variant of the Eriksen flanker task in the EC paradigm. Similarly to the original Flanker paradigm, we implemented a target-distracter logic by introducing the CS as the task-relevant stimulus (i.e. the target) to which the participants had to respond and the US as a task-irrelevant distracter. Experiment 1 showed that CS-US congruence modulated EC if the CS had to be selected against the US. Specifically, EC was more pronounced for congruent CS-US pairs as compared to incongruent CS-US pairs. Experiment 2 disentangled CS-US congruence and CS-US compatibility and suggested that it is indeed CS-US stimulus congruence rather than CS-US response compatibility that modulates EC.

The effect of a dopamine antagonist on conditioning of sexual arousal in women.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Trimbos, Baptist; Both, Stephanie

2016-04-01

Dopamine (DA) plays a key role in reward-seeking behaviours. Accumulating evidence from animal and human studies suggests that human sexual reward learning may also depend on DA transmission. However, research on the role of DA in human sexual reward learning is completely lacking. To investigate whether DA antagonism attenuates classical conditioning of sexual response in humans. Healthy women were randomly allocated to one of two treatment conditions: haloperidol (n = 29) or placebo (n = 29). A differential conditioning paradigm was applied with genital vibrostimulation as unconditional stimulus (US) and neutral pictures as conditional stimuli (CSs). Genital arousal was assessed, and ratings of affective value and subjective sexual arousal were obtained. Haloperidol administration affected unconditional genital responding. However, no significant effects of medication were found for conditioned responding. No firm conclusions can be drawn about whether female sexual reward learning implicates DA transmission since the results do not lend themselves to unambiguous interpretation.

Unconditioned- and Conditioned- Stimuli Induce Differential Memory Reconsolidation and β-AR-Dependent CREB Activation

PubMed Central

Huang, Bing; Zhu, Huiwen; Zhou, Yiming; Liu, Xing; Ma, Lan

2017-01-01

Consolidated long-term fear memories become labile and reconsolidated upon retrieval by the presentation of conditioned stimulus (CS) or unconditioned stimulus (US). Whether CS-retrieval or US-retrieval will trigger different memory reconsolidation processes is unknown. In this study, we introduced a sequential fear conditioning paradigm in which footshock (FS) was paired with two distinct sounds (CS-A and CS-B). The treatment with propranolol, a β-adrenergic receptor (β-AR) antagonist, after US (FS)-retrieval impaired freezing behavior evoked by either CS-A or CS-B. Betaxolol, a selective β1-AR antagonist, showed similar effects. However, propranolol treatment after retrieval by one CS (e.g., CS-A) only inhibited freezing behavior evoked by the same CS (i.e., CS-A), not the other CS (CS-B). These data suggest that β-AR is critically involved in reconsolidation of fear memory triggered by US- and CS-retrieval, whereas β-AR blockade after US-retrieval disrupts more CS-US associations than CS-retrieval does. Furthermore, significant CREB activation in almost the whole amygdala and hippocampus was observed after US-retrieval, but CS-retrieval only stimulated CREB activation in the lateral amygdala and the CA3 of hippocampus. In addition, propranolol treatment suppressed memory retrieval-induced CREB activation. These data indicate that US-retrieval activates more memory traces than CS-retrieval does, leading to memory reconsolidation of more CS-US associations. PMID:28848401

Behavioral responses of deafened guinea pigs to intracochlear electrical stimulation: a new rapid psychophysical procedure.

PubMed

Agterberg, Martijn J H; Versnel, Huib

2014-07-01

In auditory research the guinea pig is often preferred above rats and mice because of the easily accessible cochlea and because the frequency range of its hearing is more comparable to that of humans. Studies of the guinea-pig auditory system primarily apply histological and electrophysiological measures. Behavioral animal paradigms, in particular in combination with these histological and electrophysiological methods, are necessary in the development of new therapeutic interventions. However, the guinea pig is not considered an attractive animal for behavioral experiments. Therefore, the purpose of this study was to develop a behavioral task suitable for guinea pigs, that can be utilized in cochlear-implant related research. Guinea pigs were trained in a modified shuttle-box in which a stream of air was used as unconditioned stimulus (UCS). A stream of air was preferred over conventionally used methods as electric foot-shocks since it produces less stress, which is a confounding factor in behavioral experiments. Hearing guinea pigs were trained to respond to acoustic stimuli. They responded correctly within only five sessions of ten minutes. The animals maintained their performance four weeks after the right cochlea was implanted with an electrode array. After systemic deafening, the animals responded in the first session immediately to intracochlear electrical stimulation. These responses were not affected by daily chronic electrical stimulation (CES). In conclusion, the present study demonstrates that guinea pigs can be trained relatively fast to respond to acoustic stimuli, and that the training has a lasting effect, which generalizes to intracochlear electrical stimulation after deafening. Furthermore, it demonstrates that bilaterally deafened guinea pigs with substantial (∼50%) loss of spiral ganglion cells (SGCs), detect intracochlear electrical stimulation. Copyright © 2014 Elsevier B.V. All rights reserved.

Verbal instructions targeting valence alter negative conditional stimulus evaluations (but do not affect reinstatement rates).

PubMed

Luck, Camilla C; Lipp, Ottmar V

2018-02-01

Negative conditional stimulus (CS) valence acquired during fear conditioning may enhance fear relapse and is difficult to remove as it extinguishes slowly and does not respond to the instruction that unconditional stimulus (US) presentations will cease. We examined whether instructions targeting CS valence would be more effective. In Experiment 1, an image of one person (CS+) was paired with an aversive US, while another (CS-) was presented alone. After acquisition, participants were given positive information about the CS+ poser and negative information about the CS- poser. Instructions reversed the pattern of differential CS valence present during acquisition and eliminated differential electrodermal responding. In Experiment 2, we compared positive and negative CS revaluation by providing positive/negative information about the CS+ and neutral information about CS-. After positive revaluation, differential valence was removed and differential electrodermal responding remained intact. After negative revaluation, differential valence was strengthened and differential electrodermal responding was eliminated. Unexpectedly, the instructions did not affect the reinstatement of differential electrodermal responding.

The role of contextual associations in producing the partial reinforcement acquisition deficit.

PubMed

Miguez, Gonzalo; Witnauer, James E; Miller, Ralph R

2012-01-01

Three conditioned suppression experiments with rats as subjects assessed the contributions of the conditioned stimulus (CS)-context and context-unconditioned stimulus (US) associations to the degraded stimulus control by the CS that is observed following partial reinforcement relative to continuous reinforcement training. In Experiment 1, posttraining associative deflation (i.e., extinction) of the training context after partial reinforcement restored responding to a level comparable to the one produced by continuous reinforcement. In Experiment 2, posttraining associative inflation of the context (achieved by administering unsignaled outcome presentations in the context) enhanced the detrimental effect of partial reinforcement. Experiment 3 found that the training context must be an effective competitor to produce the partial reinforcement acquisition deficit. When the context was down-modulated, the target regained behavioral control thereby demonstrating higher-order retrospective revaluation. The results are discussed in terms of retrospective revaluation, and are used to contrast the predictions of a performance-focused model with those of an acquisition-focused model. (c) 2012 APA, all rights reserved.

Effects of UCS intensity and duration of exposure of nonreinforced CS on conditioned electrodermal responses: an experimental analysis of the incubation theory of anxiety.

PubMed

Chorot, P; Sandín, B

1993-12-01

Eysenck's incubation theory of fear or anxiety was examined in a human Pavlovian conditioning experiment with skin-conductance responses as the dependent variable. The conditioned stimuli (CSs) were fear-relevant slides (snakes and spiders) and the unconditioned stimuli (UCSs) were aversive tones. Different groups of subjects were presented two tone intensities during the acquisition phase and three durations of nonreinforced CS (extinction phase) in a delay differential conditioning paradigm. Resistance to extinction of conditioned skin-conductance responses (conditioned fear responses) exhibited was largest for high intensity of tone and short presentations of the nonreinforced CS (CS+presented alone). The result tends to support Eysenck's incubation theory of anxiety.

Obesity, physical activity and cancer risks: Results from the Cancer, Lifestyle and Evaluation of Risk Study (CLEAR).

PubMed

Nunez, Carlos; Bauman, Adrian; Egger, Sam; Sitas, Freddy; Nair-Shalliker, Visalini

2017-04-01

Physical activity (PA) has been associated with lower risk of cardiovascular diseases, but the evidence linking PA with lower cancer risk is inconclusive. We examined the independent and interactive effects of PA and obesity using body mass index (BMI) as a proxy for obesity, on the risk of developing prostate (PC), postmenopausal breast (BC), colorectal (CRC), ovarian (OC) and uterine (UC) cancers. We estimated odds ratios (OR) and 95% confidence intervals (CI), adjusting for cancer specific confounders, in 6831 self-reported cancer cases and 1992 self-reported cancer-free controls from the Cancer Lifestyle and Evaluation of Risk Study, using unconditional logistic regression. For women, BMI was positively associated with UC risk; specifically, obese women (BMI≥30kg/m 2 ) had nearly twice the risk of developing UC compared to women with healthy-BMI-range (<25kg/m 2 ) (OR=1.99;CI:1.31-3.03). For men, BMI was also positively associated with the risk of developing any cancer type, CRC and PC. In particular, obese men had 37% (OR=1.37;CI:1.11-1.70), 113% (OR=2.13;CI:1.55-2.91) and 51% (OR=1.51;CI:1.17-1.94) higher risks of developing any cancer, CRC and PC respectively, when compared to men with healthy-BMI-range (BMI<25kg/m 2 ). Among women, PA was inversely associated with the risks of CRC, UC and BC. In particular, the highest level of PA (versus nil activity) was associated with reduced risks of CRC (OR=0.60;CI:0.44-0.84) and UC (OR=0.47;CI:0.27-0.80). Reduced risks of BC were associated with low (OR=0.66;CI:0.51-0.86) and moderate (OR=0.72;CI:0.57-0.91) levels of PA. There was no association between PA levels and cancer risks for men. We found no evidence of an interaction between BMI and PA in the CLEAR study. These findings suggest that PA and obesity are independent cancer risk factors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Emotional conditioning to masked stimuli and modulation of visuospatial attention.

PubMed

Beaver, John D; Mogg, Karin; Bradley, Brendan P

2005-03-01

Two studies investigated the effects of conditioning to masked stimuli on visuospatial attention. During the conditioning phase, masked snakes and spiders were paired with a burst of white noise, or paired with an innocuous tone, in the conditioned stimulus (CS)+ and CS- conditions, respectively. Attentional allocation to the CSs was then assessed with a visual probe task, in which the CSs were presented unmasked (Experiment 1) or both unmasked and masked (Experiment 2), together with fear-irrelevant control stimuli (flowers and mushrooms). In Experiment 1, participants preferentially allocated attention to CS+ relative to control stimuli. Experiment 2 suggested that this attentional bias depended on the perceived aversiveness of the unconditioned stimulus and did not require conscious recognition of the CSs during both acquisition and expression. Copyright 2005 APA, all rights reserved.

Evaluative conditioning increases with temporal contiguity. The influence of stimulus order and stimulus interval on evaluative conditioning.

PubMed

Gast, Anne; Langer, Sebastian; Sengewald, Marie-Ann

2016-10-01

Evaluative conditioning (EC) is a change in valence that is due to pairing a conditioned stimulus (CS) with another, typically valent, unconditioned stimulus (US). This paper investigates how basic presentation parameters moderate EC effects. In two studies we tested the effectiveness of different temporal relations of the CS and the US, that is, the order in which the stimuli were presented and the temporal distance between them. Both studies showed that the size of EC effects was independent of the presentation order of CS and US within a stimulus pair. Contrary to classical conditioning effects, EC effects are thus not most pronounced after CS-first presentations. Furthermore, as shown in Experiment 2, EC effects increased in magnitude as the temporal interval between CS and US presentations decreased. Experiment 1 showed largest EC effects in the condition with simultaneous presentations - which can be seen as the condition with the temporally closest presentation. In this Experiment stimuli were presented in two different modalities, which might have facilitated simultaneous processing. In Experiment 2, in which all stimuli were presented visually, this advantage of simultaneous presentation was not found. We discuss practical and theoretical implications of our findings. Copyright © 2016 Elsevier B.V. All rights reserved.

Involvement of phosphorylated Apis mellifera CREB in gating a honeybee's behavioral response to an external stimulus

PubMed Central

Gehring, Katrin B.; Heufelder, Karin; Feige, Janina; Bauer, Paul; Dyck, Yan; Ehrhardt, Lea; Kühnemund, Johannes; Bergmann, Anja; Göbel, Josefine; Isecke, Marlene

2016-01-01

The transcription factor cAMP-response element-binding protein (CREB) is involved in neuronal plasticity. Phosphorylation activates CREB and an increased level of phosphorylated CREB is regarded as an indicator of CREB-dependent transcriptional activation. In honeybees (Apis mellifera) we recently demonstrated a particular high abundance of the phosphorylated honeybee CREB homolog (pAmCREB) in the central brain and in a subpopulation of mushroom body neurons. We hypothesize that these high pAmCREB levels are related to learning and memory formation. Here, we tested this hypothesis by analyzing brain pAmCREB levels in classically conditioned bees and bees experiencing unpaired presentations of conditioned stimulus (CS) and unconditioned stimulus (US). We demonstrate that both behavioral protocols display differences in memory formation but do not alter the level of pAmCREB in bee brains directly after training. Nevertheless, we report that bees responding to the CS during unpaired stimulus presentations exhibit higher levels of pAmCREB than nonresponding bees. In addition, Trichostatin A, a histone deacetylase inhibitor that is thought to enhance histone acetylation by CREB-binding protein, increases the bees’ CS responsiveness. We conclude that pAmCREB is involved in gating a bee's behavioral response driven by an external stimulus. PMID:27084927

Modulation of the N170 with Classical Conditioning: The Use of Emotional Imagery and Acoustic Startle in Healthy and Depressed Participants

PubMed Central

Camfield, David A.; Mills, Jessica; Kornfeld, Emma J.; Croft, Rodney J.

2016-01-01

Recent studies have suggested that classical conditioning may be capable of modulating early sensory processing in the human brain, and that there may be differences in the magnitude of the conditioned changes for individuals with major depressive disorder. The effect of conditioning on the N170 event-related potential was investigated using neutral faces as conditioned stimuli (CS+) and emotional imagery and acoustic startle as unconditioned stimuli (UCS). In the first experiment, electroencephalogram was recorded from 24 undergraduate students (M = 21.07 years, SD = 3.38 years) under the following conditions: (i) CS+/aversive imagery, (ii) CS+/aversive imagery and acoustic startle, (iii) CS+/acoustic startle, and (iv) CS+/pleasant imagery. The amplitude of the N170 was enhanced following conditioning with aversive imagery as well as acoustic startle. In the second experiment, 26 healthy control participants were tested (17 females and 9 males, age M = 25.97 years, SD = 9.42) together with 18 depressed participants (13 females and 5 males, age M = 23.26 years, SD = 4.01) and three conditions were used: CS+/aversive imagery, CS+/pleasant imagery, and CS-. N170 amplitude at P7 was increased for the CS+/aversive condition in comparison to CS- in the conditioning blocks versus baseline. No differences between depressed and healthy participants were found. Across both experiments, evaluative conditioning was absent. It was concluded that aversive UCS are capable of modulating early sensory processing of faces, although further research is also warranted in regards to positive UCS. PMID:27445773

Neurobiological mechanisms underlying the blocking effect in aversive learning.

PubMed

Eippert, Falk; Gamer, Matthias; Büchel, Christian

2012-09-19

Current theories of classical conditioning assume that learning depends on the predictive relationship between events, not just on their temporal contiguity. Here we employ the classic experiment substantiating this reasoning-the blocking paradigm-in combination with functional magnetic resonance imaging (fMRI) to investigate whether human amygdala responses in aversive learning conform to these assumptions. In accordance with blocking, we demonstrate that significantly stronger behavioral and amygdala responses are evoked by conditioned stimuli that are predictive of the unconditioned stimulus than by conditioned stimuli that have received the same pairing with the unconditioned stimulus, yet have no predictive value. When studying the development of this effect, we not only observed that it was related to the strength of previous conditioned responses, but also that predictive compared with nonpredictive conditioned stimuli received more overt attention, as measured by fMRI-concurrent eye tracking, and that this went along with enhanced amygdala responses. We furthermore observed that prefrontal regions play a role in the development of the blocking effect: ventromedial prefrontal cortex (subgenual anterior cingulate) only exhibited responses when conditioned stimuli had to be established as nonpredictive for an outcome, whereas dorsolateral prefrontal cortex also showed responses when conditioned stimuli had to be established as predictive. Most importantly, dorsolateral prefrontal cortex connectivity to amygdala flexibly switched between positive and negative coupling, depending on the requirements posed by predictive relationships. Together, our findings highlight the role of predictive value in explaining amygdala responses and identify mechanisms that shape these responses in human fear conditioning.

Compensatory and mimetic conditioned responses to effects of heroin in addicted persons.

PubMed

Trujillo, Humberto M; Oviedo-Joekes, Eugenia; Vargas, Cristina

2006-02-01

Study 1: The aim of this study was to analyze in persons detoxified of heroin, compensatory conditioned responses (CCRs) that are opposite to the unconditioned physiological, and subjective effects that are induced by this substance. The procedure consisted in presenting slides with images of neutral stimuli (NSs) and conditioned stimuli (CSs) of heroin to both non-addicted and detoxified addicted persons. The evaluated responses were heart rate (HR) and desire for heroin (DH). Study 2: The aim was to facilitate the emission of mimetic conditioned responses (MCRs) to the unconditioned physiological, and subjective effects of heroin in detoxified heroin addicts. Three different stimulus series were manipulated: SA, during which the participant remained alone; SB, administration of a needle prick given by the researcher; SC, performance of the "pump" ritual without drug by the participants. The responses measured were HR and DH. The results of both studies are considered, respectively, to be indicators of compensatory and mimetic conditioned responses.

Sign-tracking (autoshaping) in rats: a comparison of cocaine and food as unconditioned stimuli.

PubMed

Kearns, David N; Weiss, Stanley J

2004-11-01

A series of experiments was performed to determine whether sign-tracking would occur in rats with intravenous (i.v.) cocaine as the unconditioned stimulus. In Experiment 1, a retractable lever paired with food produced strong sign-tracking, but a lever paired with one of three doses of i.v. cocaine did not elicit any approach or contact behavior. Experiment 2 demonstrated that doses of cocaine that did not elicit sign-tracking would function as a positive reinforcer for a lever contact operant. In Experiment 3, an artificial consummatory response was added to make the cocaine reinforcement episode more behaviorally comparable to that occasioned by food. Although the rats readily performed this response when it was required to receive cocaine infusions, they still did not contact a lever that signaled the availability of these infusions. It appears that cocaine is different from other positive reinforcers (e.g., food, water, warmth, or intracranial stimulation) in that it will not produce sign-tracking in rats.

Open-field exposure facilitates consummatory extinction.

PubMed

Justel, Nadia; Psyrdellis, Mariana; Pautassi, Ricardo M

2016-12-07

During extinction, the organism learns that a conditioned stimulus or a conditioned response is no longer associated with an unconditioned stimulus, and as a consequence, a decrement in the response is presented. The exposure to novel situations (e.g. exploration of a novel open field) has been used widely to modulate (i.e. either enhance or deteriorate) learning and memory. The aim of the present study was to test whether open-field exposure could modulate consummatory extinction. The results indicated that open-field exposure accelerated the extinction response (i.e. experimental animals provided novelty exposure had lower consummatory behavior than control animals) when applied before - but not after - the first extinction trial, or when applied before the second extinction trial. The results suggest that environmental treatments such as novelty exposure provide a valuable, nonpharmacological alternative to potentially modulate extinction processes.

Post-Extinction Conditional Stimulus Valence Predicts Reinstatement Fear: Relevance for Long Term Outcomes of Exposure Therapy

PubMed Central

Zbozinek, Tomislav D.; Hermans, Dirk; Prenoveau, Jason M.; Liao, Betty; Craske, Michelle G.

2014-01-01

Exposure therapy for anxiety disorders is translated from fear conditioning and extinction. While exposure therapy is effective in treating anxiety, fear sometimes returns after exposure. One pathway for return of fear is reinstatement: unsignaled unconditional stimuli following completion of extinction. The present study investigated the extent to which valence of the conditional stimulus (CS+) after extinction predicts return of CS+ fear after reinstatement. Participants (N = 84) engaged in a differential fear conditioning paradigm and were randomized to reinstatement or non-reinstatement. We hypothesized that more negative post-extinction CS+ valence would predict higher CS+ fear after reinstatement relative to non-reinstatement and relative to extinction retest. Results supported the hypotheses and suggest that strategies designed to decrease negative valence of the CS+ may reduce the return of fear via reinstatement following exposure therapy. PMID:24957680

Anxiety and anxiety disorders. Toward a conceptual reorientation.

PubMed

Curtis, G C

1985-03-01

Traditionally, it has been assumed that there is only one type of anxiety; recent pharmacologic evidence suggests that there may be several. The psychoanalytic concept of "neurotic" symptoms as depressurizing mechanisms is out of keeping with most evidence now available. Spontaneous or "free-floating" anxiety may be partly biologic and genetic in origin. Anxiety symptoms evoked by specific stimuli behave in part like conditioned responses. Where conditioning theory has failed to propose a plausible unconditioned stimulus for pathologic anxiety, biology, ethology, and psychoanalysis may have been more successful.

Evidence for an expectancy-based theory of avoidance behaviour.

PubMed

Declercq, Mieke; De Houwer, Jan; Baeyens, Frank

2008-01-01

In most studies on avoidance learning, participants receive an aversive unconditioned stimulus after a warning signal is presented, unless the participant performs a particular response. Lovibond (2006) recently proposed a cognitive theory of avoidance learning, according to which avoidance behaviour is a function of both Pavlovian and instrumental conditioning. In line with this theory, we found that avoidance behaviour was based on an integration of acquired knowledge about, on the one hand, the relation between stimuli and, on the other hand, the relation between behaviour and stimuli.

Classic conditioning of the ventilatory responses in rats.

PubMed

Nsegbe, E; Vardon, G; Perruchet, P; Gallego, J

1997-10-01

Recent authors have stressed the role of conditioning in the control of breathing, but experimental evidence of this role is still sparse and contradictory. To establish that classic conditioning of the ventilatory responses can occur in rats, we performed a controlled experiment in which a 1-min tone [conditioned stimulus (CS)] was paired with a hypercapnic stimulus [8.5% CO2, unconditioned stimulus (US)]. The experimental group (n = 9) received five paired CS-US presentations, followed by one CS alone to test conditioning. This sequence was repeated six times. The control group (n = 7) received the same number of CS and US, but each US was delivered 3 min after the CS. We observed that after the CS alone, breath duration was significantly longer in the experimental than in the control group and mean ventilation was significantly lower, thus showing inhibitory conditioning. This conditioning may have resulted from the association between the CS and the inhibitory and aversive effects of CO2. The present results confirmed the high sensitivity of the respiratory controller to conditioning processes.

Time and Associative Learning.

PubMed

Balsam, Peter D; Drew, Michael R; Gallistel, C R

2010-01-01

In a basic associative learning paradigm, learning is said to have occurred when the conditioned stimulus evokes an anticipatory response. This learning is widely believed to depend on the contiguous presentation of conditioned and unconditioned stimulus. However, what it means to be contiguous has not been rigorously defined. Here we examine the empirical bases for these beliefs and suggest an alternative view based on the hypothesis that learning about the temporal relationships between events determines the speed of emergence, vigor and form of conditioned behavior. This temporal learning occurs very rapidly and prior to the appearance of the anticipatory response. The temporal relations are learned even when no anticipatory response is evoked. The speed with which an anticipatory response emerges is proportional to the informativeness of the predictive cue (CS) regarding the rate of occurrence of the predicted event (US). This analysis gives an account of what we mean by "temporal pairing" and is in accord with the data on speed of acquisition and basic findings in the cue competition literature. In this account, learning depends on perceiving and encoding temporal regularities rather than stimulus contiguities.

Time and Associative Learning

PubMed Central

Balsam, Peter D; Drew, Michael R.; Gallistel, C.R.

2010-01-01

In a basic associative learning paradigm, learning is said to have occurred when the conditioned stimulus evokes an anticipatory response. This learning is widely believed to depend on the contiguous presentation of conditioned and unconditioned stimulus. However, what it means to be contiguous has not been rigorously defined. Here we examine the empirical bases for these beliefs and suggest an alternative view based on the hypothesis that learning about the temporal relationships between events determines the speed of emergence, vigor and form of conditioned behavior. This temporal learning occurs very rapidly and prior to the appearance of the anticipatory response. The temporal relations are learned even when no anticipatory response is evoked. The speed with which an anticipatory response emerges is proportional to the informativeness of the predictive cue (CS) regarding the rate of occurrence of the predicted event (US). This analysis gives an account of what we mean by “temporal pairing” and is in accord with the data on speed of acquisition and basic findings in the cue competition literature. In this account, learning depends on perceiving and encoding temporal regularities rather than stimulus contiguities. PMID:21359131

Developmental differences in aversive conditioning, extinction, and reinstatement: A study with children, adolescents, and adults.

PubMed

Waters, Allison M; Theresiana, Cindy; Neumann, David L; Craske, Michelle G

2017-07-01

This study investigated developmental differences in aversive conditioning, extinction, and reinstatement (i.e., the recovery of conditioned aversive associations following reexposure to the unconditioned stimulus [US] post-extinction). This study examined these mechanisms in children (M age =8.8years), adolescents (M age =16.1years), and adults (M age =32.3years) using differential aversive conditioning with a geometric shape conditional stimulus (CS+) paired with an aversive sound US and another shape (CS-) presented alone. Following an extinction phase in which both CSs were presented alone, half of the participants in each age group received three US exposures (reinstatement condition) and the other half did not (control condition), followed by all participants completing an extinction retest phase on the same day. Findings indicated (a) significant differences in generalizing aversive expectancies to safe stimuli during conditioning and extinction that persisted during retest in children relative to adults and adolescents, (b) significantly less positive CS reevaluations during extinction that persisted during retest in adolescents relative to adults and children, and (c) reinstatement of US expectancies to the CS+ relative to the CS- in all age groups. Results suggest important differences in stimulus safety learning in children and stimulus valence reevaluation in adolescents relative to adults. Copyright © 2017 Elsevier Inc. All rights reserved.

Dual Functions of Perirhinal Cortex in Fear Conditioning

PubMed Central

Kent, Brianne A.; Brown, Thomas H.

2012-01-01

The present review examines the role of perirhinal cortex (PRC) in Pavlovian fear conditioning. The focus is on rats, partly because so much is known, behaviorally and neurobiologically, about fear conditioning in these animals. In addition, the neuroanatomy and neurophysiology of rat PRC have been described in considerable detail at the cellular and systems levels. The evidence suggests that PRC can serve at least two types of mnemonic functions in Pavlovian fear conditioning. The first function, termed "stimulus unitization," refers to the ability to treat two or more separate items or stimulus elements as a single entity. Supporting evidence for this perceptual function comes from studies of context conditioning as well as delay conditioning to discontinuous auditory cues. In a delay paradigm, the conditional stimulus (CS) and unconditional stimulus (US) overlap temporally and co-terminate. The second PRC function entails a type of "transient memory." Supporting evidence comes from studies of trace cue conditioning, where there is a temporal gap or trace interval between the CS offset and the US onset. For learning to occur, there must be a transient CS representation during the trace interval. We advance a novel neurophysiological mechanism for this transient representation. These two hypothesized functions of PRC are consistent with inferences based on non-aversive forms of learning. PMID:22903623

Impaired delay eyeblink conditioning in amnesic Korsakoff's patients and recovered alcoholics.

PubMed

McGlinchey-Berroth, R; Cermak, L S; Carrillo, M C; Armfield, S; Gabrieli, J D; Disterhoft, J F

1995-10-01

The performance of amnesic Korsakoff patients in delay eyeblink classical conditioning was compared with that of recovered chronic alcoholic subjects and healthy normal control subjects. Normal control subjects exhibited acquisition of conditioned responses (CRs) to a previously neutral, conditioned tone stimulus (CS) following repeated pairings with an unconditioned air-puff stimulus, and demonstrated extinction of CRs when the CS was subsequently presented alone. Both amnesic Korsakoff patients and recovered chronic alcoholic subjects demonstrated an impairment in their ability to acquire CRs. These results indicate that the preservation of delay eyeblink conditioning in amnesia must depend on the underlying neuropathology of the amnesic syndrome. It is known that patients with amnesia caused by medial temporal lobe pathology have preserved conditioning. We have now demonstrated that patients with amnesia caused by Korsakoff's syndrome, as well as recovered chronic alcoholic subjects, have impaired conditioning. This impairment is most likely caused by cerebellar deterioration resulting from years of alcohol abuse.

Instructed fear learning, extinction, and recall: additive effects of cognitive information on emotional learning of fear.

PubMed

Javanbakht, Arash; Duval, Elizabeth R; Cisneros, Maria E; Taylor, Stephan F; Kessler, Daniel; Liberzon, Israel

2017-08-01

The effects of instruction on learning of fear and safety are rarely studied. We aimed to examine the effects of cognitive information and experience on fear learning. Fourty healthy participants, randomly assigned to three groups, went through fear conditioning, extinction learning, and extinction recall with two conditioned stimuli (CS+). Information was presented about the presence or absence of conditioned stimulus-unconditioned stimulus (CS-US) contingency at different stages of the experiment. Information about the CS-US contingency prior to fear conditioning enhanced fear response and reduced extinction recall. Information about the absence of CS-US contingency promoted extinction learning and recall, while omission of this information prior to recall resulted in fear renewal. These findings indicate that contingency information can facilitate fear expression during fear learning, and can facilitate extinction learning and recall. Information seems to function as an element of the larger context in which conditioning occurs.

Retrospective Revaluation: The Phenomenon and Its Theoretical Implications

PubMed Central

Miller, Ralph R.; Witnauer, James E.

2015-01-01

Retrospective revaluation refers to an increase (or decrease) in responding to conditioned stimulus (CS X) as a result of decreasing (or increasing) the associative strength of another CS (A) with respect to the unconditioned stimulus (i.e., A-US) that was previously trained in compound with the target CS (e.g., AX−US or just AX). We discuss the conditions under which retrospective revaluation phenomena are most apt to be observed and their implications for various models of learning that are able to account for retrospective revaluation (e.g., Dickinson and Burke, 1996; Miller and Matzel, 1988; Van Hamme and Wasserman, 1994). Although retroactive revaluation is relatively parameter specific, it is seen to be a reliable phenomenon observed across many tasks and species. As it is not anticipated by many conventional models of learning (e.g., Rescorla and Wagner, 1972), it serves as a critical benchmark for evaluating traditional and newer models. PMID:26342855

Fear expression and return of fear following threat instruction with or without direct contingency experience.

PubMed

Mertens, Gaëtan; Kuhn, Manuel; Raes, An K; Kalisch, Raffael; De Houwer, Jan; Lonsdorf, Tina B

2016-08-01

Prior research showed that mere instructions about the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US) can generate fear reactions to the CS. Little is known, however, about the extent to which actual CS-US contingency experience adds anything beyond the effect of contingency instructions. Our results extend previous studies on this topic in that it included fear potentiated startle as an additional dependent variable and examined return of fear (ROF) following reinstatement. We observed that CS-US pairings can enhance fear reactions beyond the effect of contingency instructions. Moreover, for all measures of fear, instructions elicited immediate fear reactions that could not be completely overridden by subsequent situational safety information. Finally, ROF following reinstatement for instructed CS+s was unaffected by actual experience. In summary, our results demonstrate the power of contingency instructions and reveal the additional impact of actual experience of CS-US pairings.

The roles of the amygdala in the affective regulation of body, brain, and behaviour

NASA Astrophysics Data System (ADS)

Mirolli, Marco; Mannella, Francesco; Baldassarre, Gianluca

2010-09-01

Despite the great amount of knowledge produced by the neuroscientific literature on affective phenomena, current models tackling non-cognitive aspects of behaviour are often bio-inspired but rarely bio-constrained. This paper presents a theoretical account of affective systems centred on the amygdala (Amg). This account aims to furnish a general framework and specific pathways to implement models that are more closely related to biological evidence. The Amg, which receives input from brain areas encoding internal states, innately relevant stimuli, and innately neutral stimuli, plays a fundamental role in the motivational and emotional processes of organisms. This role is based on the fact that Amg implements the two associative processes at the core of Pavlovian learning (conditioned stimulus (CS)-unconditioned stimulus (US) and CS-unconditioned response (UR) associations), and that it has the capacity of modulating these associations on the basis of internal states. These functionalities allow the Amg to play an important role in the regulation of the three fundamental classes of affective responses (namely, the regulation of body states, the regulation of brain states via neuromodulators, and the triggering of a number of basic behaviours fundamental for adaptation) and in the regulation of three high-level cognitive processes (namely, the affective labelling of memories, the production of goal-directed behaviours, and the performance of planning and complex decision-making). Our analysis is conducted within a methodological approach that stresses the importance of understanding the brain within an evolutionary/adaptive framework and with the aim of isolating general principles that can potentially account for the wider possible empirical evidence in a coherent fashion.

The utility of the zebrafish model in conditioned place preference to assess the rewarding effects of drugs.

PubMed

Collier, Adam D; Echevarria, David J

2013-09-01

Substance abuse is a significant public health concern both domestically and worldwide. The persistent use of substances regardless of aversive consequences forces the user to give higher priority to the drug than to normal activities and obligations. The harmful and hazardous use of psychoactive substances can lead to a dependence syndrome. In this regard, the genetic and neurobiological underpinnings of reward-seeking behavior need to be fully understood in order to develop effective pharmacotherapies and other methods of treatment. Animal models are often implemented in preclinical screening for testing the efficacy of novel treatments. Several paradigms exist that model various facets of addiction including sensitization, tolerance, withdrawal, drug seeking, extinction, and relapse. Self-administration and, most notably, conditioned place preference (CPP) are relatively simple tests that serve as indicators of the aforementioned aspects of addiction by means of behavioral quantification. CPP is a commonly used technique to evaluate the motivational effects of compounds and experiences that have been associated with a positive or negative reward, which capitalizes on the basic principles of Pavlovian conditioning. During training, the unconditioned stimulus is consistently paired with a neutral set of environmental stimuli, which obtain, during conditioning, secondary motivational properties that elicit approach behavior in the absence of the unconditioned stimulus. For over 50 years, rodents have been the primary test subjects. However, the zebrafish (Danio rerio) is gaining favor as a valuable model organism in the fields of biology, genetics, and behavioral neuroscience. This paper presents a discussion on the merits, advantages, and limitations of the zebrafish model and its utility in relation to CPP.

Selective loss of dopaminergic neurons in the substantia nigra pars compacta after systemic administration of MPTP facilitates extinction learning.

PubMed

Kinoshita, Ken-ichi; Tada, Yayoi; Muroi, Yoshikage; Unno, Toshihiro; Ishii, Toshiaki

2015-09-15

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In PD, thinking and retrieval deficits often arise from cognitive impairments. However, the mechanism of cognitive disorders in PD remains unknown. Therefore, we investigated cognitive function in PD model mice produced by intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which specifically destroys the DAergic neurons in the SNpc. We evaluated the cognitive function of MPTP-treated mice (PD mice) using the contextual fear conditioning test. In the test, each experiment consists of three phases: training, re-exposure, and testing. Mice were trained with a foot shock (a weak unconditioned stimulus: 1mA/2s duration, once, or an intense unconditioned stimulus: 2mA/2s duration, twice), and 24h later, mice were re-exposed to the training context for 3min to determine reconsolidation or 30min to determine extinction. The percentage of time spent freezing was measured during the test session as indexes of memory consolidation, reconsolidation, and extinction. Reconsolidation of PD mice occurred normally but memory extinction was facilitated in PD mice compared to control mice. Moreover, memory retention in PD mice was attenuated earlier than in controls following repeated conditioned stimuli every day. PD mice with selective loss of DAergic neurons in the SNpc showed attenuated memory retention, probably via facilitated extinction learning. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of unconditioned stimulus intensity and fear extinction on subsequent sleep architecture in an afternoon nap.

PubMed

Sturm, Anna; Czisch, Michael; Spoormaker, Victor I

2013-12-01

Impaired fear extinction and disturbed sleep coincide in post-traumatic stress disorder (PTSD), but the nature of this relationship is unclear. Rapid eye movement (REM) sleep deprivation impairs fear extinction recall in rodents and young healthy subjects, and animal models have demonstrated both disrupted sleep after fear conditioning and normalized sleep after extinction learning. As a correlation between unconditioned stimulus (US) responding and subsequent sleep architecture has been observed in healthy subjects, the goal of this study was to test whether US intensity would causally affect subsequent sleep. Twenty-four young healthy subjects underwent a fear conditioning session with skin conductance response measurements before an afternoon session of polysomnographically recorded sleep (up to 120 min) in the sleep laboratory. Two factors were manipulated experimentally in a 2 × 2 design: US (electrical shock) was set at high or low intensity, and subjects did or did not receive an extinction session after fear conditioning. We observed that neither factor affected REM sleep amount, that high US intensity nominally increased sleep fragmentation (more Stage 1 sleep, stage shifts and wake after sleep onset), and that extinction increased Stage 4 amount. Moreover, reduced Stage 1 and increased Stage 4 and REM sleep were associated with subjective sleep quality of the afternoon nap. These results provide evidence for the notion that US intensity and extinction affect subsequent sleep architecture in young healthy subjects, which may provide a translational bridge from findings in animal studies to correlations observed in PTSD patients. © 2013 European Sleep Research Society.

Lamina propria macrophage phenotypes in relation to Escherichia coli in Crohn's disease.

PubMed

Elliott, Timothy R; Rayment, Neil B; Hudspith, Barry N; Hands, Rebecca E; Taylor, Kirstin; Parkes, Gareth C; Prescott, Natalie J; Petrovska, Liljana; Hermon-Taylor, John; Brostoff, Jonathan; Boussioutas, Alex; Mathew, Christopher G; Bustin, Stephen A; Sanderson, Jeremy D

2015-07-03

Abnormal handling of E. coli by lamina propria (LP) macrophages may contribute to Crohn's disease (CD) pathogenesis. We aimed to determine LP macrophage phenotypes in CD, ulcerative colitis (UC) and healthy controls (HC), and in CD, to compare macrophage phenotypes according to E. coli carriage. Mucosal biopsies were taken from 35 patients with CD, 9 with UC and 18 HCs. Laser capture microdissection was used to isolate E. coli-laden and unladen LP macrophages from ileal or colonic biopsies. From these macrophages, mRNA was extracted and cytokine and activation marker expression measured using RT-qPCR. E. coli-laden LP macrophages were identified commonly in mucosal biopsies from CD patients (25/35, 71 %), rarely in UC (1/9, 11 %) and not at all in healthy controls (0/18). LP macrophage cytokine mRNA expression was greater in CD and UC than healthy controls. In CD, E. coli-laden macrophages expressed high IL-10 & CD163 and lower TNFα, IL-23 & iNOS irrespective of macroscopic inflammation. In inflamed tissue, E. coli-unladen macrophages expressed high TNFα, IL-23 & iNOS and lower IL-10 & CD163. In uninflamed tissue, unladen macrophages had low cytokine mRNA expression, closer to that of healthy controls. In CD, intra-macrophage E. coli are commonly found and LP macrophages express characteristic cytokine mRNA profiles according to E. coli carriage. Persistence of E. coli within LP macrophages may provide a stimulus for chronic inflammation.

Effects of dopamine D1 modulation of the anterior cingulate cortex in a fear conditioning procedure

PubMed Central

Pezze, M.A.; Marshall, H.J.; Domonkos, A.; Cassaday, H.J.

2016-01-01

The anterior cingulate cortex (AC) component of the medial prefrontal cortex (mPFC) has been implicated in attention and working memory as measured by trace conditioning. Since dopamine (DA) is a key modulator of mPFC function, the present study evaluated the role of DA receptor agents in rat AC, using trace fear conditioning. A conditioned stimulus (CS, noise) was followed by an unconditioned stimulus (US, shock) with or without a 10 s trace interval interposed between these events in a between-subjects design. Conditioned suppression of drinking was assessed in response to presentation of the CS or an experimental background stimulus (flashing lights, previously presented for the duration of the conditioning session). The selective D1 agonist SKF81297 (0.05 μg/side) or D1 antagonist SCH23390 (0.5 μg/side) was administered by intra-cerebral microinfusion directly into AC. It was predicted that either of these manipulations should be sufficient to impair trace (but not delay) conditioning. Counter to expectation, there was no effect of DA D1 modulation on trace conditioning as measured by suppression to the noise CS. However, rats infused with SKF81297 acquired stronger conditioned suppression to the experimental background stimulus than those infused with SCH23390 or saline. Thus, the DA D1 agonist SKF81297 increased conditioned suppression to the contextual background light stimulus but was otherwise without effect on fear conditioning. PMID:26343307

Relationship between vomiting and taste aversion learning in the ferret: studies with ionizing radiation, lithium chloride, and amphetamine.

PubMed

Rabin, B M; Hunt, W A

1992-09-01

The relationship between emesis and taste aversion learning was studied in ferrets (Mustela putorius furo) following exposure to ionizing radiation (50-200 cGy) or injection of lithium chloride (1.5-3.0 mEq/kg, ip). When 10% sucrose or 0.1% saccharin was used as the conditioned stimulus, neither unconditioned stimulus produced a taste aversion, even when vomiting was produced by the stimulus (Experiments 1 and 2). When a canned cat food was used as the conditioned stimulus, lithium chloride, but not ionizing radiation, produced a taste aversion (Experiment 3). Lithium chloride was effective in producing a conditioned taste aversion when administration of the toxin was delayed by up to 90 min following the ingestion of the canned cat food, indicating that the ferrets are capable of showing long-delay learning (Experiment 4). Experiment 5 examined the capacity of amphetamine, which is a qualitatively different stimulus than lithium chloride or ionizing radiation, to produce taste aversion learning in rats and cats as well as in ferrets. Injection of amphetamine (3 mg/kg, ip) produced a taste aversion in rats and cats but not in ferrets which required a higher dose (> 5 mg/kg). The results of these experiments are interpreted as indicating that, at least for the ferret, there is no necessary relationship between toxin-induced illness and the acquisition of a CTA and that gastrointestinal distress is not a sufficient condition for CTA learning.

Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific.

PubMed

Ng, Siew C; Tang, Whitney; Leong, Rupert W; Chen, Minhu; Ko, Yanna; Studd, Corrie; Niewiadomski, Ola; Bell, Sally; Kamm, Michael A; de Silva, H J; Kasturiratne, Anuradhani; Senanayake, Yasith Udara; Ooi, Choon Jin; Ling, Khoon-Lin; Ong, David; Goh, Khean Lee; Hilmi, Ida; Ouyang, Qin; Wang, Yu-Fang; Hu, PinJin; Zhu, Zhenhua; Zeng, Zhirong; Wu, Kaichun; Wang, Xin; Xia, Bing; Li, Jin; Pisespongsa, Pises; Manatsathit, Sathaporn; Aniwan, Satimai; Simadibrata, Marcellus; Abdullah, Murdani; Tsang, Steve W C; Wong, Tai Chiu; Hui, Aric J; Chow, Chung Mo; Yu, Hon Ho; Li, Mo Fong; Ng, Ka Kei; Ching, Jessica; Wu, Justin C Y; Chan, Francis K L; Sung, Joseph J Y

2015-07-01

The rising incidence of inflammatory bowel disease in Asia supports the importance of environmental risk factors in disease aetiology. This prospective population-based case-control study in Asia-Pacific examined risk factors prior to patients developing IBD. 442 incident cases (186 Crohn's disease (CD); 256 UC; 374 Asians) diagnosed between 2011 and 2013 from eight countries in Asia and Australia and 940 controls (frequency-matched by sex, age and geographical location; 789 Asians) completed an environmental factor questionnaire at diagnosis. Unconditional logistic regression models were used to estimate adjusted ORs (aOR) and 95% CIs. In multivariate model, being breast fed >12 months (aOR 0.10; 95% CI 0.04 to 0.30), antibiotic use (aOR 0.19; 0.07 to 0.52), having dogs (aOR 0.54; 0.35 to 0.83), daily tea consumption (aOR 0.62; 0.43 to 0.91) and daily physical activity (aOR 0.58; 0.35 to 0.96) decreased the odds for CD in Asians. In UC, being breast fed >12 months (aOR 0.16; 0.08 to 0.31), antibiotic use (aOR 0.48; 0.27 to 0.87), daily tea (aOR 0.63; 0.46 to 0.86) or coffee consumption (aOR 0.51; 0.36 to 0.72), presence of hot water tap (aOR 0.65; 0.46 to 0.91) and flush toilet in childhood (aOR 0.71; 0.51 to 0.98) were protective for UC development whereas ex-smoking (aOR 2.02; 1.22 to 3.35) increased the risk of UC. This first population-based study of IBD risk factors in Asia-Pacific supports the importance of childhood immunological, hygiene and dietary factors in the development of IBD, suggesting that markers of altered intestinal microbiota may modulate risk of IBD later in life. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Double Dissociation of Conditioning and Declarative Knowledge Relative to the Amygdala and Hippocampus in Humans

NASA Astrophysics Data System (ADS)

Bechara, Antoine; Tranel, Daniel; Damasio, Hanna; Adolphs, Ralph; Rockland, Charles; Damasio, Antonio R.

1995-08-01

A patient with selective bilateral damage to the amygdala did not acquire conditioned autonomic responses to visual or auditory stimuli but did acquire the declarative facts about which visual or auditory stimuli were paired with the unconditioned stimulus. By contrast, a patient with selective bilateral damage to the hippocampus failed to acquire the facts but did acquire the conditioning. Finally, a patient with bilateral damage to both amygdala and hippocampal formation acquired neither the conditioning nor the facts. These findings demonstrate a double dissociation of conditioning and declarative knowledge relative to the human amygdala and hippocampus.

Efectos Especiales de Anclaje (Estudio sobre Regresiones de Juicios Condicionales). Parte 2: Invariancia del Juicio No-Condicional Como Valor Estandar Para el Juicio Condicional (Special Effects of Anchoring (Study of Regression of Conditional Judgements) Part 2: Invariance of Unconditional Judgments as Standard Value for the Conditional Judgment). Publication No. 31.

ERIC Educational Resources Information Center

Lopez Alonso, A. O.

From the best-fit lines corresponding to sets of families of conditional judgements, the constant stimulus family and the constant condition family, both defined for a same scale object, the coordinate values of the point of intersection of both lines (indifference point) are obtained. These values are studied in relation to the mean values of the…

I like it because I said that I like it: evaluative conditioning effects can be based on stimulus-response learning.

PubMed

Gast, Anne; Rothermund, Klaus

2011-10-01

Evaluative conditioning (EC) effects are often assumed to be based on a learned mental link between the CS (conditioned stimulus) and the US (unconditioned stimulus). We demonstrate that this link is not the only one that can underlie EC effects, but that if evaluative responses are actually given during the learning phase also a direct link between the CS and an evaluative response-a CS-ER link-can be learned and lead to EC effects. In Experiment 1, CSs were paired with USs and participants were asked to evaluate the pairs during the conditioning phase. Resulting EC effects were unaffected by a later revaluation of the USs, suggesting that these EC effects can be attributed to CS-ER learning rather than to CS-US learning. Experiment 2 replicated Experiment 1 with the difference that no evaluative responses were given during the learning phase. EC effects in this study were influenced by US revaluation, suggesting that these EC effects are mainly based on CS-US learning. In Experiment 3, it was shown that EC effects can be found even if the USs are entirely removed from the procedure and the CSs are only paired with enforced evaluative responses. Together the experiments show that the valence of a stimulus can change because of a contingency with an evaluative response. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Striatal-Limbic Activation is Associated with Intensity of Anticipatory Anxiety

PubMed Central

Yang, Hongyu; Spence, Jeffrey S.; Devous, Michael D.; Briggs, Richard W.; Goyal, Aman; Xiao, Hong; Yadav, Hardik; Adinoff, Bryon

2013-01-01

Anxiety experienced in anticipation of impending aversive events induces striatal-limbic activation. However, previous functional magnetic imaging (fMRI) studies of anticipatory anxiety have utilized post-test measures of anxiety, making a direct association between neural activation and distress problematic. This paradigm was designed to assess the BOLD response to an aversive conditioned stimulus while simultaneously measuring subjective anxiety. Fifteen male healthy subjects (45.5±8.5 years old) were studied. A high threat conditioned stimulus (CS) was paired with either an unpredictable, highly aversive (painful) or a non-aversive (non-painful) unconditioned stimulus and compared to a low threat CS paired with a predictable, non-aversive stimulus. Neural response was assessed with fMRI, and subjective anxiety (1 to 4) was recorded upon the presentation of each CS. High subjective ratings of real-time anticipatory anxiety (2, 3, and 4), relative to low anticipatory anxiety (1), elicited increased activation in the bilateral striatum, bilateral orbital frontal cortex, left anterior insula, and anterior cingulate cortex (ACC) and decreased activation in the posterior cingulate cortex (PCC). The amplitude of BOLD signal change generally paralleled the subjective rating of anxiety. Real-time measures of anticipatory anxiety confirm previous reports, using post-test measures of anxiety, of striatal-limbic activation during anticipatory anxiety while simultaneously demonstrating an increase in BOLD response in parallel with heightened anxiety. PMID:23137803

Double dissociation of the anterior and posterior dorsomedial caudate-putamen in the acquisition and expression of associative learning with the nicotine stimulus.

PubMed

Charntikov, Sergios; Pittenger, Steven T; Swalve, Natashia; Li, Ming; Bevins, Rick A

2017-07-15

Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the main addictive component of tobacco products and is a moderate stimulant and a mild reinforcer. Importantly, besides its unconditional effects, nicotine also has conditioned stimulus effects that may contribute to the tenacity of the smoking habit. Because the neurobiological substrates underlying these processes are virtually unexplored, the present study investigated the functional involvement of the dorsomedial caudate putamen (dmCPu) in learning processes with nicotine as an interoceptive stimulus. Rats were trained using the discriminated goal-tracking task where nicotine injections (0.4 mg/kg; SC), on some days, were paired with intermittent (36 per session) sucrose deliveries; sucrose was not available on interspersed saline days. Pre-training excitotoxic or post-training transient lesions of anterior or posterior dmCPu were used to elucidate the role of these areas in acquisition or expression of associative learning with nicotine stimulus. Pre-training lesion of p-dmCPu inhibited acquisition while post-training lesions of p-dmCPu attenuated the expression of associative learning with the nicotine stimulus. On the other hand, post-training lesions of a-dmCPu evoked nicotine-like responding following saline treatment indicating the role of this area in disinhibition of learned motor behaviors. These results, for the first time, show functionally distinct involvement of a- and p-dmCPu in various stages of associative learning using nicotine stimulus and provide an initial account of neural plasticity underlying these learning processes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Amygdala's involvement in facilitating associative learning-induced plasticity: a promiscuous role for the amygdala in memory acquisition

PubMed Central

Chau, Lily S.; Galvez, Roberto

2012-01-01

It is widely accepted that the amygdala plays a critical role in acquisition and consolidation of fear-related memories. Some of the more widely employed behavioral paradigms that have assisted in solidifying the amygdala's role in fear-related memories are associative learning paradigms. With most associative learning tasks, a neutral conditioned stimulus (CS) is paired with a salient unconditioned stimulus (US) that elicits an unconditioned response (UR). After multiple CS-US pairings, the subject learns that the CS predicts the onset or delivery of the US, and thus elicits a learned conditioned response (CR). Most fear-related associative paradigms have suggested that an aspect of the fear association is stored in the amygdala; however, some fear-motivated associative paradigms suggest that the amygdala is not a site of storage, but rather facilitates consolidation in other brain regions. Based upon various learning theories, one of the most likely sites for storage of long-term memories is the neocortex. In support of these theories, findings from our laboratory, and others, have demonstrated that trace-conditioning, an associative paradigm where there is a separation in time between the CS and US, induces learning-specific neocortical plasticity. The following review will discuss the amygdala's involvement, either as a site of storage or facilitating storage in other brain regions such as the neocortex, in fear- and non-fear-motivated associative paradigms. In this review, we will discuss recent findings suggesting a broader role for the amygdala in increasing the saliency of behaviorally relevant information, thus facilitating acquisition for all forms of memory, both fear- and non-fear-related. This proposed promiscuous role of the amygdala in facilitating acquisition for all memories further suggests a potential role of the amygdala in general learning disabilities. PMID:23087626

Amygdala's involvement in facilitating associative learning-induced plasticity: a promiscuous role for the amygdala in memory acquisition.

PubMed

Chau, Lily S; Galvez, Roberto

2012-01-01

It is widely accepted that the amygdala plays a critical role in acquisition and consolidation of fear-related memories. Some of the more widely employed behavioral paradigms that have assisted in solidifying the amygdala's role in fear-related memories are associative learning paradigms. With most associative learning tasks, a neutral conditioned stimulus (CS) is paired with a salient unconditioned stimulus (US) that elicits an unconditioned response (UR). After multiple CS-US pairings, the subject learns that the CS predicts the onset or delivery of the US, and thus elicits a learned conditioned response (CR). Most fear-related associative paradigms have suggested that an aspect of the fear association is stored in the amygdala; however, some fear-motivated associative paradigms suggest that the amygdala is not a site of storage, but rather facilitates consolidation in other brain regions. Based upon various learning theories, one of the most likely sites for storage of long-term memories is the neocortex. In support of these theories, findings from our laboratory, and others, have demonstrated that trace-conditioning, an associative paradigm where there is a separation in time between the CS and US, induces learning-specific neocortical plasticity. The following review will discuss the amygdala's involvement, either as a site of storage or facilitating storage in other brain regions such as the neocortex, in fear- and non-fear-motivated associative paradigms. In this review, we will discuss recent findings suggesting a broader role for the amygdala in increasing the saliency of behaviorally relevant information, thus facilitating acquisition for all forms of memory, both fear- and non-fear-related. This proposed promiscuous role of the amygdala in facilitating acquisition for all memories further suggests a potential role of the amygdala in general learning disabilities.

Studies on the organization and regeneration of bone marrow: origin, growth, and differentiation of endocloned hematopoietic colonies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lambertsen, R.H.; Weiss, L.

1983-04-01

Hematopoietic colonies were studied by light microscopy in the marrow of alternate fraction x-irradiated mice (C576J/B1) to investigate the microenvironmental organization of marrow and identify early hematopoietic cell-stromal cell interactions. Undifferentiated colonies (UC) were detected at 3 days postirradiation, showed a marked predilection for bone surfaces, and disappeared as differentiated colonies developed. Some UC occurred along marrow arteries. Neutrophilic granulocyte colonies (GC) occurred in all areas at 3 days but grew rapidly only subosteally. Few eosinophilic colonies (GCe) occurred. Erythrocytic colonies (EC) appeared at 4 days as dispersed populations of motile cells within a localized area of marrow; these tendedmore » to proliferate initially in intermediate and central marrow zones. Macrophage colonies (M phi C) of two ''subtypes'' were detected, peaking in relative frequency at 4 days. These appeared active in stromal repair and monocytopoiesis. Megakaryocyte colonies (MC) originated along bone and differentiated away from bone. These results were interpreted as evidence that in x-irradiated marrow: (1) hematopoietic microenvironments (HMs) for stem-cell proliferation and commitment to differentiation, with the possible exception of HMs determining erythroid differentiation, occur in endosteal and periarterial regions; (2) a proliferative and/or chemotactic stimulus to erythroid progenitors exists in intermediate and central marrow regions; and (3) some subosteal regions may exclude erythropoiesis, or preferentially support nonerythroid differentiation. Elaborate associations occurred between macrophages and early UC, GC, and EC, but not MC hematopoietic cells. UC and GC often associated with osteoclasts. Reticular and other fibroblastic cells associated with the cells of all colony types.« less

Evidence of Pavlovian conditioned fear following electrical stimulation of the periaqueductal grey in the rat.

PubMed

Di Scala, G; Mana, M J; Jacobs, W J; Phillips, A G

1987-01-01

Stimulation of the periaqueductal grey (PAG) has been used to support aversive conditioning in a variety of species with several experimental paradigms. However, it has not been clearly demonstrated whether the behavioral changes produced by PAG stimulation in these paradigms are mediated by associative or nonassociative mechanisms. The present studies demonstrate that electrical stimulation of the PAG in the rat may be used to support associative learning in a Pavlovian paradigm. In each experiment, a fully controlled conditional emotional response (CER) procedure was used to examine the unconditional aversive properties of PAG stimulation. In Experiment 1a, weak associative conditioning was observed when a light CS was paired with PAG stimulation over 6 conditioning trials. In Experiment 1b, robust associative conditioning was obtained with a light CS when 18 conditioning trials were used. In Experiment 2, robust associative conditioning was demonstrated with a tone CS when 6 conditioning trials were used. The results parallel those found when other aversive stimuli are used as a UCS (e.g., footshock or intraorbital air puff), and because the present experiments included the proper control procedures the results clearly indicate that the behavioral changes produced by PAG stimulation are mediated by associative Pavlovian learning mechanisms rather than nonassociative mechanisms such as sensitization or pseudoconditioning. The present technique may be useful for assessing the neuroanatomical and neurochemical substrates underlying the aversive effects of brain-stimulation, and for screening the effects of drugs on the conditional and unconditional responses produced by such stimulation.

Effect of conditioned stimulus exposure during slow wave sleep on fear memory extinction in humans.

PubMed

He, Jia; Sun, Hong-Qiang; Li, Su-Xia; Zhang, Wei-Hua; Shi, Jie; Ai, Si-Zhi; Li, Yun; Li, Xiao-Jun; Tang, Xiang-Dong; Lu, Lin

2015-03-01

Repeated exposure to a neutral conditioned stimulus (CS) in the absence of a noxious unconditioned stimulus (US) elicits fear memory extinction. The aim of the current study was to investigate the effects of mild tone exposure (CS) during slow wave sleep (SWS) on fear memory extinction in humans. The healthy volunteers underwent an auditory fear conditioning paradigm on the experimental night, during which tones served as the CS, and a mild shock served as the US. They were then randomly assigned to four groups. Three groups were exposed to the CS for 3 or 10 min or an irrelevant tone (control stimulus, CtrS) for 10 min during SWS. The fourth group served as controls and was not subjected to any interventions. All of the subjects completed a memory test 4 h after SWS-rich stage to evaluate the effect on fear extinction. Moreover, we conducted similar experiments using an independent group of subjects during the daytime to test whether the memory extinction effect was specific to the sleep condition. Ninety-six healthy volunteers (44 males) aged 18-28 y. Participants exhibited undisturbed sleep during 2 consecutive nights, as assessed by sleep variables (all P > 0.05) from polysomnographic recordings and power spectral analysis. Participants who were re-exposed to the 10 min CS either during SWS and wakefulness exhibited attenuated fear responses (wake-10 min CS, P < 0.05; SWS-10 min CS, P < 0.01). Conditioned stimulus re-exposure during SWS promoted fear memory extinction without altering sleep profiles. © 2015 Associated Professional Sleep Societies, LLC.

Expectancy bias in a selective conditioning procedure: trait anxiety increases the threat value of a blocked stimulus.

PubMed

Boddez, Yannick; Vervliet, Bram; Baeyens, Frank; Lauwers, Stephanie; Hermans, Dirk; Beckers, Tom

2012-06-01

In a blocking procedure, a single conditioned stimulus (CS) is paired with an unconditioned stimulus (US), such as electric shock, in the first stage. During the subsequent stage, the CS is presented together with a second CS and this compound is followed by the same US. Fear conditioning studies in non-human animals have demonstrated that fear responding to the added second CS typically remains low, despite its being paired with the US. Accordingly, the blocking procedure is well suited as a laboratory model for studying (deficits in) selective threat appraisal. The present study tested the relation between trait anxiety and blocking in human aversive conditioning. Healthy participants filled in a trait anxiety questionnaire and underwent blocking treatment in the human aversive conditioning paradigm. Threat appraisal was measured through shock expectancy ratings and skin conductance. As hypothesized, trait anxiety was positively associated with shock expectancy ratings to the blocked stimulus. In skin conductance responding, no significant effects of stimulus type could be detected during blocking training or testing. The current study does not allow strong claims to be made regarding the theoretical process underlying the expectancy bias we observed. The observed shock expectancy bias might be one of the mechanisms leading to non-specific fear in individuals at risk for developing anxiety disorders. A deficit in blocking, or a deficit in selective threat appraisal at the more general level, indeed results in fear becoming non-specific and disconnected from the most likely causes or predictors of danger. Copyright © 2011 Elsevier Ltd. All rights reserved.

Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning

PubMed Central

Kalmbach, Brian; Chitwood, Raymond A.; Mauk, Michael D.

2012-01-01

We have addressed the source and nature of the persistent neural activity that bridges the stimulus-free gap between the conditioned stimulus (CS) and unconditioned stimulus (US) during trace eyelid conditioning. Previous work has demonstrated that this persistent activity is necessary for trace eyelid conditioning: CS-elicited activity in mossy fiber inputs to the cerebellum does not extend into the stimulus-free trace interval, which precludes the cerebellar learning that mediates conditioned response expression. In behaving rabbits we used in vivo recordings from a region of medial prefrontal cortex (mPFC) that is necessary for trace eyelid conditioning to test the hypothesis that neurons there generate activity that persists beyond CS offset. These recordings revealed two patterns of activity during the trace interval that would enable cerebellar learning. Activity in some cells began during the tone CS and persisted to overlap with the US, whereas in other cells, activity began during the stimulus-free trace interval. Injection of anterograde tracers into this same region of mPFC revealed dense labeling in the pontine nuclei, where recordings also revealed tone-evoked persistent activity during trace conditioning. These data suggest a corticopontine pathway that provides an input to the cerebellum during trace conditioning trials that bridges the temporal gap between the CS and US to engage cerebellar learning. As such, trace eyelid conditioning represents a well-characterized and experimentally tractable system that can facilitate mechanistic analyses of cortical persistent activity and how it is used by downstream brain structures to influence behavior. PMID:21957220

Fear conditioning and stimulus generalization in patients with social anxiety disorder.

PubMed

Ahrens, Lea M; Pauli, Paul; Reif, Andreas; Mühlberger, Andreas; Langs, Gernot; Aalderink, Tim; Wieser, Matthias J

2016-12-01

Although overgeneralization seems to be a hallmark of several anxiety disorders, this until now has not been investigated in social anxiety disorder (SAD). Therefore, we examined fear generalization in 26 SAD patients and 29 healthy controls (HC) using two faces as conditioned stimuli (CS+, CS-), and a loud scream and a fearful face as unconditioned stimulus (US). Generalization was tested by presenting both CS and four morphs of the two faces (generalization stimuli [GSs]), while ratings, heart rate (HR) and skin conductance responses (SCR) were recorded. Results revealed that SAD patients rated all stimuli as less pleasant and more arousing compared to HC. Moreover, ratings and SCR indicated that both groups generalized their acquired fear from the CS+ to GSs. Remarkably, only SAD patients showed generalization in HR responses (fear bradycardia). Overall, SAD seems not to be characterized by strong overgeneralization but discrepancies in fear responses to both conditioned and generalized threat stimuli. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluative Conditioning Induces Changes in Sound Valence

PubMed Central

Bolders, Anna C.; Band, Guido P. H.; Stallen, Pieter Jan

2012-01-01

Through evaluative conditioning (EC) a stimulus can acquire an affective value by pairing it with another affective stimulus. While many sounds we encounter daily have acquired an affective value over life, EC has hardly been tested in the auditory domain. To get a more complete understanding of affective processing in auditory domain we examined EC of sound. In Experiment 1 we investigated whether the affective evaluation of short environmental sounds can be changed using affective words as unconditioned stimuli (US). Congruency effects on an affective priming task for conditioned sounds demonstrated successful EC. Subjective ratings for sounds paired with negative words changed accordingly. In Experiment 2 we investigated whether extinction occurs, i.e., whether the acquired valence remains stable after repeated presentation of the conditioned sound without the US. The acquired affective value remained present, albeit weaker, even after 40 extinction trials. These results provide clear evidence for EC effects in the auditory domain. We will argue that both associative as well as propositional processes are likely to underlie these effects. PMID:22514545

Propositional Versus Dual-Process Accounts of Evaluative Conditioning: I. The Effects of Co-Occurrence and Relational Information on Implicit and Explicit Evaluations.

PubMed

Hu, Xiaoqing; Gawronski, Bertram; Balas, Robert

2017-01-01

Evaluative conditioning (EC) is defined as the change in the evaluation of a conditioned stimulus (CS) due to its pairing with a valenced unconditioned stimulus (US). According to propositional accounts, EC effects should be qualified by the relation between the CS and the US. Dual-process accounts suggest that relational information should qualify EC effects on explicit evaluations, whereas implicit evaluations should reflect the frequency of CS-US co-occurrences. Experiments 1 and 2 showed that, when relational information was provided before the encoding of CS-US pairings, it moderated EC effects on explicit, but not implicit, evaluations. In Experiment 3, relational information moderated EC effects on both explicit and implicit evaluations when it was provided simultaneously with CS-US pairings. Frequency of CS-US pairings had no effect on implicit evaluations. Although the results can be reconciled with both propositional and dual-process accounts, they are more parsimoniously explained by propositional accounts.

Effects of Caffeine on Olfactory Learning in Crickets.

PubMed

Sugimachi, Seigo; Matsumoto, Yukihisa; Mizunami, Makoto; Okada, Jiro

2016-10-01

Caffeine is a plant-derived alkaloid that is generally known as a central nervous system (CNS) stimulant. In order to examine the effects of caffeine on higher CNS functions in insects, we used an appetitive olfactory learning paradigm for the cricket Gryllus bimaculatus. Crickets can form significant long-term memories (LTMs) after repetitive training sessions, during which they associate a conditioned stimulus (CS: odor) with an unconditioned stimulus (US: reward). Administration of hemolymphal injections of caffeine established LTM after only single-trial conditioning over a wide range of caffeine dosages (1.6 µµg/kg to 39 mg/kg). We investigated the physiological mechanisms underlying this enhancement of olfactory learning performance pharmacologically, focusing on three major physiological roles of caffeine: 1) inhibition of phosphodiesterase (PDE), 2) agonism of ryanodine receptors, and 3) antagonism of adenosine receptors. Application of drugs relevant to these actions resulted in significant effects on LTM formation. These results suggest that externally applied caffeine enhances LTM formation in insect olfactory learning via multiple cellular mechanisms.

Learning about associations: evidence for a hierarchical account of occasion setting.

PubMed

Bonardi, Charlotte; Jennings, Dómhnall

2009-07-01

In 2 experiments rats were trained on a switching discrimination, with 4 occasion setters, A, B, C, and D and 2 target stimuli, x and y. When signaled either by A or by B, x was reinforced with food and y was not, whereas when signaled either by C or by D these reinforcement relations were reversed (i.e., A: --> x+, A: y --> -, B: x --> +, B: y --> -, C: x --> -, C: y --> +, D: x --> -, D: y --> +). In a subsequent Stage A was paired with shock, and then the degree to which food-reinforced (Experiment 1a) and nonreinforced (Experiment 1b) presentations of x and y were capable of eliciting fear was assessed. Those conditioned stimulus (CS)/unconditioned stimulus (US) relations that had been operative in the presence of the fear-eliciting occasion setter A (i.e., x --> +, y --> -) elicited more fear than the alternative CS/US combinations (i.e., x --> -, y --> +). The implications of these findings are discussed with reference to theories of occasion setting and of configural learning.

Behavioral characteristics and neurobiological substrates shared by Pavlovian sign-tracking and drug abuse.

PubMed

Tomie, Arthur; Grimes, Kathryn L; Pohorecky, Larissa A

2008-06-01

Drug abuse researchers have noted striking similarities between behaviors elicited by Pavlovian sign-tracking procedures and prominent symptoms of drug abuse. In Pavlovian sign-tracking procedures, repeated paired presentations of a small object (conditioned stimulus, CS) with a reward (unconditioned stimulus, US) elicits a conditioned response (CR) that typically consists of approaching the CS, contacting the CS, and expressing consummatory responses at the CS. Sign-tracking CR performance is poorly controlled and exhibits spontaneous recovery and long-term retention, effects that resemble relapse. Sign-tracking resembles psychomotor activation, a syndrome of behavioral responses evoked by addictive drugs, and the effects of sign-tracking on corticosterone levels and activation of dopamine pathways resemble the neurobiological effects of abused drugs. Finally, the neurobiological profile of individuals susceptible to sign-tracking resembles the pathophysiological profile of vulnerability to drug abuse, and vulnerability to sign-tracking predicts vulnerability to impulsive responding and alcohol self-administration. Implications of sign-tracking for models of drug addiction are considered.

Encoding of Discriminative Fear Memory by Input-Specific LTP in the Amygdala.

PubMed

Kim, Woong Bin; Cho, Jun-Hyeong

2017-08-30

In auditory fear conditioning, experimental subjects learn to associate an auditory conditioned stimulus (CS) with an aversive unconditioned stimulus. With sufficient training, animals fear conditioned to an auditory CS show fear response to the CS, but not to irrelevant auditory stimuli. Although long-term potentiation (LTP) in the lateral amygdala (LA) plays an essential role in auditory fear conditioning, it is unknown whether LTP is induced selectively in the neural pathways conveying specific CS information to the LA in discriminative fear learning. Here, we show that postsynaptically expressed LTP is induced selectively in the CS-specific auditory pathways to the LA in a mouse model of auditory discriminative fear conditioning. Moreover, optogenetically induced depotentiation of the CS-specific auditory pathways to the LA suppressed conditioned fear responses to the CS. Our results suggest that input-specific LTP in the LA contributes to fear memory specificity, enabling adaptive fear responses only to the relevant sensory cue. VIDEO ABSTRACT. Copyright © 2017 Elsevier Inc. All rights reserved.

Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning.

PubMed

Pang, Min-Hee; Kim, Nam-Soo; Kim, Il-Hwan; Kim, Hyun; Kim, Hyun-Taek; Choi, June-Seek

2010-09-01

Although cholinergic mechanisms have been widely implicated in learning and memory processes, few studies have investigated the specific contribution of hippocampal cholinergic transmission during trace fear conditioning, a form of associative learning involving a temporal gap between two stimuli. Microinfusions of scopolamine, a muscarinic receptor antagonist, into the dorsal hippocampus (DH) produced dose-dependent impairment in the acquisition and expression of a conditioned response (CR) following trace fear conditioning with a tone conditioned stimulus (CS) and a footshock unconditioned stimulus (US) in rats. The same infusions, however, had no effect on delay conditioning, general activity, pain sensitivity or attentional modulation. Moreover, scopolamine infusions attenuated phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala, indicating that cholinergic signals in the DH are important for trace fear conditioning. Taken together, the current study provides evidence that cholinergic neurotransmission in the DH is essential for the cellular processing of CS-US association in the amygdala when the two stimuli are temporally disconnected. Copyright 2010 Elsevier Inc. All rights reserved.

Forward conditioning with wheel running causes place aversion in rats.

PubMed

Masaki, Takahisa; Nakajima, Sadahiko

2008-09-01

Backward pairings of a distinctive chamber as a conditioned stimulus and wheel running as an unconditioned stimulus (i.e., running-then-chamber) can produce a conditioned place preference in rats. The present study explored whether a forward conditioning procedure with these stimuli (i.e., chamber-then-running) would yield place preference or aversion. Confinement of a rat in one of two distinctive chambers was followed by a 20- or 60-min running opportunity, but confinement in the other was not. After four repetitions of this treatment (i.e., differential conditioning), a choice preference test was given in which the rat had free access to both chambers. This choice test showed that the rats given 60-min running opportunities spent less time in the running-paired chamber than in the unpaired chamber. Namely, a 60-min running opportunity after confinement in a distinctive chamber caused conditioned aversion to that chamber after four paired trials. This result was discussed with regard to the opponent-process theory of motivation.

Behavioral Characteristics and Neurobiological Substrates Shared by Pavlovian Sign-Tracking and Drug Abuse

PubMed Central

Tomie, Arthur; Grimes, Kathryn L.; Pohorecky, Larissa A.

2008-01-01

Drug abuse researchers have noted striking similarities between behaviors elicited by Pavlovian sign-tracking procedures and prominent symptoms of drug abuse. In Pavlovian sign-tracking procedures, repeated paired presentations of a small object (conditioned stimulus, CS) with a reward (unconditioned stimulus, US) elicits a conditioned response (CR) that typically consists of approaching the CS, contacting the CS, and expressing consummatory responses at the CS. Sign-tracking CR performance is poorly controlled and exhibits spontaneous recovery and long-term retention, effects that resemble relapse. Sign-tracking resembles psychomotor activation, a syndrome of behavioral responses evoked by addictive drugs, and the effects of sign-tracking on corticosterone levels and activation of dopamine pathways resemble the neurobiological effects of abused drugs. Finally, the neurobiological profile of individuals susceptible to sign-tracking resembles the pathophysiological profile of vulnerability to drug abuse, and vulnerability to sign-tracking predicts vulnerability to impulsive responding and alcohol self-administration. Implications of sign-tracking for models of drug addiction are considered. PMID:18234349

Autoshaping of ethanol drinking: an animal model of binge drinking.

PubMed

Tomie, Arthur; di Poce, Jason; Derenzo, Christopher C; Pohorecky, Larissa A

2002-01-01

To examine the hypothesis that Pavlovian autoshaping provides an animal learning model of drug abuse, two studies evaluated the induction of ethanol drinking by autoshaping procedures. In Experiment 1, the sipper tube conditioned stimulus (CS) contained saccharin/ethanol solution and was repeatedly paired with food as an unconditioned stimulus (US). The CS-US paired group consumed more of the 0.1% saccharin-6% ethanol solution than did the CS-US random group, revealing that autoshaping conditioned responses (CR) induce ethanol drinking not attributable to pseudo-conditioning. Experiment 2 employed saccharin-fading procedures and showed that the paired vs random group differences in ethanol drinking were maintained, even as the saccharin was eliminated from the solution. The results show that Pavlovian autoshaping procedures induce high volumes of ethanol drinking when the presentation of a sipper tube containing an ethanol solution precedes the response-independent delivery of food. The high volume of ethanol consumed in a brief period of time suggests that Pavlovian autoshaping may be a model of binge drinking.

Investigating motion sickness using the conditioned taste aversion paradigm

NASA Technical Reports Server (NTRS)

Fox, Robert A.

1990-01-01

The use of conditioned taste aversion (CTA) to study motion sickness is reviewed. The use of CTA to measure motion sickness is supported by studies showing that an intact vestibular system is essential for the production of CTA when motion is the unconditioned stimulus. The magnitude of CTA is assessed at a time removed from exposure to motion, and therefore is not affected by residual effects of motion. Since the magnitude of CTA is assessed as volume or weight of flood or fluid, the degree of sickness is reflected in a continuous measure rather than in the discrete, all-or-none fashion characteristic of vomiting.

Body temperature as a conditional response measure for pavlovian fear conditioning.

PubMed

Godsil, B P; Quinn, J J; Fanselow, M S

2000-01-01

On six days rats were exposed to each of two contexts. They received an electric shock in one context and nothing in the other. Rats were tested later in each environment without shock. The rats froze and defecated more often in the shock-paired environment; they also exhibited a significantly larger elevation in rectal temperature in that environment. The rats discriminated between each context, and we suggest that the elevation in temperature is the consequence of associative learning. Thus, body temperature can be used as a conditional response measure in Pavlovian fear conditioning experiments that use footshock as the unconditional stimulus.

A Variable Oscillator Underlies the Measurement of Time Intervals in the Rostral Medial Prefrontal Cortex during Classical Eyeblink Conditioning in Rabbits.

PubMed

Caro-Martín, C Rocío; Leal-Campanario, Rocío; Sánchez-Campusano, Raudel; Delgado-García, José M; Gruart, Agnès

2015-11-04

We were interested in determining whether rostral medial prefrontal cortex (rmPFC) neurons participate in the measurement of conditioned stimulus-unconditioned stimulus (CS-US) time intervals during classical eyeblink conditioning. Rabbits were conditioned with a delay paradigm consisting of a tone as CS. The CS started 50, 250, 500, 1000, or 2000 ms before and coterminated with an air puff (100 ms) directed at the cornea as the US. Eyelid movements were recorded with the magnetic search coil technique and the EMG activity of the orbicularis oculi muscle. Firing activities of rmPFC neurons were recorded across conditioning sessions. Reflex and conditioned eyelid responses presented a dominant oscillatory frequency of ≈12 Hz. The firing rate of each recorded neuron presented a single peak of activity with a frequency dependent on the CS-US interval (i.e., ≈12 Hz for 250 ms, ≈6 Hz for 500 ms, and≈3 Hz for 1000 ms). Interestingly, rmPFC neurons presented their dominant firing peaks at three precise times evenly distributed with respect to CS start and also depending on the duration of the CS-US interval (only for intervals of 250, 500, and 1000 ms). No significant neural responses were recorded at very short (50 ms) or long (2000 ms) CS-US intervals. rmPFC neurons seem not to encode the oscillatory properties characterizing conditioned eyelid responses in rabbits, but are probably involved in the determination of CS-US intervals of an intermediate range (250-1000 ms). We propose that a variable oscillator underlies the generation of working memories in rabbits. The way in which brains generate working memories (those used for the transient processing and storage of newly acquired information) is still an intriguing question. Here, we report that the firing activities of neurons located in the rostromedial prefrontal cortex recorded in alert behaving rabbits are controlled by a dynamic oscillator. This oscillator generated firing frequencies in a variable band of 3-12 Hz depending on the conditioned stimulus-unconditioned stimulus intervals (1 s, 500 ms, 250 ms) selected for classical eyeblink conditioning of behaving rabbits. Shorter (50 ms) and longer (2 s) intervals failed to activate the oscillator and prevented the acquisition of conditioned eyelid responses. This is an unexpected mechanism to generate sustained firing activities in neural circuits generating working memories. Copyright © 2015 the authors 0270-6474/15/3514809-13$15.00/0.

Higher-order associative processing in Hermissenda suggests multiple sites of neuronal modulation.

PubMed

Rogers, R F; Matzel, L D

1996-01-01

Two important features of modern accounts of associative learning are (1) the capacity for contextual stimuli to serve as a signal for an unconditioned stimulus (US) and (2) the capacity for a previously conditioned (excitatory) stimulus to "block" learning about a redundant stimulus when both stimuli serve as a signal for the same US. Here, we examined the process of blocking, thought by some to reflect a cognitive aspect of classical conditioning, and its underlying mechanisms in the marine mollusc Hermissenda. In two behavioral experiments, a context defined by chemosensory stimuli was made excitatory by presenting unsignalled USs (rotation) in that context. The excitatory context subsequently blocked overt learning about a discrete conditioned stimulus (CS; light) paired with the US in that context. In a third experiment, the excitability of the B photoreceptors in the Hermissenda eye, which typically increases following light-rotation pairings, was examined in behaviorally blocked animals, as well as in animals that had acquired a normal CS-US association or animals that had been exposed to the CS and US unpaired. Both the behaviorally blocked and the "normal" learning groups exhibited increases in neuronal excitability relative to unpaired animals. However, light-induced multiunit activity in pedal nerves was suppressed following normal conditioning but not in blocked or unpaired control animals, suggesting that the expression of blocking is mediated by neuronal modifications not directly reflected in B-cell excitability, possibly within an extensive network of central light-responsive interneurons.

Effects of orbitofrontal cortex lesions on autoshaped lever pressing and reversal learning.

PubMed

Chang, Stephen E

2014-10-15

A cue associated with a rewarding event can trigger behavior towards the cue itself due to the cue acquiring incentive value through its pairing with the rewarding outcome (i.e., sign-tracking). For example, rats will approach, press, and attempt to "consume" a retractable lever conditioned stimulus (CS) that signals delivery of a food unconditioned stimulus (US). Attending to food-predictive CSs is important when seeking out food, and it is just as important to be able to modify one's behavior when the relationships between CSs and USs are changed. Using a discriminative autoshaping procedure with lever CSs, the present study investigated the effects of orbitofrontal cortex (OFC) lesions on sign-tracking and reversal learning. Insertion of one lever was followed by sucrose delivery upon retraction, and insertion of another lever was followed by nothing. After the acquisition phase, the contingencies between the levers and outcomes were reversed. Bilateral OFC lesions had no effect on the acquisition of sign-tracking. However, OFC-lesioned rats showed substantial deficits in acquiring sign-tracking compared to sham-lesioned rats once the stimulus-outcome contingencies were reversed. Over the course of reversal learning, OFC-lesioned rats were able to reach comparable levels of sign-tracking as sham-lesioned rats. These findings suggest that OFC is not necessary for the ability of a CS to acquire incentive value and provide more evidence that OFC is critical for modifying behavior appropriately following a change in stimulus-outcome contingencies. Copyright © 2014 Elsevier B.V. All rights reserved.

Neuronal Correlates of Cross-Modal Transfer in the Cerebellum and Pontine Nuclei

PubMed Central

Campolattaro, Matthew M.; Kashef, Alireza; Lee, Inah; Freeman, John H.

2011-01-01

Cross-modal transfer occurs when learning established with a stimulus from one sensory modality facilitates subsequent learning with a new stimulus from a different sensory modality. The current study examined neuronal correlates of cross-modal transfer of Pavlovian eyeblink conditioning in rats. Neuronal activity was recorded from tetrodes within the anterior interpositus nucleus (IPN) of the cerebellum and basilar pontine nucleus (PN) during different phases of training. After stimulus pre-exposure and unpaired training sessions with a tone conditioned stimulus (CS), light CS, and periorbital stimulation unconditioned stimulus (US), rats received associative training with one of the CSs and the US (CS1-US). Training then continued on the same day with the other CS to assess cross-modal transfer (CS2-US). The final training session included associative training with both CSs on separate trials to establish stronger cross-modal transfer (CS1/CS2). Neurons in the IPN and PN showed primarily unimodal responses during pre-training sessions. Learning-related facilitation of activity correlated with the conditioned response (CR) developed in the IPN and PN during CS1-US training. Subsequent CS2-US training resulted in acquisition of CRs and learning-related neuronal activity in the IPN but substantially less little learning-related activity in the PN. Additional CS1/CS2 training increased CRs and learning-related activity in the IPN and PN during CS2-US trials. The findings suggest that cross-modal neuronal plasticity in the PN is driven by excitatory feedback from the IPN to the PN. Interacting plasticity mechanisms in the IPN and PN may underlie behavioral cross-modal transfer in eyeblink conditioning. PMID:21411647

Acquisition of heroin conditioned immunosuppression requires IL-1 signaling in the dorsal hippocampus.

PubMed

Lebonville, Christina L; Jones, Meghan E; Hutson, Lee W; Cooper, Letty B; Fuchs, Rita A; Lysle, Donald T

2016-08-01

Opioid users experience increased incidence of infection, which may be partially attributable to both direct opiate-immune interactions and conditioned immune responses. Previous studies have investigated the neural circuitry governing opioid conditioned immune responses, but work remains to elucidate the mechanisms mediating this effect. Our laboratory has previously shown that hippocampal IL-1 signaling, specifically, is required for the expression of heroin conditioned immunosuppression following learning. The current studies were designed to further characterize the role of hippocampal IL-1 in this phenomenon by manipulating IL-1 during learning. Experiment 1 tested whether hippocampal IL-1 is also required for the acquisition of heroin conditioned immunosuppression, while Experiment 2 tested whether hippocampal IL-1 is required for the expression of unconditioned heroin immunosuppression. We found that blocking IL-1 signaling in the dorsal hippocampus with IL-1RA during each conditioning session, but not on interspersed non-conditioning days, significantly attenuated the acquisition of heroin conditioned immunosuppression. Strikingly, we found that the same IL-1RA treatment did not alter unconditioned immunosuppression to a single dose of heroin. Thus, IL-1 signaling is not a critical component of the response to heroin but rather may play a role in the formation of the association between heroin and the context. Collectively, these studies suggest that IL-1 signaling, in addition to being involved in the expression of a heroin conditioned immune response, is also involved in the acquisition of this effect. Importantly, this effect is likely not due to blocking the response to the unconditioned stimulus since IL-1RA did not affect heroin's immunosuppressive effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Acquisition of Heroin Conditioned Immunosuppression Requires IL-1 Signaling in the Dorsal Hippocampus

PubMed Central

Lebonville, Christina L.; Jones, Meghan E.; Hutson, Lee W.; Cooper, Letty B.; Lysle, Donald T.

2016-01-01

Opioid users experience increased incidence of infection, which may be partially attributable to both direct opiate-immune interactions and conditioned immune responses. Previous studies have investigated the neural circuitry governing opioid conditioned immune responses, but work remains to elucidate the mechanisms mediating this effect. Our laboratory has previously shown that hippocampal IL-1 signaling, specifically, is required for the expression of heroin conditioned immunosuppression following learning. The current studies were designed to further characterize the role of hippocampal IL-1 in this phenomenon by manipulating IL-1 during learning. Experiment 1 tested whether hippocampal IL-1 is also required for the acquisition of heroin conditioned immunosuppression, while Experiment 2 tested whether hippocampal IL-1 is required for the expression of unconditioned heroin immunosuppression. We found that blocking IL-1 signaling in the dorsal hippocampus with IL-1RA during each conditioning session, but not on interspersed non-conditioning days, significantly attenuated the acquisition of heroin conditioned immunosuppression. Strikingly, we found that the same IL-1RA treatment did not alter unconditioned immunosuppression to a single dose of heroin. Thus, IL-1 signaling is not a critical component of the response to heroin but rather may play a role in the formation of the association between heroin and the context. Collectively, these studies suggest that IL-1 signaling, in addition to being involved in the expression of a heroin conditioned immune response, is also involved in the acquisition of this effect. Importantly, this effect is likely not due to blocking the response to the unconditioned stimulus since IL-1RA did not affect heroin’s immunosuppressive effects. PMID:27072068

Initial Localization of the Memory Trace for a Basic Form of Learning

NASA Astrophysics Data System (ADS)

McCormick, David A.; Clark, Gregory A.; Lavond, David G.; Thompson, Richard F.

1982-04-01

Electrophysiological recording of neuronal unit activity during paired training trials from various regions of the ipsilateral cerebellum in rabbits well trained in the classically conditioned eyelid/nictitating membrane response have revealed both stimulus-evoked responses and responses that form an amplitude/temporal model of the learned behavioral response. Ablation of the ipsilateral, lateral cerebellum completely and permanently abolished the behavioral conditioned response in well-trained animals but had no effect at all on the unconditioned reflex response. In marked contrast, conditioned responses were easily trained in the eye contralateral to the cerebellar lesion. We suggest that at least part of the essential neuronal plasticity that codes the learned response may be localized to the cerebellum.

Effect of Conditioned Stimulus Exposure during Slow Wave Sleep on Fear Memory Extinction in Humans

PubMed Central

He, Jia; Sun, Hong-Qiang; Li, Su-Xia; Zhang, Wei-Hua; Shi, Jie; Ai, Si-Zhi; Li, Yun; Li, Xiao-Jun; Tang, Xiang-Dong; Lu, Lin

2015-01-01

Study Objectives: Repeated exposure to a neutral conditioned stimulus (CS) in the absence of a noxious unconditioned stimulus (US) elicits fear memory extinction. The aim of the current study was to investigate the effects of mild tone exposure (CS) during slow wave sleep (SWS) on fear memory extinction in humans. Design: The healthy volunteers underwent an auditory fear conditioning paradigm on the experimental night, during which tones served as the CS, and a mild shock served as the US. They were then randomly assigned to four groups. Three groups were exposed to the CS for 3 or 10 min or an irrelevant tone (control stimulus, CtrS) for 10 min during SWS. The fourth group served as controls and was not subjected to any interventions. All of the subjects completed a memory test 4 h after SWS-rich stage to evaluate the effect on fear extinction. Moreover, we conducted similar experiments using an independent group of subjects during the daytime to test whether the memory extinction effect was specific to the sleep condition. Participants: Ninety-six healthy volunteers (44 males) aged 18–28 y. Measurements and Results: Participants exhibited undisturbed sleep during 2 consecutive nights, as assessed by sleep variables (all P > 0.05) from polysomnographic recordings and power spectral analysis. Participants who were re-exposed to the 10 min CS either during SWS and wakefulness exhibited attenuated fear responses (wake-10 min CS, P < 0.05; SWS-10 min CS, P < 0.01). Conclusions: Conditioned stimulus re-exposure during slow wave sleep promoted fear memory extinction without altering sleep profiles. Citation: He J, Sun HQ, Li SX, Zhang WH, Shi J, Ai SZ, Li Y, Li XJ, Tang XD, Lu L. Effect of conditioned stimulus exposure during slow wave sleep on fear memory extinction in humans. SLEEP 2015;38(3):423–431. PMID:25348121

Pavlovian second-order conditioned analgesia.

PubMed

Ross, R T

1986-01-01

Three experiments with rat subjects assessed conditioned analgesia in a Pavlovian second-order conditioning procedure by using inhibition of responding to thermal stimulation as an index of pain sensitivity. In Experiment 1, rats receiving second-order conditioning showed longer response latencies during a test of pain sensitivity in the presence of the second-order conditioned stimulus (CS) than rats receiving appropriate control procedures. Experiment 2 found that extinction of the first-order CS had no effect on established second-order conditioned analgesia. Experiment 3 evaluated the effects of post second-order conditioning pairings of morphine and the shock unconditioned stimulus (US). Rats receiving paired morphine-shock presentations showed significantly shorter response latencies during a hot-plate test of pain sensitivity in the presence of the second-order CS than did groups of rats receiving various control procedures; second-order analgesia was attenuated. These data extend the associative account of conditioned analgesia to second-order conditioning situations and are discussed in terms of the mediation of both first- and second-order analgesia by an association between the CS and a representation or expectancy of the US, which may directly activate endogenous pain inhibition systems.

Single-trial evaluative conditioning can be moderated by instructed forgetting.

PubMed

Gast, Anne; Kattner, Florian

2016-09-01

Evaluative conditioning (EC) is a change in the valence of a conditioned stimulus (CS) due to previous pairing with an affective unconditioned stimulus (US). Several previous studies indicate that EC is related to memory of the CS-US pairs. Previous studies, however, typically cannot distinguish between the influence of CS-US knowledge during measurement and during encoding. In addition, by measuring rather than manipulating memory, they do not test the causal effect of memory on EC. The present study employed a "directed forgetting" procedure to the EC paradigm instructing participants to either forget or remember certain CS-US pairs. We found that EC effects after single learning trials were stronger for to-be-remembered than for to-be-forgotten pairs. Manipulation checks showed that the forgetting manipulation also successfully modulated memory for the target pairs and reduced both retroactive and proactive interference on memory for other pairs. Item-based analyses further demonstrated that the size of EC depended on CS-US memory. The results suggest that EC relies on available memory during measurement of the EC effect.

Does evaluative conditioning depend on awareness? Evidence from a continuous flash suppression paradigm.

PubMed

Högden, Fabia; Hütter, Mandy; Unkelbach, Christian

2018-02-26

The role of awareness in evaluative learning has been thoroughly investigated with a variety of theoretical and methodological approaches. We investigated evaluative conditioning (EC) without awareness with an approach that conceptually provides optimal conditions for unaware learning - the Continuous Flash Suppression paradigm (CFS). In CFS, a stimulus presented to one eye can be rendered invisible for a prolonged duration by presenting a high-contrast dynamic pattern to the other eye. The suppressed stimulus is nevertheless processed. First, Experiment 1 established EC effects in a pseudo-CFS setup without suppression. Experiment 2 then employed CFS to suppress conditioned stimuli (CSs) from awareness while the unconditioned stimuli (USs) were visible. While Experiment 1 and 2 used a between-participants manipulation of CS suppression, Experiments 3 and 4 both manipulated suppression within participants. We observed EC effects when CSs were not suppressed, but found no EC effects when the CS was suppressed from awareness. We relate our finding to previous research and discuss theoretical implications for EC. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

In the Blink of an Eye: Investigating the Role of Awareness in Fear Responding by Measuring the Latency of Startle Potentiation

PubMed Central

Åsli, Ole; Flaten, Magne A.

2012-01-01

The latency of startle reflex potentiation may shed light on the aware and unaware processes underlying associative learning, especially associative fear learning. We review research suggesting that single-cue delay classical conditioning is independent of awareness of the contingency between the conditioned stimulus (CS) and the unconditioned stimulus (US). Moreover, we discuss research that argues that conditioning independent of awareness has not been proven. Subsequently, three studies from our lab are presented that have investigated the role of awareness in classical conditioning, by measuring the minimum latency from CS onset to observed changes in reflexive behavior. In sum, research using this method shows that startle is potentiated 30 to 100 ms after CS onset following delay conditioning. Following trace fear conditioning, startle is potentiated 1500 ms after CS presentation. These results indicate that the process underlying delay conditioned responding is independent of awareness, and that trace fear conditioned responding is dependent on awareness. Finally, this method of investigating the role of awareness is discussed and future research possibilities are proposed. PMID:24962686

Cue competition in evaluative conditioning as a function of the learning process.

PubMed

Kattner, Florian; Green, C Shawn

2015-11-01

Evaluative conditioning (EC) is the change in the valence of a stimulus resulting from pairings with an affective (unconditioned) stimulus (US). With some exceptions, previous work has indicated that this form of conditioning might be insensitive to cue competition effects such as blocking and overshadowing. Here we assessed whether the extent of cue competition in EC depends upon the type of contingency learning during conditioning. Specifically, we contrasted a learning task that biased participants toward cognitive/inferential learning (i.e., predicting the US) with a learning task that prevented prolonged introspection (i.e., a rapid response made to the US). In all cases, standard EC effects were observed, with the subjective liking of stimuli changed in the direction of the valence of the US. More importantly, when inferential learning was likely, larger EC effects occurred for isolated stimuli than for compounds (indicating overshadowing). No blocking effects on explicit evaluations were observed for either learning task. Contingency judgments and implicit evaluations, however, were sensitive to blocking, indicating that the absence of a blocking effect on explicit evaluations might be due to inferences that occur during testing.

Activation of Gαq Signaling Enhances Memory Consolidation and Slows Cognitive Decline.

PubMed

Arey, Rachel N; Stein, Geneva M; Kaletsky, Rachel; Kauffman, Amanda; Murphy, Coleen T

2018-05-02

Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function G αq signaling pathway mutant that forms a long-term (cAMP response element binding protein [CREB]-dependent) memory following one conditioned stimulus-unconditioned stimulus (CS-US) pairing, which usually requires seven CS-US pairings. Increased CREB activity in AIM interneurons reduces the threshold for memory consolidation through transcription of a set of previously identified "long-term memory" genes. Enhanced G αq signaling in the AWC sensory neuron is both necessary and sufficient for improved memory and increased AIM CREB activity, and activation of G αq specifically in aged animals rescues the ability to form memory. Activation of G αq in AWC sensory neurons non-cell autonomously induces consolidation after one CS-US pairing, enabling both cognitive function maintenance with age and restoration of memory function in animals with impaired memory performance without decreased longevity. Copyright © 2018 Elsevier Inc. All rights reserved.

Influence of mRNA and protein synthesis inhibitors on the long-term memory acquisition of classically conditioned earthworms.

PubMed

Watanabe, Hikaru; Takaya, Tomohiro; Shimoi, Toshinobu; Ogawa, Hiroto; Kitamura, Yoshiichiro; Oka, Kotaro

2005-03-01

We investigated the process of memory consolidation following classical conditioning of earthworms. Earthworms were conditioned in paired trials by a weak vibration as a conditioned stimulus (CS), and by light as an unconditioned stimulus (US). The occurrence of a shrinking response upon exposure to the CS increased steadily with the number of paired training trials. When the training procedure was changed by increasing the intertrial interval (ITI), it was found that only those worms trained with a 68 s ITI exhibited long-term memory retention for at least 24 h. The influence of mRNA synthesis inhibition by actinomycin-D or of protein synthesis by anisomycin on memory consolidation was also examined. Induction of the long-term memory was blocked when either of these two compounds was injected into the body cavity of the worm within 25 min of conditioning with the 68 s ITI. These results demonstrate that the long-term memory is dependent upon protein synthesis in response to the upregulation of new transcription messengers.

Neural circuitry and plasticity mechanisms underlying delay eyeblink conditioning

PubMed Central

Freeman, John H.; Steinmetz, Adam B.

2011-01-01

Pavlovian eyeblink conditioning has been used extensively as a model system for examining the neural mechanisms underlying associative learning. Delay eyeblink conditioning depends on the intermediate cerebellum ipsilateral to the conditioned eye. Evidence favors a two-site plasticity model within the cerebellum with long-term depression of parallel fiber synapses on Purkinje cells and long-term potentiation of mossy fiber synapses on neurons in the anterior interpositus nucleus. Conditioned stimulus and unconditioned stimulus inputs arise from the pontine nuclei and inferior olive, respectively, converging in the cerebellar cortex and deep nuclei. Projections from subcortical sensory nuclei to the pontine nuclei that are necessary for eyeblink conditioning are beginning to be identified, and recent studies indicate that there are dynamic interactions between sensory thalamic nuclei and the cerebellum during eyeblink conditioning. Cerebellar output is projected to the magnocellular red nucleus and then to the motor nuclei that generate the blink response(s). Tremendous progress has been made toward determining the neural mechanisms of delay eyeblink conditioning but there are still significant gaps in our understanding of the necessary neural circuitry and plasticity mechanisms underlying cerebellar learning. PMID:21969489

Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations.

PubMed

Nader, K; LeDoux, J E

1999-10-01

Previous findings have demonstrated that systemic dopaminergic manipulations impair the retrieval of Pavlovian conditioned fear. A second-order fear-conditioning paradigm was used to test whether the dopaminergic projection from the ventral tegmental area (VTA) to the lateral and basal amygdala (LBA) can affect conditioned fear. Phase 1 entailed conditioned stimulus-unconditioned stimulus (CS1-US) pairings. In Phase 2, drugs were infused in either the LBA or VTA prior to pairings of CS2 (a second cue) with CS1. In Phase 3, freezing behavior elicited by CS2 was tested without drugs. Infusions of the D2 agonist quinpirole into the VTA or of the D1 antagonist SCH 23390 into the LBA caused a decrease in freezing to CS2. Both manipulations decrease D1 receptor activation in the LBA. Infusions of the D1 agonist SKF 38393 into the LBA had no effect. This pattern of results is consistent with the hypothesis that the VTA-LBA dopaminergic projection modulates the retrieval of an association between a CS and footshock US.

Drug Therapy.

PubMed

He, Ri-Hui; Tao, Ran

2017-01-01

This chapter first summarizes the therapy of addiction disorder, and elaborates on the progress of medication. First, the difference between dependency and addiction are introduced. The basic principles of the therapy of substance and non-substance addiction are then put forward. It is also pointed out in this chapter that with the progress of the study, the goal of addiction disorder therapy is expected to transfer from reducing the relapse and harm of the addiction to completely eliminating and recovering from it. This chapter also introduces the progress of psychological addiction elimination technology, especially the "Unconditioned Stimulus Retrieval Extinction Paradigm and Conditioned Stimulus Retrieval Extinction Paradigm" and PITDH technology. Finally it is pointed out that in addiction disorder therapy, comprehensive intervention has become a trend. With regard to the medication for addiction disorders, this chapter also includes the progress and deficiencies of substance and non-substance addiction. In terms of addiction disorder rehabilitation, the foundation of substance addiction is medication which is, however, limited for non-substance addiction. The key to the rehabilitation of addiction disorder is psycho-behavioral therapy, which is especially effective in eliminating craving.

Learning to breathe? Feedforward regulation of the inspiratory motor drive.

PubMed

Zaman, Jonas; Van den Bergh, Omer; Fannes, Stien; Van Diest, Ilse

2014-09-15

Claims have been made that breathing is in part controlled by feedforward regulation. In a classical conditioning paradigm, we investigated anticipatory increases in the inspiratory motor drive as measured by inspiratory occlusion pressure (P100). In an acquisition phase, an experimental group (N=13) received a low-intensity resistive load (5 cmH2O/l/s) for three consecutive inspirations as Conditioned Stimulus (CS), preceding a load of a stronger intensity (20 cmH2O/l/s) for three subsequent inspirations as unconditioned stimulus (US). The control group (N=11) received the low-intensity load for six consecutive inspirations. In a post-acquisition phase both groups received the low-intensity load for six consecutive inspirations. Responses to the CS-load only differed between groups during the first acquisition trials and a strong increase in P100 during the US-loads was observed, which habituated across the experiment. Our results suggest that the disruption caused by adding low to moderate resistive loads to three consecutive inspirations results in a short-lasting anticipatory increase in inspiratory motor drive. Copyright © 2014 Elsevier B.V. All rights reserved.

Reprint of "Learning to breathe? Feedforward regulation of the inspiratory motor drive".

PubMed

Zaman, Jonas; Van den Bergh, Omer; Fannes, Stien; Van Diest, Ilse

2014-12-01

Claims have been made that breathing is in part controlled by feedforward regulation. In a classical conditioning paradigm, we investigated anticipatory increases in the inspiratory motor drive as measured by inspiratory occlusion pressure (P100). In an acquisition phase, an experimental group (N = 13) received a low-intensity resistive load (5 cmH2O/l/s) for three consecutive inspirations as Conditioned Stimulus (CS), preceding a load of a stronger intensity (20 cmH2O/l/s) for three subsequent inspirations as unconditioned stimulus (US). The control group (N = 11) received the low-intensity load for six consecutive inspirations. In a post-acquisition phase both groups received the low-intensity load for six consecutive inspirations. Responses to the CS-load only differed between groups during the first acquisition trials and a strong increase in P100 during the US-loads was observed, which habituated across the experiment. Our results suggest that the disruption caused by adding low to moderate resistive loads to three consecutive inspirations results in a short-lasting anticipatory increase in inspiratory motor drive. Copyright © 2014 Elsevier B.V. All rights reserved.

Learned together, extinguished apart: reducing fear to complex stimuli

PubMed Central

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie-H.

2013-01-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window attenuates fear responding and prevents the return of fear in pure tone Pavlovian fear conditioning. Here we sought to examine whether this effect also applies to a more complex fear memory. First, we show that after fear conditioning to the simultaneous presentation of a tone and a light (T+L) coterminating with a shock, the compound memory that ensues is more resistant to fear extinction than simple tone-shock pairings. Next, we demonstrate that the compound memory can be disrupted by interrupting the reconsolidation of the two individual components using a sequential retrieval+extinction paradigm, provided the stronger compound component is retrieved first. These findings provide insight into how compound memories are encoded, and could have important implications for PTSD treatment. PMID:24241750

Acquired appetitive responding to intravenous nicotine reflects a Pavlovian conditioned association

PubMed Central

Murray, Jennifer E.; Bevins, Rick A.

2008-01-01

Recent research examining Pavlovian appetitive conditioning has extended the associative properties of nicotine from the unconditioned stimulus or reward to include the role of a conditional stimulus (CS), capable of acquiring the ability to evoke a conditioned response. To date, published research has used pre-session extravascular injections to examine nicotine as a contextual CS in that appetitive Pavlovian drug discrimination task. Two studies in the current research examined whether a nicotine CS can function discretely, multiple times within a session using passive intravenous infusions. In Experiment 1, rats readily acquired a discrimination in conditioned responding between nicotine and saline infusions when nicotine was selectively paired with sucrose presentations. In Experiment 2, rats were either trained with nicotine paired with sucrose or explicitly unpaired with sucrose. The results showed that rats trained with explicitly unpaired nicotine and sucrose did not increase dipper entries after the infusions. Nicotine was required to be reliably paired with sucrose for control of conditioned responding to develop. Implications of these findings are discussed in relation to tobacco addiction, learning theory, and pharmacology. PMID:19170434

Auditory Gap-in-Noise Detection Behavior in Ferrets and Humans

PubMed Central

2015-01-01

The precise encoding of temporal features of auditory stimuli by the mammalian auditory system is critical to the perception of biologically important sounds, including vocalizations, speech, and music. In this study, auditory gap-detection behavior was evaluated in adult pigmented ferrets (Mustelid putorius furo) using bandpassed stimuli designed to widely sample the ferret’s behavioral and physiological audiogram. Animals were tested under positive operant conditioning, with psychometric functions constructed in response to gap-in-noise lengths ranging from 3 to 270 ms. Using a modified version of this gap-detection task, with the same stimulus frequency parameters, we also tested a cohort of normal-hearing human subjects. Gap-detection thresholds were computed from psychometric curves transformed according to signal detection theory, revealing that for both ferrets and humans, detection sensitivity was worse for silent gaps embedded within low-frequency noise compared with high-frequency or broadband stimuli. Additional psychometric function analysis of ferret behavior indicated effects of stimulus spectral content on aspects of behavioral performance related to decision-making processes, with animals displaying improved sensitivity for broadband gap-in-noise detection. Reaction times derived from unconditioned head-orienting data and the time from stimulus onset to reward spout activation varied with the stimulus frequency content and gap length, as well as the approach-to-target choice and reward location. The present study represents a comprehensive evaluation of gap-detection behavior in ferrets, while similarities in performance with our human subjects confirm the use of the ferret as an appropriate model of temporal processing. PMID:26052794

Biased Intensity Judgements of Visceral Sensations After Learning to Fear Visceral Stimuli: A Drift Diffusion Approach.

PubMed

Zaman, Jonas; Madden, Victoria J; Iven, Julie; Wiech, Katja; Weltens, Nathalie; Ly, Huynh Giao; Vlaeyen, Johan W S; Van Oudenhove, Lukas; Van Diest, Ilse

2017-10-01

A growing body of research has identified fear of visceral sensations as a potential mechanism in the development and maintenance of visceral pain disorders. However, the extent to which such learned fear affects visceroception remains unclear. To address this question, we used a differential fear conditioning paradigm with nonpainful esophageal balloon distensions of 2 different intensities as conditioning stimuli (CSs). The experiment comprised of preacquisition, acquisition, and postacquisition phases during which participants categorized the CSs with respect to their intensity. The CS+ was always followed by a painful electrical stimulus (unconditioned stimulus) during the acquisition phase and in 60% of the trials during postacquisition. The second stimulus (CS-) was never associated with pain. Analyses of galvanic skin and startle eyeblink responses as physiological markers of successful conditioning showed increased fear responses to the CS+ compared with the CS-, but only in the group with the low-intensity stimulus as CS+. Computational modeling of response times and response accuracies revealed that differential fear learning affected perceptual decision-making about the intensities of visceral sensations such that sensations were more likely to be categorized as more intense. These results suggest that associative learning might indeed contribute to visceral hypersensitivity in functional gastrointestinal disorders. This study shows that associative fear learning biases intensity judgements of visceral sensations toward perceiving such sensations as more intense. Learning-induced alterations in visceroception might therefore contribute to the development or maintenance of visceral pain. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

Temporal patterns of inputs to cerebellum necessary and sufficient for trace eyelid conditioning.

PubMed

Kalmbach, Brian E; Ohyama, Tatsuya; Mauk, Michael D

2010-08-01

Trace eyelid conditioning is a form of associative learning that requires several forebrain structures and cerebellum. Previous work suggests that at least two conditioned stimulus (CS)-driven signals are available to the cerebellum via mossy fiber inputs during trace conditioning: one driven by and terminating with the tone and a second driven by medial prefrontal cortex (mPFC) that persists through the stimulus-free trace interval to overlap in time with the unconditioned stimulus (US). We used electric stimulation of mossy fibers to determine whether this pattern of dual inputs is necessary and sufficient for cerebellar learning to express normal trace eyelid responses. We find that presenting the cerebellum with one input that mimics persistent activity observed in mPFC and the lateral pontine nuclei during trace eyelid conditioning and another that mimics tone-elicited mossy fiber activity is sufficient to produce responses whose properties quantitatively match trace eyelid responses using a tone. Probe trials with each input delivered separately provide evidence that the cerebellum learns to respond to the mPFC-like input (that overlaps with the US) and learns to suppress responding to the tone-like input (that does not). This contributes to precisely timed responses and the well-documented influence of tone offset on the timing of trace responses. Computer simulations suggest that the underlying cerebellar mechanisms involve activation of different subsets of granule cells during the tone and during the stimulus-free trace interval. These results indicate that tone-driven and mPFC-like inputs are necessary and sufficient for the cerebellum to learn well-timed trace conditioned responses.

Effect of Dorsal and Ventral Hippocampal Lesions on Contextual Fear Conditioning and Unconditioned Defensive Behavior Induced by Electrical Stimulation of the Dorsal Periaqueductal Gray

PubMed Central

Ballesteros, Carolina Irurita; de Oliveira Galvão, Bruno; Maisonette, Silvia; Landeira-Fernandez, J.

2014-01-01

The dorsal (DH) and ventral (VH) subregions of the hippocampus are involved in contextual fear conditioning. However, it is still unknown whether these two brain areas also play a role in defensive behavior induced by electrical stimulation of the dorsal periaqueductal gray (dPAG). In the present study, rats were implanted with electrodes into the dPAG to determine freezing and escape response thresholds after sham or bilateral electrolytic lesions of the DH or VH. The duration of freezing behavior that outlasted electrical stimulation of the dPAG was also measured. The next day, these animals were subjected to contextual fear conditioning using footshock as an unconditioned stimulus. Electrolytic lesions of the DH and VH impaired contextual fear conditioning. Only VH lesions disrupted conditioned freezing immediately after footshock and increased the thresholds of aversive freezing and escape responses to dPAG electrical stimulation. Neither DH nor VH lesions disrupted post-dPAG stimulation freezing. These results indicate that the VH but not DH plays an important role in aversively defensive behavior induced by dPAG electrical stimulation. Interpretations of these findings should be made with caution because of the fact that a non-fiber-sparing lesion method was employed. PMID:24404134

OPERANT CONDITIONING OF A SPINAL REFLEX CAN IMPROVE LOCOMOTION AFTER SPINAL CORD INJURY IN HUMANS

PubMed Central

Thompson, Aiko K.; Pomerantz, Ferne; Wolpaw, Jonathan R.

2013-01-01

Operant conditioning protocols can modify the activity of specific spinal cord pathways and can thereby affect behaviors that use these pathways. To explore the therapeutic application of these protocols, we studied the impact of down-conditioning the soleus H-reflex in people with impaired locomotion caused by chronic incomplete spinal cord injury. After a baseline period in which soleus H-reflex size was measured and locomotion was assessed, subjects completed either 30 H-reflex down-conditioning sessions (DC subjects) or 30 sessions in which the H-reflex was simply measured (Unconditioned (UC) subjects), and locomotion was reassessed. Over the 30 sessions, the soleus H-reflex decreased in two-thirds of the DC subjects (a success rate similar to that in normal subjects) and remained smaller several months later. In these subjects, locomotion became faster and more symmetrical, and the modulation of EMG activity across the step-cycle increased bilaterally. Furthermore, beginning about halfway through the conditioning sessions, all of these subjects commented spontaneously that they were walking faster and farther in their daily lives, and several noted less clonus, easier stepping, and/or other improvements. The H-reflex did not decrease in the other DC subjects or in any of the UC subjects; and their locomotion did not improve. These results suggest that reflex conditioning protocols can enhance recovery of function after incomplete spinal cord injuries and possibly in other disorders as well. Because they are able to target specific spinal pathways, these protocols could be designed to address each individual’s particular deficits, and might thereby complement other rehabilitation methods. PMID:23392666

Children with autism spectrum disorders show abnormal conditioned response timing on delay, but not trace, eyeblink conditioning

PubMed Central

Oristaglio, Jeff; West, Susan Hyman; Ghaffari, Manely; Lech, Melissa S.; Verma, Beeta R.; Harvey, John A.; Welsh, John P.; Malone, Richard P.

2013-01-01

Children with autism spectrum disorder (ASD) and age-matched typically-developing (TD) peers were tested on two forms of eyeblink conditioning (EBC), a Pavlovian associative learning paradigm where subjects learn to execute an appropriately-timed eyeblink in response to a previously neutral conditioning stimulus (CS). One version of the task, trace EBC, interposes a stimulus-free interval between the presentation of the CS and the unconditioned stimulus (US), a puff of air to the eye which causes subjects to blink. In delay EBC, the CS overlaps in time with the delivery of the US, usually with both stimuli terminating simultaneously. ASD children performed normally during trace EBC, exhibiting no differences from typically-developing (TD) subjects with regard to learning rate or the timing of the CR. However, when subsequently tested on delay EBC, subjects with ASD displayed abnormally-timed conditioned eye blinks that began earlier and peaked sooner than those of TD subjects, consistent with previous findings. The results suggest an impaired ability of children with ASD to properly time conditioned eye blinks which appears to be specific to delay EBC. We suggest that this deficit may reflect a dysfunction of cerebellar cortex in which increases in the intensity or duration of sensory input can temporarily disrupt the accuracy of motor timing over short temporal intervals. PMID:23769889

Socially acquired predator avoidance: is it just classical conditioning?

PubMed

Griffin, Andrea S

2008-06-15

Associative learning theories presume the existence of a general purpose learning process, the structure of which does not mirror the demands of any particular learning problem. In contrast, learning scientists working within an Evolutionary Biology tradition believe that learning processes have been shaped by ecological demands. One potential means of exploring how ecology may have modified properties of acquisition is to use associative learning theory as a framework within which to analyse a particular learning phenomenon. Recent work has used this approach to examine whether socially transmitted predator avoidance can be conceptualised as a classical conditioning process in which a novel predator stimulus acts as a conditioned stimulus (CS) and acquires control over an avoidance response after it has become associated with alarm signals of social companions, the unconditioned stimulus (US). I review here a series of studies examining the effect of CS/US presentation timing on the likelihood of acquisition. Results suggest that socially acquired predator avoidance may be less sensitive to forward relationships than traditional classical conditioning paradigms. I make the case that socially acquired predator avoidance is an exciting novel one-trial learning paradigm that could be studied along side fear conditioning. Comparisons between social and non-social learning of danger at both the behavioural and neural level may yield a better understanding of how ecology might shape properties and mechanisms of learning.

Visual reaction time for chromaticity changes at constant luminance in different color representation systems

NASA Astrophysics Data System (ADS)

Jimenezdel Barco, L.; Jimenez, J. R.; Rubino, M.; Diaz, J. A.

1996-09-01

The results obtained by different authors show that when a color stimulus changes in both luminance and chromaticity, the visual reaction time (VRT) of an observer in detecting this chromatic change depends on nothing more than the luminance change and is regulated by Pieron's law. In the present work, we evaluate the VRT needed by an observer to detect the chromaticity difference between an adapting and variable stimulus. For this, we have used the experimental method of hue substitution, which allows us to maintain the luminance channel constant and thereby study the temporal response to changes only in chromaticity. The experiments were carried out with a CRT color monitor and the experimental results are expressed in different color-representation systems. The systems UCS-CIE 1964 (U*, V*, W*) and CIELUV show good correlations between the VRT and the chromaticity difference expressed in these systems, adjusting the VRT to an expression following Pieron's law: VRT-VRTon=k( Delta E)- beta .

Augmentation of Fear Extinction by Transcranial Direct Current Stimulation (tDCS)

PubMed Central

Dittert, Natalie; Hüttner, Sandrina; Polak, Thomas; Herrmann, Martin J.

2018-01-01

Although posttraumatic stress disorder (PTSD; DSM-V 309.82) and anxiety disorders (DSM-V 300.xx) are widely spread mental disorders, the effectiveness of their therapy is still unsatisfying. Non-invasive brain-stimulation techniques like transcranial direct current stimulation (tDCS) might be an option to improve extinction learning, which is a main functional factor of exposure-based therapy for anxiety disorders. To examine this hypothesis, we used a fear conditioning paradigm with female faces as conditioned stimuli (CS) and a 95-dB female scream as unconditioned stimulus (UCS). We aimed to perform a tDCS of the ventromedial prefrontal cortex (vmPFC), which is mainly involved in the control of extinction-processes. Therefore, we applied two 4 × 4 cm electrodes approximately at the EEG-positions F7 and F8 and used a direct current of 1.5 mA. The 20-min stimulation was started during a 10-min break between acquisition and extinction and went on overall extinction-trials. The healthy participants were randomly assigned in two double-blinded process into two sham stimulation and two verum stimulation groups with opposite current flow directions. To measure the fear reactions, we used skin conductance responses (SCR) and subjective ratings. We performed a generalized estimating equations model for the SCR to assess the impact of tDCS and current flow direction on extinction processes for all subjects that showed a successful conditioning (N = 84). The results indicate that tDCS accelerates early extinction processes with a significantly faster loss of CS+/CS– discrimination. The discrimination loss was driven by a significant decrease in reaction toward the CS+ as well as an increase in reaction toward the CS– in the tDCS verum groups, whereas the sham groups showed no significant reaction changes during this period. Therefore, we assume that tDCS of the vmPFC can be used to enhance early extinction processes successfully. But before it should be tested in a clinical context further investigation is needed to assess the reason for the reaction increase on CS–. If this negative side effect can be avoided, tDCS may be a tool to improve exposure-based anxiety therapies. PMID:29922133

Non-competitive liking for brands. No blocking in evaluative conditioning.

PubMed

Laane, Kristjan; Aru, Juhan; Dickinson, Anthony

2010-02-01

In the first experiment, we demonstrated evaluative conditioning using a novel across-modality procedure in which pictorial abstract brand logos acted as conditioned stimulus (CSs) and self-selected foods of different hedonic valence functioned as unconditioned stimuli (USs). We then investigated whether this form of learning of likes discriminates against redundant CSs using a blocking paradigm in the second experiment. The strength of evaluative conditioning accruing to the target CSs during compound training was unaffected by whether the other element of the compound was pretrained with a hedonic US. The observation that contingency learning about the target CS was blocked by the pretraining suggests that learning of likes and predictive learning are mediated by different processes. 2009 Elsevier Ltd. All rights reserved.

No effect of trait anxiety on differential fear conditioning or fear generalization.

PubMed

Torrents-Rodas, David; Fullana, Miquel A; Bonillo, Albert; Caseras, Xavier; Andión, Oscar; Torrubia, Rafael

2013-02-01

Previous studies have shown that individuals with anxiety disorders exhibit deficits in fear inhibition and excessive generalization of fear, but little data exist on individuals at risk from these disorders. The present study examined the role of trait anxiety in the acquisition and generalization of fear in 126 healthy participants selected on the basis of their trait-anxiety scores. Measures of conditioning included fear-potentiated startle, skin conductance response and online risk ratings for the unconditioned stimulus. Contrary to our hypotheses, trait anxiety did not have any effect either on the acquisition or the generalization of fear. Our results suggest that these fear conditioning processes are not impaired in individuals at risk from anxiety. Copyright © 2012 Elsevier B.V. All rights reserved.

Extinction of specific stimulus-outcome (S-O) associations in Pavlovian learning with an extended CS procedure.

PubMed

Delamater, Andrew R; Schneider, Kevin; Derman, Rifka C

2017-07-01

Three experiments with male and female rats were conducted to examine the effects of Pavlovian extinction training on Pavlovian-to-instrumental transfer (PIT) in a task in which the unconditioned stimulus (US) was presented at an early time point within an extended conditioned stimulus (CS). Two instrumental responses were trained with different reinforcing outcomes (R1-O1, R2-O2) and then, independently, 2 stimuli were trained with those outcomes (S1-O1, S2-O2). One group then underwent an extinction treatment (S1-, S2-) and a second was merely exposed to the experimental contexts without any stimulus events. Finally, the effects of the 2 stimuli on instrumental responding were assessed in PIT tests. Across experiments we varied the number of Pavlovian training trials prior to extinction (8, 16, or 64 trials) and the length of time following extinction prior to test (i.e., 1 or 21 days, in a test for spontaneous recovery). We observed that outcome-specific PIT was reduced by extinction in all of our training conditions and that this extinction effect was durable, surviving a 3-week spontaneous recovery interval even though conditioned magazine approach spontaneously recovered over this interval. Although extinction reduced the magnitude of PIT, the temporal expression of PIT was mostly unaffected. We found these effects in both male and female rats, though in 1 study females were extinction-resistant. These data suggest that under the conditions studied here Pavlovian extinction may permanently weaken the ability of Pavlovian cues to retrieve a representation of their associated outcomes without impacting the temporal organization of responding. This suggests that different features of learning may be differentially sensitive to extinction. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Enhanced conditioned eyeblink response acquisition and proactive interference in anxiety vulnerable individuals

PubMed Central

Holloway, Jacqueline L.; Trivedi, Payal; Myers, Catherine E.; Servatius, Richard J.

2012-01-01

In classical conditioning, proactive interference may arise from experience with the conditioned stimulus (CS), the unconditional stimulus (US), or both, prior to their paired presentations. Interest in the application of proactive interference has extended to clinical populations as either a risk factor for disorders or as a secondary sign. Although the current literature is dense with comparisons of stimulus pre-exposure effects in animals, such comparisons are lacking in human subjects. As such, interpretation of proactive interference over studies as well as its generalization and utility in clinical research is limited. The present study was designed to assess eyeblink response acquisition after equal numbers of CS, US, and explicitly unpaired CS and US pre-exposures, as well as to evaluate how anxiety vulnerability might modulate proactive interference. In the current study, anxiety vulnerability was assessed using the State/Trait Anxiety Inventories as well as the adult and retrospective measures of behavioral inhibition (AMBI and RMBI, respectively). Participants were exposed to 1 of 4 possible pre-exposure contingencies: 30 CS, 30 US, 30 CS, and 30 US explicitly unpaired pre-exposures, or Context pre-exposure, immediately prior to standard delay training. Robust proactive interference was evident in all pre-exposure groups relative to Context pre-exposure, independent of anxiety classification, with CR acquisition attenuated at similar rates. In addition, trait anxious individuals were found to have enhanced overall acquisition as well as greater proactive interference relative to non-vulnerable individuals. The findings suggest that anxiety vulnerable individuals learn implicit associations faster, an effect which persists after the introduction of new stimulus contingencies. This effect is not due to enhanced sensitivity to the US. Such differences would have implications for the development of anxiety psychopathology within a learning framework. PMID:23162449

Enhanced conditioned eyeblink response acquisition and proactive interference in anxiety vulnerable individuals.

PubMed

Holloway, Jacqueline L; Trivedi, Payal; Myers, Catherine E; Servatius, Richard J

2012-01-01

In classical conditioning, proactive interference may arise from experience with the conditioned stimulus (CS), the unconditional stimulus (US), or both, prior to their paired presentations. Interest in the application of proactive interference has extended to clinical populations as either a risk factor for disorders or as a secondary sign. Although the current literature is dense with comparisons of stimulus pre-exposure effects in animals, such comparisons are lacking in human subjects. As such, interpretation of proactive interference over studies as well as its generalization and utility in clinical research is limited. The present study was designed to assess eyeblink response acquisition after equal numbers of CS, US, and explicitly unpaired CS and US pre-exposures, as well as to evaluate how anxiety vulnerability might modulate proactive interference. In the current study, anxiety vulnerability was assessed using the State/Trait Anxiety Inventories as well as the adult and retrospective measures of behavioral inhibition (AMBI and RMBI, respectively). Participants were exposed to 1 of 4 possible pre-exposure contingencies: 30 CS, 30 US, 30 CS, and 30 US explicitly unpaired pre-exposures, or Context pre-exposure, immediately prior to standard delay training. Robust proactive interference was evident in all pre-exposure groups relative to Context pre-exposure, independent of anxiety classification, with CR acquisition attenuated at similar rates. In addition, trait anxious individuals were found to have enhanced overall acquisition as well as greater proactive interference relative to non-vulnerable individuals. The findings suggest that anxiety vulnerable individuals learn implicit associations faster, an effect which persists after the introduction of new stimulus contingencies. This effect is not due to enhanced sensitivity to the US. Such differences would have implications for the development of anxiety psychopathology within a learning framework.

Why trace and delay conditioning are sometimes (but not always) hippocampal dependent: A computational model

PubMed Central

Moustafa, Ahmed A.; Wufong, Ella; Servatius, Richard J.; Pang, Kevin C. H.; Gluck, Mark A.; Myers, Catherine E.

2013-01-01

A recurrent-network model provides a unified account of the hippocampal region in mediating the representation of temporal information in classical eyeblink conditioning. Much empirical research is consistent with a general conclusion that delay conditioning (in which the conditioned stimulus CS and unconditioned stimulus US overlap and co-terminate) is independent of the hippocampal system, while trace conditioning (in which the CS terminates before US onset) depends on the hippocampus. However, recent studies show that, under some circumstances, delay conditioning can be hippocampal-dependent and trace conditioning can be spared following hippocampal lesion. Here, we present an extension of our prior trial-level models of hippocampal function and stimulus representation that can explain these findings within a unified framework. Specifically, the current model includes adaptive recurrent collateral connections that aid in the representation of intra-trial temporal information. With this model, as in our prior models, we argue that the hippocampus is not specialized for conditioned response timing, but rather is a general-purpose system that learns to predict the next state of all stimuli given the current state of variables encoded by activity in recurrent collaterals. As such, the model correctly predicts that hippocampal involvement in classical conditioning should be critical not only when there is an intervening trace interval, but also when there is a long delay between CS onset and US onset. Our model simulates empirical data from many variants of classical conditioning, including delay and trace paradigms in which the length of the CS, the inter-stimulus interval, or the trace interval is varied. Finally, we discuss model limitations, future directions, and several novel empirical predictions of this temporal processing model of hippocampal function and learning. PMID:23178699

Can experimentally induced positive affect attenuate generalization of fear of movement-related pain?

PubMed

Geschwind, Nicole; Meulders, Michel; Peters, Madelon L; Vlaeyen, Johan W S; Meulders, Ann

2015-03-01

Recent experimental data show that associative learning processes are involved not only in the acquisition but also in the spreading of pain-related fear. Clinical studies suggest involvement of positive affect in resilience against chronic pain. Surprisingly, the role of positive affect in associative learning in general, and in fear generalization in particular, has received scant attention. In a voluntary movement paradigm, in which one arm movement (reinforced conditioned stimulus [CS+]) was followed by a painful stimulus and another was not (unreinforced conditioned stimulus [CS-]), we tested generalization of fear inhibition in response to 5 novel but related generalization movements (GSs; within-subjects) after either a positive affect induction or a control exercise (Group = between-subjects) in healthy participants (N = 50). The GSs' similarity with the original CS+ movement and CS- movement varied. Fear learning was assessed via verbal ratings. Results indicated that there was an interaction between the increase in positive affect and the linear generalization gradient. Stronger increases in positive affect were associated with steeper generalization curves because of relatively lower pain-unconditioned stimulus expectancy and less fear of stimuli more similar to the CS-. There was no Group by Stimulus interaction. Results thus suggest that positive affect may enhance safety learning through promoting generalization from known safe movements to novel yet related movements. Improved safety learning may be a central mechanism underlying the association between positive affect and increased resilience against chronic pain. We investigated the extent to which positive affect influences the generalization (ie, spreading) of pain-related fear inhibition in response to situations similar to the original, pain-eliciting situation. Results suggest that increasing positive affect in the acute pain stage may limit the spreading of pain-related fear, thereby potentially inhibiting transition to chronic pain conditions. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Transfer of classical eyeblink conditioning with electrical stimulation of mPFC or tone as conditioned stimulus in guinea pigs.

PubMed

Yao, Juan; Wu, Guang-Yan; Liu, Guo-Long; Liu, Shu-Lei; Yang, Yi; Wu, Bing; Li, Xuan; Feng, Hua; Sui, Jian-Feng

2014-11-01

Learning with a stimulus from one sensory modality can facilitate subsequent learning with a new stimulus from a different sensory modality. To date, the characteristics and mechanism of this phenomenon named transfer effect still remain ambiguous. Our previous work showed that electrical stimulation of medial prefrontal cortex (mPFC) as a conditioned stimulus (CS) could successfully establish classical eyeblink conditioning (EBC). The present study aimed to (1) observe whether transfer of EBC learning would occur when CSs shift between central (mPFC electrical stimulation as a CS, mPFC-CS) and peripheral (tone as a CS, tone CS); (2) compare the difference in transfer effect between the two paradigms, delay EBC (DEBC) and trace EBC (TEBC). A total of 8 groups of guinea pigs were tested in the study, including 4 experimental groups and 4 control groups. Firstly, the experimental groups accepted central (or peripheral) CS paired with corneal airpuff unconditioned stimulus (US); then, CS shifted to the peripheral (or central) and paired with US. The control groups accepted corresponding central (or peripheral) CS and pseudo-paired with US, and then shifted CS from central (or peripheral) to peripheral (or central) and paired with US. The results showed that the acquisition rates of EBC were higher in experimental groups than in control groups after CS switching from central to peripheral or vice versa, and the CR acquisition rate was remarkably higher in DEBC than in TEBC in both transfer ways. The results indicate that EBC transfer can occur between learning established with mPFC-CS and tone CS. Memory of CS-US association for delay paradigm was less disturbed by the sudden switch of CS than for trace paradigm. This study provides new insight into neural mechanisms underlying conditioned reflex as well as the role of mPFC. Copyright © 2014 Elsevier B.V. All rights reserved.

Amphetamine-induced sensitization and reward uncertainty similarly enhance incentive salience for conditioned cues.

PubMed

Robinson, Mike J F; Anselme, Patrick; Suchomel, Kristen; Berridge, Kent C

2015-08-01

Amphetamine and stress can sensitize mesolimbic dopamine-related systems. In Pavlovian autoshaping, repeated exposure to uncertainty of reward prediction can enhance motivated sign-tracking or attraction to a discrete reward-predicting cue (lever-conditioned stimulus; CS+), as well as produce cross-sensitization to amphetamine. However, it remains unknown how amphetamine sensitization or repeated restraint stress interact with uncertainty in controlling CS+ incentive salience attribution reflected in sign-tracking. Here rats were tested in 3 successive phases. First, different groups underwent either induction of amphetamine sensitization or repeated restraint stress, or else were not sensitized or stressed as control groups (either saline injections only, or no stress or injection at all). All next received Pavlovian autoshaping training under either certainty conditions (100% CS-UCS association) or uncertainty conditions (50% CS-UCS association and uncertain reward magnitude). During training, rats were assessed for sign-tracking to the CS+ lever versus goal-tracking to the sucrose dish. Finally, all groups were tested for psychomotor sensitization of locomotion revealed by an amphetamine challenge. Our results confirm that reward uncertainty enhanced sign-tracking attraction toward the predictive CS+ lever, at the expense of goal-tracking. We also reported that amphetamine sensitization promoted sign-tracking even in rats trained under CS-UCS certainty conditions, raising them to sign-tracking levels equivalent to the uncertainty group. Combining amphetamine sensitization and uncertainty conditions did not add together to elevate sign-tracking further above the relatively high levels induced by either manipulation alone. In contrast, repeated restraint stress enhanced subsequent amphetamine-elicited locomotion, but did not enhance CS+ attraction. (c) 2015 APA, all rights reserved).

Causal Superlearning Arising from Interactions Among Cues

PubMed Central

Urushihara, Kouji; Miller, Ralph R.

2017-01-01

Superconditioning refers to supernormal responding to a conditioned stimulus (CS) that sometimes occurs in classical conditioning when the CS is paired with an unconditioned stimulus (US) in the presence of a conditioned inhibitor for that US. In the present research, we conducted four experiments to investigate causal superlearning, a phenomenon in human causal learning analogous to superconditioning. Experiment 1 demonstrated superlearning relative to appropriate control conditions. Experiment 2 showed that superlearning wanes when the number of cues used in an experiment is relatively large. Experiment 3 determined that even when relatively many cues are used, superlearning can be observed provided testing is conducted immediately after training, which is problematic for explanations by most contemporary learning theories. Experiment 4 found that ratings of a superlearning cue are weaker than those to the training excitor which gives basis to the conditioned inhibitor-like causal preventor used during causal superlearning training. This is inconsistent with the prediction by propositional reasoning accounts of causal cue competition, but is readily explained by associative learning models. In sum, the current experiments revealed some weaknesses of both the associative and propositional reasoning models with respect to causal superlearning. PMID:28383940

The "where is it?" reflex: autoshaping the orienting response.

PubMed

Buzsáki, G

1982-05-01

The goal of this review is to compare two divergent lines of research on signal-centered behavior: the orienting reflex (OR) and autoshaping. A review of conditioning experiments in animals and humans suggests that the novelty hypothesis of the OR is no longer tenable. Only stimuli that represent biological "relevance" elicit ORs. A stimulus may be relevant a priori (i.e., unconditioned) or as a result of conditioning. Exposure to a conditioned stimulus (CS) that predicts a positive reinforcer causes the animal to orient to it throughout conditioning. Within the CS-US interval, the initial CS-directed orienting response is followed by US-directed tendencies. Experimental evidence is shown that the development and maintenance of the conditioned OR occur in a similar fashion both in response-independent (classical) and response-dependent (instrumental) paradigms. It is proposed that the conditioned OR and the signal-directed autoshaped response are identical. Signals predicting aversive events repel the subject from the source of the CS. It is suggested that the function of the CS is not only to signal the probability of US occurrence, but also to serve as a spatial cue to guide the animal in the environment.

Is evaluative conditioning really uncontrollable? A comparative test of three emotion-focused strategies to prevent the acquisition of conditioned preferences.

PubMed

Gawronski, Bertram; Mitchell, Derek G V; Balas, Robert

2015-10-01

Evaluative conditioning (EC) is defined as the change in the evaluation of a conditioned stimulus (CS) because of its pairing with a valenced unconditioned stimulus (US). Counter to views that EC is the product of automatic learning processes, recent research has revealed various characteristics of nonautomatic processing in EC. The current research investigated the controllability of EC by testing the effectiveness of 3 emotion-focused strategies in preventing the acquisition of conditioned preferences: (a) suppression of emotional reactions to the US, (b) reappraisal of the valence of the US, and (c) facial blocking of emotional responses. Although all 3 strategies reduced EC effects on self-reported evaluations by impairing recollective memory for CS-US pairings, they were ineffective in reducing EC effects on an evaluative priming measure. Regardless of the measure, effective control did not depend on the level of arousal elicited by the US. The results suggest that the 3 strategies can influence deliberate CS evaluations through memory-related processes, but they are ineffective in reducing EC effects on spontaneous evaluative responses. Implications for mental process theories of EC are discussed. (c) 2015 APA, all rights reserved).

The role of working memory and declarative memory in trace conditioning

PubMed Central

Connor, David A.; Gould, Thomas J.

2017-01-01

Translational assays of cognition that are similarly implemented in both lower and higher-order species, such as rodents and primates, provide a means to reconcile preclinical modeling of psychiatric neuropathology and clinical research. To this end, Pavlovian conditioning has provided a useful tool for investigating cognitive processes in both lab animal models and humans. This review focuses on trace conditioning, a form of Pavlovian conditioning typified by the insertion of a temporal gap (i.e., trace interval) between presentations of a conditioned stimulus (CS) and an unconditioned stimulus (US). This review aims to discuss pre-clinical and clinical work investigating the mnemonic processes recruited for trace conditioning. Much work suggests that trace conditioning involves unique neurocognitive mechanisms to facilitate formation of trace memories in contrast to standard Pavlovian conditioning. For example, the hippocampus and prefrontal cortex (PFC) appear to play critical roles in trace conditioning. Moreover, cognitive mechanistic accounts in human studies suggest that working memory and declarative memory processes are engaged to facilitate formation of trace memories. The aim of this review is to integrate cognitive and neurobiological accounts of trace conditioning from preclinical and clinical studies to examine involvement of working and declarative memory. PMID:27422017

Repeated nicotine exposure enhances reward-related learning in the rat.

PubMed

Olausson, Peter; Jentsch, J David; Taylor, Jane R

2003-07-01

Repeated exposure to addictive drugs causes neuroadaptive changes in cortico-limbic-striatal circuits that may underlie alterations in incentive-motivational processes and reward-related learning. Such drug-induced alterations may be relevant to drug addiction because enhanced incentive motivation and increased control over behavior by drug-associated stimuli may contribute to aspects of compulsive drug-seeking and drug-taking behaviors. This study investigated the consequences of repeated nicotine treatment on the acquisition and performance of Pavlovian discriminative approach behavior, a measure of reward-related learning, in male rats. Water-restricted rats were trained to associate a compound conditioned stimulus (tone+light) with the availability of water (the unconditioned stimulus) in 15 consecutive daily sessions. In separate experiments, rats were repeatedly treated with nicotine (0.35 mg/kg, s.c.) either (1) prior to the onset of training, (2) after each daily training session was completed (ie postsession injections), or (3) received nicotine both before the onset of training as well as after each daily training session. In this study, all nicotine treatment schedules increased Pavlovian discriminative approach behavior and, thus, prior repeated exposure to nicotine, repeated postsession nicotine injections, or both, facilitated reward-related learning.

Associative Processes in Early Olfactory Preference Acquisition

PubMed Central

Sullivan, Regina M.; Wilson, Donald A.; Leon, Michael

2007-01-01

Acquisition of behavioral conditioned responding and learned odor preferences during olfactory classical conditioning in rat pups requires forward or simultaneous pairings of the conditioned stimulus (CS) and the unconditioned stimulus (US). Other temporal relationships between the CS and US do not usually result in learning. The present study examined the influence of this CS-US relationship upon the neural olfactory bulb modifications that are acquired during early classical conditioning. Wistar rat pups were trained from Postnatal Days (PN) 1-18 with either forward (odor overlapping temporally with reinforcing stroking) or backward (stroking followed by odor) CS-US pairings. On PN 19, pups received either a behavioral odor preference test to the odor CS or an injection of 14C 2-DG and exposure to the odor CS, or olfactory bulb single unit responses were recorded in response to exposure to the odor CS. Only pups that received forward presentations of the CS and US exhibited both a preference for the CS and modified olfactory bulb neural responses to the CS. These results, then, suggest that the modified olfactory bulb neural responses acquired during classical conditioning are guided by the same temporal constraints as those which govern the acquisition of behavioral conditioned responses. PMID:17572798

Biologically based neural circuit modelling for the study of fear learning and extinction

NASA Astrophysics Data System (ADS)

Nair, Satish S.; Paré, Denis; Vicentic, Aleksandra

2016-11-01

The neuronal systems that promote protective defensive behaviours have been studied extensively using Pavlovian conditioning. In this paradigm, an initially neutral-conditioned stimulus is paired with an aversive unconditioned stimulus leading the subjects to display behavioural signs of fear. Decades of research into the neural bases of this simple behavioural paradigm uncovered that the amygdala, a complex structure comprised of several interconnected nuclei, is an essential part of the neural circuits required for the acquisition, consolidation and expression of fear memory. However, emerging evidence from the confluence of electrophysiological, tract tracing, imaging, molecular, optogenetic and chemogenetic methodologies, reveals that fear learning is mediated by multiple connections between several amygdala nuclei and their distributed targets, dynamical changes in plasticity in local circuit elements as well as neuromodulatory mechanisms that promote synaptic plasticity. To uncover these complex relations and analyse multi-modal data sets acquired from these studies, we argue that biologically realistic computational modelling, in conjunction with experiments, offers an opportunity to advance our understanding of the neural circuit mechanisms of fear learning and to address how their dysfunction may lead to maladaptive fear responses in mental disorders.

Re-evaluation of the reward comparison hypothesis for alcohol abuse.

PubMed

He, Alan Bo-Han; Chang, Yu-Chieh; Meng, Anna Wan Yun; Huang, Andrew Chih Wei

2017-08-14

This study examined whether various doses of ethanol induced reward or aversion and then evaluated Grigson's reward comparison hypothesis (1997). Rats were given a 0.1% saccharin solution (conditioned stimulus 1 [CS1]) 15min prior to administration of a 0, 0.05, 0.125, 0.20, 0.35, or 0.50g/kg dose of ethanol (unconditioned stimulus [US]). The rats were then exposed to a paired compartment (CS2) for 30min. The low dose of 0.05g/kg ethanol did not induce conditioned suppression (i.e., conditioned taste aversion [CTA]) or conditioned place preference (CPP). The dose of 0.125g/kg ethanol induced CPP but not CTA. High doses of ethanol, including 0.35g/kg and 0.50g/kg, produced CTA but not CPP. The middle dose of 0.20g/kg ethanol simultaneously induced CTA and CPP. As a result, the reward comparison hypothesis cannot explain the present finding that the middle dose of ethanol induced CTA and CPP. Meanwhile, the high doses of ethanol induced motivationally aversive CTA but not rewarding CPP. The reward comparison hypothesis should be updated further. Copyright © 2017 Elsevier B.V. All rights reserved.

Muscarinic ACh Receptors Contribute to Aversive Olfactory Learning in Drosophila.

PubMed

Silva, Bryon; Molina-Fernández, Claudia; Ugalde, María Beatriz; Tognarelli, Eduardo I; Angel, Cristian; Campusano, Jorge M

2015-01-01

The most studied form of associative learning in Drosophila consists in pairing an odorant, the conditioned stimulus (CS), with an unconditioned stimulus (US). The timely arrival of the CS and US information to a specific Drosophila brain association region, the mushroom bodies (MB), can induce new olfactory memories. Thus, the MB is considered a coincidence detector. It has been shown that olfactory information is conveyed to the MB through cholinergic inputs that activate acetylcholine (ACh) receptors, while the US is encoded by biogenic amine (BA) systems. In recent years, we have advanced our understanding on the specific neural BA pathways and receptors involved in olfactory learning and memory. However, little information exists on the contribution of cholinergic receptors to this process. Here we evaluate for the first time the proposition that, as in mammals, muscarinic ACh receptors (mAChRs) contribute to memory formation in Drosophila. Our results show that pharmacological and genetic blockade of mAChRs in MB disrupts olfactory aversive memory in larvae. This effect is not explained by an alteration in the ability of animals to respond to odorants or to execute motor programs. These results show that mAChRs in MB contribute to generating olfactory memories in Drosophila.

Is Perruchet's dissociation between eyeblink conditioned responding and outcome expectancy evidence for two learning systems?

PubMed

Weidemann, Gabrielle; Tangen, Jason M; Lovibond, Peter F; Mitchell, Christopher J

2009-04-01

P. Perruchet (1985b) showed a double dissociation of conditioned responses (CRs) and expectancy for an airpuff unconditioned stimulus (US) in a 50% partial reinforcement schedule in human eyeblink conditioning. In the Perruchet effect, participants show an increase in CRs and a concurrent decrease in expectancy for the airpuff across runs of reinforced trials; conversely, participants show a decrease in CRs and a concurrent increase in expectancy for the airpuff across runs of nonreinforced trials. Three eyeblink conditioning experiments investigated whether the linear trend in eyeblink CRs in the Perruchet effect is a result of changes in associative strength of the conditioned stimulus (CS), US sensitization, or learning the precise timing of the US. Experiments 1 and 2 demonstrated that the linear trend in eyeblink CRs is not the result of US sensitization. Experiment 3 showed that the linear trend in eyeblink CRs is present with both a fixed and a variable CS-US interval and so is not the result of learning the precise timing of the US. The results are difficult to reconcile with a single learning process model of associative learning in which expectancy mediates CRs. Copyright (c) 2009 APA, all rights reserved.

Lesions of the lateral habenula facilitate active avoidance learning and threat extinction.

PubMed

Song, Mihee; Jo, Yong Sang; Lee, Yeon-Kyung; Choi, June-Seek

2017-02-01

The lateral habenula (LHb) is an epithalamic brain structure that provides strong projections to midbrain monoaminergic systems that are involved in motivation, emotion, and reinforcement learning. LHb neurons are known to convey information about aversive outcomes and negative prediction errors, suggesting a role in learning from aversive events. To test this idea, we examined the effects of electrolytic lesions of the LHb on signaled two-way active avoidance learning in which rats were trained to avoid an unconditioned stimulus (US) by taking a proactive shuttling response to an auditory conditioned stimulus (CS). The lesioned animals learned the avoidance response significantly faster than the control groups. In a separate experiment, we also investigated whether the LHb contributes to Pavlovian threat (fear) conditioning and extinction. Following paired presentations of the CS and the US, LHb-lesioned animals showed normal acquisition of conditioned response (CR) measured with freezing. However, extinction of the CR in the subsequent CS-only session was significantly faster. The enhanced performance in avoidance learning and in threat extinction jointly suggests that the LHb normally plays an inhibitory role in learning driven by absence of aversive outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.

Contextual fear conditioning differs for infant, adolescent, and adult rats

PubMed Central

Esmorís-Arranz, Francisco J.; Méndez, Cástor; Spear, Norman E.

2009-01-01

Contextual fear conditioning was tested in infant, adolescent, and adult rats in terms of Pavlovian conditioned suppression. When a discrete auditory conditioned stimulus (CS) was paired with footshock (unconditioned stimulus, US) within the largely olfactory context, infants and adolescents conditioned to the context with substantial effectiveness but adult rats did not. When unpaired presentations of the CS and US occurred within the context, contextual fear conditioning was strong for adults, weak for infants, but about as strong for adolescents as when pairings of CS and US occurred in the context. Nonreinforced presentations of either the CS or context markedly reduced contextual fear conditioning in infants, but, in adolescents, CS extinction had no effect on contextual fear conditioning, although context extinction significantly reduced it. Neither CS extinction nor context extinction affected responding to the CS-context compound in infants, suggesting striking discrimination between the compound and its components. Female adolescents showed the same lack of effect of component extinction on response to the compound as infants, but CS extinction reduced responding to the compound in adolescent males, a sex difference seen also in adults. Theoretical implications are discussed for the development of perceptual-cognitive processing and hippocampus role. PMID:18343048

Fearing shades of grey: individual differences in fear responding towards generalisation stimuli.

PubMed

Arnaudova, Inna; Krypotos, Angelos-Miltiadis; Effting, Marieke; Kindt, Merel; Beckers, Tom

2017-09-01

Individual differences in fear generalisation have been proposed to play a role in the aetiology and/or maintenance of anxiety disorders, but few data are available to directly support that claim. The research that is available has focused mostly on generalisation of peripheral and central physiological fear responses. Far less is known about the generalisation of avoidance, the behavioural component of fear. In two experiments, we evaluated how neuroticism, a known vulnerability factor for anxiety, modulates an array of fear responses, including avoidance tendencies, towards generalisation stimuli (GS). Participants underwent differential fear conditioning, in which one conditioned stimulus (CS+) was repeatedly paired with an aversive outcome (shock; unconditioned stimulus, US), whereas another was not (CS-). Fear generalisation was observed across measures in Experiment 1 (US expectancy and evaluative ratings) and Experiment 2 (US expectancy, evaluative ratings, skin conductance, startle responses, safety behaviours), with overall highest responding to the CS+, lowest to the CS- and intermediate responding to the GSs. Neuroticism had very little impact on fear generalisation (but did affect GS recognition rates in Experiment 1), in line with the idea that fear generalisation is largely an adaptive process.

Pharmacogenetic reactivation of the original engram evokes an extinguished fear memory.

PubMed

Yoshii, Takahiro; Hosokawa, Hiroshi; Matsuo, Naoki

2017-02-01

Fear memory extinction has several characteristic behavioral features, such as spontaneous recovery, renewal, and reinstatement, suggesting that extinction training does not erase the original association between the conditioned stimulus (CS) and the unconditioned stimulus (US). However, it is unclear whether reactivation of the original physical record of memory (i.e., memory trace) is sufficient to produce conditioned fear response after extinction. Here, we performed pharmacogenetic neuronal activation using transgenic mice expressing hM3Dq DREADD (designer receptor exclusively activated by designer drug) under the control of the activity-dependent c-fos gene promoter. Neuronal ensembles activated during fear-conditioned learning were tagged with hM3Dq and subsequently reactivated after extinction training. The mice exhibited significant freezing, even when the fear memory was no longer triggered by external CS, indicating that the artificial reactivation of a specific neuronal ensemble was sufficient to evoke the extinguished fear response. This freezing was not observed in non-fear-conditioned mice expressing hM3dq in the same brain areas. These results directly demonstrated that at least part of the original fear memory trace remains after extinction, and such residual plasticity might reflect the persistent memory. Copyright © 2016 Elsevier Ltd. All rights reserved.

Updating of aversive memories after temporal error detection is differentially modulated by mTOR across development

PubMed Central

Tallot, Lucille; Diaz-Mataix, Lorenzo; Perry, Rosemarie E.; Wood, Kira; LeDoux, Joseph E.; Mouly, Anne-Marie; Sullivan, Regina M.; Doyère, Valérie

2017-01-01

The updating of a memory is triggered whenever it is reactivated and a mismatch from what is expected (i.e., prediction error) is detected, a process that can be unraveled through the memory's sensitivity to protein synthesis inhibitors (i.e., reconsolidation). As noted in previous studies, in Pavlovian threat/aversive conditioning in adult rats, prediction error detection and its associated protein synthesis-dependent reconsolidation can be triggered by reactivating the memory with the conditioned stimulus (CS), but without the unconditioned stimulus (US), or by presenting a CS–US pairing with a different CS–US interval than during the initial learning. Whether similar mechanisms underlie memory updating in the young is not known. Using similar paradigms with rapamycin (an mTORC1 inhibitor), we show that preweaning rats (PN18–20) do form a long-term memory of the CS–US interval, and detect a 10-sec versus 30-sec temporal prediction error. However, the resulting updating/reconsolidation processes become adult-like after adolescence (PN30–40). Our results thus show that while temporal prediction error detection exists in preweaning rats, specific infant-type mechanisms are at play for associative learning and memory. PMID:28202715

CS-duration and partial-reinforcement effects counteract overshadowing in select situations

PubMed Central

Urushihara, Kouji; Miller, Ralph R.

2008-01-01

Two experiments used rats in a conditioned lick suppression preparation to investigate how the conditioned stimulus (CS)-duration and partial-reinforcement effects (i.e., weakened responding due to conditioning with a CS of longer duration and presenting nonreinforced CSs intermingled with CS-unconditioned stimulus [US] pairings, respectively) interact with overshadowing. Experiment 1 found that when overshadowing treatment was combined with either extended CS duration or partial reinforcement, the response deficit was weaker than when either of these three treatments was administered alone. In Experiment 2, the generality of the findings in Experiment 1 was investigated by replicating it with various US-US intervals. This time counteraction was observed only when both the absolute duration of total CS exposure and the US-US interval were short. The results support neither the view that the ratio between the total CS exposure and total time in the context determines the CS-duration and the partial-reinforcement effects nor the view that these two effects arise from a loss of effectiveness of the excitatory CS-US association during CS-alone exposures in partial reinforcement or early periods of CS exposure with long CSs. PMID:18047218

Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies.

PubMed

Shi, C; Davis, M

1999-01-01

It is well established that the basolateral amygdala is critically involved in the association between an unconditioned stimulus (US), such as a foot shock, and a conditioned stimulus (CS), such as a light, during classic fear conditioning. However, little is known about how the US (pain) inputs are relayed to the basolateral amygdala. The present studies were designed to define potential US pathways to the amygdala using lesion methods. Electrolytic lesions before or after training were placed in caudal granular/dysgranular insular cortex (IC) alone or in conjunction with the posterior intralaminar nuclei of the thalamus (PoT/PIL), and the effects on fear conditioning were examined. Pretraining lesions of both IC and PoT/PIL, but not lesions of IC alone, blocked the acquisition of fear-potentiated startle. However, post-training combined lesions of IC and PoT/PIL did not prevent expression of conditioned fear. Given that previous studies have shown that lesions of PoT/PIL alone had no effect on acquisition of conditioned fear, these results suggest that two parallel cortical (insula-amygdala) and subcortical (PoT/PIL-amygdala) pathways are involved in relaying shock information to the basolateral amygdala during fear conditioning.

Hippocampal theta activity is selectively associated with contingency detection but not discrimination in rabbit discrimination-reversal eyeblink conditioning.

PubMed

Nokia, Miriam S; Wikgren, Jan

2010-04-01

The relative power of the hippocampal theta-band ( approximately 6 Hz) activity (theta ratio) is thought to reflect a distinct neural state and has been shown to affect learning rate in classical eyeblink conditioning in rabbits. We sought to determine if the theta ratio is mostly related to the detection of the contingency between the stimuli used in conditioning or also to the learning of more complex inhibitory associations when a highly demanding delay discrimination-reversal eyeblink conditioning paradigm is used. A high hippocampal theta ratio was not only associated with a fast increase in conditioned responding in general but also correlated with slow emergence of discriminative responding due to sustained responding to the conditioned stimulus not paired with an unconditioned stimulus. The results indicate that the neural state reflected by the hippocampal theta ratio is specifically linked to forming associations between stimuli rather than to the learning of inhibitory associations needed for successful discrimination. This is in line with the view that the hippocampus is responsible for contingency detection in the early phase of learning in eyeblink conditioning. (c) 2009 Wiley-Liss, Inc.

Individual Differences in Anticipatory Somatosensory Cortex Activity for Shock is Positively Related with Trait Anxiety and Multisensory Integration

PubMed Central

Greening, Steven G.; Lee, Tae-Ho; Mather, Mara

2016-01-01

Anxiety is associated with an exaggerated expectancy of harm, including overestimation of how likely a conditioned stimulus (CS+) predicts a harmful unconditioned stimulus (US). In the current study we tested whether anxiety-associated expectancy of harm increases primary sensory cortex (S1) activity on non-reinforced (i.e., no shock) CS+ trials. Twenty healthy volunteers completed a differential-tone trace conditioning task while undergoing fMRI, with shock delivered to the left hand. We found a positive correlation between trait anxiety and activity in right, but not left, S1 during CS+ versus CS− conditions. Right S1 activity also correlated with individual differences in both primary auditory cortices (A1) and amygdala activity. Lastly, a seed-based functional connectivity analysis demonstrated that trial-wise S1 activity was positively correlated with regions of dorsolateral prefrontal cortex (dlPFC), suggesting that higher-order cognitive processes contribute to the anticipatory sensory reactivity. Our findings indicate that individual differences in trait anxiety relate to anticipatory reactivity for the US during associative learning. This anticipatory reactivity is also integrated along with emotion-related sensory signals into a brain network implicated in fear-conditioned responding. PMID:26751483

Individual Differences in Anticipatory Somatosensory Cortex Activity for Shock is Positively Related with Trait Anxiety and Multisensory Integration.

PubMed

Greening, Steven G; Lee, Tae-Ho; Mather, Mara

2016-01-06

Anxiety is associated with an exaggerated expectancy of harm, including overestimation of how likely a conditioned stimulus (CS+) predicts a harmful unconditioned stimulus (US). In the current study we tested whether anxiety-associated expectancy of harm increases primary sensory cortex (S1) activity on non-reinforced (i.e., no shock) CS+ trials. Twenty healthy volunteers completed a differential-tone trace conditioning task while undergoing fMRI, with shock delivered to the left hand. We found a positive correlation between trait anxiety and activity in right, but not left, S1 during CS+ versus CS- conditions. Right S1 activity also correlated with individual differences in both primary auditory cortices (A1) and amygdala activity. Lastly, a seed-based functional connectivity analysis demonstrated that trial-wise S1 activity was positively correlated with regions of dorsolateral prefrontal cortex (dlPFC), suggesting that higher-order cognitive processes contribute to the anticipatory sensory reactivity. Our findings indicate that individual differences in trait anxiety relate to anticipatory reactivity for the US during associative learning. This anticipatory reactivity is also integrated along with emotion-related sensory signals into a brain network implicated in fear-conditioned responding.

Response rate and reinforcement rate in Pavlovian conditioning.

PubMed

Harris, Justin A; Carpenter, Joanne S

2011-10-01

Four experiments used delay conditioning of magazine approach in rats to investigate the relationship between the rate of responding, R, to a conditioned stimulus (CS) and the rate, r, at which the CS is reinforced with the unconditioned stimulus (US). Rats were concurrently trained with four variable-duration CSs with different rs, either as a result of differences in the mean CS-US interval or in the proportion of CS presentations that ended with the US. In each case, R was systematically related to r, and the relationship was very accurately characterized by a hyperbolic function, R = Ar/(r +c). Accordingly, the reciprocal of these two variables-response interval, I (= 1/R), and CS-US interval, i (= 1/r) - were related by a simple affine (straight line) transformation, I = mi+b. This latter relationship shows that each increment in the time that the rats had to wait for food produced a linear increment in the time they waited between magazine entries. We discuss the close agreement between our findings and the Matching Law (Herrnstein, 1970) and consider their implications for both associative theories (e.g., Rescorla & Wagner, 1972) and nonassociative theories (Gallistel & Gibbon, 2000) of conditioning. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

The "where is it?" reflex: autoshaping the orienting response.

PubMed Central

Buzsáki, G

1982-01-01

The goal of this review is to compare two divergent lines of research on signal-centered behavior: the orienting reflex (OR) and autoshaping. A review of conditioning experiments in animals and humans suggests that the novelty hypothesis of the OR is no longer tenable. Only stimuli that represent biological "relevance" elicit ORs. A stimulus may be relevant a priori (i.e., unconditioned) or as a result of conditioning. Exposure to a conditioned stimulus (CS) that predicts a positive reinforcer causes the animal to orient to it throughout conditioning. Within the CS-US interval, the initial CS-directed orienting response is followed by US-directed tendencies. Experimental evidence is shown that the development and maintenance of the conditioned OR occur in a similar fashion both in response-independent (classical) and response-dependent (instrumental) paradigms. It is proposed that the conditioned OR and the signal-directed autoshaped response are identical. Signals predicting aversive events repel the subject from the source of the CS. It is suggested that the function of the CS is not only to signal the probability of US occurrence, but also to serve as a spatial cue to guide the animal in the environment. PMID:7097153

Autoshaping and automaintenance: a neural-network approach.

PubMed

Burgos, José E

2007-07-01

This article presents an interpretation of autoshaping, and positive and negative automaintenance, based on a neural-network model. The model makes no distinction between operant and respondent learning mechanisms, and takes into account knowledge of hippocampal and dopaminergic systems. Four simulations were run, each one using an A-B-A design and four instances of feedfoward architectures. In A, networks received a positive contingency between inputs that simulated a conditioned stimulus (CS) and an input that simulated an unconditioned stimulus (US). Responding was simulated as an output activation that was neither elicited by nor required for the US. B was an omission-training procedure. Response directedness was defined as sensory feedback from responding, simulated as a dependence of other inputs on responding. In Simulation 1, the phenomena were simulated with a fully connected architecture and maximally intense response feedback. The other simulations used a partially connected architecture without competition between CS and response feedback. In Simulation 2, a maximally intense feedback resulted in substantial autoshaping and automaintenance. In Simulation 3, eliminating response feedback interfered substantially with autoshaping and automaintenance. In Simulation 4, intermediate autoshaping and automaintenance resulted from an intermediate response feedback. Implications for the operant-respondent distinction and the behavior-neuroscience relation are discussed.

Parallel learning in an autoshaping paradigm.

PubMed

Naeem, Maliha; White, Norman M

2016-08-01

In an autoshaping task, a single conditioned stimulus (CS; lever insertion) was repeatedly followed by the delivery of an unconditioned stimulus (US; food pellet into an adjacent food magazine) irrespective of the rats' behavior. After repeated training trials, some rats responded to the onset of the CS by approaching and pressing the lever (sign-trackers). Lesions of dorsolateral striatum almost completely eliminated responding to the lever CS while facilitating responding to the food magazine (US). Lesions of the dorsomedial striatum attenuated but did not eliminate responding to the lever CS. Lesions of the basolateral or central nucleus of the amygdala had no significant effects on sign-tracking, but combined lesions of the 2 structures impaired sign-tracking by significantly increasing latency to the first lever press without affecting the number of lever presses. Lesions of the dorsal hippocampus had no effect on any of the behavioral measures. The findings suggest that sign-tracking with a single lever insertion as the CS may consist of 2 separate behaviors learned in parallel: An amygdala-mediated conditioned orienting and approach response and a dorsal striatum-mediated instrumental response. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Autoshaping and Automaintenance: A Neural-Network Approach

PubMed Central

Burgos, José E

2007-01-01

This article presents an interpretation of autoshaping, and positive and negative automaintenance, based on a neural-network model. The model makes no distinction between operant and respondent learning mechanisms, and takes into account knowledge of hippocampal and dopaminergic systems. Four simulations were run, each one using an A-B-A design and four instances of feedfoward architectures. In A, networks received a positive contingency between inputs that simulated a conditioned stimulus (CS) and an input that simulated an unconditioned stimulus (US). Responding was simulated as an output activation that was neither elicited by nor required for the US. B was an omission-training procedure. Response directedness was defined as sensory feedback from responding, simulated as a dependence of other inputs on responding. In Simulation 1, the phenomena were simulated with a fully connected architecture and maximally intense response feedback. The other simulations used a partially connected architecture without competition between CS and response feedback. In Simulation 2, a maximally intense feedback resulted in substantial autoshaping and automaintenance. In Simulation 3, eliminating response feedback interfered substantially with autoshaping and automaintenance. In Simulation 4, intermediate autoshaping and automaintenance resulted from an intermediate response feedback. Implications for the operant–respondent distinction and the behavior–neuroscience relation are discussed. PMID:17725055

Lmo4 in the Basolateral Complex of the Amygdala Modulates Fear Learning

PubMed Central

Maiya, Rajani; Kharazia, Viktor; Lasek, Amy W.; Heberlein, Ulrike

2012-01-01

Pavlovian fear conditioning is an associative learning paradigm in which mice learn to associate a neutral conditioned stimulus with an aversive unconditioned stimulus. In this study, we demonstrate a novel role for the transcriptional regulator Lmo4 in fear learning. LMO4 is predominantly expressed in pyramidal projection neurons of the basolateral complex of the amygdala (BLC). Mice heterozygous for a genetrap insertion in the Lmo4 locus (Lmo4gt/+), which express 50% less Lmo4 than their wild type (WT) counterparts display enhanced freezing to both the context and the cue in which they received the aversive stimulus. Small-hairpin RNA-mediated knockdown of Lmo4 in the BLC, but not the dentate gyrus region of the hippocampus recapitulated this enhanced conditioning phenotype, suggesting an adult- and brain region-specific role for Lmo4 in fear learning. Immunohistochemical analyses revealed an increase in the number of c-Fos positive puncta in the BLC of Lmo4gt/+ mice in comparison to their WT counterparts after fear conditioning. Lastly, we measured anxiety-like behavior in Lmo4gt/+ mice and in mice with BLC-specific downregulation of Lmo4 using the elevated plus maze, open field, and light/dark box tests. Global or BLC-specific knockdown of Lmo4 did not significantly affect anxiety-like behavior. These results suggest a selective role for LMO4 in the BLC in modulating learned but not unlearned fear. PMID:22509321

Changes in complex spike activity during classical conditioning

PubMed Central

Rasmussen, Anders; Jirenhed, Dan-Anders; Wetmore, Daniel Z.; Hesslow, Germund

2014-01-01

The cerebellar cortex is necessary for adaptively timed conditioned responses (CRs) in eyeblink conditioning. During conditioning, Purkinje cells acquire pause responses or “Purkinje cell CRs” to the conditioned stimuli (CS), resulting in disinhibition of the cerebellar nuclei (CN), allowing them to activate motor nuclei that control eyeblinks. This disinhibition also causes inhibition of the inferior olive (IO), via the nucleo-olivary pathway (N-O). Activation of the IO, which relays the unconditional stimulus (US) to the cortex, elicits characteristic complex spikes in Purkinje cells. Although Purkinje cell activity, as well as stimulation of the CN, is known to influence IO activity, much remains to be learned about the way that learned changes in simple spike firing affects the IO. In the present study, we analyzed changes in simple and complex spike firing, in extracellular Purkinje cell records, from the C3 zone, in decerebrate ferrets undergoing training in a conditioning paradigm. In agreement with the N-O feedback hypothesis, acquisition resulted in a gradual decrease in complex spike activity during the conditioned stimulus, with a delay that is consistent with the long N-O latency. Also supporting the feedback hypothesis, training with a short interstimulus interval (ISI), which does not lead to acquisition of a Purkinje cell CR, did not cause a suppression of complex spike activity. In contrast, observations that extinction did not lead to a recovery in complex spike activity and the irregular patterns of simple and complex spike activity after the conditioned stimulus are less conclusive. PMID:25140129

Central cannabinoid receptors modulate acquisition of eyeblink conditioning

PubMed Central

Steinmetz, Adam B.; Freeman, John H.

2010-01-01

Delay eyeblink conditioning is established by paired presentations of a conditioned stimulus (CS) such as a tone or light, and an unconditioned stimulus (US) that elicits the blink reflex. Conditioned stimulus information is projected from the basilar pontine nuclei to the cerebellar interpositus nucleus and cortex. The cerebellar cortex, particularly the molecular layer, contains a high density of cannabinoid receptors (CB1R). The CB1Rs are located on the axon terminals of parallel fibers, stellate cells, and basket cells where they inhibit neurotransmitter release. The present study examined the effects of a CB1R agonist WIN55,212-2 and antagonist SR141716A on the acquisition of delay eyeblink conditioning in rats. Rats were given subcutaneous administration of 1, 2, or 3 mg/kg of WIN55,212-2 or 1, 3, or 5 mg/kg of SR141716A before each day of acquisition training (10 sessions). Dose-dependent impairments in acquisition were found for WIN55,212-2 and SR141716A, with no effects on spontaneous or nonassociative blinking. However, the magnitude of impairment was greater for WIN55,212-2 than SR141716A. Dose-dependent impairments in conditioned blink response (CR) amplitude and timing were found with WIN55,212-2 but not with SR141716A. The findings support the hypothesis that CB1Rs in the cerebellar cortex play an important role in plasticity mechanisms underlying eyeblink conditioning. PMID:21030483

Pre-attentive, context-specific representation of fear memory in the auditory cortex of rat.

PubMed

Funamizu, Akihiro; Kanzaki, Ryohei; Takahashi, Hirokazu

2013-01-01

Neural representation in the auditory cortex is rapidly modulated by both top-down attention and bottom-up stimulus properties, in order to improve perception in a given context. Learning-induced, pre-attentive, map plasticity has been also studied in the anesthetized cortex; however, little attention has been paid to rapid, context-dependent modulation. We hypothesize that context-specific learning leads to pre-attentively modulated, multiplex representation in the auditory cortex. Here, we investigate map plasticity in the auditory cortices of anesthetized rats conditioned in a context-dependent manner, such that a conditioned stimulus (CS) of a 20-kHz tone and an unconditioned stimulus (US) of a mild electrical shock were associated only under a noisy auditory context, but not in silence. After the conditioning, although no distinct plasticity was found in the tonotopic map, tone-evoked responses were more noise-resistive than pre-conditioning. Yet, the conditioned group showed a reduced spread of activation to each tone with noise, but not with silence, associated with a sharpening of frequency tuning. The encoding accuracy index of neurons showed that conditioning deteriorated the accuracy of tone-frequency representations in noisy condition at off-CS regions, but not at CS regions, suggesting that arbitrary tones around the frequency of the CS were more likely perceived as the CS in a specific context, where CS was associated with US. These results together demonstrate that learning-induced plasticity in the auditory cortex occurs in a context-dependent manner.

Genotypic Influence on Aversive Conditioning in Honeybees, Using a Novel Thermal Reinforcement Procedure

PubMed Central

Junca, Pierre; Carcaud, Julie; Moulin, Sibyle; Garnery, Lionel; Sandoz, Jean-Christophe

2014-01-01

In Pavlovian conditioning, animals learn to associate initially neutral stimuli with positive or negative outcomes, leading to appetitive and aversive learning respectively. The honeybee (Apis mellifera) is a prominent invertebrate model for studying both versions of olfactory learning and for unraveling the influence of genotype. As a queen bee mates with about 15 males, her worker offspring belong to as many, genetically-different patrilines. While the genetic dependency of appetitive learning is well established in bees, it is not the case for aversive learning, as a robust protocol was only developed recently. In the original conditioning of the sting extension response (SER), bees learn to associate an odor (conditioned stimulus - CS) with an electric shock (unconditioned stimulus - US). This US is however not a natural stimulus for bees, which may represent a potential caveat for dissecting the genetics underlying aversive learning. We thus first tested heat as a potential new US for SER conditioning. We show that thermal stimulation of several sensory structures on the bee’s body triggers the SER, in a temperature-dependent manner. Moreover, heat applied to the antennae, mouthparts or legs is an efficient US for SER conditioning. Then, using microsatellite analysis, we analyzed heat sensitivity and aversive learning performances in ten worker patrilines issued from a naturally inseminated queen. We demonstrate a strong influence of genotype on aversive learning, possibly indicating the existence of a genetic determinism of this capacity. Such determinism could be instrumental for efficient task partitioning within the hive. PMID:24828422

Interactions between prefrontal cortex and cerebellum revealed by trace eyelid conditioning.

PubMed

Kalmbach, Brian E; Ohyama, Tatsuya; Kreider, Joy C; Riusech, Frank; Mauk, Michael D

2009-01-01

Eyelid conditioning has proven useful for analysis of learning and computation in the cerebellum. Two variants, delay and trace conditioning, differ only by the relative timing of the training stimuli. Despite the subtlety of this difference, trace eyelid conditioning is prevented by lesions of the cerebellum, hippocampus, or medial prefrontal cortex (mPFC), whereas delay eyelid conditioning is prevented by cerebellar lesions and is largely unaffected by forebrain lesions. Here we test whether these lesion results can be explained by two assertions: (1) Cerebellar learning requires temporal overlap between the mossy fiber inputs activated by the tone conditioned stimulus (CS) and the climbing fiber inputs activated by the reinforcing unconditioned stimulus (US), and therefore (2) trace conditioning requires activity that outlasts the presentation of the CS in a subset of mossy fibers separate from those activated directly by the CS. By use of electrical stimulation of mossy fibers as a CS, we show that cerebellar learning during trace eyelid conditioning requires an input that persists during the stimulus-free trace interval. By use of reversible inactivation experiments, we provide evidence that this input arises from the mPFC and arrives at the cerebellum via a previously unidentified site in the pontine nuclei. In light of previous PFC recordings in various species, we suggest that trace eyelid conditioning involves an interaction between the persistent activity of delay cells in mPFC-a putative mechanism of working memory-and motor learning in the cerebellum.

The effects of Toxoplasma infection on rodent behavior are dependent on dose of the stimulus

PubMed Central

Vyas, Ajai; Kim, Seon-Kyeong; Sapolsky, Robert M

2007-01-01

Parasite Toxoplasma gondii blocks the innate aversion of rats for cat urine, putatively increasing the likelihood of a cat predating a rat. This is thought to reflect an adaptive behavioral manipulation, because Toxoplasma can reproduce only in cat intestines. While it will be adaptive for the parasite to cause an absolute behavioral change, fitness costs associated with the manipulation itself suggest that the change be optimized and not maximized. We investigate these conflicting suggestions in the present report. Furthermore, exposure to cat odor causes long-lasting acquisition of learnt fear in the rodents. If Toxoplasma manipulates emotional valence of cat odor rather than just sensory response, infection should affect learning driven by the aversive properties of the odor. As a second aim of the present study, we investigate this assertion. We demonstrate that behavioral changes in rodents induced by Toxoplasma infection do not represent absolute all-or-none effects. Rather, these effects follow a non-monotonous function dependent on strength of stimulus, roughly resembling an inverted-U curve. Furthermore, infection affects conditioning to cat odor in a manner dependent upon strength of unconditioned stimulus employed. Non-monotonous relationship between behavioral manipulation and strength of cat odor agrees with the suggestion that a dynamic balance exists between benefit obtained and costs incurred by the parasite during the manipulation. This report also demonstrates that Toxoplasma affects emotional valence of the cat odor as indicated by altered learned fear induced by cat odor. PMID:17683872

Situational relevance: Context as a factor in serial overshadowing of taste aversion learning.

PubMed

Kwok, Dorothy W S; Boakes, Robert A

2017-08-31

In a serial overshadowing procedure a target stimulus, A, is followed after an interval by a potentially interfering stimulus, B, and this is then followed by an unconditioned stimulus, US. Revusky (1977) proposed that the degree to which B overshadows conditioning of A depends on whether or not the two events take place in the same context. To test this proposal two experiments used a 1-trial long-delay conditioned taste aversion (CTA) procedure; sucrose served as the target taste (A) and dilute hydrochloric acid (HCl) as the overshadowing taste (B), with lithium chloride injection providing the US. In Experiment 1 these tastes were novel; weaker overshadowing by HCl of an aversion to sucrose was found when the two tastes were presented in different contexts. Experiment 2 tested whether the effect of pre-exposure to HCl, thereby rendering it less effective in overshadowing a sucrose aversion, was also context-dependent. In the conditioning session rats again received either context-same or context-different presentations of sucrose and HCl. However, for some rats HCl was pre-exposed in the same context to which it was later presented during conditioning (Consistent), while others were pre-exposed to HCl in a different context to the one in which it was presented during conditioning (Inconsistent). The Inconsistent group produced greater overshadowing than the Consistent group and thus confirmed that the latent inhibition effect was also context dependent. This study supports Revusky's (1977) idea of situational relevance.

Effect of Hydrofluoric Acid Concentration on Resin Adhesion to a Feldspathic Ceramic.

PubMed

Venturini, Andressa Borin; Prochnow, Catina; Rambo, Dagma; Gundel, Andre; Valandro, Luiz Felipe

2015-08-01

To evaluate the effect of different concentrations of hydrofluoric acid (HF) on the contact angle and the resin bond strength durability to feldspathic ceramic. To evaluate the contact angles of distilled water on etched feldspathic ceramic, 25 specimens (12×10×2.4 mm) of VitaBlocks Mark II were used, divided into 5 groups (n=5): one unconditioned control (UC) group with no ceramic surface treatment, and 4 other groups that were etched for 60 s with different concentrations of HF: 1% (HF1), 3% (HF3), 5% (HF5) and 10% (HF10). The bond testing utilized 40 ceramic blocks (12×10×4 mm) that were fabricated and subjected to the same surface treatments as previously mentioned (excluding the control). The etched surfaces were silanized and resin cement was applied. After 24 h, the blocks were sectioned to produce bar specimens that were divided into two groups, non-aged (immediate testing) and aged (storage for 230 days+12,000 thermocycles at 5°C and 55°C), and subjected to microtensile testing (μTBS). Micromorphogical analysis of the treated surfaces was also performed (atomic force and scanning electron microscopy). One-way ANOVA and Tukey's tests were applied for data analysis. UC had the highest contact angle (61.4°), whereas HF10 showed the lowest contact angle (17.5°). In non-aged conditions, different acids promoted statistically similar bond strengths (14.2 to 15.7 MPa) (p>0.05); in terms of bond durability, only the bond strength of the HF1 group presented a statistically significant decrease comparing before and after aging (14.5 to 10.2 MPa). When etched with 3%, 5%, or 10% hydrofluoric acid, the ceramic tested showed stable resin adhesion after long-term aging.

Effects of Aversive Classical Conditioning on Sexual Response in Women With Dyspareunia and Sexually Functional Controls.

PubMed

Both, Stephanie; Brauer, Marieke; Weijenborg, Philomeen; Laan, Ellen

2017-05-01

In dyspareunia-a somatically unexplained vulvovaginal pain associated with sexual intercourse-learned pain-related fear and inhibited sexual arousal are supposed to play a pivotal role. Based on research findings indicating that enhanced pain conditioning is involved in the etiology and maintenance of chronic pain, in the present study it was hypothesized that enhanced pain conditioning also might be involved in dyspareunia. To test whether learned associations between pain and sex negatively affect sexual response; whether women with dyspareunia show stronger aversive learning; and whether psychological distress, pain-related anxiety, vigilance, catastrophizing, and sexual excitation and inhibition were associated with conditioning effects. Women with dyspareunia (n = 36) and healthy controls (n = 35) completed a differential conditioning experiment, with one erotic picture (the CS + ) paired with a painful unconditional stimulus and one erotic picture never paired with pain (the CS - ). Genital sexual response was measured by vaginal photoplethysmography, and ratings of affective value and sexual arousal in response to the CS + and CS - were obtained. Psychological distress, pain cognitions, and sexual excitation and inhibition were assessed by validated questionnaires. The two groups showed stronger negative affect and weaker subjective sexual arousal to the CS + during the extinction phase, but, contrary to expectations, women with dyspareunia showed weaker differential responding. Controls showed more prominent lower genital response to the CS + during acquisition than women with dyspareunia. In addition, women with dyspareunia showed stronger expectancy for the unconditional stimulus in response to the safe CS - . Higher levels of pain-related fear, pain catastrophizing, and sexual inhibition were associated with weaker differential conditioning effects. Pairing of sex with pain negatively affects sexual response. The results indicate that a learned association of sex with pain and possibly deficient safety learning play a role in dyspareunia. Both S, Brauer M, Weijenborg P, Laan E. Effects of Aversive Classical Conditioning on Sexual Response in Women With Dyspareunia and Sexually Functional Controls. J Sex Med 2017;14:687-701. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

An animal model of fetal alcohol spectrum disorder: Trace conditioning as a window to inform memory deficits and intervention tactics.

PubMed

Hunt, Pamela S; Barnet, Robert C

2015-09-01

Animal models of Fetal Alcohol Spectrum Disorders (FASD) afford the unique capacity to precisely control timing of alcohol exposure and alcohol exposure amounts in the developing animal. These models have powerfully informed neurophysiological alterations associated with fetal and perinatal alcohol. In two experiments presented here we expand use of the Pavlovian Trace Conditioning procedure to examine cognitive deficits and intervention strategies in a rat model of FASD. Rat pups were exposed to 5g/kg/day ethanol on postnatal days (PD) 4-9, simulating alcohol exposure in the third trimester in humans. During early adolescence, approximately PD 30, the rats were trained in the trace conditioning task in which a light conditioned stimulus (CS) and shock unconditioned stimulus (US) were paired but separated by a 10-s stimulus free trace interval. Learning was assessed in freezing behavior during shock-free tests. Experiment 1 revealed that neonatal ethanol exposure significantly impaired hippocampus-dependent trace conditioning relative to controls. In Experiment 2 a serial compound conditioning procedure known as 'gap filling' completely reversed the ethanol-induced deficit in trace conditioning. We also discuss prior data regarding the beneficial effects of supplemental choline and novel preliminary data regarding the pharmacological cognitive enhancer physostigmine, both of which mitigate the alcohol-induced cognitive deficit otherwise seen in trace conditioning controls. We suggest trace conditioning as a useful tool for characterizing some of the core cognitive deficits seen in FASD, and as a model for developing effective environmental as well as nutritional and pharmacological interventions. Copyright © 2014 Elsevier Inc. All rights reserved.

Trace conditioning in insects—keep the trace!

PubMed Central

Dylla, Kristina V.; Galili, Dana S.; Szyszka, Paul; Lüdke, Alja

2013-01-01

Trace conditioning is a form of associative learning that can be induced by presenting a conditioned stimulus (CS) and an unconditioned stimulus (US) following each other, but separated by a temporal gap. This gap distinguishes trace conditioning from classical delay conditioning, where the CS and US overlap. To bridge the temporal gap between both stimuli and to form an association between CS and US in trace conditioning, the brain must keep a neural representation of the CS after its termination—a stimulus trace. Behavioral and physiological studies on trace and delay conditioning revealed similarities between the two forms of learning, like similar memory decay and similar odor identity perception in invertebrates. On the other hand differences were reported also, like the requirement of distinct brain structures in vertebrates or disparities in molecular mechanisms in both vertebrates and invertebrates. For example, in commonly used vertebrate conditioning paradigms the hippocampus is necessary for trace but not for delay conditioning, and Drosophila delay conditioning requires the Rutabaga adenylyl cyclase (Rut-AC), which is dispensable in trace conditioning. It is still unknown how the brain encodes CS traces and how they are associated with a US in trace conditioning. Insects serve as powerful models to address the mechanisms underlying trace conditioning, due to their simple brain anatomy, behavioral accessibility and established methods of genetic interference. In this review we summarize the recent progress in insect trace conditioning on the behavioral and physiological level and emphasize similarities and differences compared to delay conditioning. Moreover, we examine proposed molecular and computational models and reassess different experimental approaches used for trace conditioning. PMID:23986710

An Animal Model of Fetal Alcohol Spectrum Disorder: Trace Conditioning as a Window to Inform Memory Deficits and Intervention Tactics

PubMed Central

Hunt, Pamela S.; Barnet, Robert C.

2014-01-01

Animal models of Fetal Alcohol Spectrum Disorders (FASD) afford the unique capacity to precisely control timing of alcohol exposure and alcohol exposure amounts in the developing animal. These models have powerfully informed neurophysiological alterations associated with fetal and perinatal alcohol. In two experiments presented here we expand use of the Pavlovian Trace Conditioning procedure to examine cognitive deficits and intervention strategies in a rat model of FASD. Rat pups were exposed to 5 g/kg/day ethanol on postnatal days (PD) 4–9, simulating alcohol exposure in the third trimester in humans. During early adolescence, approximately PD 30, the rats were trained in the trace conditioning task in which a light conditioned stimulus (CS) and shock unconditioned stimulus (US) were paired but separated by a 10-s stimulus free trace interval. Learning was assessed in freezing behavior during shock-free tests. Experiment 1 revealed that neonatal ethanol exposure significantly impaired hippocampus-dependent trace conditioning relative to controls. In Experiment 2 a serial compound conditioning procedure known as ‘gap filling’ completely reversed the ethanol-induced deficit in trace conditioning. We also discuss prior data regarding the beneficial effects of supplemental choline and novel preliminary data regarding the pharmacological cognitive enhancer physostigmine, both of which mitigate the alcohol-induced cognitive deficit otherwise seen in trace conditioning controls. We suggest trace conditioning as a useful tool for characterizing some of the core cognitive deficits seen in FASD, and as a model for developing effective environmental as well as nutritional and pharmacological interventions. PMID:25477227

Roles of Aminergic Neurons in Formation and Recall of Associative Memory in Crickets

PubMed Central

Mizunami, Makoto; Matsumoto, Yukihisa

2010-01-01

We review recent progress in the study of roles of octopaminergic (OA-ergic) and dopaminergic (DA-ergic) signaling in insect classical conditioning, focusing on our studies on crickets. Studies on olfactory learning in honey bees and fruit-flies have suggested that OA-ergic and DA-ergic neurons convey reinforcing signals of appetitive unconditioned stimulus (US) and aversive US, respectively. Our work suggested that this is applicable to olfactory, visual pattern, and color learning in crickets, indicating that this feature is ubiquitous in learning of various sensory stimuli. We also showed that aversive memory decayed much faster than did appetitive memory, and we proposed that this feature is common in insects and humans. Our study also suggested that activation of OA- or DA-ergic neurons is needed for appetitive or aversive memory recall, respectively. To account for this finding, we proposed a model in which it is assumed that two types of synaptic connections are strengthened by conditioning and are activated during memory recall, one type being connections from neurons representing conditioned stimulus (CS) to neurons inducing conditioned response and the other being connections from neurons representing CS to OA- or DA-ergic neurons representing appetitive or aversive US, respectively. The former is called stimulus–response (S–R) connection and the latter is called stimulus–stimulus (S–S) connection by theorists studying classical conditioning in vertebrates. Results of our studies using a second-order conditioning procedure supported our model. We propose that insect classical conditioning involves the formation of S–S connection and its activation for memory recall, which are often called cognitive processes. PMID:21119781

Spontaneous Recovery But Not Reinstatement of the Extinguished Conditioned Eyeblink Response in the Rat

PubMed Central

Thanellou, Alexandra; Green, John T.

2011-01-01

Reinstatement, the return of an extinguished conditioned response (CR) after reexposure to the unconditioned stimulus (US), and spontaneous recovery, the return of an extinguished CR with the passage of time, are two of four well-established phenomena which demonstrate that extinction does not erase the conditioned stimulus (CS)-US association. However, reinstatement of extinguished eyeblink CRs has never been demonstrated and spontaneous recovery of extinguished eyeblink CRs has not been systematically demonstrated in rodent eyeblink conditioning. In Experiment 1, US reexposure was administered 24 hours prior to a reinstatement test. In Experiment 2, US reexposure was administered 5 min prior to a reinstatement test. In Experiment 3, a long, discrete cue (a houselight), present in all phases of training and testing, served as a context within which each trial occurred to maximize context processing, which in other preparations has been shown to be required for reinstatement. In Experiment 4, an additional group was included that received footshock exposure, rather than US reexposure, between extinction and test, and contextual freezing was measured prior to test. Spontaneous recovery was robust in Experiments 3 and 4. In Experiment 4, context freezing was strong in a group given footshock exposure but not in a group given eyeshock US reexposure. There was no reinstatement observed in any experiment. With stimulus conditions that produce eyeblink conditioning and research designs that produce reinstatement in other forms of classical conditioning, we observed spontaneous recovery but not reinstatement of extinguished eyeblink CRs. This suggests that reinstatement, but not spontaneous recovery, is a preparation- or substrate-dependent phenomenon. PMID:21517145

Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases.

PubMed

Lonsdorf, Tina B; Haaker, Jan; Schümann, Dirk; Sommer, Tobias; Bayer, Janine; Brassen, Stefanie; Bunzeck, Nico; Gamer, Matthias; Kalisch, Raffael

2015-11-01

Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism, most experimental studies are conducted in male participants and studies focusing on sex differences are sparse. In addition, the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs), fear and unconditioned stimulus expectancy ratings were obtained. We included 377 individuals (261 women) in our study. Robust sex differences were observed in all dependent measures. Women generally displayed higher subjective ratings but smaller SCRs than men and showed reduced excitatory/inhibitory conditioned stimulus (CS+/CS-) discrimination in all dependent measures. Furthermore, women using hormonal contraceptives showed reduced SCR CS discrimination on day 2 than men and free-cycling women, while menstrual cycle phase had no effect. Possible limitations include the simultaneous testing of up to 4 participants in cubicles, which might have introduced a social component, and not assessing postexperimental contingency awareness. The response pattern in women shows striking similarity to previously reported sex differences in patients with anxiety. Our results suggest that pronounced deficits in associative discrimination learning and subjective expression of safety information (CS- responses) might underlie higher prevalence and higher symptom rates seen in women with anxiety disorders. The data call for consideration of biological sex and hormonal contraceptive use in future studies and may suggest that targeting inhibitory learning during therapy might aid precision medicine.

Differing Presynaptic Contributions to LTP and Associative Learning in Behaving Mice

PubMed Central

Madroñal, Noelia; Gruart, Agnès; Delgado-García, José M.

2009-01-01

The hippocampal CA3-CA1 synapse is an excellent experimental model for studying the interactions between short- and long-term plastic changes taking place following high-frequency stimulation (HFS) of Schaffer collaterals and during the acquisition and extinction of a classical eyeblink conditioning in behaving mice. Input/output curves and a full-range paired-pulse study enabled determining the optimal intensities and inter-stimulus intervals for evoking paired-pulse facilitation (PPF) or depression (PPD) at the CA3-CA1 synapse. Long-term potentiation (LTP) induced by HFS lasted ≈10 days. HFS-induced LTP evoked an initial depression of basal PPF. Recovery of PPF baseline values was a steady and progressive process lasting ≈20 days, i.e., longer than the total duration of the LTP. In a subsequent series of experiments, we checked whether PPF was affected similarly during activity-dependent synaptic changes. Animals were conditioned using a trace paradigm, with a tone as a conditioned stimulus (CS) and an electrical shock to the trigeminal nerve as an unconditioned stimulus (US). A pair of pulses (40 ms interval) was presented to the Schaffer collateral-commissural pathway to evoke field EPSPs (fEPSPs) during the CS-US interval. Basal PPF decreased steadily across conditioning sessions (i.e., in the opposite direction to that during LTP), reaching a minimum value during the 10th conditioning session. Thus, LTP and classical eyeblink conditioning share some presynaptic mechanisms, but with an opposite evolution. Furthermore, PPF and PPD might play a homeostatic role during long-term plastic changes at the CA3-CA1 synapse. PMID:19636387

Brain response to visceral aversive conditioning: a functional magnetic resonance imaging study.

PubMed

Yágüez, Lidia; Coen, Steven; Gregory, Lloyd J; Amaro, Edson; Altman, Christian; Brammer, Michael J; Bullmore, Edward T; Williams, Steven C R; Aziz, Qasim

2005-06-01

Brain-imaging studies to date have confounded visceral pain perception with anticipation. We used functional magnetic resonance imaging of the human brain to study the neuroanatomic network involved in aversive conditioning of visceral pain and, thus, anticipation. Eight healthy volunteers (5 male) participated in the study. We used a classic conditioning paradigm in which 3 neutral stimuli (differently colored circles) that acted as conditioned stimuli were paired with painful esophageal distention, air puff to the wrist, or nothing, which acted as unconditioned stimuli. Neural activity was measured during learning, anticipation (pairing only 50% of conditioned stimuli with their unconditioned stimuli), and extinction (unpaired conditioned stimuli) phases. For magnetic resonance imaging, axial slices depicting blood oxygen level-dependent contrast were acquired with a 1.5-T system. Neural responses during the learning phase included areas commonly associated with visceral pain (anterior cingulate cortex, insula, and primary and secondary somatosensory cortices) and innocuous somatosensory perception (primary and secondary somatosensory cortices and insula). During the anticipation and extinction phases of aversive stimulation, brain activity resembled that seen during actual painful esophageal stimulation. In contrast, anticipation and extinction of the innocuous somatic stimulus failed to show that effect. We have shown that actual and anticipated visceral pain elicit similar cortical responses. These results have implications for the design and interpretation of brain-imaging studies of visceral pain. They not only contribute to our understanding of the processing of visceral pain, but also have clinical implications for the management of chronic pain states.

Tcf4 transgenic female mice display delayed adaptation in an auditory latent inhibition paradigm.

PubMed

Brzózka, M M; Rossner, M J; de Hoz, L

2016-09-01

Schizophrenia (SZ) is a severe mental disorder affecting about 1 % of the human population. Patients show severe deficits in cognitive processing often characterized by an improper filtering of environmental stimuli. Independent genome-wide association studies confirmed a number of risk variants for SZ including several associated with the gene encoding the transcription factor 4 (TCF4). TCF4 is widely expressed in the central nervous system of mice and humans and seems to be important for brain development. Transgenic mice overexpressing murine Tcf4 (Tcf4tg) in the adult brain display cognitive impairments and sensorimotor gating disturbances. To address the question of whether increased Tcf4 gene dosage may affect cognitive flexibility in an auditory associative task, we tested latent inhibition (LI) in female Tcf4tg mice. LI is a widely accepted translational endophenotype of SZ and results from a maladaptive delay in switching a response to a previously unconditioned stimulus when this becomes conditioned. Using an Audiobox, we pre-exposed Tcf4tg mice and their wild-type littermates to either a 3- or a 12-kHz tone before conditioning them to a 12-kHz tone. Tcf4tg animals pre-exposed to a 12-kHz tone showed significantly delayed conditioning when the previously unconditioned tone became associated with an air puff. These results support findings that associate TCF4 dysfunction with cognitive inflexibility and improper filtering of sensory stimuli observed in SZ patients.

Importance of associative learning processes for one-trial behavioral sensitization of preweanling rats.

PubMed

McDougall, Sanders A; Pothier, Alexandria G; Der-Ghazarian, Taleen; Herbert, Matthew S; Kozanian, Olga O; Castellanos, Kevin A; Flores, Ana T

2011-10-01

During adulthood, associative learning is necessary for the expression of one-trial behavioral sensitization; however, it is uncertain whether the same associative processes are operative during the preweanling period. Two strategies were used to assess the importance of associative learning for one-trial behavioral sensitization of preweanling rats. In the initial experiments, we varied both the sequence and time interval between presentation of the conditioned stimulus (CS, novel environment) and unconditioned stimulus (US, cocaine). In the final experiment, we determined whether electroconvulsive shock-induced retrograde amnesia would disrupt one-trial behavioral sensitization. Results showed that robust-sensitized responding was apparent regardless of the sequence in which cocaine and the novel environment (the presumptive CS) were presented. Varying the time between CS and US presentation (0, 3, or 6 h) was also without effect. Results from experiment 3 showed that single or multiple electroconvulsive shock treatments did not alter the expression of the sensitized response. Therefore, these data indicated that one-trial behavioral sensitization of preweanling rats was exclusively mediated by nonassociative mechanisms and that associative processes did not modulate sensitized responding. These findings are in contrast to what is observed during adulthood, as adult rats exhibit one-trial behavioral sensitization only when associative processes are operative.

Simultaneous conditioning of valence and arousal.

PubMed

Gawronski, Bertram; Mitchell, Derek G V

2014-01-01

Evaluative conditioning (EC) refers to the change in the valence of a conditioned stimulus (CS) due to its pairing with a positive or negative unconditioned stimulus (US). To the extent that core affect can be characterised by the two dimensions of valence and arousal, EC has important implications for the origin of affective responses. However, the distinction between valence and arousal is rarely considered in research on EC or conditioned responses more generally. Measuring the subjective feelings elicited by a CS, the results from two experiments showed that (1) repeated pairings of a CS with a positive or negative US of either high or low arousal led to corresponding changes in both CS valence and CS arousal, (2) changes in CS arousal, but not changes in CS valence, were significantly related to recollective memory for CS-US pairings, (3) subsequent presentations of the CS without the US reduced the conditioned valence of the CS, with conditioned arousal being less susceptible to extinction and (4) EC effects were stronger for high arousal than low arousal USs. The results indicate that the conditioning of affective responses can occur simultaneously along two independent dimensions, supporting evidence in related areas that calls for a consideration of both valence and arousal. Implications for research on EC and the acquisition of emotional dispositions are discussed.

Is evaluative conditioning really resistant to extinction? Evidence for changes in evaluative judgements without changes in evaluative representations.

PubMed

Gawronski, Bertram; Gast, Anne; De Houwer, Jan

2015-01-01

Evaluative conditioning (EC) is defined as the change in the evaluation of a conditioned stimulus (CS) due to its pairing with a positive or negative unconditioned stimulus (US). Although several individual studies suggest that EC is unaffected by unreinforced presentations of the CS without the US, a recent meta-analysis indicates that EC effects are less pronounced for post-extinction measurements than post-acquisition measurements. The disparity in research findings suggests that extinction of EC may depend on yet unidentified conditions. In an attempt to uncover these conditions, three experiments (N = 784) investigated the influence of unreinforced post-acquisition CS presentations on EC effects resulting from simultaneous versus sequential pairings and pairings with single versus multiple USs. For all four types of CS-US pairings, EC effects on self-reported evaluations were reduced by unreinforced CS presentations, but only when the CSs had been rated after the initial presentation of CS-US pairings. EC effects on an evaluative priming measure remained unaffected by unreinforced CS presentations regardless of whether the CSs had been rated after acquisition. The results suggest that reduced EC effects resulting from unreinforced CS presentations are due to judgement-related processes during the verbal expression of CS evaluations rather than genuine changes in the underlying evaluative representations.

Shaking that icky feeling: effects of extinction and counterconditioning on disgust-related evaluative learning.

PubMed

Engelhard, Iris M; Leer, Arne; Lange, Emma; Olatunji, Bunmi O

2014-09-01

Learned disgust appears to play an important role in certain anxiety disorders, and can be explained by the process of evaluative conditioning, in which an affective evaluative reaction evoked by an unconditional stimulus (US) is transferred to a conditional stimulus (CS). Much remains unknown about how disgust-related evaluative learning can be effectively eliminated. Study 1 of the present investigation examined the effects of extinction on reducing the negative evaluation of a CS that was acquired during disgust conditioning. Participants completed acquisition trials, with a disgusting picture as US and two neutral pictures as CS (CS+ was paired with the US; CS- was unpaired), followed by extinction trials ("CS only"; experimental condition) or a filler task (control condition). Extinction trials reduced acquired US expectancy to the CS+, but did not extinguish negative evaluations of the CS+. Study 2 examined the effects of counterconditioning on evaluative learned disgust. After disgust acquisition trials, counterconditioning trials followed in which the CS+ was paired with a pleasant US (experimental condition) or a filler task (control condition). Counterconditioning trials reduced acquired US expectancy to the CS+ and reduced evaluative conditioned disgust. Implications of the potential differential effects of extinction and counterconditioning on evaluative learning for exposure-based treatment of specific anxiety disorders are discussed. Copyright © 2014. Published by Elsevier Ltd.

Eyeblink Classical Conditioning and Post-Traumatic Stress Disorder – A Model Systems Approach

PubMed Central

Schreurs, Bernard G.; Burhans, Lauren B.

2015-01-01

Not everyone exposed to trauma suffers flashbacks, bad dreams, numbing, fear, anxiety, sleeplessness, hyper-vigilance, hyperarousal, or an inability to cope, but those who do may suffer from post-traumatic stress disorder (PTSD). PTSD is a major physical and mental health problem for military personnel and civilians exposed to trauma. There is still debate about the incidence and prevalence of PTSD especially among the military, but for those who are diagnosed, behavioral therapy and drug treatment strategies have proven to be less than effective. A number of these treatment strategies are based on rodent fear conditioning research and are capable of treating only some of the symptoms because the extinction of fear does not deal with the various forms of hyper-vigilance and hyperarousal experienced by people with PTSD. To help address this problem, we have developed a preclinical eyeblink classical conditioning model of PTSD in which conditioning and hyperarousal can both be extinguished. We review this model and discuss findings showing that unpaired stimulus presentations can be effective in reducing levels of conditioning and hyperarousal even when unconditioned stimulus intensity is reduced to the point where it is barely capable of eliciting a response. These procedures have direct implications for the treatment of PTSD and could be implemented in a virtual reality environment. PMID:25904874

Fruit or aposematic insect? Context-dependent colour preferences in domestic chicks.

PubMed Central

Gamberale-Stille, G.; Tullberg, B. S.

2001-01-01

Colours are common stimuli in signalling systems. Requirements to function well as a signal sometimes conflict between different signallers, and the same colour stimulus is used to convey completely different messages to the same receiver. Fruits and aposematic insects both use red coloration as a signal, in the former case to signal profitability and in the latter case as a warning signal. In two experiments, we investigated whether the domestic chick, an omnivorous predator, differed in its unconditioned preference or avoidance of red and green stimuli depending on whether or not the stimulus was an insect. The experiments were designed as preference tests between red and green painted prey. The prey were live insects and artificial fruits (experiment 1), and, to investigate the effect of movement, live and dead insects (experiment 2). The chicks did not show any difference in pecking preference between red and green when fruit-like stimuli were used, but when the prey were insects, green prey were strongly preferred to red prey, and prey movement did not affect this bias. Thus, young chicks may recognize prey as insects and then discriminate between different prey colorations, or one type of food may elicit an unlearned colour preference-avoidance response that is absent with another type of food. PMID:11749705

Muscarinic ACh Receptors Contribute to Aversive Olfactory Learning in Drosophila

PubMed Central

Silva, Bryon; Molina-Fernández, Claudia; Ugalde, María Beatriz; Tognarelli, Eduardo I.; Angel, Cristian; Campusano, Jorge M.

2015-01-01

The most studied form of associative learning in Drosophila consists in pairing an odorant, the conditioned stimulus (CS), with an unconditioned stimulus (US). The timely arrival of the CS and US information to a specific Drosophila brain association region, the mushroom bodies (MB), can induce new olfactory memories. Thus, the MB is considered a coincidence detector. It has been shown that olfactory information is conveyed to the MB through cholinergic inputs that activate acetylcholine (ACh) receptors, while the US is encoded by biogenic amine (BA) systems. In recent years, we have advanced our understanding on the specific neural BA pathways and receptors involved in olfactory learning and memory. However, little information exists on the contribution of cholinergic receptors to this process. Here we evaluate for the first time the proposition that, as in mammals, muscarinic ACh receptors (mAChRs) contribute to memory formation in Drosophila. Our results show that pharmacological and genetic blockade of mAChRs in MB disrupts olfactory aversive memory in larvae. This effect is not explained by an alteration in the ability of animals to respond to odorants or to execute motor programs. These results show that mAChRs in MB contribute to generating olfactory memories in Drosophila. PMID:26380118

Neural correlates of appetitive-aversive interactions in Pavlovian fear conditioning.

PubMed

Nasser, Helen M; McNally, Gavan P

2013-03-19

We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of fear responses was retarded in rats that had received Stage I appetitive training. This counterconditioning was associated with increased levels of phosphorylated mitogen activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions, including midline thalamus, rostral agranular insular cortex (RAIC), lateral amygdala, and nucleus accumbens core and shell, but decreased expression in the ventrolateral quadrant of the midbrain periaqueductal gray. These brain regions showing differential pMAPK-IR have previously been identified as part of the fear prediction error circuit. We then examined the causal role of RAIC MAPK in fear learning and showed that Stage II fear learning was prevented by RAIC infusions of the MEK inhibitor PD098059 (0.5 µg/hemisphere). Taken together, these results show that there are opponent interactions between the appetitive and aversive motivational systems during fear learning and that the transformation of a reward CS into a fear CS is linked to heightened activity in the fear prediction error circuit.

Effects of OEF/OIF-Related Physical and Emotional Co-Morbidities on Associative Learning: Concurrent Delay and Trace Eyeblink Classical Conditioning

PubMed Central

McGlinchey, Regina E.; Fortier, Catherine B.; Venne, Jonathan R.; Maksimovskiy, Arkadiy L.; Milberg, William P.

2014-01-01

This study examined the performance of veterans and active duty personnel who served in Operation Enduring Freedom and/or Operation Iraqi Freedom (OEF/OIF) on a basic associative learning task. Eighty-eight individuals participated in this study. All received a comprehensive clinical evaluation to determine the presence and severity of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). The eyeblink conditioning task was composed of randomly intermixed delay and trace conditioned stimulus (CS) and unconditioned stimulus (US) pairs (acquisition) followed by a series of CS only trials (extinction). Results revealed that those with a clinical diagnosis of PTSD or a diagnosis of PTSD with comorbid mTBI acquired delay and trace conditioned responses (CRs) to levels and at rates similar to a deployed control group, thus suggesting intact basic associative learning. Differential extinction impairment was observed in the two clinical groups. Acquisition of CRs for both delay and trace conditioning, as well as extinction of trace CRs, was associated with alcoholic behavior across all participants. These findings help characterize the learning and memory function of individuals with PTSD and mTBI from OEF/OIF and raise the alarming possibility that the use of alcohol in this group may lead to more significant cognitive dysfunction. PMID:24625622

Both trace and delay conditioned eyeblink responding can be dissociated from outcome expectancy.

PubMed

Weidemann, Gabrielle; Broderick, Joshua; Lovibond, Peter F; Mitchell, Christopher J

2012-01-01

Squire and colleagues have proposed that trace and delay eyeblink conditioning are fundamentally different kinds of learning: trace conditioning requires acquisition of a conscious declarative memory for the stimulus contingencies whereas delay conditioning does not. Declarative memory in trace conditioning is thought to generate conditioned responding through the activation of a conscious expectancy for when the unconditioned stimulus (US) is going to occur. Perruchet (1985) has previously shown that in a 50% partial reinforcement design it is possible to dissociate single cue delay eyeblink conditioning from conscious expectancy for the US by examining performance over runs of reinforced and nonreinforced trials. Clark, Manns, and Squire (2001) claim that this dissociation does not occur in trace eyeblink conditioning. In the present experiment we examined the Perruchet effect for short, moderate, and long trace intervals (600, 1000, and 1400 ms) and for the equivalent interstimulus intervals (ISIs) in a delay conditioning procedure. We found evidence for a dissociation of eyeblink CRs and US expectancy over runs regardless of whether there was a delay or a trace arrangement of cues. The reasons for the Perruchet effect are still unclear, but the present data suggest that it does not depend on a separate nondeclarative system of the type proposed by Squire and colleagues. (c) 2012 APA, all rights reserved.

Eye-blink conditioning deficits indicate temporal processing abnormalities in schizophrenia.

PubMed

Bolbecker, Amanda R; Mehta, Crystal S; Edwards, Chad R; Steinmetz, Joseph E; O'Donnell, Brian F; Hetrick, William P

2009-06-01

Theoretical models suggest that symptoms of schizophrenia may be due to a dysfunctional modulatory system associated with the cerebellum. Although it has long been known that the cerebellum plays a critical role in associative learning and motor timing, recent evidence suggests that it also plays a role in nonmotor psychological processes. Indeed, cerebellar anomalies in schizophrenia have been linked to cognitive dysfunction and poor long-term outcome. To test the hypothesis that schizophrenia is associated with cerebellar dysfunction, cerebellar-dependent, delay eye-blink conditioning was examined in 62 individuals with schizophrenia and 62 age-matched non-psychiatric comparison subjects. The conditioned stimulus was a 400 ms tone, which co-terminated with a 50 ms unconditioned stimulus air puff. A subset of participants (25 with schizophrenia and 29 controls) also completed the Wechsler Abbreviated Scale of Intelligence. Participants with schizophrenia exhibited lower rates of eye-blink conditioning, including earlier (less adaptively timed) conditioned response latencies. Cognitive functioning was correlated with the rate of conditioned responsing in the non-psychiatric comparison subjects but not among those with schizophrenia, and the magnitude of these correlations significantly differed between groups. These findings are consistent with models of schizophrenia in which disruptions within the cortico-cerebellar-thalamic-cortical (CCTC) brain circuit are postulated to underlie the cognitive fragmentation that characterizes the disorder.

Eye-Blink Conditioning Deficits Indicate Temporal Processing Abnormalities in Schizophrenia

PubMed Central

Bolbecker, Amanda R.; Mehta, Crystal; Edwards, Chad R.; Steinmetz, Joseph E.; O’Donnell, Brian F.; Hetrick, William P.

2009-01-01

Theoretical models suggest that symptoms of schizophrenia may be due to a dysfunctional modulatory system associated with the cerebellum. Although it has long been known that the cerebellum plays a critical role in associative learning and motor timing, recent evidence suggests that it also plays a role in nonmotor psychological processes. Indeed, cerebellar anomalies in schizophrenia have been linked to cognitive dysfunction and poor long-term outcome. To test the hypothesis that schizophrenia is associated with cerebellar dysfunction, cerebellar-dependent, delay eye-blink conditioning was examined in 62 individuals with schizophrenia and 62 age-matched non-psychiatric comparison subjects. The conditioned stimulus was a 400 ms tone, which co-terminated with a 50 ms unconditioned stimulus air puff. A subset of participants (25 with schizophrenia and 29 controls) also completed the Wechsler Abbreviated Scale of Intelligence. Participants with schizophrenia exhibited lower rates of eye-blink conditioning, including earlier (less adaptively timed) conditioned response latencies. Cognitive functioning was correlated with the rate of conditioned responsing in the non-psychiatric comparison subjects but not among those with schizophrenia, and the magnitude of these correlations significantly differed between groups. These findings are consistent with models of schizophrenia in which disruptions within the cortico-cerebellar-thalamic-cortical (CCTC) brain circuit are postulated to underlie the cognitive fragmentation that characterizes the disorder. PMID:19351577

Critical Period of Memory Enhancement during Taste Avoidance Conditioning in Lymnaea stagnalis

PubMed Central

Sunada, Hiroshi; Lukowiak, Ken; Sakakibara, Manabu

2013-01-01

The present study investigated the optimal training procedure leading to long-lasting taste avoidance behavior in Lymnaea. A training procedure comprising 5 repeated pairings of a conditional stimulus (CS, sucrose), with an unconditional stimulus (US, a tactile stimulation to the animal’s head), over a 4-day period resulted in an enhanced memory formation than 10 CS-US repeated pairings over a 2-day period or 20 CS-US repeated pairings on a single day. Backward conditioning (US-CS) pairings did not result in conditioning. Thus, this taste avoidance conditioning was CS-US pairing specific. Food avoidance behavior was not observed following training, however, if snails were immediately subjected to a cold-block (4°C for 10 min). It was critical that the cold-block be applied within 10 min to block long-term memory (LTM) formation. Further, exposure to the cold-block 180 min after training also blocked both STM and LTM formation. The effects of the cold-block on subsequent learning and memory formation were also examined. We found no long lasting effects of the cold-block on subsequent memory formation. If protein kinase C was activated before the conditioning paradigm, snails could still acquire STM despite exposure to the cold-block. PMID:24098373

Temporal Discontiguity Is neither Necessary nor Sufficient for Learning-Induced Effects on Adult Neurogenesis

PubMed Central

Leuner, Benedetta; Waddell, Jaylyn; Gould, Elizabeth; Shors, Tracey J.

2012-01-01

Some, but not all, types of learning and memory can influence neurogenesis in the adult hippocampus. Trace eyeblink conditioning has been shown to enhance the survival of new neurons, whereas delay eyeblink conditioning has no such effect. The key difference between the two training procedures is that the conditioning stimuli are separated in time during trace but not delay conditioning. These findings raise the question of whether temporal discontiguity is necessary for enhancing the survival of new neurons. Here we used two approaches to test this hypothesis. First, we examined the influence of a delay conditioning task in which the duration of the conditioned stimulus (CS) was increased nearly twofold, a procedure that critically engages the hippocampus. Although the CS and unconditioned stimulus are contiguous, this very long delay conditioning procedure increased the number of new neurons that survived. Second, we examined the influence of learning the trace conditioned response (CR) after having acquired the CR during delay conditioning, a procedure that renders trace conditioning hippocampal-independent. In this case, trace conditioning did not enhance the survival of new neurons. Together, these results demonstrate that associative learning increases the survival of new neurons in the adult hippocampus, regardless of temporal contiguity. PMID:17192426

Unconscious classical conditioning of sexual arousal: evidence for the conditioning of female genital arousal to subliminally presented sexual stimuli.

PubMed

Both, Stephanie; Spiering, Mark; Laan, Ellen; Belcome, Sarah; van den Heuvel, Birre; Everaerd, Walter

2008-01-01

Although the assumption that sexual behavior is at least partly learned is common across theories of sexual behavior, classical conditioning of sexual response in women has been seldom studied. The study of unconscious classical conditioning of appetitive sexual responses in women. Vaginal pulse amplitude assessed by vaginal photoplethysmography, and ratings of sexual affective value. Pavlovian conditioning was examined in 18 sexually functional women by using two erotic pictures as conditional stimuli (CSs) and genital vibrotactile stimulation as unconditional stimulus (US). During the acquisition phase, the CSs were presented briefly (30 ms) and were masked by an immediately following masking stimulus. Only one CS (the CS+) was followed by the US during the acquisition phase. Conditioned responses were assessed during the extinction phase with supraliminal presentations of the CS+ and the CS-. Vaginal pulse amplitude was higher in response to the CS+ than during the CS- during the first extinction trial. There was no conditioning effect on ratings of affective value. The experiment demonstrates evidence for unconscious conditioning of genital responses in women, but no evidence for evaluative conditioning. The results add to the limited evidence for classical conditioning of sexual arousal in women, and to increasing evidence for associative emotional learning without awareness.

Associative learning performance is impaired in zebrafish (Danio rerio) by the NMDA-R antagonist MK-801

PubMed Central

Sison, Margarette; Gerlai, Robert

2011-01-01

The zebrafish is gaining popularity in behavioral neuroscience perhaps because of a promise of efficient large scale mutagenesis and drug screens that could identify a substantial number of yet undiscovered molecular players involved in complex traits. Learning and memory are complex functions of the brain and the analysis of their mechanisms may benefit from such large scale zebrafish screens. One bottleneck in this research is the paucity of appropriate behavioral screening paradigms, which may be due to the relatively uncharacterized nature of the behavior of this species. Here we show that zebrafish exhibit good learning performance in a task adapted from the mammalian literature, a plus maze in which zebrafish are required to associate a neutral visual stimulus with the presence of conspecifics, the rewarding unconditioned stimulus. Furthermore, we show that MK-801, a non-competitive NMDA-R antagonist, impairs memory performance in this maze when administered right after training or just before recall but not when given before training at a dose that does not impair motor function, perception or motivation. These results suggest that the plus maze associative learning paradigm has face and construct validity and that zebrafish may become an appropriate and translationally relevant study species for the analysis of the mechanisms of vertebrate, including mammalian, learning and memory. PMID:21596149

Taste avoidance induced by wheel running: effects of backward pairings and robustness of conditioned taste aversion.

PubMed

Salvy, Sarah-Jeanne; Pierce, W David; Heth, Donald C; Russell, James C

2004-09-15

Rats repeatedly exposed to a distinctive novel solution (conditioned stimulus, CS) followed by the opportunity to run in a wheel subsequently drink less of this solution. Investigations on this phenomenon indicate that wheel running is an effective unconditioned stimulus (US) for establishing conditioned taste aversion (CTA) when using a forward conditioning procedure (i.e., the US-wheel running follows the CS-taste). However, other studies show that wheel running produces reliable preference for a distinctive place when pairings are backward (i.e., the CS-location follows the US-wheel running). One possibility to account for these results is that rewarding aftereffects of wheel running conditioned preference to the CS. The main objective of the present study was to assess the effects of backward conditioning using wheel running as the US and a distinctive taste as the CS. In a between-groups design, two experimental groups [i.e., forward (FC) and backward conditioning (BC)] and two control groups [CS-taste alone (TA) and CS-US unpaired (UNP)] were compared. Results from this experiment indicated that there is less suppression of drinking when a CS-taste followed a bout of wheel running. In fact, rats in the BC group drank more of the paired solution than all the other groups.

Eyeblink classical conditioning and post-traumatic stress disorder - a model systems approach.

PubMed

Schreurs, Bernard G; Burhans, Lauren B

2015-01-01

Not everyone exposed to trauma suffers flashbacks, bad dreams, numbing, fear, anxiety, sleeplessness, hyper-vigilance, hyperarousal, or an inability to cope, but those who do may suffer from post-traumatic stress disorder (PTSD). PTSD is a major physical and mental health problem for military personnel and civilians exposed to trauma. There is still debate about the incidence and prevalence of PTSD especially among the military, but for those who are diagnosed, behavioral therapy and drug treatment strategies have proven to be less than effective. A number of these treatment strategies are based on rodent fear conditioning research and are capable of treating only some of the symptoms because the extinction of fear does not deal with the various forms of hyper-vigilance and hyperarousal experienced by people with PTSD. To help address this problem, we have developed a preclinical eyeblink classical conditioning model of PTSD in which conditioning and hyperarousal can both be extinguished. We review this model and discuss findings showing that unpaired stimulus presentations can be effective in reducing levels of conditioning and hyperarousal even when unconditioned stimulus intensity is reduced to the point where it is barely capable of eliciting a response. These procedures have direct implications for the treatment of PTSD and could be implemented in a virtual reality environment.

Neural correlates of olfactory learning paradigms in an identified neuron in the honeybee brain.

PubMed

Mauelshagen, J

1993-02-01

1. Sensitization and classical odor conditioning of the proboscis extension reflex were functionally analyzed by repeated intracellular recordings from a single identified neuron (PE1-neuron) in the central bee brain. This neuron belongs to the class of "extrinsic cells" arising from the pedunculus of the mushroom bodies and has extensive arborizations in the median and lateral protocerebrum. The recordings were performed on isolated bee heads. 2. Two different series of physiological experiments were carried out with the use of a similar temporal succession of stimuli as in previous behavioral experiments. In the first series, one group of animals was used for a single conditioning trial [conditioned stimulus (CS), carnation; unconditioned stimulus (US), sucrose solution to the antennae and proboscis), a second group was used for sensitization (sensitizing stimulus, sucrose solution to the antennae and/or proboscis), and the third group served as control (no sucrose stimulation). In the second series, a differential conditioning paradigm (paired odor CS+, carnation; unpaired odor CS-, orange blossom) was applied to test the associative nature of the conditioning effect. 3. The PE1-neuron showed a characteristic burstlike odor response before the training procedures. The treatments resulted in different spike-frequency modulations of this response, which were specific for the nonassociative and associative stimulus paradigms applied. During differential conditioning, there are dynamic up and down modulations of spike frequencies and of the DC potentials underlying the responses to the CS+. Overall, only transient changes in the minute range were observed. 4. The results of the sensitization procedures suggest two qualitatively different US pathways. The comparison between sensitization and one-trial conditioning shows differential effects of nonassociative and associative stimulus paradigms on the response behavior of the PE1-neuron. The results of the differential conditioning procedure reveal that the effect observed for the one-trial conditioning paradigm is of an associative nature and that there might be modulations, which are specific for single and multiple trial conditioning procedures. It is hypothesized that the PE1-neuron is a possible element involved in the short-term acquisition, rather than in the long-term storage, of an associative olfactory memory in the honeybee.

Cannabinoid modulation of zebrafish fear learning and its functional analysis investigated by c-Fos expression.

PubMed

Ruhl, Tim; Zeymer, Malou; von der Emde, Gerhard

2017-02-01

It has been shown that zebrafish fear learning proceeds in the same way as reported for rodents. However, in zebrafish fear learning it is possible to substitute the use of electric shocks as unconditioned stimulus and utilize the inborn fear responses to the alarm substance Schreckstoff, instead. The skin extract Schreckstoff elicits typical fear reactions such as preferred bottom dwelling, swimming in a tighter shoal, erratic movements and freezing. This natural fear behavior can be transferred from Schreckstoff to any other sensory stimulus by associative conditioning (fear learning). We presented Schreckstoff simultaneously with a red light stimulus and tested the effectiveness of fear learning during memory retrieval. The two brain regions known to be relevant for learning in zebrafish are the medial and the lateral pallium of the dorsal telencephalon, both containing rich expressions of the endocannabinoid receptor CB1. To test the influence of the zebrafish endocannabinoid system on fear acquisition learning, an experimental group of ten fish was pretreated with the CB1 receptor agonist THC (Δ 9 -tetrahydrocannabinol; 100nM for 1h). We found that CB1 activation significantly inhibited acquisition of fear learning, possibly by impairing stimulus encoding processes in pallial areas. This was supported by analyzes of c-Fos expression in the brains of experimental animals. Schreckstoff exposure during fear acquisition learning and memory retrieval during red light presentation increased the number of labelled cells in pallial structures, but in no other brain region investigated (e.g. striatum, thalamus, and habenula). THC administration before fear conditioning significantly decreased c-Fos expression in these structures to a level similar to the control group without Schreckstoff experience, suggesting that Schreckstoff induced fear learning requires brain circuits restricted mainly to pallial regions of the dorsal telencephalon. Copyright © 2016 Elsevier Inc. All rights reserved.

Elevated Arc/Arg 3.1 protein expression in the basolateral amygdala following auditory trace-cued fear conditioning.

PubMed

Chau, Lily S; Prakapenka, Alesia; Fleming, Stephen A; Davis, Ashley S; Galvez, Roberto

2013-11-01

The underlying neuronal mechanisms of learning and memory have been heavily explored using associative learning paradigms. Two of the more commonly employed learning paradigms have been contextual and delay fear conditioning. In fear conditioning, a subject learns to associate a neutral stimulus (conditioned stimulus; CS), such as a tone or the context of the room, with a fear provoking stimulus (unconditioned stimulus; US), such as a mild footshock. Utilizing these two paradigms, various analyses have elegantly demonstrated that the amygdala plays a role in both fear-related associative learning paradigms. However, the amygdala's involvement in trace fear conditioning, a forebrain-dependent fear associative learning paradigm that has been suggested to tap into higher cognitive processes, has not been closely investigated. Furthermore, to our knowledge, the specific amygdala nuclei involved with trace fear conditioning has not been examined. The present study used Arc expression as an activity marker to determine the amygdala's involvement in trace fear associative learning and to further explore involvement of specific amygdalar nuclei. Arc is an immediate early gene that has been shown to be associated with neuronal activation and is believed to be necessary for neuronal plasticity. Findings from the present study demonstrated that trace-conditioned mice, compared to backward-conditioned (stimulation-control), delay-conditioned and naïve mice, exhibited elevated amygdalar Arc expression in the basolateral (BLA) but not the central (CeA) or the lateral amygdala (LA). These findings are consistent with previous reports demonstrating that the amygdala plays a critical role in trace conditioning. Furthermore, these findings parallel studies demonstrating hippocampal-BLA activation following contextual fear conditioning, suggesting that trace fear conditioning and contextual fear conditioning may involve similar amygdala nuclei. Together, findings from this study demonstrate similarities in the pathway for trace and contextual fear conditioning, and further suggest possible underlying mechanisms for acquisition and consolidation of these two types of fear-related learning. Copyright © 2013 Elsevier Inc. All rights reserved.

Unconditional regard buffers children's negative self-feelings.

PubMed

Brummelman, Eddie; Thomaes, Sander; Walton, Gregory M; Poorthuis, Astrid M G; Overbeek, Geertjan; Orobio de Castro, Bram; Bushman, Brad J

2014-12-01

Unconditional regard refers to the feeling that one is accepted and valued by others without conditions. Psychological theory suggests that experiences of unconditional regard lead children to feel that they are valuable despite setbacks. We hypothesized that reflecting on experiences of unconditional regard would buffer children's negative self-feelings (eg, shame, insecurity, powerlessness) in the face of setbacks. To test this hypothesis, we randomized children to reflect on experiences of unconditional regard or other experiences, and examined their response to an academic setback 3 weeks later. Participants (11-15 years old) were randomly assigned to reflect for 15 minutes on experiences of unconditional regard (n = 91), conditional regard (n = 80), or other social experiences (n = 76). Research personnel, teachers, and classmates remained blind to condition assignment. Three weeks later, after receiving their course grades, children reported their self-feelings. Course grades were obtained from school records. Receiving low course grades represents a salient and painful real-world setback for children. Replicating previous research, children who received lower grades experienced more negative self-feelings (P < .001). As predicted, this well-established relationship was significantly attenuated among children who had reflected, 3 weeks previously, on experiences of unconditional regard (Ps < .03). Reflecting on unconditional regard specifically reduced negative self-feelings after low grades (P = .01), not after average or high grades (Ps > .17). Reflecting on unconditional regard buffered children's selves against the adverse impact of an academic setback over an extended period of time. Unconditional regard may thus be an important psychological lever to reduce negative self-feelings in youth. Copyright © 2014 by the American Academy of Pediatrics.

Tinnitus sensitization: Sensory and psychophysiological aspects of a new pathway of acquired centralization of chronic tinnitus.

PubMed

Zenner, Hans P; Pfister, Markus; Birbaumer, Niels

2006-12-01

Acquired centralized tinnitus (ACT) is the most frequent form of chronic tinnitus. The proposed ACT sensitization (ACTS) assumes a peripheral initiation of tinnitus whereby sensitizing signals from the auditory system establish new neuronal connections in the brain. Consequently, permanent neurophysiological malfunction within the information-processing modules results. Successful treatment has to target these malfunctioning information processing. We present in this study the neurophysiological and psychophysiological aspects of a recently suggested neurophysiological model, which may explain the symptoms caused by central cognitive tinnitus sensitization. Although conditioned reflexes, as a causal agent of chronic tinnitus, respond to extinction procedures, sensitization may initiate a vicious circle of overexcitation of the auditory system, resisting extinction and habituation. We used the literature database as indicated under "References" covering English and German works. For the ACTS model we extracted neurophysiological hypotheses of the auditory stimulus processing and the neuronal connections of the central auditory system with other brain regions to explain the malfunctions of auditory information processing. The model does not assume information-processing changes specific for tinnitus but treats the processing of tinnitus signals comparable with the processing of other external stimuli. The model uses the extensive knowledge available on sensitization of perception and memory processes and highlights the similarities of tinnitus with central neuropathic pain. Quality, validity, and comparability of the extracted data were evaluated by peer reviewing. Statistical techniques were not used. According to the tinnitus sensitization model, a tinnitus signal originates (as a type I-IV tinnitus) in the cochlea. In the brain, concerned with perception and cognition, the 1) conditioned associations, as postulated by the tinnitus model of Jastreboff, and the 2) unconditioned sensitized stimulus responses, as postulated in the present ACTS model, are actively connected with and attributed to the tinnitus signal. Attention to the tinnitus constitutes a typical undesired sensitized response. Some of the tinnitus-associated attributes may be called essential, unconditioned sensitization attributes. By a process called facilitation, the tinnitus' essential attributes are suggested to activate the tinnitus response. The result is an undesired increase in responsivity, such as an increase in attentional focus to the eliciting tinnitus stimulus. The mechanisms underlying sensitization are known as a specific nonassociative learning process producing a structural fixation of long-term facilitation at the synaptic level. This sensitization model may be important for the development of a sensitization-specific treatment if extinction procedures alone do not lead to satisfactory outcome. Inasmuch as this model considers sensitization as a nonassociative learning process based on cortical plasticity, it is reasonable to assume that this learning process can be altered by counteracting learning procedures. These counteracting learning procedures may consist of tinnitus-specific cognitive and behavioral procedures.

p53 expression in patients with ulcerative colitis - associated with dysplasia and carcinoma: a systematic meta-analysis.

PubMed

Lu, Xiaohong; Yu, Yuanjie; Tan, Shiyun

2017-10-25

Tumor suppressor gene p53 expression has been reported in patients with ulcerative colitis (UC). However, the correlation between p53 expression and UC remains controversial. The aim of this meta-analysis was to investigate the association between p53 expression and different pathological types of UC. Publications were searched in the PubMed, Embase, EBSCO, Wangfang, and CNKI databases. The overall odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were summarized in this study. Final 19 papers were identified in this meta-analysis, including 1068 patients with UC and 130 normal tissue samples. Immunohistochemical p53 expression was significantly higher in UC without dysplasia and carcinoma (UC group) compared to normal tissue samples (OR = 3.14, P = 0.001), higher in UC with dysplasia than in UC group (OR = 10.76, P < 0.001), and higher in UC with colorectal cancer (CRC) than in UC with dysplasia (OR = 1.69, P = 0.035). Subgroup analysis of ethnicity (UC group vs. normal tissues) showed that p53 expression was correlated with UC in Asians, but not in Caucasians. When UC with dysplasia was compared to UC group, p53 expression was linked to UC with dysplasia among both Asians and Caucasians. When UC-CRC was compared to UC with dysplasia, p53 expression was not associated with UC-CRC in both Caucasians and Asians. p53 expression was closely associated with UC-CRC development. p53 expression showed different ethnic characteristics among different pathological types of UC.

Fear-Conditioning Mechanisms Associated with Trait Vulnerability to Anxiety in Humans

PubMed Central

Indovina, Iole; Robbins, Trevor W.; Núñez-Elizalde, Anwar O.; Dunn, Barnaby D.; Bishop, Sonia J.

2011-01-01

Summary Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety. PMID:21315265

A Cartesian reflex assessment of face processing.

PubMed

Polewan, Robert J; Vigorito, Christopher M; Nason, Christopher D; Block, Richard A; Moore, John W

2006-03-01

Commands to blink were embedded within pictures of faces and simple geometric shapes or forms. The faces and shapes were conditioned stimuli (CSs), and the required responses were conditioned responses, or more properly, Cartesian reflexes (CRs). As in classical conditioning protocols, response times (RTs) were measured from CS onset. RTs provided a measure of the processing cost (PC) of attending to a CS. A PC is the extra time required to respond relative to RTs to unconditioned stimulus (US) commands presented alone. They reflect the interplay between attentional processing of the informational content of a CS and its signaling function with respect to the US command. This resulted in longer RTs to embedded commands. Differences between PCs of faces and geometric shapes represent a starting place for a new mental chronometry based on the traditional idea that differences in RT reflect differences in information processing.

Reciprocal synapses between mushroom body and dopamine neurons form a positive feedback loop required for learning.

PubMed

Cervantes-Sandoval, Isaac; Phan, Anna; Chakraborty, Molee; Davis, Ronald L

2017-05-10

Current thought envisions dopamine neurons conveying the reinforcing effect of the unconditioned stimulus during associative learning to the axons of Drosophila mushroom body Kenyon cells for normal olfactory learning. Here, we show using functional GFP reconstitution experiments that Kenyon cells and dopamine neurons from axoaxonic reciprocal synapses. The dopamine neurons receive cholinergic input via nicotinic acetylcholine receptors from the Kenyon cells; knocking down these receptors impairs olfactory learning revealing the importance of these receptors at the synapse. Blocking the synaptic output of Kenyon cells during olfactory conditioning reduces presynaptic calcium transients in dopamine neurons, a finding consistent with reciprocal communication. Moreover, silencing Kenyon cells decreases the normal chronic activity of the dopamine neurons. Our results reveal a new and critical role for positive feedback onto dopamine neurons through reciprocal connections with Kenyon cells for normal olfactory learning.

Evidence for specificity of the impact of punishment on error-related brain activity in high versus low trait anxious individuals.

PubMed

Meyer, Alexandria; Gawlowska, Magda

2017-10-01

A previous study suggests that when participants were punished with a loud noise after committing errors, the error-related negativity (ERN) was enhanced in high trait anxious individuals. The current study sought to extend these findings by examining the ERN in conditions when punishment was related and unrelated to error commission as a function of individual differences in trait anxiety symptoms; further, the current study utilized an electric shock as an aversive unconditioned stimulus. Results confirmed that the ERN was increased when errors were punished among high trait anxious individuals compared to low anxious individuals; this effect was not observed when punishment was unrelated to errors. Findings suggest that the threat-value of errors may underlie the association between certain anxious traits and punishment-related increases in the ERN. Copyright © 2017 Elsevier B.V. All rights reserved.

Adolescent cocaine exposure enhances goal-tracking behavior and impairs hippocampal cell genesis selectively in adult bred low-responder rats

PubMed Central

García-Fuster, M. Julia; Parsegian, Aram; Watson, Stanley J.; Akil, Huda; Flagel, Shelly B.

2018-01-01

Rationale Environmental challenges during adolescence, such as drug exposure, can cause enduring behavioral and molecular changes that contribute to life-long maladaptive behaviors, including addiction. Selectively bred high-responder (bHR) and low-responder (bLR) rats represent a unique model for assessing the long-term impact of adolescent environmental manipulations, as they inherently differ on a number of addiction-related traits. bHR rats are considered “addiction-prone”, whereas bLR rats are “addiction-resilient”, at least under baseline conditions. Moreover, relative to bLRs, bHR rats are more likely to attribute incentive motivational value to reward cues, or to “sign-track”. Objectives We utilized bHR and bLR rats to determine whether adolescent cocaine exposure can alter their inborn behavioral and neurobiological profiles, with a specific focus on Pavlovian conditioned approach behavior (i.e. sign- vs. goal-tracking) and hippocampal neurogenesis. Methods bHR and bLR rats were administered cocaine (15 mg/kg) or saline for 7 days during adolescence (postnatal day, PND 33–39) and subsequently tested for Pavlovian conditioned approach behavior in adulthood (PND 62–75), wherein an illuminated lever (conditioned stimulus) was followed by the response-independent delivery of a food pellet (unconditioned stimulus). Behaviors directed towards the lever and the food cup were recorded as sign- and goal-tracking, respectively. Hippocampal cell genesis was evaluated on PND 77 by immunohistochemistry. Results Adolescent cocaine exposure impaired hippocampal cell genesis (proliferation and survival) and enhanced the inherent propensity to goal-track in adult bLR, but not bHR, rats. Conclusions Adolescent cocaine exposure elicits long-lasting changes in stimulus-reward learning and enduring deficits in hippocampal neurogenesis selectively in adult bLR rats. PMID:28210781

Spatio-temporal dynamics of brain mechanisms in aversive classical conditioning: high-density event-related potential and brain electrical tomography analyses.

PubMed

Pizzagalli, Diego A; Greischar, Lawrence L; Davidson, Richard J

2003-01-01

Social cognition, including complex social judgments and attitudes, is shaped by individual learning experiences, where affect often plays a critical role. Aversive classical conditioning-a form of associative learning involving a relationship between a neutral event (conditioned stimulus, CS) and an aversive event (unconditioned stimulus, US)-represents a well-controlled paradigm to study how the acquisition of socially relevant knowledge influences behavior and the brain. Unraveling the temporal unfolding of brain mechanisms involved appears critical for an initial understanding about how social cognition operates. Here, 128-channel ERPs were recorded in 50 subjects during the acquisition phase of a differential aversive classical conditioning paradigm. The CS+ (two fearful faces) were paired 50% of the time with an aversive noise (CS upward arrow + /Paired), whereas in the remaining 50% they were not (CS upward arrow + /Unpaired); the CS- (two different fearful faces) were never paired with the noise. Scalp ERP analyses revealed differences between CS upward arrow + /Unpaired and CS- as early as approximately 120 ms post-stimulus. Tomographic source localization analyses revealed early activation modulated by the CS+ in the ventral visual pathway (e.g. fusiform gyrus, approximately 120 ms), right middle frontal gyrus (approximately 176 ms), and precuneus (approximately 240 ms). At approximately 120 ms, the CS- elicited increased activation in the left insula and left middle frontal gyrus. These findings not only confirm a critical role of prefrontal, insular, and precuneus regions in aversive conditioning, but they also suggest that biologically and socially salient information modulates activation at early stages of the information processing flow, and thus furnish initial insight about how affect and social judgments operate.

Facing Challenges in Differential Classical Conditioning Research: Benefits of a Hybrid Design for Simultaneous Electrodermal and Electroencephalographic Recording.

PubMed

Pastor, M Carmen; Rehbein, Maimu Alissa; Junghöfer, Markus; Poy, Rosario; López, Raul; Moltó, Javier

2015-01-01

Several challenges make it difficult to simultaneously investigate central and autonomous nervous system correlates of conditioned stimulus (CS) processing in classical conditioning paradigms. Such challenges include, for example, the discrepant requirements of electroencephalography (EEG) and electrodermal activity (EDA) recordings with regard to multiple repetitions of conditions and sufficient trial duration. Here, we propose a MultiCS conditioning set-up, in which we increased the number of CSs, decreased the number of learning trials, and used trials of short and long durations for meeting requirements of simultaneous EEG-EDA recording in a differential aversive conditioning task. Forty-eight participants underwent MultiCS conditioning, in which four neutral faces (CS+) were paired four times each with aversive electric stimulation (unconditioned stimulus) during acquisition, while four different neutral faces (CS-) remained unpaired. When comparing after relative to before learning measurements, EEG revealed an enhanced centro-posterior positivity to CS+ vs. CS- during 368-600 ms, and subjective ratings indicated CS+ to be less pleasant and more arousing than CS-. Furthermore, changes in CS valence and arousal were strong enough to bias subjective ratings when faces of CS+/CS- identity were displayed with different emotional expression (happy, angry) in a post-experimental behavioral task. In contrast to a persistent neural and evaluative CS+/CS- differentiation that sustained multiple unreinforced CS presentations, electrodermal differentiation was rapidly extinguished. Current results suggest that MultiCS conditioning provides a promising paradigm for investigating pre-post-learning changes under minimal influences of extinction and overlearning of simple stimulus features. Our data also revealed methodological pitfalls, such as the possibility of occurring artifacts when combining different acquisition systems for central and peripheral psychophysiological measures.

Extinction of aversive classically conditioned human sexual response.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Both, Stephanie

2015-04-01

Research has shown that acquired subjective likes and dislikes are quite resistant to extinction. Moreover, studies on female sexual response demonstrated that diminished genital arousal and positive affect toward erotic stimuli due to aversive classical conditioning did not extinguish during an extinction phase. Possible resistance to extinction of aversive conditioned sexual responses may have important clinical implications. However, resistance to extinction of aversive conditioned human sexual response has not been studied using extensive extinction trials. This article aims to study resistance to extinction of aversive conditioned sexual responses in sexually functional men and women. A differential conditioning experiment was conducted, with two erotic pictures as conditioned stimulus (CSs) and a painful stimulus as unconditioned stimuli (USs). Only one CS (the CS+) was followed by the US during the acquisition phase. Conditioned responses were assessed during the extinction phase. Penile circumference and vaginal pulse amplitude were assessed, and ratings of affective value and subjective sexual arousal were obtained. Also, a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies. Men and women rated the CS+ more negative as compared with the CS-. During the first trials of the extinction phase, vaginal pulse amplitude was lower in response to the CS+ than in response to the CS-, and on the first extinction trial women rated the CS+ as less sexually arousing. Intriguingly, men did not demonstrate attenuated genital and subjective sexual response. Aversive conditioning, by means of painful stimuli, only affects sexual responses in women, whereas it does not in men. Although conditioned sexual likes and dislikes are relatively persistent, conditioned affect eventually does extinguish. © 2014 International Society for Sexual Medicine.

Cognitive Factors Mediate Placebo Responses in Patients with House Dust Mite Allergy

PubMed Central

Benson, Sven; Rueckert, Annika; Hillen, Uwe; Schadendorf, Dirk; Schedlowski, Manfred

2013-01-01

Background Placebo effects have been reported in type I allergic reactions. However the neuropsychological mechanisms steering placebo responses in allergies are largely unknown. The study analyzed whether and to what extend a conditioned placebo response is affecting type I allergic reactions and whether this response can be reproduced at multiple occasions. Methods 62 patients with house dust mite allergy were randomly allocated to either a conditioned (n = 25), sham-conditioned (n = 25) or natural history (n = 12) group. During the learning phase (acquisition), patients in the conditioned group received the H1-receptor antagonist desloratadine (5mg) (unconditioned stimulus/US) together with a novel tasting gustatory stimulus (conditioned stimulus/CS). Patients in the sham-conditioned control group received the CS together with a placebo pill. After a wash out time of 9 days patients in the conditioned and sham-conditioned group received placebo pills together with the CS during evocation. Allergic responses documented by wheal size after skin prick test and symptom scores after nasal provocation were analyzed at baseline, after last desloratadine treatment and after the 1st and 5th CS re-exposure. Results Both conditioned and sham-conditioned patients showed significantly decreased wheal sizes after the 1st CS-evocation and significantly decreased symptom scores after the 1st as well as after the 5th evocation compared to the natural history control group. Conclusions These results indicate that placebo responses in type I allergy are not primarily mediated by learning processes, but seemed to be induced by cognitive factors such as patients’ expectation, with these effects not restricted to a single evocation. PMID:24260254

Inhibition of the amygdala central nucleus by stimulation of cerebellar output in rats: a putative mechanism for extinction of the conditioned fear response.

PubMed

Magal, Ari; Mintz, Matti

2014-11-01

The amygdala and the cerebellum serve two distinctively different functions. The amygdala plays a role in the expression of emotional information, whereas the cerebellum is involved in the timing of discrete motor responses. Interaction between these two systems is the basis of the two-stage theory of learning, according to which an encounter with a challenging event triggers fast classical conditioning of fear-conditioned responses in the amygdala and slow conditioning of motor-conditioned responses in the cerebellum. A third stage was hypothesised when an apparent interaction between amygdala and cerebellar associative plasticity was observed: an adaptive rate of cerebellum-dependent motor-conditioned responses was associated with a decrease in amygdala-dependent fear-conditioned responses, and was interpreted as extinction of amygdala-related fear-conditioned responses by the cerebellar output. To explore this hypothesis, we mimicked some components of classical eyeblink conditioning in anesthetised rats by applying an aversive periorbital pulse as an unconditioned stimulus and a train of pulses to the cerebellar output nuclei as a cerebellar neuronal-conditioned response. The central amygdala multiple unit response to the periorbital pulse was measured with or without a preceding train to the cerebellar output nuclei. The results showed that activation of the cerebellar output nuclei prior to periorbital stimulation produced diverse patterns of inhibition of the amygdala response to the periorbital aversive stimulus, depending upon the nucleus stimulated, the laterality of the nucleus stimulated, and the stimulus interval used. These results provide a putative extinction mechanism of learned fear behavior, and could have implications for the treatment of pathologies involving abnormal fear responses by using motor training as therapy. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Acute Ethanol Has Biphasic Effects on Short- and Long-Term Memory in Both Foreground and Background Contextual Fear Conditioning in C57BL/6 Mice

PubMed Central

Gulick, Danielle; Gould, Thomas J.

2009-01-01

Background Ethanol is a frequently abused, addictive drug that impairs cognitive function. Ethanol may disrupt cognitive processes by altering attention, short-term memory, and/ or long-term memory. Interestingly, some research suggests that ethanol may enhance cognitive processes at lower doses. The current research examined the dose-dependent effects of ethanol on contextual and cued fear conditioning. In addition, the present studies assessed the importance of stimulus salience in the effects of ethanol and directly compared the effects of ethanol on short-term and long-term memory. Methods This study employed both foreground and background fear conditioning, which differ in the salience of contextual stimuli, and tested conditioning at 4 hours, 24 hours, and 1 week in order to assess the effects of ethanol on short-term and long-term memory. Foreground conditioning consisted of 2 presentations of a foot shock unconditioned stimulus (US) (2 seconds, 0.57 mA). Background conditioning consisted of 2 auditory conditioned stimulus (30 seconds, 85 dB white noise)–foot shock (US; 2 seconds, 0.57 mA) pairings. Results For both foreground and background conditioning, ethanol enhanced short-term and long-term memory for contextual and cued conditioning at a low dose (0.25 g/kg) and impaired short-term and long-term memory for contextual and cued conditioning at a high dose (1.0 g/kg). Conclusions These results suggest that ethanol has long-lasting, biphasic effects on short-term and long-term memory for contextual and cued conditioning. Furthermore, the effects of ethanol on contextual fear conditioning are independent of the salience of the context. PMID:17760787

Sex differences in conditioned stimulus discrimination during context-dependent fear learning and its retrieval in humans: the role of biological sex, contraceptives and menstrual cycle phases

PubMed Central

Lonsdorf, Tina B.; Haaker, Jan; Schümann, Dirk; Sommer, Tobias; Bayer, Janine; Brassen, Stefanie; Bunzeck, Nico; Gamer, Matthias; Kalisch, Raffael

2015-01-01

Background Anxiety disorders are more prevalent in women than in men. Despite this sexual dimorphism, most experimental studies are conducted in male participants, and studies focusing on sex differences are sparse. In addition, the role of hormonal contraceptives and menstrual cycle phase in fear conditioning and extinction processes remain largely unknown. Methods We investigated sex differences in context-dependent fear acquisition and extinction (day 1) and their retrieval/expression (day 2). Skin conductance responses (SCRs), fear and unconditioned stimulus expectancy ratings were obtained. Results We included 377 individuals (261 women) in our study. Robust sex differences were observed in all dependent measures. Women generally displayed higher subjective ratings but smaller SCRs than men and showed reduced excitatory/inhibitory conditioned stimulus (CS+/CS−) discrimination in all dependent measures. Furthermore, women using hormonal contraceptives showed reduced SCR CS discrimination on day 2 than men and free-cycling women, while menstrual cycle phase had no effect. Limitations Possible limitations include the simultaneous testing of up to 4 participants in cubicles, which might have introduced a social component, and not assessing postexperimental contingency awareness. Conclusion The response pattern in women shows striking similarity to previously reported sex differences in patients with anxiety. Our results suggest that pronounced deficits in associative discrimination learning and subjective expression of safety information (CS− responses) might underlie higher prevalence and higher symptom rates seen in women with anxiety disorders. The data call for consideration of biological sex and hormonal contraceptive use in future studies and may suggest that targeting inhibitory learning during therapy might aid precision medicine. PMID:26107163

Involvement of the prelimbic cortex in contextual fear conditioning with temporal and spatial discontinuity.

PubMed

Santos, Thays Brenner; Kramer-Soares, Juliana Carlota; Favaro, Vanessa Manchim; Oliveira, Maria Gabriela Menezes

2017-10-01

Time plays an important role in conditioning, it is not only possible to associate stimuli with events that overlap, as in delay fear conditioning, but it is also possible to associate stimuli that are discontinuous in time, as shown in trace conditioning for a discrete stimuli. The environment itself can be a powerful conditioned stimulus (CS) and be associated to unconditioned stimulus (US). Thus, the aim of the present study was to determine the parameters in which contextual fear conditioning occurs by the maintenance of a contextual representation over short and long time intervals. The results showed that a contextual representation can be maintained and associated after 5s, even in the absence of a 15s re-exposure to the training context before US delivery. The same effect was not observed with a 24h interval of discontinuity. Furthermore, optimal conditioned response with a 5s interval is produced only when the contexts (of pre-exposure and shock) match. As the pre-limbic cortex (PL) is necessary for the maintenance of a continuous representation of a stimulus, the involvement of the PL in this temporal and contextual processing was investigated. The reversible inactivation of the PL by muscimol infusion impaired the acquisition of contextual fear conditioning with a 5s interval, but not with a 24h interval, and did not impair delay fear conditioning. The data provided evidence that short and long intervals of discontinuity have different mechanisms, thus contributing to a better understanding of PL involvement in contextual fear conditioning and providing a model that considers both temporal and contextual factors in fear conditioning. Copyright © 2017 Elsevier Inc. All rights reserved.

Facing Challenges in Differential Classical Conditioning Research: Benefits of a Hybrid Design for Simultaneous Electrodermal and Electroencephalographic Recording

PubMed Central

Pastor, M. Carmen; Rehbein, Maimu Alissa; Junghöfer, Markus; Poy, Rosario; López, Raul; Moltó, Javier

2015-01-01

Several challenges make it difficult to simultaneously investigate central and autonomous nervous system correlates of conditioned stimulus (CS) processing in classical conditioning paradigms. Such challenges include, for example, the discrepant requirements of electroencephalography (EEG) and electrodermal activity (EDA) recordings with regard to multiple repetitions of conditions and sufficient trial duration. Here, we propose a MultiCS conditioning set-up, in which we increased the number of CSs, decreased the number of learning trials, and used trials of short and long durations for meeting requirements of simultaneous EEG–EDA recording in a differential aversive conditioning task. Forty-eight participants underwent MultiCS conditioning, in which four neutral faces (CS+) were paired four times each with aversive electric stimulation (unconditioned stimulus) during acquisition, while four different neutral faces (CS−) remained unpaired. When comparing after relative to before learning measurements, EEG revealed an enhanced centro-posterior positivity to CS+ vs. CS− during 368–600 ms, and subjective ratings indicated CS+ to be less pleasant and more arousing than CS−. Furthermore, changes in CS valence and arousal were strong enough to bias subjective ratings when faces of CS+/CS− identity were displayed with different emotional expression (happy, angry) in a post-experimental behavioral task. In contrast to a persistent neural and evaluative CS+/CS− differentiation that sustained multiple unreinforced CS presentations, electrodermal differentiation was rapidly extinguished. Current results suggest that MultiCS conditioning provides a promising paradigm for investigating pre–post-learning changes under minimal influences of extinction and overlearning of simple stimulus features. Our data also revealed methodological pitfalls, such as the possibility of occurring artifacts when combining different acquisition systems for central and peripheral psychophysiological measures. PMID:26106318

Development of a UC781 releasing polyethylene vinyl acetate vaginal ring.

PubMed

McConville, Christopher; Major, Ian; Friend, David R; Clark, Meredith R; Malcolm, R Karl

2012-12-01

UC781 is potent, hydrophobic, non-nucleotide reverse transcriptase inhibitor (NNRTI) against the human immunodeficiency virus (HIV). UC781 is currently being investigated for use as a potential HIV microbicide. A study in rhesus macaques demonstrated that a 100-mg UC781-loaded silicone elastomer vaginal ring released limited amounts of UC781 into the vaginal fluid and tissue after 28 days. The reason for this was due to the hydrophobic nature and limited aqueous solubility of UC781. This study describes the manufacture of UC781-loaded polyethylene vinyl acetate (PEVA) vaginal rings, which have an improved in vitro release rate of UC781 when compared to UC781-loaded silicone elastomer vaginal rings. The study demonstrates that the UC781 in the PEVA rings is mostly in its amorphous form due to the rings being manufactured above UC781's melting point. Furthermore, the rings do not show any signs of UC781 degradation, such as the presence of UC22.

Apparatus bias and place conditioning with ethanol in mice.

PubMed

Cunningham, Christopher L; Ferree, Nikole K; Howard, MacKenzie A

2003-12-01

Although the distinction between "biased" and "unbiased" is generally recognized as an important methodological issue in place conditioning, previous studies have not adequately addressed the distinction between a biased/unbiased apparatus and a biased/unbiased stimulus assignment procedure. Moreover, a review of the recent literature indicates that many reports (70% of 76 papers published in 2001) fail to provide adequate information about apparatus bias. This issue is important because the mechanisms underlying a drug's effect in the place-conditioning procedure may differ depending on whether the apparatus is biased or unbiased. The present studies were designed to assess the impact of apparatus bias and stimulus assignment procedure on ethanol-induced place conditioning in mice (DBA/2 J). A secondary goal was to compare various dependent variables commonly used to index conditioned place preference. Apparatus bias was manipulated by varying the combination of tactile (floor) cues available during preference tests. Experiment 1 used an unbiased apparatus in which the stimulus alternatives were equally preferred during a pre-test as indicated by the group average. Experiment 2 used a biased apparatus in which one of the stimuli was strongly preferred by most mice (mean % time on cue = 67%) during the pre-test. In both studies, the stimulus paired with drug (CS+) was assigned randomly (i.e., an "unbiased" stimulus assignment procedure). Experimental mice received four pairings of CS+ with ethanol (2 g/kg, i.p.) and four pairings of the alternative stimulus (CS-) with saline; control mice received saline on both types of trial. Each experiment concluded with a 60-min choice test. With the unbiased apparatus (experiment 1), significant place conditioning was obtained regardless of whether drug was paired with the subject's initially preferred or non-preferred stimulus. However, with the biased apparatus (experiment 2), place conditioning was apparent only when ethanol was paired with the initially non-preferred cue, and not when it was paired with the initially preferred cue. These conclusions held regardless of which dependent variable was used to index place conditioning, but only if the counterbalancing factor was included in statistical analyses. These studies indicate that apparatus bias plays a major role in determining whether biased assignment of an ethanol-paired stimulus affects ability to demonstrate conditioned place preference. Ethanol's ability to produce conditioned place preference in an unbiased apparatus, regardless of the direction of the initial cue bias, supports previous studies that interpret such findings as evidence of a primary rewarding drug effect. Moreover, these studies suggest that the asymmetrical outcome observed in the biased apparatus is most likely due to a measurement problem (e.g., ceiling effect) rather than to an interaction between the drug's effect and an unconditioned motivational response (e.g., "anxiety") to the initially non-preferred stimulus. More generally, these findings illustrate the importance of providing clear information on apparatus bias in all place-conditioning studies.

Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice

PubMed Central

Kotajima-Murakami, Hiroko; Narumi, Sakae; Yuzaki, Michisuke; Yanagihara, Dai

2016-01-01

Lesions in the cerebellar vermis abolish acquisition of fear-conditioned bradycardia in animals and human patients. The δ2 glutamate receptor (GluD2) is predominantly expressed in cerebellar Purkinje cells. The mouse mutant ho15J carries a spontaneous mutation in GluD2 and these mice show a primary deficiency in parallel fiber-Purkinje cell synapses, multiple innervations of Purkinje cells by climbing fibers, and impairment of long-term depression. In the present study, we used ho15J mice to investigate the role of the cerebellum in fear-conditioned bradycardia. We recorded changes in heart rate of ho15J mice induced by repeated pairing of an acoustic (conditioned) stimulus (CS) with an aversive (unconditioned) stimulus (US). The mice acquired conditioned bradycardia on Day 1 of the CS-US phase, similarly to wild-type mice. However, the magnitude of the conditioned bradycardia was not stable in the mutant mice, but rather was exaggerated on Days 2–5 of the CS-US phase. We examined the effects of reversibly inactivating the cerebellum by injection of an antagonist against the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR). The antagonist abolished expression of conditioned responses in both wild-type and ho15J mice. We conclude that the GluD2 mutation in the ho15J mice affects stable retention of the acquired conditioned bradycardia. PMID:27820843

Involvement of GluD2 in Fear-Conditioned Bradycardia in Mice.

PubMed

Kotajima-Murakami, Hiroko; Narumi, Sakae; Yuzaki, Michisuke; Yanagihara, Dai

2016-01-01

Lesions in the cerebellar vermis abolish acquisition of fear-conditioned bradycardia in animals and human patients. The δ2 glutamate receptor (GluD2) is predominantly expressed in cerebellar Purkinje cells. The mouse mutant ho15J carries a spontaneous mutation in GluD2 and these mice show a primary deficiency in parallel fiber-Purkinje cell synapses, multiple innervations of Purkinje cells by climbing fibers, and impairment of long-term depression. In the present study, we used ho15J mice to investigate the role of the cerebellum in fear-conditioned bradycardia. We recorded changes in heart rate of ho15J mice induced by repeated pairing of an acoustic (conditioned) stimulus (CS) with an aversive (unconditioned) stimulus (US). The mice acquired conditioned bradycardia on Day 1 of the CS-US phase, similarly to wild-type mice. However, the magnitude of the conditioned bradycardia was not stable in the mutant mice, but rather was exaggerated on Days 2-5 of the CS-US phase. We examined the effects of reversibly inactivating the cerebellum by injection of an antagonist against the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR). The antagonist abolished expression of conditioned responses in both wild-type and ho15J mice. We conclude that the GluD2 mutation in the ho15J mice affects stable retention of the acquired conditioned bradycardia.

Aversive Learning and Trait Aggression Influence Retaliatory Behavior.

PubMed

Molapour, Tanaz; Lindström, Björn; Olsson, Andreas

2016-01-01

In two experiments (n = 35, n = 34), we used a modified fear-conditioning paradigm to investigate the role of aversive learning in retaliatory behavior in social context. Participants first completed an initial aversive learning phase in which the pairing of a neutral conditioned stimulus (CS; i.e., neutral face) with a naturally aversive unconditioned stimulus (US; electric shock) was learned. Then they were given an opportunity to interact (i.e., administer 0-2 shocks) with the same faces again, during a Test phase. In Experiment 2, we used the same paradigm with the addition of online trial-by-trial ratings (e.g., US expectancy and anger) to examine the role of aversive learning, anger, and the learned expectancy of receiving punishment more closely. Our results indicate that learned aversions influenced future retaliation in a social context. In both experiments, participants showed largest skin conductance responses (SCRs) to the faces paired with one or two shocks, demonstrating successful aversive learning. Importantly, participants administered more shocks to the faces paired with the most number of shocks when the opportunity was given during test. Also, our results revealed that aggressive traits (Buss and Perry Aggression scale) were associated with retaliation only toward CSs associated with aversive experiences. These two experiments show that aggressive traits, when paired with aversive learning experiences enhance the likelihood to act anti-socially toward others.

Distinct state anxiety after predictable and unpredictable fear training in mice.

PubMed

Seidenbecher, Thomas; Remmes, Jasmin; Daldrup, Thiemo; Lesting, Jörg; Pape, Hans-Christian

2016-05-01

Sustained fear paradigms in rodents have been developed to monitor states of anxious apprehension and to model situations in patients suffering from long-lasting anxiety disorders. A recent report describes a fear conditioning paradigm, allowing distinction between phasic and sustained states of conditioned fear in non-restrained mice. However, so far no prospective studies have yet been conducted to elucidate whether induction of phasic or sustained fear can affect states of anxiety. Here, we used CS (conditioned stimulus) and US (unconditioned stimulus) pairing with predictable and unpredictable timing to induce phasic and sustained fear in mice. State anxiety during various fear response components was assessed using the elevated plus-maze test. Training with unpredictable CS-US timing resulted in CS-evoked sustained components of fear (freezing), while predictable CS-US timing resulted in rapid decline. Data suggested the influence of training procedure on state anxiety which is dependent on progression of conditioned fear during fear memory retrieval. Animals trained with unpredictable CS-US timing showed an unchanged high anxiety state throughout behavioral observation. In contrast, mice trained with predictable CS-US timing showed anxiolytic-like behavior 3 min after CS onset, which was accompanied by a fast decline of the fear conditioned response (freezing). Further systematic studies are needed to validate the phasic/sustained fear model in rodents as translational model for anxiety disorders in humans. Copyright © 2016 Elsevier B.V. All rights reserved.

Cross-modal Savings in the Contralateral Eyelid Conditioned Response

PubMed Central

Campolattaro, Matthew M.; Buss, Eric W.; Freeman, John H.

2015-01-01

The present experiment monitored bilateral eyelid responses during eyeblink conditioning in rats trained with a unilateral unconditioned stimulus (US). Three groups of rats were used to determine if cross-modal savings occurs when the location of the US is switched from one eye to the other. Rats in each group first received paired or unpaired eyeblink conditioning with a conditioned stimulus (tone or light; CS) and a unilateral periorbital electrical stimulation US. All rats were subsequently given paired training, but with the US location (Group 1), CS modality (Group 2), or US location and CS modality (Group 3) changed. Changing the location of the US alone resulted in an immediate transfer of responding in both eyelids (Group 1) in rats that received paired training prior to the transfer session. Rats in groups 2 and 3 that initially received paired training showed facilitated learning to the new CS modality during the transfer sessions, indicating that cross-modal savings occurs whether or not the location of the US is changed. All rats that were initially given unpaired training acquired conditioned eyeblink responses similar to de novo acquisition rate during the transfer sessions. Savings of CR incidence was more robust than savings of CR amplitude when the US switched sides, a finding that has implications for elucidating the neural mechanisms of cross-modal savings. PMID:26501170

Extinction of Pavlovian conditioning: The influence of trial number and reinforcement history.

PubMed

Chan, C K J; Harris, Justin A

2017-08-01

Pavlovian conditioning is sensitive to the temporal relationship between the conditioned stimulus (CS) and the unconditioned stimulus (US). This has motivated models that describe learning as a process that continuously updates associative strength during the trial or specifically encodes the CS-US interval. These models predict that extinction of responding is also continuous, such that response loss is proportional to the cumulative duration of exposure to the CS without the US. We review evidence showing that this prediction is incorrect, and that extinction is trial-based rather than time-based. We also present two experiments that test the importance of trials versus time on the Partial Reinforcement Extinction Effect (PREE), in which responding extinguishes more slowly for a CS that was inconsistently reinforced with the US than for a consistently reinforced one. We show that increasing the number of extinction trials of the partially reinforced CS, relative to the consistently reinforced CS, overcomes the PREE. However, increasing the duration of extinction trials by the same amount does not overcome the PREE. We conclude that animals learn about the likelihood of the US per trial during conditioning, and learn trial-by-trial about the absence of the US during extinction. Moreover, what they learn about the likelihood of the US during conditioning affects how sensitive they are to the absence of the US during extinction. Copyright © 2017 Elsevier B.V. All rights reserved.

The Influence of Emotion Upregulation on the Expectation of Sexual Reward.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Trimbos, Baptist; Both, Stephanie

2016-01-01

Emotion regulation research has shown successful altering of unwanted aversive emotional reactions. Cognitive strategies can also downregulate expectations of reward arising from conditioned stimuli, including sexual stimuli. However, little is known about whether such strategies can also efficiently upregulate expectations of sexual reward arising from conditioned stimuli, and possible gender differences therein. The present study examined whether a cognitive upregulatory strategy could successfully upregulate sexual arousal elicited by sexual reward-conditioned cues in men and women. Men (n = 40) and women (n = 53) participated in a study using a differential conditioning paradigm, with genital vibrostimulation as unconditioned stimulus (US) and sexually relevant pictures as conditional stimuli. Penile circumference and vaginal pulse amplitude were assessed and ratings of US expectancy, affective value, and sexual arousal value were obtained. Also a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies. Evidence was found for emotion upregulation to increase genital arousal response in the acquisition phase in both sexes, and to enhance resistance to extinction of conditioned genital responding in women. In men, the emotion upregulatory strategy resulted in increased conditioned positive affect. The findings support that top-down modulation may indeed influence conditioned sexual responses. This knowledge may have implications for treating disturbances in sexual appetitive responses, such as low sexual arousal and desire. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Eyeblink Conditioning in Healthy Adults: A Positron Emission Tomography Study

PubMed Central

Andreasen, Nancy C.; Liu, Dawei; Freeman, John H.; Boles Ponto, Laura L.; O’Leary, Daniel S.

2013-01-01

Eyeblink conditioning is a paradigm commonly used to investigate the neural mechanisms underlying motor learning. It involves the paired presentation of a toneconditioning stimulus which precedes and co-terminates with an airpuff unconditioned stimulus. Following repeated paired presentations a conditioned eyeblink develops which precedes the airpuff. This type of learning has been intensively studied and the cerebellum is known to be essential in both humans and animals. The study presented here was designed to investigate the role of the cerebellum during eyeblink conditioning in humans using positron emission tomography (PET). The sample includes 20 subjects (10 male and 10 female) with an average age of 29.2 years. PET imaging was used to measure regional cerebral blood flow (rCBF) changes occurring during the first, second, and third blocks of conditioning. In addition, stimuli-specific rCBF to unpaired tones and airpuffs (“pseudoconditioning”) was used as a baseline level that was subtracted from each block. Conditioning was performed using three, 15-trial blocks of classical eyeblink conditioning with the last five trials in each block imaged. As expected, subjects quickly acquired conditioned responses. A comparison between the conditioning tasks and the baseline task revealed that during learning there was activation of the cerebellum and recruitment of several higher cortical regions. Specifically, large peaks were noted in cerebellar lobules IV/V, the frontal lobes, and cingulate gyri. PMID:22430943

Pavlovian conditioned approach, extinction, and spontaneous recovery to an audiovisual cue paired with an intravenous heroin infusion.

PubMed

Peters, Jamie; De Vries, Taco J

2014-01-01

Novel stimuli paired with exposure to addictive drugs can elicit approach through Pavlovian learning. While such approach behavior, or sign tracking, has been documented for cocaine and alcohol, it has not been shown to occur with opiate drugs like heroin. Most Pavlovian conditioned approach paradigms use an operandum as the sign, so that sign tracking can be easily automated. We were interested in assessing whether approach behavior occurs to an audiovisual cue paired with an intravenous heroin infusion. If so, would this behavior exhibit characteristics of other Pavlovian conditioned behaviors, such as extinction and spontaneous recovery? Rats were repeatedly exposed to an audiovisual cue, similar to that used in standard self-administration models, along with an intravenous heroin infusion. Sign tracking was measured in an automated fashion by analyzing motion pixels within the cue zone during each cue presentation. We were able to observe significant sign tracking after only five pairings of the conditioned stimulus (CS) with the unconditioned stimulus (US). This behavior rapidly extinguished over 2 days, but exhibited pronounced spontaneous recovery 3 weeks later. We conclude that sign tracking measured by these methods exhibits all the characteristics of a classically conditioned behavior. This model can be used to examine the Pavlovian component of drug memories, alone, or in combination with self-administration methods.

Pavlovian conditioning and cumulative reinforcement rate.

PubMed

Harris, Justin A; Patterson, Angela E; Gharaei, Saba

2015-04-01

In 5 experiments using delay conditioning of magazine approach with rats, reinforcement rate was varied either by manipulating the mean interval between onset of the conditioned stimulus (CS) and unconditioned stimulus (US) or by manipulating the proportion of CS presentations that ended with the US (trial-based reinforcement rate). Both manipulations influenced the acquisition of responding. In each experiment, a specific comparison was made between 2 CSs that differed in their mean CS-US interval and in their trial-based reinforcement rate, such that the cumulative reinforcement rate-the cumulative duration of the CS between reinforcements-was the same for the 2 CSs. For example, a CS reinforced on 100% of trials with a mean CS-US interval of 60 s was compared with a CS reinforced on 33% of trials and a mean duration of 20 s. Across the 5 experiments, conditioning was virtually identical for the 2 CSs with matched cumulative reinforcement rate. This was true as long as the timing of the US was unpredictable and, thus, response rates were uniform across the length of the CS. We conclude that the effects of CS-US interval and of trial-based reinforcement rate are reducible entirely to their common effect on cumulative reinforcement rate. We discuss the implications of this for rate-based, trial-based, and real-time associative models of conditioning. (c) 2015 APA, all rights reserved).

Neural circuits involved in the renewal of extinguished fear.

PubMed

Chen, Weihai; Wang, Yan; Wang, Xiaqing; Li, Hong

2017-07-01

The last 10 years have witnessed a substantial progress in understanding the neural mechanisms for the renewal of the extinguished fear memory. Based on the theory of fear extinction, exposure therapy has been developed as a typical cognitive behavioral therapy for posttraumatic stress disorder. Although the fear memory can be extinguished by repeated presentation of conditioned stimulus without unconditioned stimulus, the fear memory is not erased and tends to relapse outside of extinction context, which is referred to as renewal. Therefore, the renewal is regarded as a great obstruction interfering with the effect of exposure therapy. In recent years, there has been a great deal of studies in understanding the neurobiological underpinnings of fear renewal. These offer a foundation upon which novel therapeutic interventions for the renewal may be built. This review focuses on behavioral, anatomical and electrophysiological studies that interpret roles of the hippocampus, prelimbic cortex and amygdala as well as the connections between them for the renewal of the extinguished fear. Additionally, this review suggests the possible pathways for the renewal: (1) the prelimbic cortex may integrate contextual information from hippocampal inputs and project to the basolateral amygdala to mediate the renewal of extinguished fear memory; the ventral hippocampus may innervate the activities of the basolateral amygdala or the central amygdala directly for the renewal. © 2017 IUBMB Life, 69(7):470-478, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Aversive Learning and Trait Aggression Influence Retaliatory Behavior

PubMed Central

Molapour, Tanaz; Lindström, Björn; Olsson, Andreas

2016-01-01

In two experiments (n = 35, n = 34), we used a modified fear-conditioning paradigm to investigate the role of aversive learning in retaliatory behavior in social context. Participants first completed an initial aversive learning phase in which the pairing of a neutral conditioned stimulus (CS; i.e., neutral face) with a naturally aversive unconditioned stimulus (US; electric shock) was learned. Then they were given an opportunity to interact (i.e., administer 0–2 shocks) with the same faces again, during a Test phase. In Experiment 2, we used the same paradigm with the addition of online trial-by-trial ratings (e.g., US expectancy and anger) to examine the role of aversive learning, anger, and the learned expectancy of receiving punishment more closely. Our results indicate that learned aversions influenced future retaliation in a social context. In both experiments, participants showed largest skin conductance responses (SCRs) to the faces paired with one or two shocks, demonstrating successful aversive learning. Importantly, participants administered more shocks to the faces paired with the most number of shocks when the opportunity was given during test. Also, our results revealed that aggressive traits (Buss and Perry Aggression scale) were associated with retaliation only toward CSs associated with aversive experiences. These two experiments show that aggressive traits, when paired with aversive learning experiences enhance the likelihood to act anti-socially toward others. PMID:27375520

Preventing the return of fear memories with postretrieval extinction: A human study using a burst of white noise as an aversive stimulus.

PubMed

Fernandez-Rey, Jose; Gonzalez-Gonzalez, Daniel; Redondo, Jaime

2018-06-07

Standard extinction procedures seem to imply an inhibition of the fear response, but not a modification of the original fear-memory trace, which remains intact (Bouton, 2002, 2004). Typically, the behavioral procedure used to modify this trace is the so-called postretrieval extinction, consisting of fear-memory reactivation followed by extinction applied within the reconsolidation window. However, the application of this technique yields mixed results, probably due to a series of boundary conditions that limit the effectiveness of postretrieval-extinction effects. In this study a number of potential, and hitherto unexplored, moderators of such effects are considered. Using an interval of 48 hr between extinction and re-extinction, the findings show a spontaneous recovery similar to that found in studies that use a 24-hr interval. Also, the use of intervals of 10 and 20 min between reactivation and extinction led to a similar fear return. Finally, the burst of white noise used as an unconditioned stimulus (US) here was shown to be as effective as the electric shock normally used in the study of fear-memory reconsolidation. These findings suggest that postretrieval extinction is an effective behavioral technique for modifying the original fear memory and for the elimination of the fear return. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Lesions of the entorhinal cortex or fornix disrupt the context-dependence of fear extinction in rats.

PubMed

Ji, Jinzhao; Maren, Stephen

2008-12-12

Recent studies have shown that the hippocampus is critical for the context-dependent expression of extinguished fear memories. Here we used Pavlovian fear conditioning in rats to explore whether the entorhinal cortex and fornix, which are the major cortical and subcortical interfaces of the hippocampus, are also involved in the context-dependence of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US) in one context, rats received an extinction session in which the CS was presented without the US in another context. Conditional fear to the CS was then tested in either the extinction context or a third familiar context; freezing behavior served as the index of fear. Sham-operated rats exhibited little conditional freezing to the CS in the extinction context, but showed a robust renewal of fear when tested outside of the extinction context. In contrast, rats with neurotoxic lesions in the entorhinal cortex or electrolytic lesions in the fornix did not exhibit a renewal of fear when tested outside the extinction context. Impairments in freezing behavior to the auditory CS were not able to account for the observed results, insofar as rats with either entorhinal cortex or fornix lesions exhibited normal freezing behavior during the conditioning session. Thus, contextual memory retrieval requires not only the hippocampus proper, but also its cortical and subcortical interfaces.

Autoshaping induces ethanol drinking in nondeprived rats: evidence of long-term retention but no induction of ethanol preference.

PubMed

Tomie, Arthur; Kuo, Teresa; Apor, Khristine R; Salomon, Kimberly E; Pohorecky, Larissa A

2004-04-01

The effects of autoshaping procedures (paired vs. random) and sipper fluid (ethanol vs. water) on sipper-directed drinking were evaluated in male Long-Evans rats maintained with free access to food and water. For the paired/ethanol group (n=16), autoshaping procedures consisted of presenting the ethanol sipper (containing 0% to 28% unsweetened ethanol) conditioned stimulus (CS) followed by the response-independent presentation of food unconditioned stimulus (US). The random/ethanol group (n=8) received the sipper CS and food US randomly with respect to one another. The paired/water group (n=8) received only water in the sipper CS. The paired/ethanol group showed higher grams per kilogram ethanol intake than the random/ethanol group did at ethanol concentrations of 8% to 28%. The paired/ethanol group showed higher sipper CS-directed milliliter fluid consumption than the paired/water group did at ethanol concentrations of 1% to 6%, and 15%, 16%, 18%, and 20%. Following a 42-day retention interval, the paired/ethanol group showed superior retention of CS-directed drinking of 18% ethanol, relative to the random/ethanol group, and superior retention of CS-directed milliliter fluid drinking relative to the paired/water group. When tested for home cage ethanol preference using limited access two-bottle (28% ethanol vs. water) procedures, the paired/ethanol and random/ethanol groups did not differ on any drinking measures.

Autoshaping of chlordiazepoxide drinking in non-deprived rats.

PubMed

Tomie, Arthur; Wong, Lauren E; Pohorecky, Larissa A

2005-02-28

Effects of autoshaping procedures (Paired versus Random) and sipper fluid [chlordiazepoxide (CDP) versus water] on sipper-directed drinking were evaluated in 32 male Long-Evans rats maintained with free access to food and water. For the Paired/CDP group (n = 16), autoshaping procedures consisted of the presentation of the CDP sipper conditioned stimulus (CS) followed by the response-independent presentation of the food unconditioned stimulus (US). The concentration of CDP in the sipper CS (0.05, 0.10, 0.15, 0.20, and 0.25 mg/ml CDP) was increased across sessions. The Paired/Water group (n = 8) received only water in the sipper CS. The Random/CDP group (n = 8) received the CDP sipper CS and food US randomly with respect to one another. The Paired/CDP group drank significantly more of the 0.20 mg/ml and 0.25 mg/ml CDP solutions than the Random/CDP control, and more fluid than the Paired/Water control group when the sipper CS for the Paired/CDP group contained the three highest concentrations of CDP. CS-Only extinction procedures reliably reduced sipper CS-directed drinking in the Paired/CDP and the Paired/Water groups, but not in the Random/CDP group. Data are consistent with the hypothesis that Pavlovian autoshaping procedures induce sipper CS-directed drinking of CDP in rats deprived of neither food nor fluid. Implications for the autoshaping model of drug abuse are discussed.

Enhanced cell survival and paracrine effects of mesenchymal stem cells overexpressing hepatocyte growth factor promote cardioprotection in myocardial infarction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhao, Liyan; Liu, Xiaolin; Zhang, Yuelin

Poor cell survival post transplantation compromises the therapeutic benefits of mesenchymal stem cells (MSCs) in myocardial infarction (MI). Hepatocyte growth factor (HGF) is an important cytokine for angiogenesis, anti-inflammation and anti-apoptosis. This study aimed to evaluate the cardioprotective effects of MSCs overexpressing HGF in a mouse model of MI. The apoptosis of umbilical cord-derived MSCs (UC-MSCs) and HGF-UC-MSCs under normoxic and hypoxic conditions was detected. The conditioned medium (CdM) of UC-MSCs and HGF-UC-MSCs under a hypoxic condition was harvested and its protective effect on neonatal cardiomyocytes (NCMs) exposed to a hypoxic challenge was examined. UC-MSCs and HGF-UC-MSCs were transplanted intomore » the peri-infarct region in mice following MI and heart function assessed 4 weeks post transplantation. The apoptosis of HGF-UC-MSCs under hypoxic conditions was markedly decreased compared with that of UC-MSCs. NCMs treated with HGF-UC-MSC hypoxic CdM (HGF-UC-MSCs-hy-CdM) exhibited less cell apoptosis in response to hypoxic challenge than those treated with UC-MSC hypoxic CdM (UC-MSCs-hy-CdM). HGF-UC-MSCs-hy-CdM released the inhibited p-Akt and lowered the enhanced ratio of Bax/Bcl-2 induced by hypoxia in the NCMs. HGF-UC-MSCs-hy-CdM expressed higher levels of HGF, EGF, bFGF and VEGF than UC-MSCs-hy-CdM. Transplantation of HGF-UC-MSCs or UC-MSCs greatly improved heart function in the mouse model of MI. Compared with UC-MSCs, transplantation of HGF-UC-MSCs was associated with less cardiomyocyte apoptosis, enhanced angiogenesis and increased proliferation of cardiomyocytes. This study may provide a novel therapeutic strategy for MSC-based therapy in cardiovascular disease.« less

The potential of volatile organic compounds for the detection of active disease in patients with ulcerative colitis.

PubMed

Smolinska, A; Bodelier, A G L; Dallinga, J W; Masclee, A A M; Jonkers, D M; van Schooten, F-J; Pierik, M J

2017-05-01

To optimise treatment of ulcerative colitis (UC), patients need repeated assessment of mucosal inflammation. Current non-invasive biomarkers and clinical activity indices do not accurately reflect disease activity in all patients and cannot discriminate UC from non-UC colitis. Volatile organic compounds (VOCs) in exhaled air could be predictive of active disease or remission in Crohn's disease. To investigate whether VOCs are able to differentiate between active UC, UC in remission and non-UC colitis. UC patients participated in a 1-year study. Clinical activity index, blood, faecal and breath samples were collected at each out-patient visit. Patients with clear defined active faecal calprotectin >250 μg/g and inactive disease (Simple Clinical Colitis Activity Index <3, C-reactive protein <5 mg/L and faecal calprotectin <100 μg/g) were included for cross-sectional analysis. Non-UC colitis was confirmed by stool culture or radiological evaluation. Breath samples were analysed by gas chromatography time-of-flight mass spectrometry and kernel-based method to identify discriminating VOCs. In total, 72 UC (132 breath samples; 62 active; 70 remission) and 22 non-UC-colitis patients (22 samples) were included. Eleven VOCs predicted active vs. inactive UC in an independent internal validation set with 92% sensitivity and 77% specificity (AUC 0.94). Non-UC colitis patients could be clearly separated from active and inactive UC patients with principal component analysis. Volatile organic compounds can accurately distinguish active disease from remission in UC and profiles in UC are clearly different from profiles in non-UC colitis patients. VOCs have demonstrated potential as new non-invasive biomarker to monitor inflammation in UC. © 2017 John Wiley & Sons Ltd.

An evaluation of resistance to change with unconditioned and conditioned reinforcers.

PubMed

Vargo, Kristina K; Ringdahl, Joel E

2015-09-01

Several reinforcer-related variables influence a response's resistance to change (Nevin, 1974). Reinforcer type (i.e., conditioned or unconditioned) is a reinforcer-related variable that has not been studied with humans but may have clinical implications. In Experiment 1, we identified unconditioned and conditioned reinforcers of equal preference. In Experiments 2, 3, and 4, we reinforced participants' behavior during a baseline phase using a multiple variable-interval (VI) 30-s VI 30-s schedule with either conditioned (i.e., token) or unconditioned (i.e., food; one type of reinforcement in each component) reinforcement. After equal reinforcement rates across components, we introduced a disruptor. Results of Experiments 2 and 3 showed that behaviors were more resistant to extinction and distraction, respectively, with conditioned than with unconditioned reinforcers. Results of Experiment 4, however, showed that when prefeeding disrupted responding, behaviors were more resistant to change with unconditioned reinforcers than with conditioned reinforcers. © Society for the Experimental Analysis of Behavior.

Involvement of WNT Signaling in the Regulation of Gestational Age-Dependent Umbilical Cord-Derived Mesenchymal Stem Cell Proliferation

PubMed Central

Shono, Akemi; Yoshida, Makiko; Yamana, Keiji; Thwin, Khin Kyae Mon; Kuroda, Jumpei; Kurokawa, Daisuke; Koda, Tsubasa; Nishida, Kosuke; Ikuta, Toshihiko; Mizobuchi, Masami; Taniguchi-Ikeda, Mariko

2017-01-01

Mesenchymal stem cells (MSCs) are a heterogeneous cell population that is isolated initially from the bone marrow (BM) and subsequently almost all tissues including umbilical cord (UC). UC-derived MSCs (UC-MSCs) have attracted an increasing attention as a source for cell therapy against various degenerative diseases due to their vigorous proliferation and differentiation. Although the cell proliferation and differentiation of BM-derived MSCs is known to decline with age, the functional difference between preterm and term UC-MSCs is poorly characterized. In the present study, we isolated UC-MSCs from 23 infants delivered at 22–40 weeks of gestation and analyzed their gene expression and cell proliferation. Microarray analysis revealed that global gene expression in preterm UC-MSCs was distinct from term UC-MSCs. WNT signaling impacts on a variety of tissue stem cell proliferation and differentiation, and its pathway genes were enriched in differentially expressed genes between preterm and term UC-MSCs. Cell proliferation of preterm UC-MSCs was significantly enhanced compared to term UC-MSCs and counteracted by WNT signaling inhibitor XAV939. Furthermore, WNT2B expression in UC-MSCs showed a significant negative correlation with gestational age (GA). These results suggest that WNT signaling is involved in the regulation of GA-dependent UC-MSC proliferation. PMID:29138639

Reciprocal responsiveness of nucleus accumbens shell and core dopamine to food- and drug-conditioned stimuli.

PubMed

Bassareo, Valentina; Musio, Paolo; Di Chiara, Gaetano

2011-04-01

Drugs of abuse and palatable food share the ability to stimulate dopamine (DA) transmission in the nucleus accumbens shell. However, while the stimulation of shell DA by food undergoes habituation, that by drugs of abuse does not. This study aims to directly compare the changes of extracellular DA, by microdialysis, in shell and core and prefrontal cortex (PFCX) in response to food- and drug-conditioned stimuli (CSs). Rats were trace-conditioned by Fonzies box (FB) or vanilla box (VB; CS), followed by food: Fonzies, intraoral chocolate solution (food-unconditioned stimulus (US)) and morphine (1.0 mg/Kg sc; drug US). Control (unconditioned) rats received standard food instead of Fonzies, tap water instead of chocolate, saline instead of morphine. Food-CSs increased core but not shell DA, while drug-CSs did the opposite. Food and drug-CSs both increased PFCX DA. Exposure to food-CSs potentiated core and PFCX DA response to food while shell responsiveness was dependent upon the relative CS and US nature. If the CS was intrinsic to the food US (CS = FB/US = Fonzies) the response of shell DA to the US was abolished. If the CS was extrinsic to the food US (CS = FB/US = chocolate; CS = VB/US = Fonzies), shell DA increased in response to the US. Exposure to the drug-CS potentiated the DA response to the drug-US in the shell and in the PFCX, but not in the core. Drug-CSs differentially activate DA as compared to food-CSs in shell and core and differentially affect DA response to the US in these areas. These differences might be relevant for the role of DA in the mechanism of drug addiction.

Adolescents' unconditional acceptance by parents and teachers and educational outcomes: A structural model of gender differences.

PubMed

Makri-Botsari, Evi

2015-08-01

The purpose of this study was to detect gender specific patterns in the network of relations between unconditionality of parental and teacher acceptance in the form of unconditional positive regard and a range of educational outcomes, as indexed by academic self-perception, academic intrinsic motivation, and academic achievement. To test the role of gender as a moderator, a multi-group analysis was employed within the framework of structural equation modelling with increasing restrictions placed on the structural paths across genders. The results on a sample of 427 adolescents in grades 7-9 showed that conditionality of acceptance undermined level of perceived acceptance for both social agents. Moreover, unconditionality of teacher acceptance exerted stronger influences on students' educational outcomes than unconditionality of parental acceptance, with effect sizes being larger for girls than for boys. Copyright © 2015 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

Characterization of Intestinal Microbiota in Ulcerative Colitis Patients with and without Primary Sclerosing Cholangitis.

PubMed

Kevans, D; Tyler, A D; Holm, K; Jørgensen, K K; Vatn, M H; Karlsen, T H; Kaplan, G G; Eksteen, B; Gevers, D; Hov, J R; Silverberg, M S

2016-03-01

There is an unexplained association between ulcerative colitis [UC] and primary sclerosing cholangitis [PSC], with the intestinal microbiota implicated as an important factor. The study aim was to compare the structure of the intestinal microbiota of patients with UC with and without PSC. UC patients with PSC [PSC-UC] and without PSC [UC] were identified from biobanks at Oslo University Hospital, Foothills Hospital Calgary and Mount Sinai Hospital Toronto. Microbial DNA was extracted from colonic tissue and sequencing performed of the V4 region of the 16S rRNA gene on Illumina MiSeq. Sequences were assigned to operational taxonomic units [OTUs] using Quantitative Insights Into Microbial Ecology [QIIME]. Microbial alpha diversity, beta diversity, and relative abundance were compared between PSC-UC and UC phenotypes. In all, 31 PSC-UC patients and 56 UC patients were included. Principal coordinate analysis [PCoA] demonstrated that city of sample collection was the strongest determinant of taxonomic profile. In the Oslo cohort, Chao 1 index was modestly decreased in PSC-UC compared with UC [p = 0.04] but did not differ significantly in the Calgary cohort. No clustering by PSC phenotype was observed using beta diversity measures. For multiple microbial genera there were nominally significant differences between UC and PSC-UC, but results were not robust to false-discovery rate correction. No strong PSC-specific microbial associations in UC patients consistent across different cohorts were identified. Recruitment centre had a strong effect on microbial composition. Future studies should include larger cohorts to increase power and the ability to control for confounding factors. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Appendectomy does not decrease the risk of future colectomy in UC: results from a large cohort and meta-analysis.

PubMed

Parian, Alyssa; Limketkai, Berkeley; Koh, Joyce; Brant, Steven R; Bitton, Alain; Cho, Judy H; Duerr, Richard H; McGovern, Dermot P; Proctor, Deborah D; Regueiro, Miguel D; Rioux, John D; Schumm, Phil; Taylor, Kent D; Silverberg, Mark S; Steinhart, A Hillary; Hernaez, Ruben; Lazarev, Mark

2017-08-01

Early appendectomy is inversely associated with the development of UC. However, the impact of appendectomy on the clinical course of UC is controversial, generally favouring a milder disease course. We aim to describe the effect appendectomy has on the disease course of UC with focus on the timing of appendectomy in relation to UC diagnosis. Using the National Institute of Diabetes and Digestive and Kidney Diseases Inflammatory Bowel Disease Genetics Consortium database of patients with UC, the risk of colectomy was compared between patients who did and did not undergo appendectomy. In addition, we performed a meta-analysis of studies that examined the association between appendectomy and colectomy. 2980 patients with UC were initially included. 111 (4.4%) patients with UC had an appendectomy; of which 63 were performed prior to UC diagnosis and 48 after diagnosis. In multivariable analysis, appendectomy performed at any time was an independent risk factor for colectomy (OR 1.9, 95% CI 1.1 to 3.1), with appendectomy performed after UC diagnosis most strongly associated with colectomy (OR 2.2, 95% CI 1.1 to 4.5). An updated meta-analysis showed appendectomy performed either prior to or after UC diagnosis had no effect on colectomy rates. Appendectomy performed at any time in relation to UC diagnosis was not associated with a decrease in severity of disease. In fact, appendectomy after UC diagnosis may be associated with a higher risk of colectomy. These findings question the proposed use of appendectomy as treatment for UC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Approaches to improve the stability of the antiviral agent UC781 in aqueous solutions.

PubMed

Damian, Festo; Fabian, Judit; Friend, David R; Kiser, Patrick F

2010-08-30

In this work, we evaluated the chemical stability profiles of UC781 based solutions to identify excipients that stabilize the microbicidal agent UC781. When different antioxidants were added to UC781 in sulfobutylether-beta-cyclodextrin (SBE-beta-CD) solutions and subjected to a 50 degrees C stability study, it was observed that EDTA was a better stabilizing agent than sodium metabisulfite, glutathione or ascorbic acid. Some antioxidants accelerated the degradation of UC781, suggesting metal-catalyzed degradation of UC781. Furthermore, we observed substantial degradation of UC781 when stored in 1% Tween 80 and 1% DMSO solutions alone or in those with 10mM EDTA. On the other hand, improved stability of UC781 in the presence of 100 and 200mM of EDTA was observed in these solutions. The addition of both EDTA and citric acid in the stock solutions resulted in recovery of more than 60% of UC781 after 12 weeks. Generally, 10% SBE-beta-CD in the presence of EDTA and citric acid stabilized UC781 solutions: the amount of UC781 recovered approaching 95% after 12 weeks of storage at 40 degrees C. We also showed that the desulfuration reaction of the UC781 thioamide involves oxygen by running solution stability studies in deoxygenated media. Improved stability of UC781 in the present study indicates that the incorporation of EDTA, citric acid and SBE-beta-CD and the removal of oxygen in formulations of this drug will aid in increasing the stability of UC781 where solutions of the drug are required. Published by Elsevier B.V.

Disposition and metabolism of 2,3-( UC)dichloropropene in rats after inhalation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bond, J.A.; Medinsky, M.A.; Dutcher, J.S.

1985-01-01

2,3-Dichloropropene (2,3-DCP) is a constituent of some commercially available preplant soil fumigants for the control of plant parasitic nematodes. The purpose of this investigation was to determine the disposition and metabolism of 2,3-( UC)DCP in rats after inhalation. Male Fischer-344 rats were exposed nose-only to a vapor concentration of 250 nmol 2,3-( UC)DCP/liter air (7.5 ppm; 25C, 620 Torr) for 6 hr. Blood samples were taken during exposure, and urine, feces, expired air, and tissues were collected for up to 65 hr after exposure. Urinary excretion was the major route of elimination of UC (55% of estimated absorbed 2,3-DCP). Half-timemore » for elimination of UC in urine was 9.8 +/- 0.05 hr (anti x +/- SE). Half-time for elimination of UC feces (17% of absorbed 2,3-DCP) was 12.9 +/- 0.14 hr (anti x +/- SE). Approximately 1 and 3% of the estimated absorbed 2,3-( UC)DCP were exhaled as either 2,3-( UC)DCP or UCO2, respectively. Concentrations of UC in blood increased during 240 min of exposure, after which no further increases in blood concentration of UC were seen. UC was widely distributed in tissues analyzed after a 6-hr exposure of rats to 2,3-( UC)DCP. Urinary bladder (150 nmol/g), nasal turbinates (125 nmol/g), kidneys (84 nmol/g), small intestine (61 nmol/g), and liver (35 nmol/g) were tissues with the highest concentrations of UC immediately after exposure. Over 90% of the UC in tissues analyzed was 2,3-DCP metabolites. Half-times for elimination of UC from tissues examined ranged from 3 to 11 hr. The data from this study indicate that after inhalation 2,3-DCP is metabolized in tissues and readily excreted. 21 references. 2 figures, 4 tables.« less

Human Umbilical Cord Mesenchymal Stem Cells: Subpopulations and Their Difference in Cell Biology and Effects on Retinal Degeneration in RCS Rats.

PubMed

Wang, L; Li, P; Tian, Y; Li, Z; Lian, C; Ou, Q; Jin, C; Gao, F; Xu, J-Y; Wang, J; Wang, F; Zhang, J; Zhang, J; Li, W; Tian, H; Lu, L; Xu, G-T

2017-01-01

Human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential candidates for treating retinal degeneration (RD). To further study the biology and therapeutic effects of the hUC-MSCs on retinal degeneration. Two hUC-MSC subpopulations, termed hUC-MSC1 and hUC-MSC2, were isolated by single-cell cloning method and their therapeutic functions were compared in RCS rat, a RD model. Although both subsets satisfied the basic requirements for hUC-MSCs, they were significantly different in morphology, proliferation rate, differentiation capacity, phenotype and gene expression. Furthermore, only the smaller, fibroblast-like, faster growing subset hUC-MSC1 displayed stronger colony forming potential as well as adipogenic and osteogenic differentiation capacities. When the two subsets were respectively transplanted into the subretinal spaces of RCS rats, both subsets survived, but only hUC-MSC1 expressed RPE cell markers Bestrophin and RPE65. More importantly, hUC-MSC1 showed stronger rescue effect on the retinal function as indicated by the higher b-wave amplitude on ERG examination, thicker retinal nuclear layer, and decreased apoptotic photoreceptors. When both subsets were treated with interleukin-6, mimicking the inflammatory environment when the cells were transplanted into the eyes with degenerated retina, hUC-MSC1 expressed much higher levels of trophic factors in comparison with hUC-MSC2. The data here, in addition to prove the heterogeneity of hUC-MSCs, confirmed that the stronger therapeutic effects of hUC-MSC1 were attributed to its stronger anti-apoptotic effect, paracrine of trophic factors and potential RPE cell differentiation capacity. Thus, the subset hUC-MSC1, not the other subset or the ungrouped hUC-MSCs should be used for effective treatment of RD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Receptivity of a Cryogenic Coaxial Gas-Liquid Jet to Acoustic Disturbances (Briefing Charts)

DTIC Science & Technology

2014-03-01

meas = Δt Δs Uc,meas 2/12/1 0 2/12/1 0 , i iio thc UUU      DISTRIBUTION STATEMENT A. Approved for public release; distribution unlimited...this point, dynamic pressures are approximately equal. Uc Uo – Uc Uc – Ui (Uo > Ui) 2/12/1 2/12/1 io iioo c UUU      St = Uc fnatD If St, D, Uc

Long-term outcome of patients with distal ulcerative colitis and inflammation of the appendiceal orifice.

PubMed

Naves, Juan E; Lorenzo-Zúñiga, Vicente; Marín, Laura; Mañosa, Míriam; Oller, Blanca; Moreno, Vicente; Zabana, Yamile; Boix, Jaume; Cabré, Eduard; Domènech, Eugeni

2011-12-01

Skip inflammation of the appendiceal orifice has been described in distal UC (UC-IAO) but long-term clinical outcomes are poorly established. Our aim was to evaluate the long-term clinical outcomes of UC-IAO as compared to classic distal UC. Patients with UC-IAO were identified from the local IBD database. Disease outcome and therapeutic requirements during follow-up were accurately collected, and compared with a control group of patients with distal UC without peri-appendiceal involvement matched by disease extent (proctitis/distal), smoking habit, and date and age at diagnosis. Fourteen UC patients were found to have UC-IAO, most of them with initial extent of UC limited to the rectum. All patients were initially managed with mesalazine administered orally (28.5%), topically (28.5%), or in combination (43%). After a median follow-up of 78 months (interquartile range--IQR 45-123) most UC-IAO patients were successfully managed with oral and/or topical aminosalicylates. Only one of them developed proximal disease progression. As compared to controls, no differences in clinical outcomes or therapeutic requirements were found. Patients with UC-IAO tend to present a mild course, with a low probability to develop proximal progression of disease extent or to require immunosuppressive therapy or colectomy.

The influence of emotion down-regulation on the expectation of sexual reward.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Cousijn, Janna; Both, Stephanie

2015-05-01

Emotion regulation research has shown successful altering of unwanted aversive emotional reactions. Cognitive strategies can also regulate expectations of reward arising from conditioned stimuli. However, less is known about the efficacy of such strategies with expectations elicited by conditioned appetitive sexual stimuli, and possible sex differences therein. In the present study it was examined whether a cognitive strategy (attentional deployment) could successfully down-regulate sexual arousal elicited by sexual reward-conditioned cues in men and women. A differential conditioning paradigm was applied, with genital vibrostimulation as unconditioned stimulus (US) and sexually relevant pictures as conditional stimuli (CSs). Evidence was found for emotion down-regulation to effect extinction of conditioned sexual responding in men. In women, the emotion down-regulatory strategy resulted in attenuated conditioned approach tendencies towards the CSs. The findings support that top-down modulation may indeed influence conditioned sexual responses. This knowledge may have implications for treating disturbances in sexual appetitive responses. Copyright © 2015. Published by Elsevier Ltd.

Fear of losing money? Aversive conditioning with secondary reinforcers.

PubMed

Delgado, M R; Labouliere, C D; Phelps, E A

2006-12-01

Money is a secondary reinforcer that acquires its value through social communication and interaction. In everyday human behavior and laboratory studies, money has been shown to influence appetitive or reward learning. It is unclear, however, if money has a similar impact on aversive learning. The goal of this study was to investigate the efficacy of money in aversive learning, comparing it with primary reinforcers that are traditionally used in fear conditioning paradigms. A series of experiments were conducted in which participants initially played a gambling game that led to a monetary gain. They were then presented with an aversive conditioning paradigm, with either shock (primary reinforcer) or loss of money (secondary reinforcer) as the unconditioned stimulus. Skin conductance responses and subjective ratings indicated that potential monetary loss modulated the conditioned response. Depending on the presentation context, the secondary reinforcer was as effective as the primary reinforcer during aversive conditioning. These results suggest that stimuli that acquire reinforcing properties through social communication and interaction, such as money, can effectively influence aversive learning.

Central localization of plasticity involved in appetitive conditioning in Lymnaea

PubMed Central

Straub, Volko A.; Styles, Benjamin J.; Ireland, Julie S.; O'Shea, Michael; Benjamin, Paul R.

2004-01-01

Learning to associate a conditioned (CS) and unconditioned stimulus (US) results in changes in the processing of CS information. Here, we address directly the question whether chemical appetitive conditioning of Lymnaea feeding behavior involves changes in the peripheral and/or central processing of the CS by using extracellular recording techniques to monitor neuronal activity at two stages of the sensory processing pathway. Our data show that appetitive conditioning does not affect significantly the overall CS response of afferent nerves connecting chemosensory structures in the lips and tentacles to the central nervous system (CNS). In contrast, neuronal output from the cerebral ganglia, which represent the first central processing stage for chemosensory information, is enhanced significantly in response to the CS after appetitive conditioning. This demonstrates that chemical appetitive conditioning in Lymnaea affects the central, but not the peripheral processing of chemosensory information. It also identifies the cerebral ganglia of Lymnaea as an important site for neuronal plasticity and forms the basis for detailed cellular studies of neuronal plasticity. PMID:15537733

The conditioning and extinction of fear in youths: What’s sex got to do with it?

PubMed Central

Chauret, Mélissa; La Buissonnière-Ariza, Valérie; Tremblay, Vickie Lamoureux; Suffren, Sabrina; Servonnet, Alice; Pine, Daniel S.; Maheu, Françoise S.

2015-01-01

Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10–17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses. PMID:24929048

Embodied simulation as part of affective evaluation processes: task dependence of valence concordant EMG activity.

PubMed

Weinreich, André; Funcke, Jakob Maria

2014-01-01

Drawing on recent findings, this study examines whether valence concordant electromyography (EMG) responses can be explained as an unconditional effect of mere stimulus processing or as somatosensory simulation driven by task-dependent processing strategies. While facial EMG over the Corrugator supercilii and the Zygomaticus major was measured, each participant performed two tasks with pictures of album covers. One task was an affective evaluation task and the other was to attribute the album covers to one of five decades. The Embodied Emotion Account predicts that valence concordant EMG is more likely to occur if the task necessitates a somatosensory simulation of the evaluative meaning of stimuli. Results support this prediction with regard to Corrugator supercilii in that valence concordant EMG activity was only present in the affective evaluation task but not in the non-evaluative task. Results for the Zygomaticus major were ambiguous. Our findings are in line with the view that EMG activity is an embodied part of the evaluation process and not a mere physical outcome.

The effects of area postrema lesions and selective vagotomy on motion-induced conditioned taste aversion

NASA Technical Reports Server (NTRS)

Fox, Robert A.; Sutton, R. L.; Mckenna, Susan

1991-01-01

Conditioned taste aversion (CTA) is one of several behaviors which was suggested as a putative measure of motion sickness in rats. A review is made of studies which used surgical disruption of area postrema or the vagus nerve to investigate whether CTA and vomiting induced by motion may depend on common neural pathways or structures. When the chemoreceptive function of the area postrema (AP) is destroyed by complete ablation, rats develop CTA and cats and monkeys develop CTA and vomit. Thus the AP is not crucially involved in either CTA or vomiting induced by motion. However, after complete denervation of the stomach or after labyrinthectomy rats do not develop CTA when motion is used as the unconditioned stimulus. Studies of brainstem projections of the vagus nerve, the area postrema, the periaqueductal grey, and the vestibular system are used as the basis for speculation about regions which could mediate both motion-induced vomiting and behavioral food aversion.

Stress hormones are associated with the neuronal correlates of instructed fear conditioning.

PubMed

Merz, Christian Josef; Stark, Rudolf; Vaitl, Dieter; Tabbert, Katharina; Wolf, Oliver Tobias

2013-01-01

The effects of sex and stress hormones on classical fear conditioning have been subject of recent experimental studies. A correlation approach between basal cortisol concentrations and neuronal activation in fear-related structures seems to be a promising alternative approach in order to foster our understanding of how cortisol influences emotional learning. In this functional magnetic resonance imaging study, participants with varying sex hormone status (20 men, 15 women taking oral contraceptives, 15 women tested in the luteal phase) underwent an instructed fear conditioning protocol with geometrical figures as conditioned stimuli and an electrical stimulation as unconditioned stimulus. Salivary cortisol concentrations were measured and afterwards correlated with fear conditioned brain responses. Results revealed a positive correlation between basal cortisol levels and differential activation in the amygdala in men and OC women only. These results suggest that elevated endogenous cortisol levels are associated with enhanced fear anticipation depending on current sex hormone availability. Copyright © 2012 Elsevier B.V. All rights reserved.

A System Computational Model of Implicit Emotional Learning

PubMed Central

Puviani, Luca; Rama, Sidita

2016-01-01

Nowadays, the experimental study of emotional learning is commonly based on classical conditioning paradigms and models, which have been thoroughly investigated in the last century. Unluckily, models based on classical conditioning are unable to explain or predict important psychophysiological phenomena, such as the failure of the extinction of emotional responses in certain circumstances (for instance, those observed in evaluative conditioning, in post-traumatic stress disorders and in panic attacks). In this manuscript, starting from the experimental results available from the literature, a computational model of implicit emotional learning based both on prediction errors computation and on statistical inference is developed. The model quantitatively predicts (a) the occurrence of evaluative conditioning, (b) the dynamics and the resistance-to-extinction of the traumatic emotional responses, (c) the mathematical relation between classical conditioning and unconditioned stimulus revaluation. Moreover, we discuss how the derived computational model can lead to the development of new animal models for resistant-to-extinction emotional reactions and novel methodologies of emotions modulation. PMID:27378898

A System Computational Model of Implicit Emotional Learning.

PubMed

Puviani, Luca; Rama, Sidita

2016-01-01

Nowadays, the experimental study of emotional learning is commonly based on classical conditioning paradigms and models, which have been thoroughly investigated in the last century. Unluckily, models based on classical conditioning are unable to explain or predict important psychophysiological phenomena, such as the failure of the extinction of emotional responses in certain circumstances (for instance, those observed in evaluative conditioning, in post-traumatic stress disorders and in panic attacks). In this manuscript, starting from the experimental results available from the literature, a computational model of implicit emotional learning based both on prediction errors computation and on statistical inference is developed. The model quantitatively predicts (a) the occurrence of evaluative conditioning, (b) the dynamics and the resistance-to-extinction of the traumatic emotional responses, (c) the mathematical relation between classical conditioning and unconditioned stimulus revaluation. Moreover, we discuss how the derived computational model can lead to the development of new animal models for resistant-to-extinction emotional reactions and novel methodologies of emotions modulation.

Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans.

PubMed

Indovina, Iole; Robbins, Trevor W; Núñez-Elizalde, Anwar O; Dunn, Barnaby D; Bishop, Sonia J

2011-02-10

Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety. Copyright © 2011 Elsevier Inc. All rights reserved.

Receptivity of a Cryogenic Coaxial Liquid Jet to Acoustic Disturbances

DTIC Science & Technology

2014-05-21

i iio thc UUU DISTRIBUTION STATEMENT A. Approved for public release; distribution unlimited. PA Clearance 14208 12Place Proper DISTRIBUTION STATEMENT...dynamic pressures are approximately equal. Uc Uo – Uc Uc – Ui (Uo > Ui) 2/12/1 2/12/1 io iioo c UUU St = Uc fnatD If St, D, Uc are held constant then

Comparing the context specificity of extinction and latent inhibition.

PubMed

Miller, Ralph R; Laborda, Mario A; Polack, Cody W; Miguez, Gonzalo

2015-12-01

Exposure to a cue alone either before (i.e., latent inhibition treatment) or after (i.e., extinction) the cue is paired with an unconditioned stimulus results in attenuated conditioned responding to the cue. Here we report two experiments in which potential parallels between the context specificity of the effects of extinction and latent inhibition treatments were directly compared in a lick suppression preparation with rats. The reversed ordering of conditioning and nonreinforcement in extinction and latent inhibition designs allowed us to examine the effect of training order on the context specificity of what is learned given phasic reinforcement and nonreinforcement of a target cue. Experiment 1 revealed that when conditioned-stimulus (CS) conditioning and CS nonreinforcement were administered in the same context, both extinction and latent inhibition treatments had reduced impacts on test performance, relative to excitatory conditioning when testing occurred outside the treatment context. Similarly, Experiment 2 showed that when conditioning was administered in one context and nonreinforcement was administered in a second context, the effects of both extinction and latent inhibition treatments were attenuated when testing occurred in a neutral context, relative to the context in which the CS was nonreinforced. The observed context specificity of extinction and latent inhibition treatments has been previously reported in both cases, but not in a single experiment under otherwise identical conditions. The results of the two experiments convergently suggest that memory of nonreinforcement becomes context dependent after a cue is both reinforced and nonreinforced, independent of the order of training.

DCS facilitation of fear extinction and exposure-based therapy may rely on lower-level, automatic mechanisms

PubMed Central

Grillon, Christian

2009-01-01

Exposure-based therapy (EBT), a leading technique in the treatment of a range of anxiety disorders, is facilitated by D-cycloserine (DCS), a partial N-methyl-D-aspartate (NMDA) receptor agonist. This review discusses the potential mechanisms involved in this facilitation, and its implications for developing theories of fear conditioning in humans. Basic research in rodents suggests that DCS acts by speeding up extinction. However, several lab-based investigations found that DCS had no effect on extinction in humans. This paper proposes that these observations can be accounted for by a dual-model theory of fear conditioning in humans that engages two complementary defensive systems: a reflexive lower-order system independent of conscious awareness and a higher-order cognitive system associated with conscious awareness of danger and expectation. DCS studies in animals appear to have explored lower-order conditioning mechanisms, whereas human studies have explored higher-order cognitive processes. These observations suggest that DCS may act preferentially on lower- rather than higher-order learning. This paper presents evidence suggesting that, in humans, DCS may similarly affect lower-order learning during EBT and, consequently, may be less effective during cognitive therapy (e.g., cognitive restructuring). Finally, it is recommended that extinction studies using DCS in humans be conducted using fear-relevant stimuli (e.g., snakes), short conditional stimulus-unconditioned stimulus (CS-US) intervals, and intense US in order to promote lower-order conditioning processes. PMID:19520359

Transient inhibition of protein synthesis in the rat insular cortex delays extinction of conditioned taste aversion with cyclosporine A.

PubMed

Hadamitzky, Martin; Orlowski, Kathrin; Schwitalla, Jan Claudius; Bösche, Katharina; Unteroberdörster, Meike; Bendix, Ivo; Engler, Harald; Schedlowski, Manfred

2016-09-01

Conditioned responses gradually weaken and eventually disappear when subjects are repeatedly exposed to the conditioned stimulus (CS) in the absence of the unconditioned stimulus (US), a process called extinction. Studies have demonstrated that extinction of conditioned taste aversion (CTA) can be prevented by interfering with protein synthesis in the insular cortex (IC). However, it remained unknown whether it is possible to pharmacologically stabilize the taste aversive memory trace over longer periods of time. Thus, the present study aimed at investigating the time frame during which extinction of CTA can be efficiently prevented by blocking protein synthesis in the IC. Employing an established conditioning paradigm in rats with saccharin as CS, and the immunosuppressant cyclosporine A (CsA) as US, we show here that daily bilateral intra-insular injections of the protein synthesis inhibitor anisomycin (120μg/μl) immediately after retrieval significantly diminished CTA extinction over a period of five retrieval days and subsequently reached levels of saline-infused controls. These findings demonstrate that it is possible to efficiently delay but not to fully prevent CTA extinction during repeated retrieval trials by blocking protein translation with daily bilateral infusions of anisomycin in the IC. These data confirm and extent earlier reports indicating that the role of protein synthesis in CTA extinction learning is not limited to gastrointestinal malaise-inducing drugs such as lithium chloride (LiCl). Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of blonanserin on methamphetamine-induced disruption of latent inhibition and c-Fos expression in rats.

PubMed

Kuramashi, Aki; Abe, Hiroshi; Koganemaru, Go; Matsuo, Hisae; Ikeda, Tetsuya; Ebihara, Kosuke; Funahashi, Hideki; Takeda, Ryuichiro; Nishimori, Toshikazu; Ishida, Yasushi

2013-08-09

To clarify the psychopharmacological profile of blonanserin, a novel antipsychotic, we examined its effect on the methamphetamine-induced disruption of latent inhibition (LI) and the neural activation related to this effect in rats. To evaluate the LI, we used a conditioned emotional response in which a tone (conditioned stimulus) was paired with a mild foot shock (unconditioned stimulus). This paradigm was presented to rats licking water. Methamphetamine-induced (1.0mg/kg, i.p.) disruption of LI was significantly improved by the administration of a higher dose (3.0mg/kg, i.p.) of blonanserin and tended to be improved by 1.0-mg/kg blonanserin and 0.2-mg/kg haloperidol but not by a lower dose (0.3mg/kg) of blonanserin. Immunohistochemical examination showed blonanserin (3.0mg/kg, i.p.) increased c-Fos expression in the shell area but not in the core area of the nucleus accumbens while methamphetamine (3.0mg/kg, i.p.) produced the opposite expression pattern. Blonanserin also increased the number of c-Fos expressions in the central amygdala nucleus but not in the basolateral amygdala nucleus or the prefrontal cortex. Blonanserin ameliorates the methamphetamine-induced disruption of LI, as other antipsychotics do, and a neuronal activation and/or modulation of neurotransmission in the nucleus accumbens is related to the disruption of LI by methamphetamine and to its amelioration by blonanserin. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Extinction after fear memory reactivation fails to eliminate renewal in rats.

PubMed

Goode, Travis D; Holloway-Erickson, Crystal M; Maren, Stephen

2017-07-01

Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the extinction context. Rats first underwent Pavlovian fear conditioning with an auditory CS and footshock unconditional stimulus (US); freezing behavior served as the index of conditioned fear. Twenty-four hours later, the rats underwent a retrieval-extinction procedure. Specifically, 1h prior to extinction (45 CS-alone trials; 44 for rats receiving a CS reminder), fear memory was retrieved by either a single exposure to the CS alone, the US alone, a CS paired with the US, or exposure to the conditioning context itself. Over the next few days, conditional freezing to the extinguished CS was tested in the extinction and conditioning context in that order (i.e., an ABBA design). In the extinction context, rats that received a CS+US trial before extinction exhibited higher levels of conditional freezing than animals in all other groups, which did not differ from one another. In the renewal context, all groups showed renewal, and none of the reactivation procedures reduced renewal relative to a control group that did not receive a reactivation procedure prior to extinction. These data suggest retrieval-extinction procedures may have limited efficacy in preventing fear renewal. Copyright © 2017 Elsevier Inc. All rights reserved.

Building physiological toughness: Some aversive events during extinction may attenuate return of fear.

PubMed

Culver, Najwa C; Stevens, Stephan; Fanselow, Michael S; Craske, Michelle G

2018-03-01

Although exposure therapy is an effective treatment for anxiety disorders, fear sometimes returns following successful therapy. Recent literature in animal models indicates that incorporating some aversive events into extinction training may offset these return of fear effects. The effect of occasional reinforced extinction trials was investigated in a sample of thirty-nine participants using a fear conditioning and extinction paradigm. Participants either underwent traditional extinction procedures during which the conditional stimulus which had been paired with the unconditional stimulus (US) during acquisition training (CS+) was presented alone with no presentations of the US or partially reinforced extinction during which there were several unpredicted CS+/US pairings. As measured by skin conductance responses, physiological fear responding remained elevated during extinction for participants who experienced partially reinforced extinction; however, these participants demonstrated protection from rapid reacquisition effects. Results from the subjective US-expectancy ratings did not provide evidence of protection against rapid reacquisition in the partially reinforced extinction group; however, there was evidence of protection from spontaneous recovery effects. Lastly, as measured by valence ratings, it was unclear whether partially reinforced extinction provided protection from fear recovery effects. Although participants who experienced partially reinforced extinction demonstrated protection from rapid reacquisition as measured by skin conductance responses, they also demonstrated significantly higher levels of physiological fear responding during extinction which made the results of the spontaneous recovery test more difficult to interpret. Occasional CS-US pairings during extinction may protect against return of fear effects. Clinical implications are discussed. Published by Elsevier Ltd.

Pavlovian disgust conditioning as a model for contamination-based OCD: Evidence from an analogue study

PubMed Central

Armstrong, Thomas; Olatunji, Bunmi O.

2017-01-01

Pavlovian fear conditioning provides a model for anxiety-related disorders, including obsessive-compulsive disorder (OCD). However, disgust is the predominant emotional response to contamination, which is a common theme in OCD. The present study sought to identify disgust conditioning abnormalities that may underlie excessive contamination concerns relevant to OCD. Individuals high and low in contamination concern (HCC, n = 32; LCC, n = 30) completed an associative learning task in which one neutral face (conditioned stimulus; CS+) was followed by a disgusting image (unconditioned stimulus; US) and another neutral face (CS−) was unreinforced. Following this acquisition procedure, there was an extinction procedure in which both CSs were presented unreinforced. The groups did not show significant differences in discriminant responding to the CSs following acquisition. However, following extinction, the HCC group reported less reduction in their expectancy of the US following the CS+, and also reported greater disgust to the CS+, compared to the LCC group. Increased disgust to the CS+ following both acquisition and extinction was correlated with increased symptoms of contamination-based OCD and increased disgust sensitivity. Additionally, disgust sensitivity mediated group differences in disgust responding to the CS+ at acquisition and extinction. Also, failure to adjust US expectancy in response to extinction partially mediated group differences in disgust to the CS+ following extinction. Together, these findings suggest that excessive contamination concerns observed in OCD may be related to difficulty inhibiting acquired disgust, possibly due to elevated disgust sensitivity that characterizes the disorder. PMID:28391115

Disruptive Effect of Amphetamines on Pavlovian to Instrumental Transfer

PubMed Central

Hall, Darien A.; Gulley, Joshua M.

2010-01-01

Reward seeking behavior can be powerfully modulated by exposure to a conditioned stimulus (CS) that was previously associated with that reward. This can be demonstrated in a Pavlovian-to-instrumental transfer (PIT) task where presentation of a CS (e.g., tone and light) previously paired with a rewarding unconditioned stimulus (US; e.g., food) leads to increases in a behavioral response, such as a lever press, that was also paired with the same US. The transfer effect can be enhanced in rats by exposing them repeatedly to amphetamine after they have undergone Pavlovian conditioning and instrumental training. However, it is not clear if amphetamine injections given immediately after Pavlovian conditioning, which are predicted to enhance memory consolidation for the CS-US association, would also enhance the transfer effect. We tested this hypothesis by giving male, Sprague-Dawley rats i.p. injections of saline or drug (0.5, 1.0, or 3.0 mg/kg amphetamine or methamphetamine) immediately following Pavlovian conditioning sessions. We found that amphetamine, but not methamphetamine, enhanced Pavlovian approach behavior. During a subsequent PIT test done under extinction conditions, we found that rats given either drug, particularly at the highest dose, exhibited deficits in PIT relative to saline-treated controls. These results suggest that treatment with amphetamines after Pavlovian conditioning sessions, when memory consolidation of the CS-US association is hypothesized to occur, inhibits the ability of the CS to subsequently elicit reward-seeking behavior. PMID:20817041

Extinction during reconsolidation eliminates recovery of fear conditioned to fear-irrelevant and fear-relevant stimuli.

PubMed

Thompson, Alina; Lipp, Ottmar V

2017-05-01

Extant literature suggests that extinction training delivered during the memory reconsolidation period is superior to traditional extinction training in the reduction of fear recovery, as it targets the original fear memory trace. At present it is debated whether different types of fear memories are differentially sensitive to behavioral manipulations of reconsolidation. Here, we examined post-reconsolidation recovery of fear as a function of conditioned stimulus (CS) fear-relevance, using the unconditioned stimulus (US) to reactivate and destabilize conditioned fear memories. Participants (N = 56; 25 male; M = 24.39 years, SD = 7.71) in the US-reactivation and control group underwent differential fear conditioning to fear-relevant (spiders/snakes) and fear-irrelevant (geometric shapes) CSs on Day 1. On Day 2, participants received either reminded (US-reactivation) or non-reminded extinction training. Tests of fear recovery, conducted 24 h later, revealed recovery of differential electrodermal responding to both classes of CSs in the control group, but not in the US-reactivation group. These findings indicate that the US reactivation-extinction procedure eliminated recovery of extinguished responding not only to fear-irrelevant, but also to fear-relevant CSs. Contrasting previous reports, our findings show that post-reconsolidation recovery of conditioned responding is not a function of CS fear-relevance and that persistent reduction of fear, conditioned to fear-relevant CSs, can be achieved through behavioral manipulations of reconsolidation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pavlovian autoshaping procedures increase plasma corticosterone and levels of norepinephrine and serotonin in prefrontal cortex in rats.

PubMed

Tomie, Arthur; Tirado, Aidaluz D; Yu, Lung; Pohorecky, Larissa A

2004-08-12

Pavlovian autoshaping procedures provide for pairings of a small object conditioned stimulus (CS) with a rewarding substance unconditioned stimulus (US), resulting in the acquisition of complex sequences of CS-directed skeletal-motor responses or autoshaping conditioned responses (CRs). Autoshaping procedures induce higher post-session levels of corticosterone than in controls receiving CS and US randomly, and the enhanced post-session corticosterone levels have been attributed to the appetitive or arousal-inducing effects of autoshaping procedures. Enhanced corticosterone release can be induced by aversive stimulation or stressful situations, where it is often accompanied by higher levels of norepinephrine (NE) and serotonin (5-HT) in prefrontal cortex (PFC) but not in striatum (ST). Effects of autoshaping procedures on post-session corticosterone levels, NE contents in PFC, and 5-HT contents in PFC and ST were investigated in male Long-Evans rats. Post-session blood samples revealed higher corticosterone levels in the CS-US Paired group (n = 46) than in the CS-US Random control group (n = 21), and brain samples revealed higher levels of PFC NE and 5-HT in CS-US Paired group. Striatal 5-HT levels were unaltered by the autoshaping procedures. Autoshaping procedures provide for appetitive stimulation and induce an arousal-like state, as well as simultaneous stress-like changes in plasma corticosterone and monoamine levels in PFC. Autoshaping, therefore, may be useful for the study of endocrine and central processes associated with appetitive conditions.

Turning negative memories around: Contingency versus devaluation techniques.

PubMed

Dibbets, Pauline; Lemmens, Anke; Voncken, Marisol

2018-09-01

It is assumed that fear responses can be altered by changing the contingency between a conditioned stimulus (CS) and an unconditioned stimulus (US), or by devaluing the present mental representation of the US. The aim of the present study was to compare the efficacy of contingency- and devaluation-based intervention techniques on the diminishment in - and return of fear. We hypothesized that extinction (EXT, contingency-based) would outperform devaluation-based techniques regarding contingency measures, but that devaluation-based techniques would be most effective in reducing the mental representation of the US. Additionally, we expected that incorporations of the US during devaluation would result in less reinstatement of the US averseness. Healthy participants received a fear conditioning paradigm followed by one of three interventions: extinction (EXT, contingency-based), imagery rescripting (ImRs, devaluation-based) or eye movement desensitization and reprocessing (EMDR, devaluation-based). A reinstatement procedure and test followed the next day. EXT was indeed most successful in diminishing contingency-based US expectancies and skin conductance responses (SCRs), but all interventions were equally successful in reducing the averseness of the mental US representation. After reinstatement EXT showed lowest expectancies and SCRs; no differences were observed between the conditions concerning the mental US representation. A partial reinforcement schedule was used, resulting in a vast amount of contingency unaware participants. Additionally, a non-clinical sample was used, which may limit the generalizability to clinical populations. EXT is most effective in reducing conditioned fear responses. Copyright © 2018 Elsevier Ltd. All rights reserved.

Ulcerative colitis-associated colorectal cancer

PubMed Central

Yashiro, Masakazu

2014-01-01

The association between ulcerative colitis (UC) and colorectal cancer (CRC) has been acknowledged. One of the most serious and life threatening consequences of UC is the development of CRC (UC-CRC). UC-CRC patients are younger, more frequently have multiple cancerous lesions, and histologically show mucinous or signet ring cell carcinomas. The risk of CRC begins to increase 8 or 10 years after the diagnosis of UC. Risk factors for CRC with UC patients include young age at diagnosis, longer duration, greater anatomical extent of colonic involvement, the degree of inflammation, family history of CRC, and presence of primary sclerosing cholangitis. CRC on the ground of UC develop from non-dysplastic mucosa to indefinite dysplasia, low-grade dysplasia, high-grade dysplasia and finally to invasive adenocarcinoma. Colonoscopy surveillance programs are recommended to reduce the risk of CRC and mortality in UC. Genetic alterations might play a role in the development of UC-CRC. 5-aminosalicylates might represent a favorable therapeutic option for chemoprevention of CRC. PMID:25469007

Unconditional and conditional incentives differentially improved general practitioners' participation in an online survey: randomized controlled trial.

PubMed

Young, Jane M; O'Halloran, Anna; McAulay, Claire; Pirotta, Marie; Forsdike, Kirsty; Stacey, Ingrid; Currow, David

2015-06-01

To compare the impact of unconditional and conditional financial incentives on response rates among Australian general practitioners invited by mail to participate in an online survey about cancer care and to investigate possible differential response bias between incentive groups. Australian general practitioners were randomly allocated to unconditional incentive (book voucher mailed with letter of invitation), conditional incentive (book voucher mailed on completion of the online survey), or control (no incentive). Nonresponders were asked to complete a small subset of questions from the online survey. Among 3,334 eligible general practitioners, significantly higher response rates were achieved in the unconditional group (167 of 1,101, 15%) compared with the conditional group (118 of 1,111, 11%) (P = 0.0014), and both were significantly higher than the control group (74 of 1,122, 7%; both P < 0.001). Although more positive opinions about cancer care were expressed by online responders compared with nonresponders, there was no evidence that the magnitude of difference varied by the incentive group. The incremental cost for each additional 1% increase above the control group response rate was substantially higher for the unconditional incentive group compared with the conditional incentive group. Both unconditional and conditional financial incentives significantly increased response with no evidence of differential response bias. Although unconditional incentives had the largest effect, the conditional approach was more cost-effective. Copyright © 2015 Elsevier Inc. All rights reserved.

Invasive urothelial carcinoma exhibiting basal cell immunohistochemical markers: A variant of urothelial carcinoma associated with aggressive features.

PubMed

Mai, Kien T; Truong, Luan D; Ball, Christopher G; Williams, Phillip; Flood, Trevor A; Belanger, Eric C

2015-08-01

We characterize invasive urothelial carcinoma (UC) exhibiting urothelial basal cell immunohistochemical markers. Consecutive invasive UCs were immunostained with CK20 and urothelial basal cell markers, cytokeratin 5 (CK5)/CD44. Immunostaining for CK5 and CD44 was scored as follows: positive for staining of more than 25% thickness of the epithelial nest or epithelium and low for lesser immunoreactivity. Invasive urothelial carcinoma (UC) exhibiting positive CK5/CD44 staining was designated as basal-like UC (BUC). In this study, of 251 invasive UC (pT1 in 57% and pT2-4 in 43%), BUC accounted for 40% of cases (accounting for most pT2-4 UC) and often presented as non-papillary UC without previous history of UC. In addition, BUC exhibited uniform nuclei with lesser degree of atypia than non BUC and decreased or negative cytokeratin 20 reactivity. Nested and microcystic variants of UC immunohistochemically stained as BUCs. Invasive non-BUCs were often papillary with marked cytologic atypia and pleomorphism, and accounted for most pT1 UC. The rates of perivesical invasion, lymph node and distant metastases were higher for BUC than non-BUC. All nine cases with absent/minimal residual in situ UC in 102 radical cystectomy specimens were from invasive non-BUC. BUC is distinguished from non-BUC due to this aggressive behavior, distinct immunohistochemical profile, and predominant non-papillary architecture. Our findings are consistent with recent studies identifying a subtype of muscle-invasive UC with molecular expression of basal cell and luminal cell molecular profiles. Our study further supports categorizing invasive UCs into these subtypes with different biological behaviors, possibly contributing to better therapeutic strategies. Copyright © 2015 Elsevier GmbH. All rights reserved.

The homing of human umbilical cord-derived mesenchymal stem cells and the subsequent modulation of macrophage polarization in type 2 diabetic mice.

PubMed

Yin, Yaqi; Hao, Haojie; Cheng, Yu; Gao, Jieqing; Liu, Jiejie; Xie, Zongyan; Zhang, Qi; Zang, Li; Han, Weidong; Mu, Yiming

2018-07-01

Umbilical cord-derived mesenchymal stem cells (UC-MSCs), with both immunomodulatory and pro-regenerative properties, are promising for the treatment of type 2 diabetes mellitus (T2DM). As efficient cell therapy largely relies on appropriate homing to target tissues, knowing where and to what extent injected UC-MSCs have homed is critically important. However, bio-distribution data for UC-MSCs in T2DM subjects are extremely limited. Beneficial effects of UC-MSCs on T2DM subjects are associated with increased M2 macrophages, but no systemic evaluation of M2 macrophages has been performed in T2DM individuals. In this study, we treated T2DM mice with CM-Dil-labelled UC-MSCs. UC-MSC infusion not only exerted anti-diabetic effects but also alleviated dyslipidemia and improved liver function in T2DM mice. To compare UC-MSC migration between T2DM and normal subjects, a collection of normal mice also received UC-MSC transplantation. UC-MSCs homed to the lung, liver and spleen in both normal and T2DM recipients. Specifically, the spleen harbored the largest number of UC-MSCs. Unlike normal mice, a certain number of UC-MSCs also homed to pancreatic islets in T2DM mice, which suggested that UC-MSC homing may be closely related to tissue damage. Moreover, the number of M2 macrophages in the islets, liver, fat and muscle significantly increased after UC-MSC infusion, which implied a strong link between the increased M2 macrophages and the improved condition in T2DM mice. Additionally, an M2 macrophage increase was also observed in the spleen, suggesting that UC-MSCs might exert systemic effects in T2DM individuals by modulating macrophages in immune organs. Copyright © 2018 Elsevier B.V. All rights reserved.

Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq.

PubMed

Maeda, Shingo; Tomiyasu, Hirotaka; Tsuboi, Masaya; Inoue, Akiko; Ishihara, Genki; Uchikai, Takao; Chambers, James K; Uchida, Kazuyuki; Yonezawa, Tomohiro; Matsuki, Naoaki

2018-04-27

Invasive urothelial carcinoma (iUC) is a major cause of death in humans, and approximately 165,000 individuals succumb to this cancer annually worldwide. Comparative oncology using relevant animal models is necessary to improve our understanding of progression, diagnosis, and treatment of iUC. Companion canines are a preferred animal model of iUC due to spontaneous tumor development and similarity to human disease in terms of histopathology, metastatic behavior, and treatment response. However, the comprehensive molecular characterization of canine iUC is not well documented. In this study, we performed transcriptome analysis of tissue samples from canine iUC and normal bladders using an RNA sequencing (RNA-Seq) approach to identify key molecular pathways in canine iUC. Total RNA was extracted from bladder tissues of 11 dogs with iUC and five healthy dogs, and RNA-Seq was conducted. Ingenuity Pathway Analysis (IPA) was used to assign differentially expressed genes to known upstream regulators and functional networks. Differential gene expression analysis of the RNA-Seq data revealed 2531 differentially expressed genes, comprising 1007 upregulated and 1524 downregulated genes, in canine iUC. IPA revealed that the most activated upstream regulator was PTGER2 (encoding the prostaglandin E 2 receptor EP2), which is consistent with the therapeutic efficiency of cyclooxygenase inhibitors in canine iUC. Similar to human iUC, canine iUC exhibited upregulated ERBB2 and downregulated TP53 pathways. Biological functions associated with cancer, cell proliferation, and leukocyte migration were predicted to be activated, while muscle functions were predicted to be inhibited, indicating muscle-invasive tumor property. Our data confirmed similarities in gene expression patterns between canine and human iUC and identified potential therapeutic targets (PTGER2, ERBB2, CCND1, Vegf, and EGFR), suggesting the value of naturally occurring canine iUC as a relevant animal model for human iUC.

Umbilical Cord-derived Mesenchymal Stem Cells Instruct Monocytes Towards an IL10-producing Phenotype by Secreting IL6 and HGF

PubMed Central

Deng, Yinan; Zhang, Yingcai; Ye, Linsen; Zhang, Tong; Cheng, Jintao; Chen, Guihua; Zhang, Qi; Yang, Yang

2016-01-01

Human UC-MSCs are regarded as an attractive alternative to BM-MSCs for clinical applications due to their easy preparation, higher proliferation and lower immunogenicity. However, the mechanisms underlying immune suppression by UC-MSCs are still unclear. We studied the mechanism of inhibition by UC-MSCs during the differentiation of monocytes into DCs and focused on the specific source and the role of the involved cytokines. We found that UC-MSCs suppressed monocyte differentiation into DCs and instructed monocytes towards other cell types, with clear decreases in the expression of co-stimulatory molecules, in the secretion of inflammatory factors and in allostimulatory capacity. IL6, HGF and IL10 might be involved in this process because they were detected at higher levels in a coculture system. UC-MSCs produce IL-6 and HGF, and neutralization of IL-6 and HGF reversed the suppressive effect of UC-MSCs. IL10 was not produced by UC-MSCs but was exclusively produced by monocytes after exposure to UC-MSCs, IL-6 or HGF. In summary, we found that the UC-MSC-mediated inhibitory effect was dependent on IL6 and HGF secreted by UC-MSCs and that this effect induced monocyte-derived cells to produce IL10, which might indirectly strengthen the suppressive effect of UC-MSCs. PMID:27917866

Umbilical Cord-derived Mesenchymal Stem Cells Instruct Monocytes Towards an IL10-producing Phenotype by Secreting IL6 and HGF.

PubMed

Deng, Yinan; Zhang, Yingcai; Ye, Linsen; Zhang, Tong; Cheng, Jintao; Chen, Guihua; Zhang, Qi; Yang, Yang

2016-12-05

Human UC-MSCs are regarded as an attractive alternative to BM-MSCs for clinical applications due to their easy preparation, higher proliferation and lower immunogenicity. However, the mechanisms underlying immune suppression by UC-MSCs are still unclear. We studied the mechanism of inhibition by UC-MSCs during the differentiation of monocytes into DCs and focused on the specific source and the role of the involved cytokines. We found that UC-MSCs suppressed monocyte differentiation into DCs and instructed monocytes towards other cell types, with clear decreases in the expression of co-stimulatory molecules, in the secretion of inflammatory factors and in allostimulatory capacity. IL6, HGF and IL10 might be involved in this process because they were detected at higher levels in a coculture system. UC-MSCs produce IL-6 and HGF, and neutralization of IL-6 and HGF reversed the suppressive effect of UC-MSCs. IL10 was not produced by UC-MSCs but was exclusively produced by monocytes after exposure to UC-MSCs, IL-6 or HGF. In summary, we found that the UC-MSC-mediated inhibitory effect was dependent on IL6 and HGF secreted by UC-MSCs and that this effect induced monocyte-derived cells to produce IL10, which might indirectly strengthen the suppressive effect of UC-MSCs.

A brief history of the Bioengineering Institute of California and the UC System-wide Symposia.

PubMed

Chien, Shu

2011-04-01

The plan to establish a Multicampus Research Unit (MRU) on Bioengineering in the University of California (UC) System started in August 1999. The cooperative efforts of the UC campuses led to the formal establishment of the Bioengineering Institute of California (BIC) in October 2003. Three years prior to the BIC establishment, the System-wide Annual Bioengineering Symposium was started at UC Davis. The Symposia were then hosted sequentially by UC Santa Barbara, UC Berkeley, UCSD, UC Santa Cruz, UC Irvine, UCSF, UCLA, and UC Riverside, with the completion of the first cycle of a decade in the newest campus of UC Merced in 2009. The second cycle began in 2010 with the Symposium returning again to UC Davis. Each campus hosted a wonderful Symposium, with the active participation of students and faculty from all campuses, with the motto of "Ten campuses united as one, learning and growing together." These Symposia have contributed significantly to the collaborative research and training of students and young scientists in bioengineering, as well as fruitful interactions with industry and government agencies, which have provided strong support for these valuable meetings. The BIC will endeavor to further enhance these efforts by fostering research collaborations and joint education and training activities, with the ultimate goal of advancing bioengineering for the improvement of human health and wellbeing.

[Basic biological characteristics of mesenchymal stem cells derived from bone marrow and human umbilical cord].

PubMed

Han, Zhen-Xia; Shi, Qing; Wang, Da-Kun; Li, Dong; Lyu, Ming

2013-10-01

Bone marrow (BM) and umbilical cord (UC) are the major sources of mesenchymal stem cells for therapeutics. This study was aimed to compare the basic biologic characteristics of bone marrow-derived and umbilical cord derived-mesenchymal stem cells (BM-MSC and UC-MSC) and their immunosuppressive capability in vitro. The BM-MSC and UC-MSC were cultured and amplified under same culture condition. The growth kinetics, phenotypic characteristics and immunosuppressive effects of UC-MSC were compared with those of BM-MSC.Gene chip was used to compare the genes differentially expressed between UC-MSC and BM-MSC. The results showed that UC-MSC shared most of the characteristics of BM-MSC, including morphology and immunophenotype. UC-MSC could be ready expanded for 30 passages without visible changes. However, BM-MSC grew slowly, and the mean doubling time increased notably after passage 6. Both UC-MSC and BM-MSC could inhibit phytohemagglutinin-stimulated peripheral blood mononuclear cell proliferation, in which BM-MSC mediated more inhibitory effect. Compared with UC-MSC, BM-MSC expressed more genes associated with immune response. Meanwhile, the categories of up-regulated genes in UC-MSC were concentrated in organ development and growth. It is concluded that the higher proliferation capacity, low human leukocyte antigen-ABC expression and immunosuppression make UC-MSC an excellent alternative to BM-MSC for cell therapy. The differences between BM-MSC and UC-MSC gene expressions can be explained by their ontogeny and different microenvironment in origin tissue. These differences can affect their efficacy in different therapeutic applications.

Altered Pain Perception and Fear-Learning Deficits in Subjects With Posttraumatic Stress Disorder.

PubMed

Jenewein, Josef; Erni, Jeannine; Moergeli, Hanspeter; Grillon, Christian; Schumacher, Sonja; Mueller-Pfeiffer, Christoph; Hassanpour, Katayun; Seiler, Annina; Wittmann, Lutz; Schnyder, Ulrich; Hasler, Gregor

2016-12-01

There is growing evidence that fear-learning abnormalities are involved in the development of posttraumatic stress disorder (PTSD) and chronic pain. More than 50% of PTSD patients suffer from chronic pain. This study aimed to examine the role of fear-learning deficits in the link between pain perception and PTSD. We included 19 subjects with PTSD and 21 age- and sex-matched healthy control subjects in a fear-conditioning experiment. The conditioned stimulus (CS) consisted of visual signs flashed upon a screen in front of each subject. The unconditioned stimulus was either a low or high temperature impulse delivered through a thermal contact thermode on the subjects' hand. A designation of 'CS-' was assigned to CS always followed by nonpainful low-temperature stimuli; a designation of 'CS+' was given to CS that were randomly followed by either a low or a more painful high temperature. Skin conductance was used as a physiological marker of fear. In healthy control subjects, CS+ induced more fear than CS-, and a low-temperature stimulus induced less subjective pain after CS- than after CS+. PTSD subjects failed to demonstrate such adaptive conditioning. Fear ratings after CS presentation were significantly higher in the PTSD group than in the control group. There were significant interaction effects between group and the type of CS on fear and pain ratings. Fear-learning deficits are a potentially promising, specific psychopathological factor in altered pain perception associated with PTSD. Deficits in safety learning may increase fear and, consequently, pain sensations. These findings may contribute to elucidating the pathogenesis behind the highly prevalent comorbidity that exists between PTSD and pain disorders, and to developing new treatments. This study provides new insights into the pathogenesis of chronic pain in patients with PTSD. The findings may help to develop new treatment strategies for this highly prevalent comorbidity in PTSD. Copyright © 2016 American Pain Society. All rights reserved.

Medial prefrontal cortex circuit function during retrieval and extinction of associative learning under anesthesia.

PubMed

Fenton, G E; Halliday, D M; Mason, R; Stevenson, C W

2014-04-18

Associative learning is encoded under anesthesia and involves the medial prefrontal cortex (mPFC). Neuronal activity in mPFC increases in response to a conditioned stimulus (CS+) previously paired with an unconditioned stimulus (US) but not during presentation of an unpaired stimulus (CS-) in anesthetized animals. Studies in conscious animals have shown dissociable roles for different mPFC subregions in mediating various memory processes, with the prelimbic (PL) and infralimbic (IL) cortex involved in the retrieval and extinction of conditioned responding, respectively. Therefore PL and IL may also play different roles in mediating the retrieval and extinction of discrimination learning under anesthesia. Here we used in vivo electrophysiology to examine unit and local field potential (LFP) activity in PL and IL before and after auditory discrimination learning and during later retrieval and extinction testing in anesthetized rats. Animals received repeated presentations of two distinct sounds, one of which was paired with footshock (US). In separate control experiments animals received footshocks without sounds. After discrimination learning the paired (CS+) and unpaired (CS-) sounds were repeatedly presented alone. We found increased unit firing and LFP power in PL and, to a lesser extent, IL after discrimination learning but not after footshocks alone. After discrimination learning, unit firing and LFP power increased in PL and IL in response to presentation of the first CS+, compared to the first CS-. However, PL and IL activity increased during the last CS- presentation, such that activity during presentation of the last CS+ and CS- did not differ. These results confirm previous findings and extend them by showing that increased PL and IL activity result from encoding of the CS+/US association rather than US presentation. They also suggest that extinction may occur under anesthesia and might be represented at the neural level in PL and IL. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Magazine approach during a signal for food depends on Pavlovian, not instrumental, conditioning.

PubMed

Harris, Justin A; Andrew, Benjamin J; Kwok, Dorothy W S

2013-04-01

In the conditioned magazine approach paradigm, rats are exposed to a contingent relationship between a conditioned stimulus (CS) and the delivery of food (the unconditioned stimulus, US). As the rats learn the CS-US association, they make frequent anticipatory head entries into the food magazine (the conditioned response, CR) during the CS. Conventionally, this is considered to be a Pavlovian paradigm because food is contingent on the CS and not on the performance of CRs during the CS. However, because magazine entries during the CS are reliably followed by food, the increase in frequency of those responses may involve adventitious ("superstitious") instrumental conditioning. The existing evidence, from experiments using an omission schedule to eliminate the possibility of instrumental conditioning (B. J. Farwell & J. J. Ayres, 1979, Stimulus-reinforcer and response-reinforcer relations in the control of conditioned appetitive headpoking (goal tracking) in rats. Learning and Motivation, 10, 295-312; P. C. Holland, 1979, Differential effects of omission contingencies on various components of Pavlovian appetitive conditioned responding in rats. Journal of Experimental Psychology: Animal Behavior Processes, 5, 178-193), is ambiguous: rats acquire magazine CRs despite the omission schedule, demonstrating that the response does not depend on instrumental conditioning, but the response rate is greatly depressed compared with that of rats trained on a yoked schedule, consistent with a contribution from instrumental conditioning under normal (nonomission) schedules. Here we describe experiments in which rats were trained on feature-positive or feature-negative type discriminations between trials that were reinforced on an omission schedule versus trials reinforced on a yoked schedule. The experiments show that the difference in responding between omission and yoked schedules is due to suppression of responding under the omission schedule rather than an elevation of responding under the yoked schedule. We conclude that magazine responses during the CS are largely or entirely Pavlovian CRs.

Investigating motion sickness using the conditioned taste aversion paradigm

NASA Technical Reports Server (NTRS)

Fox, Robert A.

1991-01-01

The avoidance of foods which are associated with uncomfortable or aversive internal states has long been recognized. Many people are aware, either directly or via anecdotal reports, of individuals who avoid foods which were eaten just before the onset of sickness. Awareness of this phenomenon can be traced to the writings of John Locke. The disruption of diet during cancer therapy is sometimes ascribed to the attribution of an unpleasant quality to foods eaten preceding the sickness induced by therapy itself. In addition, it has long been recognized by the manufacturers of rodent poisons that animals avoid the injection of food treated with nonlethal doses of poison. An important part of the laboratory study of this phenomenon was directed toward studying the role learning plays in this type of avoidance behavior. Following the lead of Garcia and his associates, this avoidance has come to be interpreted as arising from a form of classical conditioning. In typical laboratory studies of this bahavior, a novel food is ingested just prior to exposure to some stimulus, commonly poisoning or irradiation, which produces illness. Following the terminology of classical conditioning, it is common to describe this procedure as one of 'pairing' a conditioned stimulus (CS), the novel food, with an unconditioned stimulus (US), the illness induced by toxicosis or irradiation. Avoidance of the food in succeeding feeding opportunities is viewed as a learned response or a conditioned taste aversion (CTA). Garcia et al. asserted that motion sickness could produce 'gustatory' aversions, but passive motion was first reported as an US to establish CTA by Green and Rachlin. The purpose is to review the manner in which CTA has been used to study motion sickness. Numerous reviews concentrating on other aspects of CTA are available in the existing literature. Readers are encouraged to consult the various papers and edited books for extensive information on other aspects of this literature.

A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecule for the inhibition of lead-induced neuronal apoptosis

PubMed Central

Chen, Lijian; Liu, Meiling; Zhang, Nan; Zhang, Li; Luo, Yuanwei; Liu, Zhenzhong; Dai, Lijun; Jiang, Yiguo

2016-01-01

As a common toxic metal, lead has significant neurotoxicity to brain development. Long non-coding RNAs (lncRNAs) function in multiple biological processes. However, whether lncRNAs are involved in lead-induced neurotoxicity remains unclear. Uc.173 is a lncRNA from a transcribed ultra-conservative region (T-UCR) of human, mouse and rat genomes. We established a lead-induced nerve injury mouse model. It showed the levels of Uc.173 decreased significantly in hippocampus tissue and serum of the model. We further tested the expression of Uc.173 in serum of lead-exposed children, which also showed a tendency to decrease. To explore the effects of Uc.173 on lead-induced nerve injury, we overexpressed Uc.173 in an N2a mouse nerve cell line and found Uc.173 had an inhibitory effect on lead-induced apoptosis of N2a. To investigate the molecular mechanisms of Uc.173 in apoptosis associated with lead-induced nerve injury, we predicted the target microRNAs of Uc.173 by using miRanda, TargetScan and RegRNA. After performing quantitative real-time PCR and bioinformatics analysis, we showed Uc.173 might inter-regulate with miR-291a-3p in lead-induced apoptosis and regulate apoptosis-associated genes. Our study suggests Uc.173 significantly inhibits the apoptosis of nerve cells, which may be mediated by inter-regulation with miRNAs in lead-induced nerve injury. PMID:26683706

Pooled Resequencing of 122 Ulcerative Colitis Genes in a Large Dutch Cohort Suggests Population-Specific Associations of Rare Variants in MUC2.

PubMed

Visschedijk, Marijn C; Alberts, Rudi; Mucha, Soren; Deelen, Patrick; de Jong, Dirk J; Pierik, Marieke; Spekhorst, Lieke M; Imhann, Floris; van der Meulen-de Jong, Andrea E; van der Woude, C Janneke; van Bodegraven, Adriaan A; Oldenburg, Bas; Löwenberg, Mark; Dijkstra, Gerard; Ellinghaus, David; Schreiber, Stefan; Wijmenga, Cisca; Rivas, Manuel A; Franke, Andre; van Diemen, Cleo C; Weersma, Rinse K

2016-01-01

Genome-wide association studies have revealed several common genetic risk variants for ulcerative colitis (UC). However, little is known about the contribution of rare, large effect genetic variants to UC susceptibility. In this study, we performed a deep targeted re-sequencing of 122 genes in Dutch UC patients in order to investigate the contribution of rare variants to the genetic susceptibility to UC. The selection of genes consists of 111 established human UC susceptibility genes and 11 genes that lead to spontaneous colitis when knocked-out in mice. In addition, we sequenced the promoter regions of 45 genes where known variants exert cis-eQTL-effects. Targeted pooled re-sequencing was performed on DNA of 790 Dutch UC cases. The Genome of the Netherlands project provided sequence data of 500 healthy controls. After quality control and prioritization based on allele frequency and pathogenicity probability, follow-up genotyping of 171 rare variants was performed on 1021 Dutch UC cases and 1166 Dutch controls. Single-variant association and gene-based analyses identified an association of rare variants in the MUC2 gene with UC. The associated variants in the Dutch population could not be replicated in a German replication cohort (1026 UC cases, 3532 controls). In conclusion, this study has identified a putative role for MUC2 on UC susceptibility in the Dutch population and suggests a population-specific contribution of rare variants to UC.

Reduced risk of UC in families affected by appendicitis: a Danish national cohort study.

PubMed

Nyboe Andersen, Nynne; Gørtz, Sanne; Frisch, Morten; Jess, Tine

2017-08-01

The possible aetiological link between appendicitis and UC remains unclear. In order to investigate the hereditary component of the association, we studied the risk of UC in family members of individuals with appendicitis. A cohort of 7.1 million individuals was established by linkage of national registers in Denmark with data on kinship and diagnoses of appendicitis and UC. Poisson regression models were used to calculate first hospital contact rate ratios (RR) for UC with 95% CIs between individuals with or without relatives with a history of appendicitis. During 174 million person-years of follow-up between 1977 and 2011, a total of 190 004 cohort members developed appendicitis and 45 202 developed UC. Individuals having a first-degree relative with appendicitis before age 20 years had significantly reduced risk of UC (RR 0.90; 95% CI 0.86 to 0.95); this association was stronger in individuals with a family predisposition to UC (RR 0.66; 95% CI 0.51 to 0.83). Individuals with a first-degree relative diagnosed with appendicitis before age 20 years are at reduced risk of UC, particularly when there is a family predisposition to UC. Our findings question a previously hypothesised direct protective influence of appendicitis on inflammation of the large bowel. Rather, genetic or environmental factors linked to an increased risk of appendicitis while being protective against UC may explain the repeatedly reported reduced relative risk of UC in individuals with a history of appendicitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs.

PubMed

Deparle, L A; Gupta, R C; Canerdy, T D; Goad, J T; D'Altilio, M; Bagchi, M; Bagchi, D

2005-08-01

DeParle L. A., Gupta R. C., Canerdy T. D., Goad J. T., D'Altilio M., Bagchi M., Bagchi D. Efficacy and safety of glycosylated undenatured type-II collagen (UC-II) in therapy of arthritic dogs. J. vet. Pharmacol. Therap.28, 385-390. In large breed dogs, arthritis is very common because of obesity, injury, aging, immune disorder, or genetic predispositions. This study was therefore undertaken to evaluate clinical efficacy and safety of undenatured type-II collagen (UC-II) in obese-arthritic dogs. Fifteen dogs in three groups received either no UC-II (Group I) or UC-II with 1 mg/day (Group II) or 10 mg/day (Group III) for 90 days. Lameness and pain were measured on a weekly basis for 120 days (90 days treatment plus 30 days post-treatment). Blood samples were assayed for creatinine and blood urea nitrogen (markers of renal injury); and alanine aminotransferase and aspartate aminotransferase (evidence of hepatic injury). Dogs receiving 1 mg or 10 mg UC-II/day for 90 days showed significant declines in overall pain and pain during limb manipulation and lameness after physical exertion, with 10 mg showed greater improvement. At either dose of UC-II, no adverse effects were noted and no significant changes were noted in serum chemistry, suggesting that UC-II was well tolerated. In addition, dogs receiving UC-II for 90 days showed increased physical activity level. Following UC-II withdrawal for a period of 30 days, all dogs experienced a relapse of overall pain, exercise-associated lameness, and pain upon limb manipulation. These results suggest that daily treatment of arthritic dogs with UC-II ameliorates signs and symptoms of arthritis, and UC-II is well tolerated as no adverse effects were noted.

Early Transcriptomic Changes in the Ileal Pouch Provide Insight into the Molecular Pathogenesis of Pouchitis and Ulcerative Colitis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Yong; Dalal, Sushila; Antonopoulos, Dionysios

Background: Ulcerative colitis (UC) only involves the colonic mucosa. Yet, nearly 50% of patients with UC who undergo total proctocolectomy with ileal pouch anal anastomosis develop UC-like inflammation of the ileal pouch (pouchitis). By contrast, patients with familial adenomatous polyposis (FAP) with ileal pouch anal anastomosis develop pouchitis far less frequently. We hypothesized that pathogenic events associated with the development of UC are recapitulated by colonic-metaplastic transcriptomic reprogramming of the UC pouch. Methods: We prospectively sampled pouch and prepouch ileum mucosal biopsies in patients with UC with ileal pouch anal anastomosis 4, 8, and 12 months after their pouch wasmore » in continuity. Mucosal samples were also obtained from patients with FAP. Transcriptional profiles of the UC and FAP pouch and prepouch ileum were investigated via RNA sequencing and compared with data from a previously published microarray study. Results: Unlike patients with FAP, subjects with UC exhibited a large set of differentially expressed genes between the pouch and prepouch ileum as early as 4 months after pouch functionalization. Functional pathway analysis of differentially expressed genes in the UC pouch revealed an enhanced state of immune/inflammatory response and extracellular matrix remodeling. Moreover, >70% of differentially expressed genes mapped to published inflammatory bowel diseases microarray data sets displayed directional changes consistent with active UC but not with Crohn's disease. Conclusions: The UC pouch, well before histologic inflammation, already displays a systems-level gain of colon-associated genes and loss of ileum-associated genes. Patients with UC exhibit a unique transcriptomic response to ileal pouch creation that can be observed well before disease and may in part explain their susceptibility to the development of pouchitis.« less

Extinction training during the reconsolidation window prevents recovery of fear.

PubMed

Schiller, Daniela; Raio, Candace M; Phelps, Elizabeth A

2012-08-24

Fear is maladaptive when it persists long after circumstances have become safe. It is therefore crucial to develop an approach that persistently prevents the return of fear. Pavlovian fear-conditioning paradigms are commonly employed to create a controlled, novel fear association in the laboratory. After pairing an innocuous stimulus (conditioned stimulus, CS) with an aversive outcome (unconditioned stimulus, US) we can elicit a fear response (conditioned response, or CR) by presenting just the stimulus alone. Once fear is acquired, it can be diminished using extinction training, whereby the conditioned stimulus is repeatedly presented without the aversive outcome until fear is no longer expressed. This inhibitory learning creates a new, safe representation for the CS, which competes for expression with the original fear memory. Although extinction is effective at inhibiting fear, it is not permanent. Fear can spontaneously recover with the passage of time. Exposure to stress or returning to the context of initial learning can also cause fear to resurface. Our protocol addresses the transient nature of extinction by targeting the reconsolidation window to modify emotional memory in a more permanent manner. Ample evidence suggests that reactivating a consolidated memory returns it to a labile state, during which the memory is again susceptible to interference. This window of opportunity appears to open shortly after reactivation and close approximately 6 hrs later, although this may vary depending on the strength and age of the memory. By allowing new information to incorporate into the original memory trace, this memory may be updated as it reconsolidates. Studies involving non-human animals have successfully blocked the expression of fear memory by introducing pharmacological manipulations within the reconsolidation window, however, most agents used are either toxic to humans or show equivocal effects when used in human studies. Our protocol addresses these challenges by offering an effective, yet non-invasive, behavioral manipulation that is safe for humans. By prompting fear memory retrieval prior to extinction, we essentially trigger the reconsolidation process, allowing new safety information (i.e., extinction) to be incorporated while the fear memory is still susceptible to interference. A recent study employing this behavioral manipulation in rats has successfully blocked fear memory using these temporal parameters. Additional studies in humans have demonstrated that introducing new information after the retrieval of previously consolidated motor, episodic, or declarative memories leads to interference with the original memory trace. We outline below a novel protocol used to block fear recovery in humans.

Takayasu arteritis and ulcerative colitis: high rate of co-occurrence and genetic overlap.

PubMed

Terao, Chikashi; Matsumura, Takayoshi; Yoshifuji, Hajime; Kirino, Yohei; Maejima, Yasuhiro; Nakaoka, Yoshikazu; Takahashi, Meiko; Amiya, Eisuke; Tamura, Natsuko; Nakajima, Toshiki; Origuchi, Tomoki; Horita, Tetsuya; Matsukura, Mitsuru; Kochi, Yuta; Ogimoto, Akiyoshi; Yamamoto, Motohisa; Takahashi, Hiroki; Nakayamada, Shingo; Saito, Kazuyoshi; Wada, Yoko; Narita, Ichiei; Kawaguchi, Yasushi; Yamanaka, Hisashi; Ohmura, Koichiro; Atsumi, Tatsuya; Tanemoto, Kazuo; Miyata, Tetsuro; Kuwana, Masataka; Komuro, Issei; Tabara, Yasuharu; Ueda, Atsuhisa; Isobe, Mitsuaki; Mimori, Tsuneyo; Matsuda, Fumihiko

2015-05-01

Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA-B*52:01 and IL12B as genetic determinants, and since there are case reports of the co-occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large-scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases. We analyzed a total of 470 consecutive patients with TAK from 14 institutions. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with the use of UC susceptibility single-nucleotide polymorphisms by comparing risk directions and effect sizes between susceptibility to the 2 diseases. Thirty of 470 patients with TAK had UC (6.4% [95% confidence interval 4.3-9.0]). This percentage was strikingly higher than that expected from the prevalence of UC in Japan. Patients with TAK complicated with UC developed TAK at an earlier stage of life (P = 0.0070) and showed significant enrichment of HLA-B*52:01 compared to TAK patients without UC (P = 1.0 × 10(-5) ) (odds ratio 12.14 [95% confidence interval 2.96-107.23]). The 110 non-HLA markers of susceptibility to UC significantly displayed common risk directions with susceptibility to TAK (P = 0.0054) and showed significant departure of permutation P values from expected P values (P < 1.0 × 10(-10) ). UC is a major complication of TAK. These 2 diseases share a significant proportion of their genetic background, and HLA-B*52:01 may play a central role in their co-occurrence. © 2015, American College of Rheumatology.

Patients with inflammatory bowel disease (IBD) reveal increased induction capacity of intracellular interferon-gamma (IFN-γ) in peripheral CD8+ lymphocytes co-cultured with intestinal epithelial cells

PubMed Central

Bisping, G; Lügering, N; Lütke-Brintrup, S; Pauels, H -G; Schürmann, G; Domschke, W; Kucharzik, T

2001-01-01

Intestinal epithelial cells seem to play a key role during IBD. The network of cellular interactions between epithelial cells and lamina propria mononuclear cells is still incompletely understood. In the following co-culture model we investigated the influence of intestinal epithelial cells on cytokine expression of T cytotoxic and T helper cells from patients with IBD and healthy controls. Peripheral blood mononuclear cells (PBMC) were purified by a Ficoll–Hypaque gradient followed by co-incubation with epithelial cells in multiwell cell culture insert plates in direct contact as well as separated by transwell filters. We used Caco-2 cells as well as freshly isolated colonic epithelia obtained from surgical specimens. Three-colour immunofluorescence flow cytometry was performed after collection, stimulation and staining of PBMC with anti-CD4, anti-CD8, anti-IFN-γ and anti-IL-4. Patients with IBD (Crohn's disease (CD), n = 12; ulcerative colitis (UC), n = 16) and healthy controls (n = 10) were included in the study. After 24 h of co-incubation with Caco-2 cells we found a significant increase of IFN-γ-producing CD8+ lymphocytes in patients with IBD. In contrast, healthy controls did not respond to the epithelial stimulus. No significant differences could be found between CD and UC or active and inactive disease. A significant increase of IFN-γ+/CD8+ lymphocytes in patients with UC was also seen after direct co-incubation with primary cultures of colonic crypt cells. The observed epithelial–lymphocyte interaction seems to be MHC I-restricted. No significant epithelial cell-mediated effects on cytokine expression were detected in the PBMC CD4+ subsets. Patients with IBD—even in an inactive state of disease—exert an increased capacity for IFN-γ induction in CD8+ lymphocytes mediated by intestinal epithelial cells. This mechanism may be important during chronic intestinal inflammation, as in the case of altered mucosal barrier function epithelial cells may become targets for IFN-γ-producing CD8+ lymphocytes. PMID:11167992

Proteomic analysis of porcine mesenchymal stem cells derived from bone marrow and umbilical cord: implication of the proteins involved in the higher migration capability of bone marrow mesenchymal stem cells.

PubMed

Huang, Lei; Niu, Chenguang; Willard, Belinda; Zhao, Weimin; Liu, Lan; He, Wei; Wu, Tianwen; Yang, Shulin; Feng, Shutang; Mu, Yulian; Zheng, Lemin; Li, Kui

2015-04-15

Mesenchymal stem cells (MSCs) have the ability to proliferate in vivo with a large variety of differentiation potentials and therefore are widely used as an ideal material for cell therapy. MSCs derived from pig and human sources are similar in many aspects, such as cell immunophenotype and functional characteristics. However, differences in proteomics and the molecular mechanisms of cell functions between porcine bone marrow MSCs (BM-MSCs) and umbilical cord MSCs (UC-MSCs) are largely unknown. To the best of our knowledge, MSCs collected from different tissue have specific phenotype and differentiation ability in response to microenvironment, known as a niche. Porcine BM-MSCs and UC-MSCs were evaluated with flow cytometric and adipogenic and osteogenic differentiation analyses. We used isobaric tagging for relative and absolute quantitation (iTRAQ), combined with liquid chromatography-tandem mass spectrometry, to identify differentially expressed proteins (DEPs) between these two types of MSCs. Kyoto Encyclopedia of Genes and Genomes pathway and phenotype analyses were used to understand the links between cell migration ability and DEPs. Two separate iTRAQ experiments were conducted, identifying 95 DEPs (95% confidence interval). Five of these proteins were verified by Western blotting. These 95 DEPs were classified in terms of biological regulation, metabolic process, developmental process, immune system process, reproduction, death, growth, signaling, localization, response to stimulus, biological adhesion, and cellular component organization. Our study is the first to show results indicating that porcine BM-MSCs have a higher migration capability than UC-MSCs. Finally, one of the DEPs, Vimentin, was verified to have a positive role in MSC migration. These results represent the first attempt to use proteomics specifically targeted to porcine MSCs of different tissues. The identified components should help reveal a variety of tissue-specific functions in tissue-derived MSC populations and could serve as important tools for the regeneration of particular tissues in future stem cell-based tissue engineering studies using animal models.

Metallic conductance at the interface of tri-color titanate superlattices

NASA Astrophysics Data System (ADS)

Kareev, M.; Cao, Yanwei; Liu, Xiaoran; Middey, S.; Meyers, D.; Chakhalian, J.

2013-12-01

Ultra-thin tri-color (tri-layer) titanate superlattices ([3 u.c. LaTiO3/2 u.c. SrTiO3/3 u.c. YTiO3], u.c. = unit cells) were grown in a layer-by-layer way on single crystal TbScO3 (110) substrates by pulsed laser deposition. High sample quality and electronic structure were characterized by the combination of in-situ photoelectron and ex-situ structure and surface morphology probes. Temperature-dependent sheet resistance indicates the presence of metallic interfaces in both [3 u.c. LaTiO3/2 u.c. SrTiO3] bi-layers and all the tri-color structures, whereas a [3 u.c. YTiO3/2 u.c. SrTiO3] bi-layer shows insulating behavior. Considering that in the bulk YTiO3 is ferromagnetic below 30 K, the tri-color titanate superlattices provide an opportunity to induce tunable spin-polarization into the two-dimensional electron gas with Mott carriers.

An 'unconditional-like' structure for the conditional estimator of odds ratio from 2 x 2 tables.

PubMed

Hanley, James A; Miettinen, Olli S

2006-02-01

In the estimation of the odds ratio (OR), the conditional maximum-likelihood estimate (cMLE) is preferred to the more readily computed unconditional one (uMLE). However, the exact cMLE does not have a closed form to help divine it from the uMLE or to understand in what circumstances the difference between the two is appreciable. Here, the cMLE is shown to have the same 'ratio of cross-products' structure as its unconditional counterpart, but with two of the cell frequencies augmented, so as to shrink the unconditional estimator towards unity. The augmentation involves a factor, similar to the finite population correction, derived from the minimum of the marginal totals.

Key Exchange Trust Evaluation in Peer-to-Peer Sensor Networks With Unconditionally Secure Key Exchange

NASA Astrophysics Data System (ADS)

Gonzalez, Elias; Kish, Laszlo B.

2016-03-01

As the utilization of sensor networks continue to increase, the importance of security becomes more profound. Many industries depend on sensor networks for critical tasks, and a malicious entity can potentially cause catastrophic damage. We propose a new key exchange trust evaluation for peer-to-peer sensor networks, where part of the network has unconditionally secure key exchange. For a given sensor, the higher the portion of channels with unconditionally secure key exchange the higher the trust value. We give a brief introduction to unconditionally secured key exchange concepts and mention current trust measures in sensor networks. We demonstrate the new key exchange trust measure on a hypothetical sensor network using both wired and wireless communication channels.

Cytokine treatment optimises the immunotherapeutic effects of umbilical cord-derived MSC for treatment of inflammatory liver disease.

PubMed

de Witte, Samantha F H; Merino, Ana M; Franquesa, Marcella; Strini, Tanja; van Zoggel, Johanna A A; Korevaar, Sander S; Luk, Franka; Gargesha, Madhu; O'Flynn, Lisa; Roy, Debashish; Elliman, Steve J; Newsome, Philip N; Baan, Carla C; Hoogduijn, Martin J

2017-06-08

Mesenchymal stromal cells (MSC) possess immunomodulatory properties and low immunogenicity, both crucial properties for their development into an effective cellular immunotherapy. They have shown benefit in clinical trials targeting liver diseases; however the efficacy of MSC therapy will benefit from improvement of the immunomodulatory and immunogenic properties of MSC. MSC derived from human umbilical cords (ucMSC) were treated for 3 days in vitro with various inflammatory factors, interleukins, vitamins and serum deprivation. Their immunogenicity and immunomodulatory capacity were examined by gene-expression analysis, surface-marker expressions, IDO activity, PGE 2 secretion and inhibition of T cell proliferation and IFNγ production. Furthermore, their activation of NK cell cytotoxicity was investigated via CD107a expression on NK cells. The immunomodulatory capacity, biodistribution and survival of pre-treated ucMSC were investigated in a CCl 4 -induced liver disease mouse model. In addition, capacity of pre-treated MSC to ameliorate liver inflammation was examined in an ex vivo liver inflammation co-culture model. IFN-γ and a multiple cytokine cocktail (MC) consisting of IFN-γ, TGFβ and retinoic acid upregulated the expression of immunomodulatory factor PD-L1 and IDO activity. Subsequently, both treatments enhanced the capacity of ucMSC to inhibit CD4 and CD8 T cell proliferation and IFN-γ production. The susceptibility of ucMSC for NK cell lysis was decreased by IFN-β, TGFβ and MC treatment. In vivo, no immunomodulation was observed by the ucMSC. Four hours after intravenous infusion in mice with CCl 4 -induced inflammatory liver injury, the majority of ucMSC were trapped in the lungs. Rapid clearance of ucMSC(VitB 6 ), ucMSC(Starv + VitB 6 ) and ucMSC(MC) and altered bio-distribution of ucMSC(TGFβ) compared to untreated ucMSC was observed. In the ex vivo co-culture system with inflammatory liver slices ucMSC(MC) showed significantly enhanced modulatory capacity compared to untreated ucMSC. The present study demonstrates the responsiveness of ucMSC to in vitro optimisation treatment. The observed improvements in immunomodulatory capacity as well as immunogenicity after MC treatment may improve the efficacy of ucMSC as immunotherapy targeted towards liver inflammation.

Gender dimorphism and lack of day/night variation or effects of energy deprivation on undercarboxylated osteocalcin levels in humans.

PubMed

Foo, Joo-Pin; Aronis, Konstantinos N; Chamberland, John P; Thakkar, Bindiya; Hamnvik, Ole-Petter; Brinkoetter, Mary; Zaichenko, Lesya; Mantzoros, Christos S

2013-12-01

Undercarboxylated osteocalcin (ucOC) is a bone marker with potent metabolic effects. Leptin regulates Esp gene expression and osteocalcin carboxylation in animal models. We aim to elucidate day/night patterns of ucOC levels, whether short-term and/or chronic energy deprivation alters ucOC levels, and whether leptin may mediate these changes in humans. Twelve healthy males and females were studied for 72 h in the fed state to study day/night pattern of ucOC. The six female subjects were also studied in a crossover interventional study in the fasting state for 72 h with administration of either placebo or metreleptin in physiological doses. Blood samples were obtained hourly from 0800 a.m. on day 3 until 0800 a.m. on day 4. In a separate study, eleven obese subjects who underwent bariatric surgery were followed for 24 weeks to examine the effects of postsurgery weight loss on ucOC levels. Males have higher ucOC levels compared to females. There is no day/night variation pattern of circulating ucOC in humans. Short-term and chronic energy deprivation or leptin administrations do not alter ucOC levels. The hypothesis that ucOC plays a role in energy homeostasis or of leptin in regulating ucOC in humans is not supported. Copyright © 2013 The Obesity Society.

Tn4556, a 6.8-kilobase-pair transposable element of Streptomyces fradiae.

PubMed Central

Chung, S T

1987-01-01

A 6.8-kilobase-pair (kbp) transposable element (Tn4556) was found in a neomycin-producing strain of Streptomyces fradiae. This element was first observed in two 30.3-kbp plasmids (pUC1123 and pUC1124) which arose when a thiostrepton resistance gene (1 kbp) was ligated with the BclI-2 fragment (22.5 kbp) that contains the origin of replication of phage SF1. The Tn4556 segment was deleted when these plasmids were transduced into another S. fradiae host with phage SF1. These deletion plasmids (pUC1210 and pUC1211) had copy numbers of less than 1 per chromosome and were unstable. In contrast, pUC1123 and pUC1124, with copy numbers of 12 to 15 per chromosome, respectively, were relatively stable. When pUC1210 and pUC1211 were reintroduced into S. fradiae by protoplast transformation, the Tn4556 element transposed again to the plasmids at numerous new locations in either of two orientations. A copy of Tn4556 was found in the S. fradiae chromosome by hybridization studies. It appears that Tn4556 originated from the chromosome, transposed into unstable pUC1210 and pUC1211, and made stable plasmids. A temperature-sensitive hybrid plasmid carrying a viomycin resistance derivative of Tn4556 (pMT660::Tn4556::vph) was constructed. When Streptomyces lividans UC8390 containing the hybrid plasmid was grown at 39 degrees C, Tn4556::vph (Tn4560) transposed to random positions in the host chromosome. Images PMID:2820925

Investigation of novel biomarkers for predicting the clinical course in patients with ulcerative colitis.

PubMed

Hamanaka, Shinsaku; Nakagawa, Tomoo; Hiwasa, Takaki; Ohta, Yuki; Kasamatsu, Shingo; Ishigami, Hideaki; Taida, Takashi; Okimoto, Kenichiro; Saito, Keiko; Maruoka, Daisuke; Matsumura, Tomoaki; Takizawa, Hirotaka; Kashiwado, Koichi; Kobayashi, Sohei; Matsushita, Kazuyuki; Matsubara, Hisahiro; Katsuno, Tatsuro; Arai, Makoto; Kato, Naoya

2018-06-05

The clinical course of ulcerative colitis (UC) is characterized by repeated episodes of relapse and remission. We hypothesized that biomarkers that help distinguish refractory UC patients who are in remission using strong anti-immunotherapy could contribute in preventing the overuse of corticosteroids for treatment. Here we clarified novel autoantibodies for UC patients in remission as clinical indicators to distinguish between refractory and non-refractory UC. Antigen proteins recognized by serum antibodies of patients with UC in remission were screened using the protein array method. To validate the results, AlphaLISA was used to analyze the serum antibody titers with candidate protein antigens. Serum samples from 101 healthy controls, 121 patients with UC, and 39 patients with Crohn's disease were analyzed. Of 66 candidate protein antigens screened by ProtoArray™, 6 were selected for this study. The serum titers of anti-poly ADP-ribose glycohydrolase (PARG), anti-transcription elongation factor A protein-like 1 (TCEAL1), and anti-proline-rich 13 (PRR13) antibodies were significantly higher in patients with UC than in healthy controls. Anti-PARG and anti-PRR13 antibody titers were significantly higher in patients with refractory UC than in patients with non-refractory UC. There were no significant differences in any antibody titer between the active and remission phases. The serum titers of anti-PARG, anti-TCEAL1, and anti-PRR13 antibodies were elevated in patients with UC. Anti-PARG and anti-PRR13 antibody titers may be novel clinical indicators for detecting refractory UC in patients in remission. This article is protected by copyright. All rights reserved.

Prevention of urinary tract infections in palliative radiation for vertebral metastasis and spinal compression: A pilot study in 71 patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Manas, Ana; Glaria, Luis; Pena, Carmen

2006-03-01

Purpose: To assess the impact of bladder instillations of hyaluronic acid (HA) on the prevalence of urinary tract infection (UTI) in patients receiving emergency radiotherapy for metastatic spinal cord compression. Methods and Materials: Patients were recruited consecutively at one center and assigned to usual care (UC) (n = 34, mean age 62.2 years) or UC with once-weekly HA instillation (UC + HA) (Cystistat: 40 mg in 50 mL phosphate-buffered saline) (n = 37; mean age, 63.1 years). All patients had an indwelling catheter and received radiotherapy. UTI status was assessed at baseline and during hospitalization. Results: At baseline, patient groupsmore » were comparable, except for the prevalence of UTI at baseline, which was 11.8% and 0% in the UC and UC + HA patients, respectively (p = 0.0477). During hospitalization, 76.5% (vs. 11.8% at baseline, p < 0.0001) of the UC patients had a UTI compared with 13.5% (vs. 0% at baseline, p = 0.0541) of the UC + HA patients (p < 0.0001). Both groups were hospitalized for similar periods (19.8 days [UC] vs. 18.5 days, p = 0.4769) and received equivalent radiotherapy sessions (4.6 [UC] vs. 5.8 sessions, p = 0.2368). Conclusions: Patients receiving UC + HA had a 5.7-fold decrease in UTI prevalence over the hospitalization period compared to UC patients, suggesting that bladder instillations of HA effectively prevent UTI in patients with indwelling catheters receiving radiotherapy for nerve compression.« less

Preventing Overweight in USAF Personnel: Minimal Contract Program

DTIC Science & Technology

2005-05-01

Allowable Weight (MAW) and heavier. Effectiveness of MCBT + UC is compared to UC in terms of weight loss . Outcomes are being measured at 6 and 12 months...while those assigned to UC actually gained weight . Also, greater fise of the treatment website was associated with significantly more weight loss over...Effectiveness of MCBT + UC will be compared to UC in terms of weight loss . Outcomes are measured at 6 and 12 months. The ultimate goal of this study is to

Polarization-dependent extraordinary optical transmission from upconversion nanoparticles.

PubMed

Wang, Peng Hui; Salcedo, Walter J; Pichaandi, Jothirmayanantham; van Veggel, Frank C J M; Brolo, Alexandre G

2015-11-21

Enhanced upconversion (UC) emission was experimentally demonstrated using gold double antenna nanoparticles coupled to nanoslits in gold films. The transmitted red emission from UC ytterbium and erbium co-doped sodium yttrium fluoride (NaYF4:Yb(3+)/Er(3+)) nanoparticles (UC NPs) at ∼665 nm (excited with a 980 nm diode laser) was enhanced relative to the green emission at ∼550 nm. The relatively enhanced UC NP emission could be tuned by the different polarization-dependent extraordinary optical transmission modes coupled to the gold nanostructures. Finite-difference time-domain calculations suggest that the preferential enhanced UC emission is related to a combination of different surface plasmon mode excitation coupling to cavity Fabry-Perot interactions. A maximum UC enhancement of 6-fold was measured for nanoslit arrays in the absence of the double antennas. In the presence of the double nanoantennas inside the nanoslits, the UC enhancement was between 2- and 4-fold, depending on the experimental conditions.

Approach to cytomegalovirus infections in patients with ulcerative colitis

PubMed Central

Park, Sung Chul; Jeen, Yoon Mi; Jeen, Yoon Tae

2017-01-01

Cytomegalovirus (CMV) reactivation is common in patients with severe ulcerative colitis (UC), and may ref lect exacerbation of mucosal inf lammation and/or administration of immunosuppressants. The question of whether CMV is an active pathogen or ‘an innocent bystander’ in the exacerbation of UC remains controversial. Patients with UC exacerbated by reactivated CMV experience worse prognoses than those without CMV reactivation and antiviral therapy significantly reduces the need for colectomy in patients with severe UC and high-grade CMV infection, indicating that CMV plays a role in UC prognosis. Therefore, the CMV status of patients on immunosuppressants, particularly those with steroid-refractory or -dependent UC, should be tested. When CMV is detected, be performed based on should adequate treatment the extent of the viral load and the presence of certain clinical features including a large ulcer. Anti-tumor necrosis factor agents may be useful for treating CMV colitis complicating UC. PMID:28490715

The UAS control segment architecture: an overview

NASA Astrophysics Data System (ADS)

Gregory, Douglas A.; Batavia, Parag; Coats, Mark; Allport, Chris; Jennings, Ann; Ernst, Richard

2013-05-01

The Under Secretary of Defense (Acquisition, Technology and Logistics) directed the Services in 2009 to jointly develop and demonstrate a common architecture for command and control of Department of Defense (DoD) Unmanned Aircraft Systems (UAS) Groups 2 through 5. The UAS Control Segment (UCS) Architecture is an architecture framework for specifying and designing the softwareintensive capabilities of current and emerging UCS systems in the DoD inventory. The UCS Architecture is based on Service Oriented Architecture (SOA) principles that will be adopted by each of the Services as a common basis for acquiring, integrating, and extending the capabilities of the UAS Control Segment. The UAS Task Force established the UCS Working Group to develop and support the UCS Architecture. The Working Group currently has over three hundred members, and is open to qualified representatives from DoD-approved defense contractors, academia, and the Government. The UCS Architecture is currently at Release 2.2, with Release 3.0 planned for July 2013. This paper discusses the current and planned elements of the UCS Architecture, and related activities of the UCS Community of Interest.

Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients.

PubMed

Cranenburg, Ellen C M; Brandenburg, Vincent M; Vermeer, Cees; Stenger, Melanie; Mühlenbruch, Georg; Mahnken, Andreas H; Gladziwa, Ulrich; Ketteler, Markus; Schurgers, Leon J

2009-02-01

Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a potent local inhibitor of cardiovascular calcification and accumulates at areas of calcification in its uncarboxylated form (ucMGP). We previously found significantly lower circulating ucMGP levels in patients with a high vascular calcification burden. Here we report on the potential of circulating ucMGP to serve as a biomarker for vascular calcification in haemodialysis (HD) patients. Circulating ucMGP levels were measured with an ELISA-based assay in 40 HD patients who underwent multi-slice computed tomography (MSCT) scanning to quantify the extent of coronary artery calcification (CAC). The mean ucMGP level in HD patients (193 +/- 65 nM) was significantly lower as compared to apparently healthy subjects of the same age (441 +/- 97 nM; p < 0.001) and patients with rheumatoid arthritis (RA) without CAC (560 +/- 140 nM; p < 0.001). Additionally, ucMGP levels correlated inversely with CAC scores (r = -0.41; p = 0.009), and this correlation persisted after adjustment for age, dialysis vintage and high-sensitivity C-reactive protein (hs-CRP). Since circulating ucMGP levels are significantly and inversely correlated with the extent of CAC in HD patients, ucMGP may become a tool for identifying HD patients with a high probability of cardiovascular calcification.

Desmocollin 2 is a new immunohistochemical marker indicative of squamous differentiation in urothelial carcinoma.

PubMed

Hayashi, Tetsutaro; Sentani, Kazuhiro; Oue, Naohide; Anami, Katsuhiro; Sakamoto, Naoya; Ohara, Shinya; Teishima, Jun; Noguchi, Tsuyoshi; Nakayama, Hirofumi; Taniyama, Kiyomi; Matsubara, Akio; Yasui, Wataru

2011-10-01

Urothelial carcinoma (UC) with squamous differentiation tends to present at higher stages than pure UC. To distinguish UC with squamous differentiation from pure UC, a sensitive and specific marker is needed. Desmocollin 2 (DSC2) is a protein localized in desmosomal junctions of stratified epithelium, but little is known about its biological significance in bladder cancer. We examined the utility of DSC2 as a diagnostic marker. We analysed the immunohistochemical characteristics of DSC2, and studied the relationship of DSC2 expression with the expression of the known markers uroplakin III (UPIII), cytokeratin (CK)7, CK20, epidermal growth factor receptor (EGFR), and p53. DSC2 staining was detected in 24 of 25 (96%) cases of UC with squamous differentiation, but in none of 85 (0%) cases of pure UC. DSC2 staining was detected only in areas of squamous differentiation. DSC2 expression was mutually exclusive of UPIII expression, and was correlated with EGFR expression. Furthermore, DSC2 expression was correlated with higher stage (P = 0.0314) and poor prognosis (P = 0.0477). DSC2 staining offers high sensitivity (96%) and high specificity (100%) for the detection of squamous differentiation in UC. DSC2 is a useful immunohistochemical marker for separation of UC with squamous differentiation from pure UC. 2011 Blackwell Publishing Limited.

Comparison of particle morphology between commercial- and research-grade calcium hydroxide in endodontics.

PubMed

Komabayashi, Takashi; Ahn, Chul; Spears, Robert; Zhu, Qiang

2014-09-01

Ca(OH)2 aqueous slurry is widely used as an inter-appointment antimicrobial dressing in root canal treatment. The aim of this study was to quantify the particle size and shape of commercial-grade UltraCal XS (UC) and to compare it with that of research-grade Ca(OH)2 (RG) using a flow particle image analyzer (FPIA). The morphology and penetration inside the dentin tubules of the UC and RG particles were examined using a scanning electron microscope (SEM). UC and RG (10 mg) were mixed with 15 mL of alcohol, and were sonicated. Five milliliters of the dispersion was subjected to FPIA, and particle length, width, perimeter and aspect ratio were analyzed. In addition, UC paste and RG aqueous slurry were agitated on dentin discs and were prepared for SEM examination. There were significant differences between UC and RG with regard to the frequency of different length groups (P < 0.0001). UC contained smaller particles than RG (P < 0.0001). Under SEM, the agitated UC and RG particles occluded the opening of dentin tubules and penetrated inside the dentin tubules. The size of UC particles is smaller than those of RG. Both UC and RG particles were able to penetrate into open dentin tubules.

Comparison of particle morphology between commercial- and research-grade calcium hydroxide in endodontics

PubMed Central

Komabayashi, Takashi; Ahn, Chul; Spears, Robert; Zhu, Qiang

2014-01-01

Ca(OH)2 aqueous slurry is widely used as an inter-appointment antimicrobial dressing in root canal treatment. The aim of this study was to quantify the particle size and shape of commercial-grade UltraCal XS (UC) and to compare it with that of research-grade Ca(OH)2 (RG) using a flow particle image analyzer (FPIA). The morphology and penetration inside the dentin tubules of the UC and RG particles were examined using a scanning electron microscope (SEM). UC and RG (10 mg) were mixed with 15 mL of alcohol, and were sonicated. Five milliliters of the dispersion was subjected to FPIA, and particle length, width, perimeter and aspect ratio were analyzed. In addition, UC paste and RG aqueous slurry were agitated on dentin discs and were prepared for SEM examination. There were significant differences between UC and RG with regard to the frequency of different length groups (P < 0.0001). UC contained smaller particles than RG (P < 0.0001). Under SEM, the agitated UC and RG particles occluded the opening of dentin tubules and penetrated inside the dentin tubules. The size of UC particles is smaller than those of RG. Both UC and RG particles were able to penetrate into open dentin tubules. PMID:25231145

A prospective audit on the effect of training and educational workshops on the incidence of urethral catheterization injuries

PubMed Central

Bhatt, Nikita R.; Davis, Niall F.; Quinlan, Mark R.; Flynn, Robert J.; McDermott, T.E.D.; Manecksha, Rustom P.; Thornhill, John A.

2017-01-01

Introduction The incidence of iatrogenic urethral catheterization (UC) injuries is approximately 0.3%. Resultant complications are associated with patient morbidity and unnecessary healthcare costs. Our aim was to investigate whether educational training workshops decreased the incidence of UC-related injuries. Methods A prospective audit was performed to calculate incidence, morbidity, and costs associated with iatrogenic UC injury from January to July 2015. Educational workshops were then conducted with healthcare staff and training modules for junior doctors. UC-related incidence, morbidity, and costs in the subsequent six-month period were recorded prospectively and compared with the previous data. Results The incidence of iatrogenic UC injuries was reduced from 4.3/1000 catheters inserted to 3.8/1000 catheters after the intervention (p=0.59). Morbidity from UC increased in the second half in the form of increase in cumulative additional inpatient hospital stay (22 to 79 days; p=0.25), incidence of urosepsis (n=2 to n=4), and need for operative intervention (n=1 to n=2). The cost of managing UC injuries almost doubled in the period after the training intervention (€50 449 to €90 100). Conclusions Current forms of educational and training interventions for UC did not significantly change morbidity or cost of iatrogenic UC injuries despite a decrease in incidence. Improved and intensive training protocols are necessary for UC to prevent avoidable iatrogenic complications, as well as a safer urethral catheter design. PMID:28761592

MiR-29a promotes intestinal epithelial apoptosis in ulcerative colitis by down-regulating Mcl-1.

PubMed

Lv, Bo; Liu, Zhihui; Wang, Shuping; Liu, Fengbin; Yang, Xiaojun; Hou, Jiangtao; Hou, Zhengkun; Chen, Bin

2014-01-01

While it's widely accepted that the etiology of ulcerative colitis (UC) involves both genetic and environmental factors, the pathogenesis of ulcerative colitis is still poorly understood. Intestinal epithelial apoptosis is one of the most common histopathological changes of UC and the expression of a number of apoptosis genes may contribute to the progression of UC. MicroRNAs have recently emerged as powerful regulators of diverse cellular processes and have been shown to be involved in many immune-mediated disorders such as psoriasis, rheumatoid arthritis, lupus, and asthma. A unique microRNA expression profile has been identified in UC, suggesting that, microRNAs play an important role in the pathogenesis of UC. We investigated the role of miR-29a in intestinal epithelial apoptosis in UC. The expression of miR-29a and Mcl-1, an anti-apoptotic BCL-2 family member, was evaluated in both UC patients and UC mice model induced by dextran sodium sulfate (DSS). The apoptosis rate of intestinal epithelial cells was also evaluated. In UC patients and DSS-induced UC in mice, the expression of miR-29a and Mcl-1, were up-regulated and down-regulated, respectively. We identified a miR-29a binding site (7 nucleotides) on the 3'UTR of mcl-1 and mutation in this binding site on the 3'UTR of mcl-1 led to mis-match between miR-29a and mcl-1. Knockout of Mcl-1 caused apoptosis of the colonic epithelial HT29 cells. In addition, miR-29a regulated intestinal epithelial apoptosis by down-regulating the expression of Mcl-1. miR-29a is involved in the pathogenesis of UC by regulating intestinal epithelial apoptosis via Mcl-1.

Expression characteristics of long noncoding RNA uc.322 and its effects on pancreatic islet function.

PubMed

Zhao, Xiaoqin; Rong, Can; Pan, Fenghui; Xiang, Lizhi; Wang, Xinlei; Hu, Yun

2018-06-28

Increasing evidence indicates that long noncoding RNAs (lncRNAs) perform special biological functions by regulating gene expression through multiple pathways and molecular mechanisms. The aim of this study was to explore the expression characteristics of lncRNA uc.322 in pancreatic islet cells and its effects on the secretion function of islet cells. Bioinformatics analysis was used to detect the lncRNA uc.322 sequence, location, and structural features. Expression of lncRNA uc.322 in different tissues was detected by quantitative polymerase chain reaction analyses. Quantitative polymerase chain reaction, Western blot analysis, adenosine triphosphate determination, glucose-stimulated insulin secretion, and enzyme-linked immunosorbent assay were used to evaluate the effects of lncRNA uc.322 on insulin secretion. The results showed that the full-length of lncRNA uc.322 is 224 bp and that it is highly conserved in various species. Bioinformatics analysis revealed that lncRNA uc.322 is located on chr7:122893196-122893419 (GRCH37/hg19) within the SRY-related HMG-box 6 gene exon region. Compared with other tissues, lncRNA uc.322 is highly expressed in pancreatic tissue. Upregulation of lncRNA uc.322 expression increases the insulin transcription factors pancreatic and duodenal homeobox 1 and Forkhead box O1 expression, promotes insulin secretion in the extracellular fluid of Min6 cells, and increases the adenosine triphosphate concentration. On the other hand, knockdown of lncRNA uc.322 has opposite effects on Min6 cells. Overall, this study showed that upregulation of lncRNA uc.322 in islet β-cells can increase the expression of insulin transcription factors and promote insulin secretion, and it may be a new therapeutic target for diabetes. © 2018 Wiley Periodicals, Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chung, Chi-Jung; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Huang, Chao-Yuan

Inter-individual variation in the metabolism of xenobiotics, caused by factors such as cigarette smoking or inorganic arsenic exposure, is hypothesized to be a susceptibility factor for urothelial carcinoma (UC). Therefore, our study aimed to evaluate the role of gene–environment interaction in the carcinogenesis of UC. A hospital-based case–control study was conducted. Urinary arsenic profiles were measured using high-performance liquid chromatography–hydride generator-atomic absorption spectrometry. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism technique. Information about cigarette smoking exposure was acquired from a lifestyle questionnaire. Multivariate logistic regression was applied to estimate the UC risk associated with certain riskmore » factors. We found that UC patients had higher urinary levels of total arsenic, higher percentages of inorganic arsenic (InAs%) and monomethylarsonic acid (MMA%) and lower percentages of dimethylarsinic acid (DMA%) compared to controls. Subjects carrying the GSTM1 null genotype had significantly increased UC risk. However, no association was observed between gene polymorphisms of CYP1A1, EPHX1, SULT1A1 and GSTT1 and UC risk after adjustment for age and sex. Significant gene–environment interactions among urinary arsenic profile, cigarette smoking, and GSTM1 wild/null polymorphism and UC risk were observed after adjustment for potential risk factors. Overall, gene–environment interactions simultaneously played an important role in UC carcinogenesis. In the future, large-scale studies should be conducted using tag-SNPs of xenobiotic-metabolism-related enzymes for gene determination. -- Highlights: ► Subjects with GSTM1 null genotype had significantly increased UC risk. ► UC patients had poor arsenic metabolic ability compared to controls. ► GSTM1 null genotype may modify arsenic related UC risk.« less

Serology of Patients with Ulcerative Colitis After Pouch Surgery Is More Comparable with that of Patients with Crohn's Disease.

PubMed

Goren, Idan; Yahav, Lior; Tulchinsky, Hagit; Dotan, Iris

2015-10-01

The serologic status of patients with ulcerative colitis (UC) who develop postoperative pouchitis was compared with that of patients with Crohn's disease (CD) and unoperated patients with UC. Pouch patients were stratified into normal pouch, acute/recurrent acute pouchitis, and chronic pouchitis/Crohn's-like disease of the pouch groups. Antibodies against glycans associated with CD (anti-Saccharomyces cerevisiae, anti-laminaribioside, anti-chitobioside, and anti-mannobioside carbohydrate antibodies [ASCA, ALCA, ACCA, and AMCA, respectively]) were detected and correlated with type of inflammatory bowel disease and pouch behavior. A total of 501 patients with inflammatory bowel diseases were recruited: 250 (50%) CD, 124 (24.7%) unoperated UC, and 127 (25.3%) UC-pouch. At least 1 positive antibody was detected in 77.6% CD, 52.0% UC-pouch and 33.1% unoperated UC (P < 0.0001 for all). ACCA and AMCA prevalence in CD, UC-pouch and unoperated patients with UC were 33.2%, 24.4%, and 16.9% (P = 0.003 for all) and 35.2%, 26.8%, and 7.3%, respectively (P < 0.0001 for all). ALCA and ASCA were more prevalent in patients with CD than unoperated UC and UC-pouch patients. A longer interval since pouch surgery was associated with inflammatory pouch behavior: 12.45, 11.39, and 8.5 years for acute/recurrent acute pouchitis, chronic pouchitis/Crohn's-like disease of the pouch, and normal pouch, respectively, P = 0.01 for all. The prevalence of the CD-associated anti-glycan antibodies ACCA and AMCA is significantly increased in UC-pouch patients, suggesting that pouch surgery may trigger differential immune responses to glycans. The finding that the serology of UC-pouch patients shares similarities with that of patients with CD supports the notion that those 2 inflammatory bowel diseases share a common pathogenic pathway.

Enhanced Contribution of HLA in Pediatric Onset Ulcerative Colitis.

PubMed

Venkateswaran, Suresh; Prince, Jarod; Cutler, David J; Marigorta, Urko M; Okou, David T; Prahalad, Sampath; Mack, David; Boyle, Brendan; Walters, Thomas; Griffiths, Anne; Sauer, Cary G; LeLeiko, Neal; Keljo, David; Markowitz, James; Baker, Susan S; Rosh, Joel; Pfefferkorn, Marian; Heyman, Melvin B; Patel, Ashish; Otley, Anthony; Baldassano, Robert; Noe, Joshua; Rufo, Paul; Oliva-Hemker, Maria; Davis, Sonia; Zwick, Michael E; Gibson, Greg; Denson, Lee A; Hyams, Jeffrey; Kugathasan, Subra

2018-03-19

The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13). In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

Isothiocyanate-enriched moringa seed extract alleviates ulcerative colitis symptoms in mice

PubMed Central

Wu, Alex G.; Jaja-Chimedza, Asha; Graf, Brittany L.; Waterman, Carrie; Verzi, Michael P.; Raskin, Ilya

2017-01-01

Moringa (Moringa oleifera Lam.) seed extract (MSE) has anti-inflammatory and antioxidant activities. We investigated the effects of MSE enriched in moringa isothiocyanate-1 (MIC-1), its putative bioactive, on ulcerative colitis (UC) and its anti-inflammatory/antioxidant mechanism likely mediated through Nrf2-signaling pathway. Dextran sulfate sodium (DSS)-induced acute (n = 8/group; 3% DSS for 5 d) and chronic (n = 6/group; cyclic rotations of 2.5% DSS/water for 30 d) UC was induced in mice that were assigned to 4 experimental groups: healthy control (water/vehicle), disease control (DSS/vehicle), MSE treatment (DSS/MSE), or 5-aminosalicyic acid (5-ASA) treatment (positive control; DSS/5-ASA). Following UC induction, water (vehicle), 150 mg/kg MSE, or 50 mg/kg 5-ASA were orally administered for 1 or 2 wks. Disease activity index (DAI), spleen/colon sizes, and colonic histopathology were measured. From colon and/or fecal samples, pro-inflammatory biomarkers, tight-junction proteins, and Nrf2-mediated enzymes were analyzed at protein and/or gene expression levels. Compared to disease control, MSE decreased DAI scores, and showed an increase in colon lengths and decrease in colon weight/length ratios in both UC models. MSE also reduced colonic inflammation/damage and histopathological scores (modestly) in acute UC. MSE decreased colonic secretions of pro-inflammatory keratinocyte-derived cytokine (KC), tumor necrosis factor (TNF)-α, nitric oxide (NO), and myeloperoxidase (MPO) in acute and chronic UC; reduced fecal lipocalin-2 in acute UC; downregulated gene expression of pro-inflammatory interleukin (IL)-1, IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) in acute UC; upregulated expression of claudin-1 and ZO-1 in acute and chronic UC; and upregulated GSTP1, an Nrf2-mediated phase II detoxifying enzyme, in chronic UC. MSE was effective in mitigating UC symptoms and reducing UC-induced colonic pathologies, likely by suppressing pro-inflammatory biomarkers and increasing tight-junction proteins. This effect is consistent with Nrf2-mediated anti-inflammatory/antioxidant signaling pathway documented for other isothiocyanates similar to MIC-1. Therefore, MSE, enriched with MIC-1, may be useful in prevention and treatment of UC. PMID:28922365

Isothiocyanate-enriched moringa seed extract alleviates ulcerative colitis symptoms in mice.

PubMed

Kim, Youjin; Wu, Alex G; Jaja-Chimedza, Asha; Graf, Brittany L; Waterman, Carrie; Verzi, Michael P; Raskin, Ilya

2017-01-01

Moringa (Moringa oleifera Lam.) seed extract (MSE) has anti-inflammatory and antioxidant activities. We investigated the effects of MSE enriched in moringa isothiocyanate-1 (MIC-1), its putative bioactive, on ulcerative colitis (UC) and its anti-inflammatory/antioxidant mechanism likely mediated through Nrf2-signaling pathway. Dextran sulfate sodium (DSS)-induced acute (n = 8/group; 3% DSS for 5 d) and chronic (n = 6/group; cyclic rotations of 2.5% DSS/water for 30 d) UC was induced in mice that were assigned to 4 experimental groups: healthy control (water/vehicle), disease control (DSS/vehicle), MSE treatment (DSS/MSE), or 5-aminosalicyic acid (5-ASA) treatment (positive control; DSS/5-ASA). Following UC induction, water (vehicle), 150 mg/kg MSE, or 50 mg/kg 5-ASA were orally administered for 1 or 2 wks. Disease activity index (DAI), spleen/colon sizes, and colonic histopathology were measured. From colon and/or fecal samples, pro-inflammatory biomarkers, tight-junction proteins, and Nrf2-mediated enzymes were analyzed at protein and/or gene expression levels. Compared to disease control, MSE decreased DAI scores, and showed an increase in colon lengths and decrease in colon weight/length ratios in both UC models. MSE also reduced colonic inflammation/damage and histopathological scores (modestly) in acute UC. MSE decreased colonic secretions of pro-inflammatory keratinocyte-derived cytokine (KC), tumor necrosis factor (TNF)-α, nitric oxide (NO), and myeloperoxidase (MPO) in acute and chronic UC; reduced fecal lipocalin-2 in acute UC; downregulated gene expression of pro-inflammatory interleukin (IL)-1, IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) in acute UC; upregulated expression of claudin-1 and ZO-1 in acute and chronic UC; and upregulated GSTP1, an Nrf2-mediated phase II detoxifying enzyme, in chronic UC. MSE was effective in mitigating UC symptoms and reducing UC-induced colonic pathologies, likely by suppressing pro-inflammatory biomarkers and increasing tight-junction proteins. This effect is consistent with Nrf2-mediated anti-inflammatory/antioxidant signaling pathway documented for other isothiocyanates similar to MIC-1. Therefore, MSE, enriched with MIC-1, may be useful in prevention and treatment of UC.

Unconditionally secure multi-party quantum commitment scheme

NASA Astrophysics Data System (ADS)

Wang, Ming-Qiang; Wang, Xue; Zhan, Tao

2018-02-01

A new unconditionally secure multi-party quantum commitment is proposed in this paper by encoding the committed message to the phase of a quantum state. Multi-party means that there are more than one recipient in our scheme. We show that our quantum commitment scheme is unconditional hiding and binding, and hiding is perfect. Our technique is based on the interference of phase-encoded coherent states of light. Its security proof relies on the no-cloning theorem of quantum theory and the properties of quantum information.

Individual Differences in the Attribution of Incentive Salience to a Reward-Related Cue: Influence on Cocaine Sensitization

PubMed Central

Flagel, Shelly B.; Watson, Stanley J.; Akil, Huda; Robinson, Terry E.

2008-01-01

When a discrete cue (a “sign”) is presented repeatedly in anticipation of a food reward the cue can become imbued with incentive salience, leading some animals to approach and engage it, a phenomenon known as “sign-tracking” (the animals are sign-trackers; STs). In contrast, other animals do not approach the cue, but upon cue presentation go to the location where food will be delivered (the goal). These animals are known as goal-trackers (GTs). It has been hypothesized that individuals who attribute excessive incentive salience to reward-related cues may be especially vulnerable to develop compulsive behavioral disorders, including addiction. We were interested, therefore, in whether individual differences in the propensity to sign-track are associated with differences in responsivity to cocaine. Using an autoshaping procedure in which lever (conditioned stimulus) presentation was immediately followed by the response-independent delivery of a food pellet (unconditioned stimulus), rats were first characterized as STs or GTs and subsequently studied for the acute psychomotor response to cocaine and the propensity for cocaine-induced psychomotor sensitization. We found that GTs were more sensitive than STs to the acute locomotor activating effects of cocaine, but STs showed a greater propensity for psychomotor sensitization upon repeated treatment. These data suggest that individual differences in the tendency to attribute incentive salience to a discrete reward-related cue, and to approach and engage it, are associated with susceptibility to a form of cocaine-induced plasticity that may contribute to the development of addiction. PMID:17719099

Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats.

PubMed

Flagel, Shelly B; Watson, Stanley J; Robinson, Terry E; Akil, Huda

2007-04-01

The way an individual responds to cues associated with rewards may be a key determinant of vulnerability to compulsive behavioral disorders. We studied individual differences in Pavlovian conditioned approach behavior and examined the expression of neurobiological markers associated with the dopaminergic system, the same neural system implicated in incentive motivational processes. Pavlovian autoshaping procedures consisted of the brief presentation of an illuminated retractable lever (conditioned stimulus) followed by the response-independent delivery of a food pellet (unconditioned stimulus), which lead to a Pavlovian conditioned response. In situ hybridization was performed on brains obtained either following the first or last (fifth) day of training. Two phenotypes emerged. Sign-trackers (ST) exhibited behavior that seemed to be largely controlled by the cue that signaled impending reward delivery; whereas goal-trackers (GT) preferentially approached the location where the reward was delivered. Following a single training session, ST showed greater expression of dopamine D1 receptor mRNA relative to GT. After 5 days of training, GT exhibited greater expression levels of tyrosine hydroxylase, dopamine transporter, and dopamine D2 receptor mRNA relative to ST. These findings suggest that the development of approach behavior towards signals vs goal leads to distinct adaptations in the dopamine system. The sign-tracker vs goal-tracker phenotype may prove to be a valuable animal model to investigate individual differences in the way incentive salience is attributed to environmental stimuli, which may contribute to the development of addiction and other compulsive behavioral disorders.

Chasing as a model of psychogenic stress: characterization of physiological and behavioral responses.

PubMed

Lee, Ji-Hye; Kimm, Sunwhi; Han, Jung-Soo; Choi, June-Seek

2018-03-25

Being chased by a predator or a dominant conspecific can induce significant stress. However, only a limited number of laboratory studies have employed chasing by itself as a stressor. In this study, we developed a novel stress paradigm in which rats were chased by a fast-moving object in an inescapable maze. In Experiment 1, defensive behaviors and stress hormone changes induced by chasing stress were measured. During the chasing stress, the chasing-stress group (n = 9) froze and emitted 22-kHz ultrasonic vocalizations (USVs), but the no-chasing control group (n = 10) did not. Plasma corticosterone levels significantly increased following the chasing and were comparable to those of the restraint-stress group (n = 6). In Experiment 2, the long-lasting memory of the chasing event was tested after three weeks. The chasing-stress group (n = 15) showed higher levels of freezing and USV than the no-chasing group (n = 14) when they were presented with the tone associated with the object's chasing action. Subsequently, the rats were subjected to Pavlovian threat conditioning with a tone as a conditioned stimulus and footshock as an unconditioned stimulus. The chasing-stress group showed higher levels of freezing and USV during the conditioning session than the no-chasing group, indicating sensitized defensive reactions in a different threat situation. Taken together, the current results suggest that chasing stress can induce long-lasting memory and sensitization of defensive responses to a new aversive event as well as immediate, significant stress responses.

Disrupting reconsolidation: memory erasure or blunting of emotional/motivational value?

PubMed

Cogan, Elizabeth S; Shapses, Mark A; Robinson, Terry E; Tronson, Natalie C

2018-05-03

When memories are retrieved they become labile, and subject to alteration by a process known as reconsolidation. Disruption of memory reconsolidation decreases the performance of learned responses, which is often attributed to erasure of the memory; in the case of Pavlovian learning, to a loss of the association between a conditioned stimulus (CS) and unconditioned stimulus (US). However, an alternative interpretation is that disrupting reconsolidation does not erase memories, but blunts their emotional/motivational impact. It is difficult to parse the predictive vs. emotional/motivational value of CSs in non-human animals, but studies on variation in the form of conditioned responses (CRs) in a Pavlovian conditioned approach task suggest a way to do this. In this task a lever-CS paired with a food reward (US) acquires predictive value in all rats, but is attributed with emotional/motivational value to a greater extent in some rats (sign-trackers) than others (goal-trackers). We report that the post-retrieval administration of propranolol selectively attenuates a sign-tracking CR, and the associated neural activation of brain "motive circuits", while having no effect on conditioned orienting behavior in sign-trackers, or on goal-tracking CRs evoked by either a lever-CS or a tone-CS. We conclude that the disruption of reconsolidation by post-retrieval propranolol degrades the emotional/motivational impact of the CS, required for sign-tracking, but leaves the CS-US association intact. The possibility that post-retrieval interventions can reduce the emotional/motivational aspects of memories, without actually erasing them, has important implications for treating maladaptive memories that contribute to some psychiatric disorders.

Startle modulation and explicit valence evaluations dissociate during backward fear conditioning.

PubMed

Luck, Camilla C; Lipp, Ottmar V

2017-05-01

Blink startle magnitude is linearly modulated by affect such that, relative to neutral stimuli, startle magnitude is inhibited during pleasant stimuli and potentiated during unpleasant stimuli. Andreatta, Mühlberger, Yarali, Gerber, and Pauli (2010), however, report a dissociation between startle modulation and explicit valence evaluations during backward conditioning, a procedure in which the unconditional stimulus precedes the conditional stimulus (CS). Relative to controls, startles elicited during the CS were inhibited, suggesting that the CS had acquired positive valence, but participants still evaluated the CS as unpleasant after the experiment. In Experiment 1, we aimed to replicate this dissociation using a trial-by-trial measure of CS valence to measure startle modulation and CS valence simultaneously during forward and backward differential fear conditioning. In Experiment 2, we examined whether early and late portions of the CS could acquire differential valence by presenting startle probes at early and late probe positions during the CS. In both experiments, the dissociation between startle modulation and explicit valence evaluations in backward conditioning replicated, with CS+ evaluated as less pleasant than CS-, but startles elicited during CS+ inhibited relative to CS-. In Experiment 2, we provide preliminary evidence that this inhibition was present early, but not late, during the CS+. The results replicate the dissociation between implicit and explicit CS valence reported by Andreatta et al. (2010) using a trial-by-trial measure of valence. We also provide preliminary evidence that this dissociation may occur because the implicit and explicit measures are recorded at different times during the CS presentation. © 2017 Society for Psychophysiological Research.

Implicit Memory in Monkeys: Development of a Delay Eyeblink Conditioning System with Parallel Electromyographic and High-Speed Video Measurements.

PubMed

Kishimoto, Yasushi; Yamamoto, Shigeyuki; Suzuki, Kazutaka; Toyoda, Haruyoshi; Kano, Masanobu; Tsukada, Hideo; Kirino, Yutaka

2015-01-01

Delay eyeblink conditioning, a cerebellum-dependent learning paradigm, has been applied to various mammalian species but not yet to monkeys. We therefore developed an accurate measuring system that we believe is the first system suitable for delay eyeblink conditioning in a monkey species (Macaca mulatta). Monkey eyeblinking was simultaneously monitored by orbicularis oculi electromyographic (OO-EMG) measurements and a high-speed camera-based tracking system built around a 1-kHz CMOS image sensor. A 1-kHz tone was the conditioned stimulus (CS), while an air puff (0.02 MPa) was the unconditioned stimulus. EMG analysis showed that the monkeys exhibited a conditioned response (CR) incidence of more than 60% of trials during the 5-day acquisition phase and an extinguished CR during the 2-day extinction phase. The camera system yielded similar results. Hence, we conclude that both methods are effective in evaluating monkey eyeblink conditioning. This system incorporating two different measuring principles enabled us to elucidate the relationship between the actual presence of eyelid closure and OO-EMG activity. An interesting finding permitted by the new system was that the monkeys frequently exhibited obvious CRs even when they produced visible facial signs of drowsiness or microsleep. Indeed, the probability of observing a CR in a given trial was not influenced by whether the monkeys closed their eyelids just before CS onset, suggesting that this memory could be expressed independently of wakefulness. This work presents a novel system for cognitive assessment in monkeys that will be useful for elucidating the neural mechanisms of implicit learning in nonhuman primates.

Deep Cerebellar Nuclei Play an Important Role in Two-Tone Discrimination on Delay Eyeblink Conditioning in C57BL/6 Mice

PubMed Central

Sakamoto, Toshiro; Endo, Shogo

2013-01-01

Previous studies have shown that deep cerebellar nuclei (DCN)-lesioned mice develop conditioned responses (CR) on delay eyeblink conditioning when a salient tone conditioned stimulus (CS) is used, which suggests that the cerebellum potentially plays a role in more complicated cognitive functions. In the present study, we examined the role of DCN in tone frequency discrimination in the delay eyeblink-conditioning paradigm. In the first experiment, DCN-lesioned and sham-operated mice were subjected to standard simple eyeblink conditioning under low-frequency tone CS (LCS: 1 kHz, 80 dB) or high-frequency tone CS (HCS: 10 kHz, 70 dB) conditions. DCN-lesioned mice developed CR in both CS conditions as well as sham-operated mice. In the second experiment, DCN-lesioned and sham-operated mice were subjected to two-tone discrimination tasks, with LCS+ (or HCS+) paired with unconditioned stimulus (US), and HCS− (or LCS−) without US. CR% in sham-operated mice increased in LCS+ (or HCS+) trials, regardless of tone frequency of CS, but not in HCS− (or LCS−) trials. The results indicate that sham-operated mice can discriminate between LCS+ and HCS− (or HCS+ and LCS−). In contrast, DCN-lesioned mice showed high CR% in not only LCS+ (or HCS+) trials but also HCS− (or LCS−) trials. The results indicate that DCN lesions impair the discrimination between tone frequency in eyeblink conditioning. Our results suggest that the cerebellum plays a pivotal role in the discrimination of tone frequency. PMID:23555821

Uncertainty of trial timing enhances acquisition of conditioned eyeblinks in anxiety vulnerable individuals.

PubMed

Allen, M T; Myers, C E; Servatius, R J

2016-05-01

Recent work has found that behaviorally inhibited (BI) individuals exhibit enhanced eyeblink conditioning in omission and yoked training as well as with schedules of partial reinforcement. We hypothesized that spacing CS-US paired trials over a longer period of time by extending and varying the inter-trial interval (ITI) would facilitate learning. All participants completed the Adult Measure of Behavioural Inhibition (AMBI) and were grouped as behaviorally inhibited (BI) and non-behaviorally inhibited (NI) based on a median split score of 15.5. All participants received 3 US alone trials and 30CS-US paired trials for acquisition training and 20CS alone trials for extinction training in one session. Conditioning stimuli were a 500 ms tone conditioned stimulus (CS) and a 50-ms air puff unconditional stimulus (US). Participants were randomly assigned to receive a short ITI (mean=30+/- 5s), a long ITI (mean=57+/- 5s) or a variable long ITI (mean=57 s, range 25-123 s). No significant ITI effects were observed for acquisition or extinction. Overall, anxiety vulnerable individuals exhibited enhanced conditioned eyeblink responses as compared to non-vulnerable individuals. This enhanced acquisition of CRs was significant in spaced training with a variable long ITI, but not the short or long ITI. There were no significant effects of ITI or BI on extinction. These findings are interpreted based on the idea that uncertainty plays a role in anxiety and can enhance associative learning in anxiety vulnerable individuals. Copyright © 2016 Elsevier B.V. All rights reserved.

Generalization of Fear to Respiratory Sensations.

PubMed

Schroijen, Mathias; Pappens, Meike; Schruers, Koen; Van den Bergh, Omer; Vervliet, Bram; Van Diest, Ilse

2015-09-01

Interoceptive fear conditioning (IFC), fear generalization and a lack of safety learning have all been hypothesized to play a role in the pathogenesis of panic disorder, but have never been examined in a single paradigm. The present study aims to investigate whether healthy participants (N=43) can learn both fear and safety to an interoceptive sensation, and whether such learning generalizes to other, similar sensations. Two intensities of inspiratory breathing impairment (induced by two pressure threshold loads of 6 and 25 cm H2O) served as interoceptive conditional stimuli (CSs) in a differential conditioning paradigm. An inspiratory occlusion was used as the unconditioned stimulus (US). Generalization was tested 24h after conditioning, using four generalization stimuli with intensities in-between CS+ and CS- (GSs: 8-10.5-14-18.5 cm H2O). Measures included US-expectancy, startle blink EMG responses, electrodermal activity and respiration. Perceptual discrimination of interoceptive CSs and GSs was explored with a discrimination task prior to acquisition and after generalization. Results indicate that differential fear learning was established for US-expectancy ratings. The group with a low intensity CS+ and a high intensity CS- showed the typical pattern of differential fear responding and a similarity-based generalization gradient. In contrast, the high intensity CS+ and low intensity CS- group showed impaired differential learning and complete generalization of fear. Our findings suggest that interoceptive fear learning and generalization are modulated by stimulus intensity and that the occurrence of discriminatory learning is closely related to fear generalization. Copyright © 2015. Published by Elsevier Ltd.

Optimising Extinction of Conditioned Disgust.

PubMed

Bosman, Renske C; Borg, Charmaine; de Jong, Peter J

2016-01-01

Maladaptive disgust responses are tenacious and resistant to exposure-based interventions. In a similar vein, laboratory studies have shown that conditioned disgust is relatively insensitive to Conditioned Stimulus (CS)-only extinction procedures. The relatively strong resistance to extinction might be explained by disgust's adaptive function to motivate avoidance from contamination threats (pathogens) that cannot be readily detected and are invisible to the naked eye. Therefore, the mere visual presentation of unreinforced disgust eliciting stimuli might not be sufficient to correct a previously acquired threat value of the CS+. Following this, the current study tested whether the efficacy of CS-only exposure can be improved by providing additional safety information about the CS+. For the CSs we included two neutral items a pea soup and a sausage roll, whereas for the Unconditioned Stimulus (US) we used one video clip of a woman vomiting and a neutral one about glass blowing. The additional safety information was conveyed by allowing actual contact with the CS+ or by observing an actress eating the food items representing the CS+. When additional safety information was provided via allowing direct contact with the CS+, there was a relatively strong post-extinction increase in participants' willingness-to-eat the CS+. This beneficial effect was still evident at one-week follow up. Also self-reported disgust was lower at one-week follow up when additional safety information was provided. The current findings help explain why disgust is relatively insensitive to CS-only extinction procedures, and provide helpful starting points to improve interventions that are aimed to reduce distress in disgust-related psychopathology.

An automatic recording system for the study of escape from fear in rats.

PubMed

Li, Ming; He, Wei

2013-11-01

Escape from fear (EFF) is an active response to a conditioned stimulus (CS) previously paired with an unconditioned fearful stimulus (US), which typically leads to the termination of the CS. In this paradigm, animals acquire two distinct associations: S-S [CS-US] and R-O [response-outcome] through Pavlovian and instrumental conditioning, respectively. The present study describes a computer controlled automatic recording system that captures the development of EFF and allows the determination of the respective roles of S-S and R-O associations in this process. We validated this system by showing that only rats subjected to a simultaneous CS-US conditioning (i.e., CS and US occur together at the beginning of each trial) acquired EFF, not those subjected to an unpaired CS-US conditioning. Paired rats had a progressively increased number of EFF and significantly shorter escape latencies than unpaired rats across the 5-trial blocks on the test day. However, during the conditioning phase, the unpaired rats emitted more 22kHz ultrasonic vocalizations, a validated measure of conditioned reactive fear responses. Our results demonstrate that the acquisition of EFF is contingent upon pairing of the CS with the US, not simply the consequence of a high level of generalized fear. Because this commercially available system is capable of examining both conditioned active and reactive fear responses in a single setup, it could be used to determine the relative roles of S-S and R-O associations in EFF, the neurobiology of conditioned active fear response and neuropharmacology of psychotherapeutic drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction.

PubMed

Simon, Nicholas W; Setlow, Barry

2006-11-01

It has been suggested that some of the addictive potential of psychostimulant drugs of abuse such as amphetamine may result from their ability to enhance memory for drug-related experiences through actions on memory consolidation. This experiment examined whether amphetamine can specifically enhance consolidation of memory for a Pavlovian association between a neutral conditioned stimulus (CS-a light) and a rewarding unconditioned stimulus (US-food), as Pavlovian conditioning of this sort plays a major role in drug addiction. Male Long-Evans rats were given six training sessions consisting of 8 CS presentations followed by delivery of the food into a recessed food cup. After the 1st, 3rd, and 5th session, rats received subcutaneous injections of amphetamine (1.0 or 2.0 mg/kg) or saline vehicle immediately following training. Conditioned responding was assessed using the percentage of time rats spent in the food cup during the CS relative to a pre-CS baseline period. Both amphetamine-treated groups showed significantly more selective conditioned responding than saline controls. In a control experiment, there were no differences among groups given saline, 1.0 or 2.0 mg/kg amphetamine 2 h post-training, suggesting that immediate post-training amphetamine enhanced performance specifically through actions on memory consolidation rather than through non-mnemonic processes. This procedure modeled Pavlovian learning involved in drug addiction, in which the emotional valence of a drug reward is transferred to neutral drug-predictive stimuli such as drug paraphernalia. These data suggest that amphetamine may contribute to its addictive potential through actions specifically on memory consolidation.

Rats that sign-track are resistant to Pavlovian but not instrumental extinction

PubMed Central

Ahrens, Allison M.; Singer, Bryan F.; Fitzpatrick, Christopher J.; Morrow, Jonathan D.; Robinson, Terry E.

2015-01-01

Individuals vary in the extent to which they attribute incentive salience to a discrete cue (conditioned stimulus; CS) that predicts reward delivery (unconditioned stimulus; US), which results in some individuals approaching and interacting with the CS (sign-trackers; STs) more than others (goal-trackers; GTs). Here we asked how periods of non-reinforcement influence conditioned responding in STs vs. GTs, in both Pavlovian and instrumental tasks. After classifying rats as STs or GTs by pairing a retractable lever (the CS) with the delivery of a food pellet (US), we introduced periods of non-reinforcement, first by simply withholding the US (i.e., extinction training; experiment 1), then by signaling alternating periods of reward (R) and non-reward (NR) within the same session (experiments 2 and 3). We also examined how alternating R and NR periods influenced instrumental responding for food (experiment 4). STs and GTs did not differ in their ability to discriminate between R and NR periods in the instrumental task. However, in Pavlovian settings STs and GTs responded to periods of non-reward very differently. Relative to STs, GTs very rapidly modified their behavior in response to periods of non-reward, showing much faster extinction and better and faster discrimination between R and NR conditions. These results highlight differences between Pavlovian and instrumental extinction learning, and suggest that if a Pavlovian CS is strongly attributed with incentive salience, as in STs, it may continue to bias attention toward it, and to facilitate persistent and relatively inflexible responding, even when it is no longer followed by reward. PMID:26235331

Pharmacological depletion of serotonin in the basolateral amygdala complex reduces anxiety and disrupts fear conditioning.

PubMed

Johnson, Philip L; Molosh, Andrei; Fitz, Stephanie D; Arendt, Dave; Deehan, Gerald A; Federici, Lauren M; Bernabe, Cristian; Engleman, Eric A; Rodd, Zachary A; Lowry, Christopher A; Shekhar, Anantha

2015-11-01

The basolateral and lateral amygdala nuclei complex (BLC) is implicated in a number of emotional responses including conditioned fear and social anxiety. Based on previous studies demonstrating that enhanced serotonin release in the BLC leads to increased anxiety and fear responses, we hypothesized that pharmacologically depleting serotonin in the BLC using 5,7-dihydroxytryptamine (5,7-DHT) injections would lead to diminished anxiety and disrupted fear conditioning. To test this hypothesis, 5,7-DHT(a serotonin-depleting agent) was bilaterally injected into the BLC. Desipramine (a norepinephrine reuptake inhibitor) was systemically administered to prevent non-selective effects on norepinephrine. After 5days, 5-7-DHT-treated rats showed increases in the duration of social interaction (SI) time, suggestive of reduced anxiety-like behavior. We then used a cue-induced fear conditioning protocol with shock as the unconditioned stimulus and tone as the conditioned stimulus for rats pretreated with bilateral 5,7-DHT, or vehicle, injections into the BLC. Compared to vehicle-treated rats, 5,7-DHT rats had reduced acquisition of fear during conditioning (measured by freezing time during tone), also had reduced fear retrieval/recall on subsequent testing days. Ex vivo analyses revealed that 5,7-DHT reduced local 5-HT concentrations in the BLC by ~40% without altering local norepinephrine or dopamine concentrations. These data provide additional support for 5-HT playing a critical role in modulating anxiety-like behavior and fear-associated memories through its actions within the BLC. Copyright © 2015 Elsevier Inc. All rights reserved.

Lock-and-key mechanisms of cerebellar memory recall based on rebound currents.

PubMed

Wetmore, Daniel Z; Mukamel, Eran A; Schnitzer, Mark J

2008-10-01

A basic question for theories of learning and memory is whether neuronal plasticity suffices to guide proper memory recall. Alternatively, information processing that is additional to readout of stored memories might occur during recall. We formulate a "lock-and-key" hypothesis regarding cerebellum-dependent motor memory in which successful learning shapes neural activity to match a temporal filter that prevents expression of stored but inappropriate motor responses. Thus, neuronal plasticity by itself is necessary but not sufficient to modify motor behavior. We explored this idea through computational studies of two cerebellar behaviors and examined whether deep cerebellar and vestibular nuclei neurons can filter signals from Purkinje cells that would otherwise drive inappropriate motor responses. In eyeblink conditioning, reflex acquisition requires the conditioned stimulus (CS) to precede the unconditioned stimulus (US) by >100 ms. In our biophysical models of cerebellar nuclei neurons this requirement arises through the phenomenon of postinhibitory rebound depolarization and matches longstanding behavioral data on conditioned reflex timing and reliability. Although CS-US intervals<100 ms may induce Purkinje cell plasticity, cerebellar nuclei neurons drive conditioned responses only if the CS-US training interval was >100 ms. This bound reflects the minimum time for deinactivation of rebound currents such as T-type Ca2+. In vestibulo-ocular reflex adaptation, hyperpolarization-activated currents in vestibular nuclei neurons may underlie analogous dependence of adaptation magnitude on the timing of visual and vestibular stimuli. Thus, the proposed lock-and-key mechanisms link channel kinetics to recall performance and yield specific predictions of how perturbations to rebound depolarization affect motor expression.

Neurotoxic lesions of the dorsal and ventral hippocampus impair acquisition and expression of trace-conditioned fear-potentiated startle in rats.

PubMed

Trivedi, Mehul A; Coover, Gary D

2006-04-03

Pavlovian delay conditioning, in which a conditioned stimulus (CS) and unconditioned stimulus (US) co-terminate, is thought to reflect non-declarative memory. In contrast, trace conditioning, in which the CS and US are temporally separate, is thought to reflect declarative memory. Hippocampal lesions impair acquisition and expression of trace conditioning measured by the conditioned freezing and eyeblink responses, while having little effect on the acquisition of delay conditioning. Recent evidence suggests that lesions of the ventral hippocampus (VH) impair conditioned fear under conditions in which dorsal hippocampal (DH) lesions have little effect. In the present study, we examined the time-course of fear expression after delay and trace conditioning using the fear-potentiated startle (FPS) reflex, and the effects of pre- and post-training lesions to the VH and DH on trace-conditioned FPS. We found that both delay- and trace-conditioned rats displayed significant FPS near the end of the CS relative to the unpaired control group. In contrast, trace-conditioned rats displayed significant FPS throughout the duration of the trace interval, whereas FPS decayed rapidly to baseline after CS offset in delay-conditioned rats. In experiment 2, both DH and VH lesions were found to significantly reduce the overall magnitude of FPS compared to the control group, however, no differences were found between the DH and VH groups. These findings support a role for both the DH and VH in trace fear conditioning, and suggest that the greater effect of VH lesions on conditioned fear might be specific to certain measures of fear.

The effect of elevated blood cortisol levels on the extinction of a conditioned stress response in rainbow trout.

PubMed

Barreto, R E; Volpato, G L; Pottinger, T G

2006-09-01

Following previously published observations that a conditioned response (CR) was lost more quickly by rainbow trout (Oncorhynchus mykiss) exhibiting a high responsiveness to stressors than by low responding individuals this study was designed to investigate the effects of exogenous cortisol on the retention of a CR in unselected rainbow trout. Fish held in isolation were conditioned over a 10-day period by pairing an innocuous signal (conditioned stimulus, CS: a water jet played on the surface of the tank water) with a mild stressor (unconditioned stimulus, US: 30 min of confinement). This resulted in a brief elevation of plasma cortisol levels (the CR) when the fish was exposed to the CS only. The effect of exogenous cortisol on the retention of the CR was evaluated by comparing the performance of fish that received cortisol-containing slow-release intraperitoneal implants, with fish receiving vehicle-only implants. Retention of the CR was assessed at intervals up to 35 days after conditioning ceased. The CR was considered to be evident when 30 min following presentation of the CS, mean plasma cortisol levels were significantly higher in conditioned than untrained fish. On day 1 both cortisol-implanted and vehicle-implanted conditioned fish exhibited a CR. However, from day 5 onwards the CR was observed only in the vehicle-implanted and conditioned group. This finding indicates that administration of cortisol accelerated the extinction of the CR in the cortisol-implanted fish, suggesting that elevated plasma cortisol levels can impair memory processes in rainbow trout.

Extinction of a conditioned response in rainbow trout selected for high or low responsiveness to stress.

PubMed

Moreira, P S A; Pulman, K G T; Pottinger, T G

2004-11-01

Two lines of rainbow trout (Oncorhynchus mykiss) that exhibit divergent endocrine responsiveness to stressors also display disparate behavioral traits. To investigate whether the high-responding (HR) and low-responding (LR) fish also differ in cognitive function, the rate of extinction of a conditioned response was compared between the two lines. Groups of HR and LR fish were exposed to a paired conditioned stimulus (CS; water off) and unconditioned stimulus (US; confinement stressor). After exposure to 18 CS-US pairings, at least 70% of individuals of both lines acquired a conditioned response (CR) manifested as an elevation of blood cortisol levels on presentation of the CS only. Post-conditioning, the fish were tested by presentation of the CS at weekly intervals, for 4 weeks, with no further reinforcement, and the extinction of the CR in the two lines was compared. The decline in mean plasma cortisol levels after exposure to the CS over successive tests suggested that the CR was retained for a shorter period among the HR (<14 days) than LR fish (<21 days). The frequency of individuals within each line whose plasma cortisol levels indicated a stress response when exposed to the CS was significantly greater among the LR than HR fish at 14 and 21 days with no HR fish falling into this category at 21 days. At 28 days post-conditioning, there were no HR fish and only three LR fish were categorized as "stressed". These results suggest that there are differences in cognitive function between the two lines. Possible mechanisms underlying these differences are discussed.

The attribution of incentive salience to Pavlovian alcohol cues: a shift from goal-tracking to sign-tracking.

PubMed

Srey, Chandra S; Maddux, Jean-Marie N; Chaudhri, Nadia

2015-01-01

Environmental stimuli that are reliably paired with alcohol may acquire incentive salience, a property that can operate in the use and abuse of alcohol. Here we investigated the incentive salience of Pavlovian alcohol cues using a preclinical animal model. Male, Long-Evans rats (Harlan) with unrestricted access to food and water were acclimated to drinking 15% ethanol (v/v) in their home-cages. Rats then received Pavlovian autoshaping training in which the 10 s presentation of a retractable lever served as the conditioned stimulus (CS) and 15% ethanol served as the unconditioned stimulus (US) (0.2 ml/CS; 12 CS presentations/session; 27 sessions). Next, in an operant test of conditioned reinforcement, nose pokes into an active aperture delivered presentations of the lever-CS, whereas nose pokes into an inactive aperture had no consequences. Across initial autoshaping sessions, goal-tracking behavior, as measured by entries into the fluid port where ethanol was delivered, developed rapidly. However, with extended training goal-tracking diminished, and sign-tracking responses, as measured by lever-CS activations, emerged. Control rats that received explicitly unpaired CS and US presentations did not show goal-tracking or sign-tracking responses. In the test for conditioned reinforcement, rats with CS-US pairings during autoshaping training made more active relative to inactive nose pokes, whereas rats in the unpaired control group did not. Moreover, active nose pokes were positively correlated with sign-tracking behavior during autoshaping. Extended training may produce a shift in the learned properties of Pavlovian alcohol cues, such that after initially predicting alcohol availability they acquire robust incentive salience.

Electrical stimulation of the rostral medial prefrontal cortex in rabbits inhibits the expression of conditioned eyelid responses but not their acquisition

PubMed Central

Leal-Campanario, Rocío; Fairén, Alfonso; Delgado-García, José M.; Gruart, Agnès

2007-01-01

We have studied the role of rostral medial prefrontal cortex (mPFC) on reflexively evoked blinks and on classically conditioned eyelid responses in alert-behaving rabbits. The rostral mPFC was identified by its afferent projections from the medial half of the thalamic mediodorsal nuclear complex. Classical conditioning consisted of a delay paradigm using a 370-ms tone as the conditioned stimulus (CS) and a 100-ms air puff directed at the left cornea as the unconditioned stimulus (US). The CS coterminated with the US. Electrical train stimulation of the contralateral rostral mPFC produced a significant inhibition of air-puff-evoked blinks. The same train stimulation of the rostral mPFC presented during the CS–US interval for 10 successive conditioning sessions significantly reduced the generation of conditioned responses (CRs) as compared with values reached by control animals. Interestingly, the percentage of CRs almost reached control values when train stimulation of the rostral mPFC was removed from the fifth conditioning session on. The electrical stimulation of the rostral mPFC in well conditioned animals produced a significant decrease in the percentage of CRs. Moreover, the stimulation of the rostral mPFC was also able to modify the kinematics (latency, amplitude, and velocity) of evoked CRs. These results suggest that the rostral mPFC is a potent inhibitor of reflexively evoked and classically conditioned eyeblinks but that activation prevents only the expression of CRs, not their latent acquisition. Functional and behavioral implications of this inhibitory role of the rostral mPFC are discussed. PMID:17592148

First-principles study of uranium carbide: Accommodation of point defects and of helium, xenon, and oxygen impurities

NASA Astrophysics Data System (ADS)

Freyss, Michel

2010-01-01

Point defects and volatile impurities (helium, xenon, oxygen) in uranium monocarbide UC are studied by first-principles calculations. Preliminarily, bulk properties of UC and of two other uranium carbide phases, UC2 and U2C3 , are calculated in order to compare them to experimental data and to get confidence in the use of the generalized gradient approximation for this class of compounds. The subsequent study of different types of point defects shows that the carbon sublattice best accommodates the defects. The perturbation of the crystal structure induced by the defects is weak and the interaction between defects is found short range. Interstitial carbon dumbbells possibly play an important role in the diffusion of carbon atoms. The most favorable location of diluted helium, xenon, and oxygen impurities in the UC crystal lattice is then determined. The rare-gas atoms occupy preferably a uranium substitution site or a uranium site in a U-C bivacancy. But their incorporation in UC is, however, not energetically favorable, especially for xenon, suggesting their propensity to diffuse in the material and/or form bubbles. On the other hand, oxygen atoms are very favorably incorporated as diluted atoms in the UC lattice, confirming the easy oxidation of UC. The oxygen atoms preferably occupy a carbon substitution site or the carbon site of a U-C bivacancy. Our results are compared to available experimental data on UC and to similar studies by first-principles calculations for other carbides and nitrides with the rock-salt structure.

Polymorphisms of the IL-1beta and IL-1beta-inducible genes in ulcerative colitis.

PubMed

Nohara, Hiroaki; Saito, Yuki; Higaki, Singo; Okayama, Naoko; Hamanaka, Yuichiro; Okita, Kiwamu; Hinoda, Yuji

2002-11-01

Ulcerative colitis (UC) is a chronic disorder of undetermined etiology, but a genetic predisposition to UC is well recognized. Among cytokines induced in UC, interleukin 1 (IL-1) appears to have a central role because of its immunological upregulatory and proinflammatory activities. The aim of this study was to assess whether UC is associated with polymorphisms of the IL-1beta gene and three additional genes inducible with IL-1beta in Japanese subjects. A total of 96 patients with UC and 106 ethnically matched controls were genotyped at polymorphic sites in IL-1beta, matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase 3 (MMP-3), and inducible nitric oxide synthase (iNOS) genes, using polymerase chain reaction (PCR)-based methods. There was no significant difference in genotype distributions of IL-1beta, MMP-1, MMP-3, and iNOS genes between controls and UC patients in a Japanese population. Also, no significant association of those polymorphisms with various clinical parameters of the patients was found. However, concerning association of age at onset with clinical factors in UC, the frequency of pancolitis was significantly higher in UC patients with age at onset being less than 30 years than in those more than 30 years of age (P = 0.049). No association of the IL-1beta and three IL-1beta-inducible gene polymorphisms with UC was observed in a Japanese population.

Lack of in vitro-in vivo correlation for a UC781-releasing vaginal ring in macaques.

PubMed

McConville, Christopher; Smith, James M; McCoy, Clare F; Srinivasan, Priya; Mitchell, James; Holder, Angela; Otten, Ron A; Butera, Salvatore; Doncel, Gustavo F; Friend, David R; Malcolm, R Karl

2015-02-01

This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside reverse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities considered sufficient to maintain vaginal fluid concentrations at levels 82-860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal transmission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median concentrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo-in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mechanism rather than the expected diffusion-controlled mechanism.

Anti-TNF-A therapy about infliximab and adalimamab for the effectiveness in ulcerative colitis compared with conventional therapy: a meta-analysis.

PubMed

Zhou, Zheng; Dai, Cong; Liu, Wei-Xin

2015-01-01

TNF-α has an important role in the pathogenesis of ulcerative colitis (UC). It seems that anti-TNF-α therapy is beneficial in the treatment of UC. The aim was to assess the effectiveness of Infliximab and Adalimamab with UC compared with conventional therapy. The Pubmed and Embase databases were searched for studies investigating the efficacy of infliximab and adalimumab on UC. Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy, but those had not a statistically significant effects in clinical remission (RR = 1.63; 95% CI 0.84 to 3.18) and reduction of colectomy rate (RR = 0.54; 95% CI 0.26 to 1.12) of UC. And adalimumab had a statistically significant effects in induction of clinical remission (RR = 1.82; 95% CI 1.24 to 2.67) and clinical response (RR = 1.36; 95% CI 1.13 to 1.64) of UC compared with conventional therapy. Our meta-analyses suggested that Infliximab had a statistically significant effects in induction of clinical response of UC compared with conventional therapy and adalimumab had a statistically significant effects in induction of clinical remission and clinical response of UC compared with conventional therapy.

Anti-TNF-A Therapy about Infliximab and Adalimamab for the Effectiveness in Ulcerative Colitis Compared with Conventional Therapy: A Meta-Analysis.

PubMed

Zhou, Zheng; Dai, Cong; Liu, Wei-xin

2015-06-01

TNF-α has an important role in the pathogenesis of ulcerative colitis (UC). It seems that anti-TNF-α therapy is beneficial in the treatment of UC. The aim was to assess the effectiveness of Infliximab and Adalimamab with UC compared with con- ventional therapy. The Pubmed and Embase databases were searched for studies investigating the efficacy of infliximab and adalimumab on UC. Infliximab had a statistically significant effects in induction of clinical response (RR = 1.67; 95% CI 1.12 to 2.50) of UC compared with conventional therapy, but those had not a statistically significant effects in clinical remission (RR = 1.63; 95% CI 0.84 to 3.18) and reduction of colectomy rate (RR = 0.54; 95% CI 0.26 to 1.12) of UC. And adalimumab had a statistically significant effects in induction of clinical remission (RR =1.82; 95% CI 1.24 to 2.67) and clinical response (RR =1.36; 95% CI 1.13 to 1.64) of UC compared with conventional therapy. Our meta-analyses suggested that Infliximab had a statistically significant effects in induction of clinical response of UC compared with conventional therapy and adalimumab had a statistically significant effects in induction of clinical remission and clinical response of UC compared with conventional therapy.

MF2KtoMF05UC, a Program To Convert MODFLOW-2000 Files to MODFLOW-2005 and UCODE_2005 Files

USGS Publications Warehouse

Harbaugh, Arlen W.

2007-01-01

The program MF2KtoMF05UC has been developed to convert MODFLOW-2000 input files for use by MODFLOW-2005 and UCODE_2005. MF2KtoMF05UC was written in the Fortran 90 computer language. This report documents the use of MF2KtoMF05UC.

A three-stage birandom program for unit commitment with wind power uncertainty.

PubMed

Zhang, Na; Li, Weidong; Liu, Rao; Lv, Quan; Sun, Liang

2014-01-01

The integration of large-scale wind power adds a significant uncertainty to power system planning and operating. The wind forecast error is decreased with the forecast horizon, particularly when it is from one day to several hours ahead. Integrating intraday unit commitment (UC) adjustment process based on updated ultra-short term wind forecast information is one way to improve the dispatching results. A novel three-stage UC decision method, in which the day-ahead UC decisions are determined in the first stage, the intraday UC adjustment decisions of subfast start units are determined in the second stage, and the UC decisions of fast-start units and dispatching decisions are determined in the third stage is presented. Accordingly, a three-stage birandom UC model is presented, in which the intraday hours-ahead forecasted wind power is formulated as a birandom variable, and the intraday UC adjustment event is formulated as a birandom event. The equilibrium chance constraint is employed to ensure the reliability requirement. A birandom simulation based hybrid genetic algorithm is designed to solve the proposed model. Some computational results indicate that the proposed model provides UC decisions with lower expected total costs.

Golimumab in unresponsive ulcerative colitis.

PubMed

Lippert, Elisabeth; Müller, Martina; Ott, Claudia

2014-01-01

Ulcerative colitis (UC) is a chronic inflammation mainly affecting the colon mucosa. It predominantly occurs in younger patients. Until recently, the main goals in the treatment of UC were to temper the symptoms, such as diarrhea, pain, and weight loss, by using mesalazine and steroids. With newer medications, such as immunomodulators (thiopurines) and the biologics providing blockade of tumor necrosis factor (TNF), the goals of the therapy in UC have changed to long-term remission and mucosal healing. The first available anti-TNF therapy in UC included infusion therapy with infliximab every few weeks. In 2012, subcutaneously administered adalimumab gained approval for the treatment of UC in Germany. In patients with a mild disease, therapy with mesalazine, orally or topically, can be sufficient. In patients with moderate to severe disease, therapy with azathioprine or anti-TNF is often required to reach disease control; however, this is only efficient in about two-thirds of patients. Some patients either show no response or a lost response while on treatment. So, further medical options are warranted in the treatment of UC. With golimumab, a new approach in the treatment of mild to moderate UC recently became available in Germany and is a promising new option in the therapy regimen for patients with UC.

Betaine synthesis in chenopods: localization in chloroplasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanson, A.D.; May A.M.; Grumet, R.

1985-06-01

Plants from several families (Chenopodiaceae, Gramineae, Compositae) accumulate betaine (glycine betaine) in response to salt or water stress via the pathway: choline betainal (betaine aldehyde) betaine. Betaine accumulation is probably a metabolic adaptation to stress. Intact protoplasts from leaves of spinach (Spinacia oleracea) oxidized ( UC)choline to betainal and betaine, as did protoplast lysates. Upon differential centrifugation, the ( UC)choline-oxidizing activity of lysates sedimented with chloroplasts. Chloroplasts purified from protoplast lysates by a Percoll cushion procedure retained strong ( UC)choline-oxidizing activity, although the proportion of the intermediate, ( UC)betainal, in the reaction products was usually higher than for protoplasts. Isolatedmore » chloroplasts also readily oxidized ( UC)betainal to betaine. Light increased the oxidation of both ( UC)choline and ( UC)betainal by isolated chloroplasts. Similar results were obtained with another chenopod (Beta vulgaris) but not with pea (Pisum sativum), a species that accumulates no betaine. The chloroplast site for betaine synthesis in chenopods contrasts with the mitochondrial site in mammals.« less

Interleukin 27 is up-regulated in patients with active inflammatory bowel disease.

PubMed

Furuzawa Carballeda, Janette; Fonseca Camarillo, Gabriela; Yamamoto-Furusho, Jesús K

2016-08-01

The aim of the study was to characterize and quantify tissue gene and protein expression of IL-27 in ulcerative colitis (UC) and Crohn's disease (CD) patients. This is an observational and cross-sectional study. Fifty-four patients with IBD were studied: 27 active UC, 12 inactive UC, 10 active CD, and 5 inactive CD. All patients belonged to the Inflammatory Bowel Disease Clinic at the Instituto Nacional de Ciencias Médicas y Nutrición. We found that IL-27 gene expression was significantly higher in active UC versus inactive UC group (P = 0.015). The IL-27 mRNA expression was increased in patients with active CD compared with inactive CD disease (P = 0.035). The percentage of IL-27 immunoreactive cells was higher in active UC versus active CD patients and non-inflamed tissue controls. The IL-27 was significantly elevated in active UC and CD patients, and it was associated with disease severity.

First Results on High-spin States in ^179Au

NASA Astrophysics Data System (ADS)

Mueller, W. F.; Bingham, C. R.; Reviol, W.; Riedinger, L. L.; Smith, B. H.; Wauters, J.; Ahmad, I.; Amro, H. A.; Blumenthal, D. J.; Carpenter, M. P.; Davids, C. N.; Fischer, S. M.; Hackman, G.; Henderson, D. J.; Janssens, R. V. F.; Khoo, T. L.; Lauritsen, T.; Lister, C. J.; Nisius, D. T.; Seweryniak, D.; Ma, W. C.

1996-05-01

High-spin states in ^179Au were studied for the first time in two experiments at the Argonne uc(atlas) facility. The ^144Sm(^40Ar,p4n)^179Au reaction at 207 MeV was used for the first experiment and ^124Te(^58Ni,p2n)^179Au at 255 MeV in the second. The setup in the first experiment consisted of the Fragment Mass Analyzer (uc(fma)) plus Parallel Plate Avalanche Counter (uc(ppac)) system and 10 Compton-suppressed Ge detectors (CSG's). From this run, several transitions from the yrast bands were established. The latter experiment utilized the uc(fma) + uc(ppac) system in conjunction with the uc(aye-ball) array of 19 Ge detectors (eight >70% efficient CSG's, nine 25% efficient CSG's, and two LEPS; one with Compton suppression) and a double sided silicon strip detector (uc(dssd).) The results from these experiments, including a level scheme, will be presented and discussed.

Model-Driven Analysis of Eyeblink Classical Conditioning Reveals the Underlying Structure of Cerebellar Plasticity and Neuronal Activity.

PubMed

Antonietti, Alberto; Casellato, Claudia; D'Angelo, Egidio; Pedrocchi, Alessandra

The cerebellum plays a critical role in sensorimotor control. However, how the specific circuits and plastic mechanisms of the cerebellum are engaged in closed-loop processing is still unclear. We developed an artificial sensorimotor control system embedding a detailed spiking cerebellar microcircuit with three bidirectional plasticity sites. This proved able to reproduce a cerebellar-driven associative paradigm, the eyeblink classical conditioning (EBCC), in which a precise time relationship between an unconditioned stimulus (US) and a conditioned stimulus (CS) is established. We challenged the spiking model to fit an experimental data set from human subjects. Two subsequent sessions of EBCC acquisition and extinction were recorded and transcranial magnetic stimulation (TMS) was applied on the cerebellum to alter circuit function and plasticity. Evolutionary algorithms were used to find the near-optimal model parameters to reproduce the behaviors of subjects in the different sessions of the protocol. The main finding is that the optimized cerebellar model was able to learn to anticipate (predict) conditioned responses with accurate timing and success rate, demonstrating fast acquisition, memory stabilization, rapid extinction, and faster reacquisition as in EBCC in humans. The firing of Purkinje cells (PCs) and deep cerebellar nuclei (DCN) changed during learning under the control of synaptic plasticity, which evolved at different rates, with a faster acquisition in the cerebellar cortex than in DCN synapses. Eventually, a reduced PC activity released DCN discharge just after the CS, precisely anticipating the US and causing the eyeblink. Moreover, a specific alteration in cortical plasticity explained the EBCC changes induced by cerebellar TMS in humans. In this paper, for the first time, it is shown how closed-loop simulations, using detailed cerebellar microcircuit models, can be successfully used to fit real experimental data sets. Thus, the changes of the model parameters in the different sessions of the protocol unveil how implicit microcircuit mechanisms can generate normal and altered associative behaviors.The cerebellum plays a critical role in sensorimotor control. However, how the specific circuits and plastic mechanisms of the cerebellum are engaged in closed-loop processing is still unclear. We developed an artificial sensorimotor control system embedding a detailed spiking cerebellar microcircuit with three bidirectional plasticity sites. This proved able to reproduce a cerebellar-driven associative paradigm, the eyeblink classical conditioning (EBCC), in which a precise time relationship between an unconditioned stimulus (US) and a conditioned stimulus (CS) is established. We challenged the spiking model to fit an experimental data set from human subjects. Two subsequent sessions of EBCC acquisition and extinction were recorded and transcranial magnetic stimulation (TMS) was applied on the cerebellum to alter circuit function and plasticity. Evolutionary algorithms were used to find the near-optimal model parameters to reproduce the behaviors of subjects in the different sessions of the protocol. The main finding is that the optimized cerebellar model was able to learn to anticipate (predict) conditioned responses with accurate timing and success rate, demonstrating fast acquisition, memory stabilization, rapid extinction, and faster reacquisition as in EBCC in humans. The firing of Purkinje cells (PCs) and deep cerebellar nuclei (DCN) changed during learning under the control of synaptic plasticity, which evolved at different rates, with a faster acquisition in the cerebellar cortex than in DCN synapses. Eventually, a reduced PC activity released DCN discharge just after the CS, precisely anticipating the US and causing the eyeblink. Moreover, a specific alteration in cortical plasticity explained the EBCC changes induced by cerebellar TMS in humans. In this paper, for the first time, it is shown how closed-loop simulations, using detailed cerebellar microcircuit models, can be successfully used to fit real experimental data sets. Thus, the changes of the model parameters in the different sessions of the protocol unveil how implicit microcircuit mechanisms can generate normal and altered associative behaviors.

Evaluation of a multiplex PCR assay for detection of cytomegalovirus in stool samples from patients with ulcerative colitis

PubMed Central

Nahar, Saifun; Iraha, Atsushi; Hokama, Akira; Uehara, Ayako; Parrott, Gretchen; Ohira, Tetsuya; Kaida, Masatoshi; Kinjo, Tetsu; Kinjo, Takeshi; Hirata, Tetsuo; Kinjo, Nagisa; Fujita, Jiro

2015-01-01

AIM: To evaluate a multiplex PCR assay for the detection of bacterial and viral enteropathogens in stool samples from patients with ulcerative colitis (UC). METHODS: We prospectively analyzed 300 individuals, including immunocompetent patients, immunocompromised patients, and patients with UC. Stool samples were collected from the recto-sigmoid region of the colon by endoscopy. The samples were qualitatively analyzed for bacterial and viral enteropathogens with a multiplex PCR assay using a Seeplex® Kit. Additional clinical and laboratory data were collected from the medical records. RESULTS: A multiplex PCR assay detected 397 pathogens (191 bacteria and 206 viruses) in 215 samples (71.7%). The most frequently detected bacteria were Escherichia coli H7, 85 (28.3%); followed by Aeromonas spp., 43 (14.3%); and Clostridium perfringens, 36 (12.0%) samples. The most prevalent viruses were Epstein-Barr virus (EBV), 90 (30.0%); followed by human herpes virus-6 (HHV-6), 53 (17.7%); and cytomegalovirus (CMV), 37 (12.3%) samples. The prevalence rate of CMV infection was significantly higher in the immunocompromised group than in the immunocompetent group (P < 0.01). CMV infection was more common in patients with UC (26/71; 36.6%) than in the immunocompetent patients excluding UC (6/188; 3.2%) (P < 0.01). CMV infection was more prevalent in UC active patients (25/58; 43.1%) than in UC inactive patients (1/13; 7.7%) (P < 0.05). Among 4 groups which defined by the UC activity and immunosuppressive drugs, the prevalence rate of CMV infection was highest in the UC active patients with immunosuppressive drugs (19/34; 55.8%). Epstein-Barr virus (EBV) infection was more common in the immunocompromised patients excluding UC (18/41; 43.9%) than in the immunocompetent patients excluding UC (47/188; 25.0%) (P < 0.05). The simultaneous presence of CMV and EBV and/or HHV6 in UC active patients (14/58; 24.1%) was greater than in immunocompromised patients excluding UC (5/41; 12.2%) (P < 0.05). CONCLUSION: The multiplex PCR assay that was used to analyze the stool samples in this study may serve as a non-invasive approach that can be used to exclude the possibility of CMV infection in patients with active UC who are treated with immunosuppressive therapy. PMID:26640344

Unconditionally Secure Blind Signatures

NASA Astrophysics Data System (ADS)

Hara, Yuki; Seito, Takenobu; Shikata, Junji; Matsumoto, Tsutomu

The blind signature scheme introduced by Chaum allows a user to obtain a valid signature for a message from a signer such that the message is kept secret for the signer. Blind signature schemes have mainly been studied from a viewpoint of computational security so far. In this paper, we study blind signatures in unconditional setting. Specifically, we newly introduce a model of unconditionally secure blind signature schemes (USBS, for short). Also, we propose security notions and their formalization in our model. Finally, we propose a construction method for USBS that is provably secure in our security notions.

Extinction with multiple excitors

PubMed Central

McConnell, Bridget L.; Miguez, Gonzalo; Miller, Ralph R.

2012-01-01

Four conditioned suppression experiments with rats, using an ABC renewal design, investigated the effects of compounding the target conditioned excitor with additional, nontarget conditioned excitors during extinction. Experiment 1 showed stronger extinction, as evidenced by less renewal, when the target excitor was extinguished in compound with a second excitor, relative to when it was extinguished with associatively neutral stimuli. Critically, this deepened extinction effect was attenuated (i.e., more renewal occurred) when a third excitor was added during extinction training. This novel demonstration contradicts the predictions of associative learning models based on total error reduction, but it is explicable in terms of a counteraction effect within the framework of the extended comparator hypothesis. The attenuated deepened extinction effect was replicated in Experiments 2a and 3, which also showed that pretraining consisting of weakening the association between the two additional excitors (Experiments 2a and 2b) or weakening the association between one of the additional excitors and the unconditioned stimulus (Experiment 3) attenuated the counteraction effect, thereby resulting in a decrease in responding to the target excitor. These results suggest that more than simple total error reduction determines responding after extinction. PMID:23055103

Increased sign-tracking behavior in adolescent rats.

PubMed

DeAngeli, Nicole E; Miller, Sarah B; Meyer, Heidi C; Bucci, David J

2017-11-01

An autoshaping procedure was used to test the notion that conditioned stimuli (CSs) gain greater incentive salience during adolescence than young adulthood under conditions of social isolation rearing and food restriction. Rats were single-housed and placed on food restriction during 10 daily training sessions in which a lever (CS + ) was presented then followed immediately by a food unconditioned stimulus (US). A second lever (CS - ) was presented on intermixed trials and was not reinforced. Despite the fact that food delivery was not contingent on the rats' behavior, all rats exhibited behaviors directed towards the lever (i.e., sign-tracking). In the adolescent group, the rate of lever pressing and the percentage of trials with a lever press were higher than in young adults. Initially, group differences were observed when rats were retrained when the adolescents had reached young adulthood. These findings support the hypothesis that cues that come to predict reward become imbued with excessive motivational value in adolescents, perhaps contributing to the hyper-responsiveness to reward-related stimuli typically observed during this period of development. © 2017 Wiley Periodicals, Inc.

The Secretion of Areolar (Montgomery's) Glands from Lactating Women Elicits Selective, Unconditional Responses in Neonates

PubMed Central

Doucet, Sébastien; Soussignan, Robert; Sagot, Paul; Schaal, Benoist

2009-01-01

Background The communicative meaning of human areolae for newborn infants was examined here in directly exposing 3-day old neonates to the secretion from the areolar glands of Montgomery donated by non related, non familiar lactating women. Methodology/Principal Findings The effect of the areolar stimulus on the infants' behavior and autonomic nervous system was compared to that of seven reference stimuli originating either from human or non human mammalian sources, or from an arbitrarily-chosen artificial odorant. The odor of the native areolar secretion intensified more than all other stimuli the infants' inspiratory activity and appetitive oral responses. These responses appeared to develop independently from direct experience with the breast or milk. Conclusion/Significance Areolar secretions from lactating women are especially salient to human newborns. Volatile compounds carried in these substrates are thus in a position to play a key role in establishing behavioral and physiological processes pertaining to milk transfer and production, and, hence, to survival and to the early engagement of attachment and bonding. PMID:19851461

Stability and adaptability of popcorn genotypes in the State of Rio de Janeiro, Brazil.

PubMed

Pena, G F; do Amaral, A T; Gonçalves, L S A; Candido, L S; Vittorazzi, C; Ribeiro, R M; Freitas, S P

2012-08-31

This study aimed to obtain estimates of stability and adaptability of phase launched materials and materials recommended in the country, for the northern and northwestern regions of Rio de Janeiro State, Brazil, and made a comparative analysis of different methods to evaluate stability and adaptability of grain yield and popping expansion. To this end, 10 genotypes were evaluated (UNB2U-C3, UNB2U-C4, BRS Angela, Viçosa, Beija-Flor, IAC 112, IAC 125, Zélia, Jade, and UFVM2 Barão de Viçosa) in five environments. The Yates and Cochran method revealed that genotypes UFV2M Barão de Viçosa, BRS Angela and UNB2U-C3 were the most stable for grain yield. This method also indicated superiority of genotypes UNB2U-C3, UNB2U-C4, BRS Angela, Viçosa, IAC 125, and Zélia for popping expansion. The Plaisted and Peterson and Wricke methods demonstrated that genotypes Zélia and UNB2U-C4 were the most productive and stable. These methods indicated genotypes UNB2U-C3 and BRS Angela as the most stable for popping expansion. The Kang and Phan ranking system uses methods based on analysis of variance and classified population UNB2U-C4 as the genotype with the highest stability of grain production and confirmed cultivar BRS Angela as the most stable for popping expansion. Genotypes IAC 112 and UNB2U-C4 were the most stable and adapted for grain yield, according to the Lin and Binns method. The P(i) statistics also ranked UNB2U-C3 and UNB2U-C4 as the genotypes with the best predictability and capacity for popping expansion.

Thiopurine Therapy Reduces the Incidence of Colorectal Neoplasia in Patients with Ulcerative Colitis. Data from the ENEIDA Registry.

PubMed

Gordillo, Jordi; Cabré, Eduard; Garcia-Planella, Esther; Ricart, Elena; Ber-Nieto, Yolanda; Márquez, Lucía; Rodríguez-Moranta, Francisco; Ponferrada, Ángel; Vera, Isabel; Gisbert, Javier P; Barrio, Jesús; Esteve, Maria; Merino, Olga; Muñoz, Fernando; Domènech, Eugeni

2015-12-01

Patients with ulcerative colitis (UC) are at increased risk of developing colorectal cancer (CRC), but recent studies suggest a lower risk than previously reported. The aim was to evaluate the incidence of dysplasia, CRC and related risk factors in UC patients from a Spanish nationwide database. All UC patients were identified and retrospectively reviewed. Clinical-epidemiological data and the finding of dysplasia and/or CRC were collected. A total of 831 UC patients were included. Twenty-six cases of CRC in 26 patients and 29 cases of high-grade dysplasia (HGD) in 24 patients were found, accounting for 55 diagnoses of advanced neoplasia (AN = CRC and/or HGD) in 45 patients (33% of them within the first 8 years after UC diagnosis). The cumulative risk of AN was 2, 5.3 and 14.7% at 10, 20 and 30 years, respectively. Concomitant primary sclerosing cholangitis (odds ratio [OR] 10.90; 95% confidence interval [CI] 3.75-31.76, p < 0.001), extensive UC (OR 2.10, 95% CI 1.01-4.38, p = 0.048), UC diagnosis at an older age (OR 2.23, 95% CI 1.03-4.83, p = 0.043) and appendectomy prior to UC diagnosis (OR 2.66, 95% CI 1.06-6.71, p = 0.038) were independent risk factors for AN. Use of thiopurines (OR 0.21, 95% CI 0.06-0.74, p = 0.015) and being in a surveillance colonoscopy programme (OR 0.33; 95% CI 0.16-0.67; p = 0.002) were independent protective factors for AN. The risk of AN among UC patients is lower than previously reported but steadily increases from the time of UC diagnosis. The widespread use of thiopurines may have influenced this reduced incidence of UC-related neoplasias. Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Covered Metallic Stents With an Anti-Migration Design vs. Uncovered Stents for the Palliation of Malignant Gastric Outlet Obstruction: A Multicenter, Randomized Trial

PubMed Central

Lee, Hyuk; Min, Byung-Hoon; Lee, Jeong Hoon; Shin, Cheol Min; Kim, Younjoo; Chung, Hyunsoo; Lee, Sang Hyub

2015-01-01

OBJECTIVES: Previous studies reported comparable stent patency between covered self-expandable metallic stents (SEMS) and uncovered SEMS (UCS) for palliation of malignant gastric outlet obstruction (GOO). The aim of this study was to evaluate the efficacy and safety of the newly developed WAVE-covered SEMS (WCS), which has an anti-migration design, compared with UCS in gastric cancer patients with symptomatic GOO. METHODS: A total of 102 inoperable gastric cancer patients with symptomatic GOO were prospectively enrolled from five referral centers and randomized to undergo UCS or WCS placement. Stent patency and recurrence of obstructive symptoms were assessed at 8 weeks and 16 weeks after stent placement. RESULTS: At the 8-week follow-up, both stent patency rates (72.5% vs. 62.7%) and re-intervention rates (19.6% vs. 19.6%) were comparable between the WCS and the UCS groups. Both stent stenosis (2.4% vs. 8.1%) and migration rates (9.5% vs. 5.4%) were comparable between WCS and UCS groups. At the 16-week follow-up, however, the WCS group had a significantly higher stent patency rate than the UCS group (68.6% vs. 41.2%). Re-intervention rates in the WCS and UCS groups were 23.5% and 39.2%, respectively. Compared with the UCS group, the WCS group had a significantly lower stent restenosis rate (7.1% vs. 37.8%) and a comparable migration rate (9.5% vs. 5.4%). Overall stent patency was significantly longer in the WCS group than in the UCS group. No stent-associated significant adverse events occurred in either the WCS or UCS groups. In the multivariate analysis, WCS placement and chemotherapy were identified as independent predictors of 16-week stent patency. CONCLUSIONS: WCS group showed comparable migration rate and significantly more durable long-term stent patency compared with UCS group for the palliation of GOO in patients with inoperable gastric cancer. PMID:26372507

Transplanted Umbilical Cord Mesenchymal Stem Cells Modify the In Vivo Microenvironment Enhancing Angiogenesis and Leading to Bone Regeneration

PubMed Central

Todeschi, Maria Rosa; El Backly, Rania; Capelli, Chiara; Daga, Antonio; Patrone, Eugenio; Introna, Martino; Cancedda, Ranieri

2015-01-01

Umbilical cord mesenchymal stem cells (UC-MSCs) show properties similar to bone marrow mesenchymal stem cells (BM-MSCs), although controversial data exist regarding their osteogenic potential. We prepared clinical-grade UC-MSCs from Wharton's Jelly and we investigated if UC-MSCs could be used as substitutes for BM-MSCs in muscoloskeletal regeneration as a more readily available and functional source of MSCs. UC-MSCs were loaded onto scaffolds and implanted subcutaneously (ectopically) and in critical-sized calvarial defects (orthotopically) in mice. For live cell-tracking experiments, UC-MSCs were first transduced with the luciferase gene. Angiogenic properties of UC-MSCs were tested using the mouse metatarsal angiogenesis assay. Cell secretomes were screened for the presence of various cytokines using an array assay. Analysis of implanted scaffolds showed that UC-MSCs, contrary to BM-MSCs, remained detectable in the implants for 3 weeks at most and did not induce bone formation in an ectopic location. Instead, they induced a significant increase of blood vessel ingrowth. In agreement with these observations, UC-MSC-conditioned medium presented a distinct and stronger proinflammatory/chemotactic cytokine profile than BM-MSCs and a significantly enhanced angiogenic activity. When UC-MSCs were orthotopically transplanted in a calvarial defect, they promoted increased bone formation as well as BM-MSCs. However, at variance with BM-MSCs, the new bone was deposited through the activity of stimulated host cells, highlighting the importance of the microenvironment on determining cell commitment and response. Therefore, we propose, as therapy for bone lesions, the use of allogeneic UC-MSCs by not depositing bone matrix directly, but acting through the activation of endogenous repair mechanisms. PMID:25685989

Healthcare Utilisation and Drug Treatment in a Large Cohort of Patients with Inflammatory Bowel Disease

PubMed Central

Wettermark, Björn; Löfberg, Robert; Eriksson, Irene; Sundström, Johan; Lördal, Mikael

2016-01-01

Background and Aims: Crohn’s disease [CD] and ulcerative colitis [UC] are chronic diseases associated with a substantial utilisation of healthcare resources. We aimed to estimate the prevalence of inflammatory bowel disease [IBD], CD, and UC and to describe and compare healthcare utilisation and drug treatment in CD and UC patients. Methods: This was a cross-sectional study of all patients with a recorded IBD diagnosis in Stockholm County, Sweden. Data on outpatient visits, hospitalisations, surgeries, and drug treatment during 2013 were analysed. Results: A total of 13 916 patients with IBD were identified, corresponding to an overall IBD prevalence of 0.65% [CD 0.27%, UC 0.35%, inflammatory bowel disease unclassified 0.04%]; 49% of all IBD patients were treated with IBD-related drugs. Only 3.6% of the patients received high-dose corticosteroids, whereas 32.4% were treated with aminosalicylates [CD 21.2%, UC 41.0%, p < 0.0001]. More CD patients were treated with biologicals compared with UC patients [CD 9.6%, UC 2.9%, p < 0.0001] and surgery was significantly more common among CD patients [CD 3.0%, UC 0.8%, p < 0.0001]. Conclusions: This study indicates that patients with CD are the group with the highest medical needs. Patients with CD utilised significantly more healthcare resources [including outpatient visits, hospitalisations, and surgeries] than UC patients. Twice as many CD patients received immunomodulators compared with UC patients and CD patients were treated with biologicals three times more often. These results highlight that CD remains a challenge and further efforts are needed to improve care in these patients. PMID:26733406

Prevalence of inflammatory bowel disease in two districts of Sri Lanka: a hospital based survey

PubMed Central

2010-01-01

Background Inflammatory bowel disease (IBD) is being increasingly diagnosed in Asia. However there are few epidemiological data from the region. Methods To determine prevalence and clinical characteristics of IBD, a hospital-based survey was performed in the Colombo and Gampaha districts (combined population 4.5 million) in Sri Lanka. Patients with established ulcerative colitis (UC) and Crohn's disease (CD), who were permanent residents of these adjoining districts, were recruited from hospital registries and out-patient clinics. Clinical information was obtained from medical records and patient interviews. Results There were 295 cases of IBD (UC = 240, CD = 55), of which 34 (UC = 30, CD = 4) were newly diagnosed during the study year. The prevalence rate for UC was 5.3/100,000 (95% CI 5.0-5.6/100,000), and CD was 1.2/100,000 (95% CI 1.0-1.4/100,000). The incidence rates were 0.69/100,000 (95% CI 0.44-0.94/100,000) for UC and 0.09/100,000 (95% CI 0.002-0.18/100,000) for CD. Female:male ratios were 1.5 for UC and 1.0 for CD. Mean age at diagnosis was (males and females) 36.6 and 38.1y for UC and 33.4 and 36.2y for CD. Among UC patients, 51.1% had proctitis and at presentation 58.4% had mild disease. 80% of CD patients had only large bowel involvement. Few patients had undergone surgery. Conclusions The prevalence of IBD in this population was low compared to Western populations, but similar to some in Asia. There was a female preponderance for UC. UC was mainly mild, distal or left-sided, while CD mainly involved the large bowel. PMID:20302651

Are HLA-DR or TAP genes genetic markers of severity in ulcerative colitis?

PubMed

Heresbach, D; Alizadeh, M; Reumaux, D; Colombel, J F; Delamaire, M; Danze, P M; Gosselin, M; Genetet, B; Bretagne, J F; Semana, G

1996-12-01

The pathogeny of ulcerative colitis (UC) is not yet elucidated, but some arguments suggest the implication of genetic factors. Among the candidate genes, those encoding for HLA class II genotypes have been extensively studied in UC; however, discordant data may be imputable to heterogeneity, characterized by immunological markers such as atypical ANCA (p-ANCA), or to inclusion of more or less intractable UC. The aim of our study is to evaluate the interest of HLA class II and TAP genetic markers to identify different clinical forms of UC, according to p-ANCA status. Unrelated patients with a history of UC (n = 91) and healthy control subjects with no personal or family history of inflammatory bowel diseases (IBD) (n = 200) were included. HLA-DRB1*03 was less frequent in UC patients than in healthy controls (8% vs 28%, PC < 0.03). No association was found with any TAP genotypes. Moreover, there was no association with the HLA-DR2 specificity, either in the entire group of UC patients (38% vs 28%) or in the p-ANCA-positive subgroup of patients (30%). The most consistent finding in the present study is that some genetic markers may characterize intractability in UC patients. HLA-DR2 was associated with poor prognosis, regardless of p-ANCA status. In HLA-DR2 and non-HLA-DR2 groups, colectomy was done in 55% and 27% of patients, respectively, (PC < 0.05). Furthermore, in non-HLA-DR2 patients, p-ANCA could be of interest to characterize those with more severe prognosis. Our results confirm the interest of genetic studies to define UC genetic susceptibility, taking into account intractability of the disease. They do not support the hypothesis that p-ANCA is a subclinical marker of genetic susceptibility to UC.

Association of Clinical Features with Human Leukocyte Antigen in Japanese Patients with Ulcerative Colitis.

PubMed

Iwamoto, Taku; Yashima, Kazuo; Morio, Keiko; Ueda, Naoki; Ikebuchi, Yuichiro; Kawaguchi, Koichiro; Harada, Kenichi; Isomoto, Hajime

2018-03-01

The human leukocyte antigen (HLA) region has been found to be involved in the pathogenesis of inflammatory bowel disease (IBD), which is classified into ulcerative colitis (UC) and Crohn's disease (CD), by genome-wide association studies. The aim of this study was to confirm whether HLA-alleles confer susceptibility to UC and to determine whether HLA-allel1es are associated with the clinical phenotypes in Japanese patients with UC. In this study, HLA typing was performed by PCR-sequence-specific oligonucleotides (PCR-SSO) to confirm the correlation between UC and HLA alleles (for HLA-A, B, DRB1) in 45 Japanese UC patients. In addition, whether the HLA alleles are related to patient and clinical background characteristics was examined. Overall, 62.2%, and 66.7% of the 45 UC patients had HLA-B*52 and HLA-DRB1*15, respectively. These allele frequencies were significantly higher than in previously reported Japanese control persons ( P < 0.0001). The frequencies of extraintestinal manifestations [odds ratio (OR) = 0.12, P = 0.039] and a history of colectomy (OR = 0.18, P = 0.046) were lower in HLA-B*52-positive UC patients than in HLA-B*52 negative UC patients. The white blood cell (WBC) count was significantly higher in HLA-DRB1*15-positive patients (9430 ± 4592/μL) than in HLA-DRB1*15-negative patients (6729 ± 2160/μL). Thus, HLA-B*52 and DRB1*15 appear to be associated with disease features and severity in Japanese UC patients. These results indicate that HLA-B*52 and DRB1*15 are not only associated with overall UC susceptibility, but also with the clinical phenotypes in Japanese patients.

Ultrasonic scalpel causes greater depth of soft tissue necrosis compared to monopolar electrocautery at standard power level settings in a pig model

PubMed Central

2012-01-01

Background Ultrasonic scalpel (UC) and monopolar electrocautery (ME) are common tools for soft tissue dissection. However, morphological data on the related tissue alteration are discordant. We developed an automatic device for standardized sample excision and compared quality and depth of morphological changes caused by UC and ME in a pig model. Methods 100 tissue samples (5 × 3 cm) of the abdominal wall were excised in 16 pigs. Excisions were randomly performed manually or by using the self-constructed automatic device at standard power levels (60 W cutting in ME, level 5 in UC) for abdominal surgery. Quality of tissue alteration and depth of coagulation necrosis were examined histopathologically. Device (UC vs. ME) and mode (manually vs. automatic) effects were studied by two-way analysis of variance at a significance level of 5%. Results At the investigated power level settings UC and ME induced qualitatively similar coagulation necroses. Mean depth of necrosis was 450.4 ± 457.8 μm for manual UC and 553.5 ± 326.9 μm for automatic UC versus 149.0 ± 74.3 μm for manual ME and 257.6 ± 119.4 μm for automatic ME. Coagulation necrosis was significantly deeper (p < 0.01) when UC was used compared to ME. The mode of excision (manual versus automatic) did not influence the depth of necrosis (p = 0.85). There was no significant interaction between dissection tool and mode of excision (p = 0.93). Conclusions Thermal injury caused by UC and ME results in qualitatively similar coagulation necrosis. The depth of necrosis is significantly greater in UC compared to ME at investigated standard power levels. PMID:22361346

Ultrasonic scalpel causes greater depth of soft tissue necrosis compared to monopolar electrocautery at standard power level settings in a pig model.

PubMed

Homayounfar, Kia; Meis, Johanna; Jung, Klaus; Klosterhalfen, Bernd; Sprenger, Thilo; Conradi, Lena-Christin; Langer, Claus; Becker, Heinz

2012-02-23

Ultrasonic scalpel (UC) and monopolar electrocautery (ME) are common tools for soft tissue dissection. However, morphological data on the related tissue alteration are discordant. We developed an automatic device for standardized sample excision and compared quality and depth of morphological changes caused by UC and ME in a pig model. 100 tissue samples (5 × 3 cm) of the abdominal wall were excised in 16 pigs. Excisions were randomly performed manually or by using the self-constructed automatic device at standard power levels (60 W cutting in ME, level 5 in UC) for abdominal surgery. Quality of tissue alteration and depth of coagulation necrosis were examined histopathologically. Device (UC vs. ME) and mode (manually vs. automatic) effects were studied by two-way analysis of variance at a significance level of 5%. At the investigated power level settings UC and ME induced qualitatively similar coagulation necroses. Mean depth of necrosis was 450.4 ± 457.8 μm for manual UC and 553.5 ± 326.9 μm for automatic UC versus 149.0 ± 74.3 μm for manual ME and 257.6 ± 119.4 μm for automatic ME. Coagulation necrosis was significantly deeper (p < 0.01) when UC was used compared to ME. The mode of excision (manual versus automatic) did not influence the depth of necrosis (p = 0.85). There was no significant interaction between dissection tool and mode of excision (p = 0.93). Thermal injury caused by UC and ME results in qualitatively similar coagulation necrosis. The depth of necrosis is significantly greater in UC compared to ME at investigated standard power levels.

Nationwide analysis on the impact of socioeconomic land use factors and incidence of urothelial carcinoma.

PubMed

Brandt, Maximilian P; Gust, Kilian M; Mani, Jens; Vallo, Stefan; Höfner, Thomas; Borgmann, Hendrik; Tsaur, Igor; Thomas, Christian; Haferkamp, Axel; Herrmann, Eva; Bartsch, Georg

2018-02-01

Incidence rates for urothelial carcinoma (UC) have been reported to differ between countries within the European Union (EU). Besides occupational exposure to chemicals, other substances such as tobacco and nitrite in groundwater have been identified as risk factors for UC. We investigated if regional differences in UC incidence rates are associated with agricultural, industrial and residential land use. Newly diagnosed cases of UC between 2003 and 2010 were included. Information within 364 administrative districts of Germany from 2004 for land use factors were obtained and calculated as a proportion of the total area of the respective administrative district and as a smoothed proportion. Furthermore, information on smoking habits was included in our analysis. Kulldorff spatial clustering was used to detect different clusters. A negative binomial model was used to test the spatial association between UC incidence as a ratio of observed versus expected incidence rates, land use and smoking habits. We identified 437,847,834 person years with 171,086 cases of UC. Cluster analysis revealed areas with higher incidence of UC than others (p=0.0002). Multivariate analysis including significant pairwise interactions showed that the environmental factors were independently associated with UC (p<0.001). The RR was 1.066 (95% CI 1.052-1.080), 1.066 (95% CI 1.042-1.089) and 1.067 (95% CI 1.045-1.093) for agricultural, industrial and residential areas, respectively, and 0.996 (95% CI 0.869-0.999) for the proportion of never smokers. This study displays regional differences in incidence of UC in Germany. Additionally, results suggest that socioeconomic factors based on agricultural, industrial and residential land use may be associated with UC incidence rates. Copyright © 2017 Elsevier Ltd. All rights reserved.

IL-23R mutation is associated with ulcerative colitis: A systemic review and meta-analysis.

PubMed

Peng, Ling-Long; Wang, Ying; Zhu, Feng-Ling; Xu, Wang-Dong; Ji, Xue-Lei; Ni, Jing

2017-01-17

Since a genome-wide association study revealed that Interleukin-23 receptor (IL-23R) gene is a candidate gene for Ulcerative Colitis (UC), many studies have investigated the association between the IL-23R polymorphisms and UC. However, the results were controversial. The aim of the study was to determine whether the IL-23R polymorphisms confer susceptibility to UC. A systematic literature search was carried out to identify all potentially relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. A total of 33 studies in 32 articles, including 10,527 UC cases and 15,142 healthy controls, were finally involved in the meta-analysis. Overall, a significant association was found between all UC cases and the rs11209026A allele (OR = 0.665, 95% CI = 0.604~0.733, P < 0.001). Similarly, meta-analyses of the rs7517847, rs1004819, rs10889677, rs2201841, rs11209032, rs1495965, rs1343151 and rs11465804 polymorphisms also indicated significant association with all UC (all P < 0.05). Stratification by ethnicity revealed that the rs11209026, rs7517847, rs10889677, rs2201841 andrs11465804 polymorphisms were associated with UC in the Caucasian group, but not in Asians, while the rs1004819 and rs11209032 polymorphisms were found to be related to UC for both Caucasian and Asian groups. However, subgroup analysis failed to unveil any association between the rs1495965 and rs1343151 polymorphisms and UC in Caucasians or Asians. The meta-analysis suggests significant association between IL-23R polymorphisms and UC, especially in Caucasians.

AKT Pathway Affects Bone Regeneration in Nonunion Treated with Umbilical Cord-Derived Mesenchymal Stem Cells.

PubMed

Qu, Zhiguo; Guo, Shengnan; Fang, Guojun; Cui, Zhenghong; Liu, Ying

2015-04-01

We have previously grafted human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) with blood plasma to treat rat tibia nonunion. To further examine the biological characteristics of this process, we applied an established hUC-MSCs-treated rat nonunion model with the addition of an inhibitor of AKT. SD rats (80) were randomly divided into four groups: a fracture group (positive control); a nonunion group (negative control); a hUC-MSCs grafting with blood plasma group; and a hUC-MSCs grafting with blood plasma & AKT blocker group. The animals were sacrificed under deep anesthesia at 4 and 8 weeks post fracture for analysis. The fracture line became less defined at 4 weeks and disappeared at 8 weeks postoperatively in both the hUC-MSCs grafting with blood plasma and grafting with blood plasma & the AKT blocker, which is similar to the fracture group. Histological immunofluorescence studies showed that the numbers of hUC-MSCs in the calluses were significantly higher in the hUC-MSCs grafting with blood plasma than those in group with the AKT blocker. More bone morphogenetic protein 2 and bone sialoprotein expression and less osteoprotegerin and bone gla protein expression were observed in the AKT blocker group compared to the hUC-MSCs grafting with blood plasma. AKT gene expression in the AKT blocker group was decreased 50% compared to the hUC-MSCs with plasma group and decreased 70% compared to the fracture group, while the elastic modulus was decreased. In summary, our work demonstrates that AKT may play a role in modulating osteogenesis induced by hUC-MSCs.

Increased small intestinal permeability in ulcerative colitis: rather genetic than environmental and a risk factor for extensive disease?

PubMed

Büning, Carsten; Geissler, Nora; Prager, Matthias; Sturm, Andreas; Baumgart, Daniel C; Büttner, Janine; Bühner, Sabine; Haas, Verena; Lochs, Herbert

2012-10-01

A disturbed epithelial barrier could play a pivotal role in ulcerative colitis (UC). We performed a family-based study analyzing in vivo gastrointestinal permeability in patients with UC, their healthy relatives, spouses, and controls. In total, 89 patients with UC in remission, 35 first-degree relatives (UC-R), 24 nonrelated spouses (UC-NR), and 99 healthy controls (HC) were studied. Permeability was assessed by a sugar-drink test using sucrose (gastroduodenal permeability), lactulose/mannitol (intestinal permeability), and sucralose (colonic permeability). Data were correlated with clinical characteristics including medical treatment. Increased intestinal permeability was detected significantly more often in UC patients in remission (25/89, 28.1%) compared with HC (6/99, 6.1%; P < 0.001). Similar results were obtained in UC-R (7/35, 20.0%; P = 0.01 compared with HC) regardless of sharing the same household with the patients or not. No difference was found between UC-NR (3/24, 12.5%) and HC. Notably, in UC patients increased intestinal permeability was found in 12/28 patients (42.9%) with pancolitis, 7/30 (23.3%) patients with left-sided colitis, and in 2/19 (10.5%) patients with proctitis (P = 0.04). Gastroduodenal and colonic permeability were similar in all groups. Among patients on azathioprine, increased intestinal permeability was only seen in 1/18 (5.6%) patients. In contrast, in 24/70 (34.3%) patients without azathioprine, an increased intestinal permeability was found (P = 0.005). An increased intestinal but not colonic permeability was found in UC patients in clinical remission that could mark a new risk factor for extensive disease location. Similar findings in healthy relatives but not spouses suggest that this barrier defect is genetically determined. Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.

IL-23R mutation is associated with ulcerative colitis: A systemic review and meta-analysis

PubMed Central

Peng, Ling-Long; Wang, Ying; Zhu, Feng-Ling; Xu, Wang-Dong; Ji, Xue-Lei; Ni, Jing

2017-01-01

Objectives Since a genome-wide association study revealed that Interleukin-23 receptor (IL-23R) gene is a candidate gene for Ulcerative Colitis (UC), many studies have investigated the association between the IL-23R polymorphisms and UC. However, the results were controversial. The aim of the study was to determine whether the IL-23R polymorphisms confer susceptibility to UC. Methods A systematic literature search was carried out to identify all potentially relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. Results A total of 33 studies in 32 articles, including 10,527 UC cases and 15,142 healthy controls, were finally involved in the meta-analysis. Overall, a significant association was found between all UC cases and the rs11209026A allele (OR = 0.665, 95% CI = 0.604~0.733, P < 0.001). Similarly, meta-analyses of the rs7517847, rs1004819, rs10889677, rs2201841, rs11209032, rs1495965, rs1343151 and rs11465804 polymorphisms also indicated significant association with all UC (all P < 0.05). Stratification by ethnicity revealed that the rs11209026, rs7517847, rs10889677, rs2201841 andrs11465804 polymorphisms were associated with UC in the Caucasian group, but not in Asians, while the rs1004819 and rs11209032 polymorphisms were found to be related to UC for both Caucasian and Asian groups. However, subgroup analysis failed to unveil any association between the rs1495965 and rs1343151 polymorphisms and UC in Caucasians or Asians. Conclusions The meta-analysis suggests significant association between IL-23R polymorphisms and UC, especially in Caucasians. PMID:27902482

Meta-analysis of the association between appendiceal orifice inflammation and appendectomy and ulcerative colitis.

PubMed

Deng, Peng; Wu, Junchao

2016-07-01

This study aimed to investigate the relationship between appendiceal orifice inflammation (AOI) and appendectomy and ulcerative colitis (UC) by a meta-analysis. Databases were thoroughly searched for studies on AOI and UC up to January 2016. Three comparisons were performed: a) whether the previous appendectomy was a risk factor of UC; b) influence of appendectomy on UC courses; c) influence of AOI on UC severity. Odds ratios (ORs) and 95% confidence intervals (CIs) were the effects sizes. The merging of results and publication bias assessment were performed by using RevMan 5.3. Sensitivity analysis was conducted using Stata 12.0. Nineteen studies were selected in the present study. Results of comparison I showed that appendectomy was a protective factor of UC (OR = 0.44; 95% CI [0.30, 0.64]). Comparison II indicated appendectomy had no significant influence in the courses of UC (proctitis: OR = 1.03, 95% CI [0.74, 1.42]; left-sided colitis: OR = 1.01, 95% CI [0.73, 1.39]; pancolitis: OR = 0.92, 95% CI [0.59, 1.43]; colectomy: OR = 1.38, 95% CI [0.62, 3.04]). Comparison III indicated UC combined with AOI did not affect the courses of UC (proctitis: OR = 1.15, 95% CI [0.67, 1.98]; left-sided colitis: OR = 1.14, 95% CI [0.24, 5.42]; colectomy: OR = 0.36, 95% CI [0.10, 1.23]). Sensitivity analysis confirmed the robust of the results in the present study. In conclusion, this meta-analysis indicated appendectomy can reduce the risk of UC. But appendectomy or AOI had no influence on the severity of the disease and the effect of surgical treatment.

Associations between NRAMP1 Polymorphisms and Susceptibility to Ulcerative Colitis/Crohn's Disease: A Meta-Analysis.

PubMed

Sun, Manyi; Zhang, Li; Shi, Songli

2016-01-01

Multiple environmental and genetic factors contribute to the risks of ulcerative colitis (UC) and Crohn's disease (CD). Several allelic variants have been identified in natural resistance associated macrophage protein 1 (NRAMP1) gene; however, their association with UC/CD remains conflicting. The purpose of this study was to evaluate whether NRAMP1 polymorphisms are associated with the susceptibility to UC/CD. A meta-analysis on the association between the NRAMP1 polymorphisms and susceptibility to UC/CD was performed. Relevant studies were retrieved from the databases. After eligible data were extracted, Mantel-Haenszel statistics and random/fixed effects model were applied to calculate the pooled odds radio (OR) and 95% confidence interval (95% CI). Seven articles containing 536 UC cases, 997 CD cases, and 1361 controls were collected. No significant association between allele 2 frequency of NRAMP1 and susceptibility to UC/CD was detected in overall population (all p > 0.05). However, increased UC/CD risk for allele 3 was observed in Caucasian population (OR = 1.27, 95% CI = 1.08~1.50, p = 0.04), whereas decreased UC/CD risk was detected in non-Caucasian population (OR = 0.72, 95% CI = 0.60~0.87, p < 0.001), under "allele 3 vs. other alleles" model. Moreover, a significant increase in CD risk for T carrier frequency of -237 C/T (OR = 0.44, 95% CI, 0.26~0.75, p = 0.003) was detected, but not 274 C/T and 1729+55del4 (TGTG) +/del. The polymorphism of -237 C/T is related to the risk of CD; and the association of allele 3 with UC/CD risk differs in Caucasian and non-Caucasian population, which might be the potential biomarkers for clinical diagnosis of UC/CD.

Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates, in Ulcerative Colitis: systematic review and meta-analysis.

PubMed

Ford, Alexander C; Khan, Khurram J; Achkar, Jean-Paul; Moayyedi, Paul

2012-02-01

Efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, no recent meta-analysis has studied the relative efficacies of differing routes of administration. MEDLINE, EMBASE, and the Cochrane central register of controlled trials were searched (through May 2011). Eligible trials recruited adults with mildly to moderately active UC, or quiescent UC, and compared oral 5-ASAs with either topical 5-ASAs or a combination of oral and topical 5-ASAs. Dichotomous data were pooled to obtain relative risk (RR) of failure to achieve remission in active UC, and RR of relapse of disease activity in quiescent UC, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference. The search identified 3,061 citations, and 12 randomized controlled trials (RCTs) were eligible. Four compared topical with oral 5-ASAs in active UC remission, with an RR of no remission with topical 5-ASAs of 0.82 (95% CI=0.52-1.28). Four trials compared combined with oral 5-ASAs in active UC (RR of no remission=0.65; 95% CI=0.47-0.91; NNT=5). Three RCTs compared intermittent topical with oral 5-ASAs in preventing relapse of quiescent UC (RR=0.64; 95% CI=0.43-0.95; NNT=4), and two compared combined with oral 5-ASAs (RR of relapse=0.48; 95% CI=0.17-1.38). Combined 5-ASA therapy appeared superior to oral 5-ASAs for induction of remission of mildly to moderately active UC. Intermittent topical 5-ASAs appeared superior to oral 5-ASAs for preventing relapse of quiescent UC.

Ulcerative colitis in smokers, non-smokers and ex-smokers

PubMed Central

Bastida, Guillermo; Beltrán, Belén

2011-01-01

Smoking is a major environmental factor that interferes in the establishment and clinical course of ulcerative colitis (UC). Firstly, the risk of smoking status impact in the development of UC is reviewed, showing that current smoking has a protective association with UC. Similarly, being a former smoker is associated with an increased risk of UC. The concept that smoking could have a role in determining the inflammatory bowel disease phenotype is also discussed. Gender may also be considered, as current smoking delays disease onset in men but not in women. No clear conclusions can be driven from the studies trying to clarify whether childhood passive smoking or prenatal smoke exposure have an influence on the development of UC, mainly due to methodology flaws. The influence of smoking on disease course is the second aspect analysed. Some studies show a disease course more benign in smokers that in non-smokers, with lower hospitalizations rates, less flare-ups, lower use of oral steroids and even less risk of proximal extension. This is not verified by some other studies. Similarly, the rate of colectomy does not seem to be determined by the smoking status of the patient. The third issue reviewed is the use of nicotine as a therapeutic agent. The place of nicotine in the treatment of UC is unclear, although it could be useful in selected cases, particularly in recent ex-smokers with moderate but refractory attacks of UC. Finally, the effect of smoking cessation in UC patients is summarised. Given that smoking represents a major worldwide cause of death, for inpatients with UC the risks of smoking far outweigh any possible benefit. Thus, physicians should advise, encourage and assist UC patients who smoke to quit. PMID:21734782

Investigation of Crohn’s Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship

PubMed Central

ANDERSON, CARL A.; MASSEY, DUNECAN C. O.; BARRETT, JEFFREY C.; PRESCOTT, NATALIE J.; TREMELLING, MARK; FISHER, SHEILA A.; GWILLIAM, RHIAN; JACOB, JEMIMA; NIMMO, ELAINE R.; DRUMMOND, HAZEL; LEES, CHARLIE W.; ONNIE, CLIVE M.; HANSON, CATHERINE; BLASZCZYK, KATARZYNA; RAVINDRARAJAH, RADHI; HUNT, SARAH; VARMA, DHIRAJ; HAMMOND, NAOMI; LEWIS, GREGORY; ATTLESEY, HEATHER; WATKINS, NICK; OUWEHAND, WILLEM; STRACHAN, DAVID; MCARDLE, WENDY; LEWIS, CATHRYN M.; LOBO, ALAN; SANDERSON, JEREMY; JEWELL, DEREK P.; DELOUKAS, PANOS; MANSFIELD, JOHN C.; MATHEW, CHRISTOPHER G.; SATSANGI, JACK; PARKES, MILES

2009-01-01

Background & Aims Identifying shared and disease-specific susceptibility loci for Crohn’s disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. Methods We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. Results Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 × 10-8; odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. Conclusions Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis. PMID:19068216

Human umbilical cord mesenchymal stromal cells suppress MHC class II expression on rat vascular endothelium and prolong survival time of cardiac allograft

PubMed Central

Qiu, Ying; Yun, Mark M; Han, Xia; Zhao, Ruidong; Zhou, Erxia; Yun, Sheng

2014-01-01

Background: Human umbilical cord mesenchymal stromal cells (UC-MSCs) have low immunogenicity and immune regulation. To investigate immunomodulatory effects of human UC-MSCs on MHC class II expression and allograft, we transplanted heart of transgenic rats with MHC class II expression on vascular endothelium. Methods: UC-MSCs were obtained from human umbilical cords and confirmed with flow cytometry analysis. Transgenic rat line was established using the construct of human MHC class II transactivator gene (CIITA) under mouse ICAM-2 promoter control. The induced MHC class II expression on transgenic rat vascular endothelial cells (VECs) was assessed with immunohistological staining. And the survival time of cardiac allograft was compared between the recipients with and without UC-MSC transfusion. Results: Flow cytometry confirmed that the human UC-MSCs were positive for CD29, CD44, CD73, CD90, CD105, CD271, and negative for CD34 and HLA-DR. Repeated infusion of human UC-MSCs reduced MHC class II expression on vascular endothelia of transplanted hearts, and increased survival time of allograft. The UC-MSCs increased regulatory cytokines IL10, transforming growth factor (TGF)-β1 and suppressed proinflammatory cytokines IL2 and IFN-γ in vivo. The UC-MSC culture supernatant had similar effects on cytokine expression, and decreased lymphocyte proliferation in vitro. Conclusions: Repeated transfusion of the human UC-MSCs reduced MHC class II expression on vascular endothelia and prolonged the survival time of rat cardiac allograft. PMID:25126177

Profound loss of neprilysin accompanied by decreased levels of neuropeptides and increased CRP in ulcerative colitis.

PubMed

Sargın, Zeynep Gök; Erin, Nuray; Tazegul, Gokhan; Elpek, Gülsüm Özlem; Yıldırım, Bülent

2017-01-01

Neprilysin (NEP, CD10) acts to limit excessive inflammation partly by hydrolyzing neuropeptides. Although deletion of NEP exacerbates intestinal inflammation in animal models, its role in ulcerative colitis (UC) is not well explored. Herein, we aimed to demonstrate changes in NEP and associated neuropeptides at the same time in colonic tissue. 72 patients with UC and 27 control patients were included. Patients' demographic data and laboratory findings, five biopsy samples from active colitis sites and five samples from uninvolved mucosa were collected. Substance P (SP), calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) were extracted from freshly frozen tissues and measured using ELISA. Levels of NEP expression were determined using immunohistochemistry and immunoreactivity scores were calculated. GEBOES grading system was also used. We demonstrated a profound loss (69.4%) of NEP expression in UC, whereas all healthy controls had NEP expression. Patients with UC had lower neuronal SP; however non-neuronal SP remained similar. UC patients had also lower neuronal and non-neuronal VIP levels. CGRP were low in general and no significant changes were observed. Additionally, CRP positive patients with UC had higher rates of NEP loss (80% vs 51.9%) and lower SP levels when compared with CRP negative patients with UC. Concurrent decreases in SP and VIP with profound loss of NEP expression observed in UC is likely to be one of the factors in pathogenesis. Further studies are required to define the role of neuropeptides and NEP in UC.

Profound loss of neprilysin accompanied by decreased levels of neuropeptides and increased CRP in ulcerative colitis

PubMed Central

Sargın, Zeynep Gök; Tazegul, Gokhan; Elpek, Gülsüm Özlem; Yıldırım, Bülent

2017-01-01

Neprilysin (NEP, CD10) acts to limit excessive inflammation partly by hydrolyzing neuropeptides. Although deletion of NEP exacerbates intestinal inflammation in animal models, its role in ulcerative colitis (UC) is not well explored. Herein, we aimed to demonstrate changes in NEP and associated neuropeptides at the same time in colonic tissue. 72 patients with UC and 27 control patients were included. Patients’ demographic data and laboratory findings, five biopsy samples from active colitis sites and five samples from uninvolved mucosa were collected. Substance P (SP), calcitonin gene related peptide (CGRP) and vasoactive intestinal peptide (VIP) were extracted from freshly frozen tissues and measured using ELISA. Levels of NEP expression were determined using immunohistochemistry and immunoreactivity scores were calculated. GEBOES grading system was also used. We demonstrated a profound loss (69.4%) of NEP expression in UC, whereas all healthy controls had NEP expression. Patients with UC had lower neuronal SP; however non-neuronal SP remained similar. UC patients had also lower neuronal and non-neuronal VIP levels. CGRP were low in general and no significant changes were observed. Additionally, CRP positive patients with UC had higher rates of NEP loss (80% vs 51.9%) and lower SP levels when compared with CRP negative patients with UC. Concurrent decreases in SP and VIP with profound loss of NEP expression observed in UC is likely to be one of the factors in pathogenesis. Further studies are required to define the role of neuropeptides and NEP in UC. PMID:29232715

Immunosuppressive function of mesenchymal stem cells from human umbilical cord matrix in immune thrombocytopenia patients.

PubMed

Ma, Li; Zhou, Zeping; Zhang, Donglei; Yang, Shaoguang; Wang, Jinhong; Xue, Feng; Yang, Yanhui; Yang, Renchi

2012-05-01

Human umbilical cord matrix/Wharton's jelly (hUC)-derived mesenchymal stem cells (MSC) have been shown to have marked therapeutic effects in a number of inflammatory diseases and autoimmune diseases in humans based on their potential for immunosuppression and their low immunogenicity. Currently, no data are available on the effectiveness of UC-MSC transplantation in immune thrombocytopenia (ITP) patients. It was the objective of this study to assess the effect of allogeneic UC-MSCs on ITP patients in vitro and in vivo. Peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BM-MNCs) from ITP patients and healthy controls were co-cultured with UC-MSCs for three days and seven days, respectively. Flow cytometry and ELISA were applied to assess the various parameters. In PBMCs from ITP patients, the proliferation of autoreactive T, B lymphocytes and destruction of autologous platelets were dramatically suppressed by UC-MSCs. UC-MSCs not only suppressed co-stimulatory molecules CD80, CD40L and FasL expression but also in shifting Th1/Th2/Treg cytokines profile in ITP patients. UC-MSCs obviously reversed the dysfunctions of megakaryocytes by promoting platelet production and decreasing the number of living megakaryocytes as well as early apoptosis. In addition, the level of thrombopoietin was increased significantly. Our clinical study showed that UC-MSCs play a role in alleviating refractory ITP by increasing platelet numbers. These findings suggested that UC-MSCs transplantation might be a potential therapy for ITP.

Avoiding restorative proctocolectomy for colorectal cancer in patients with ulcerative colitis based on preoperative diagnosis involving p53 immunostaining: report of a case.

PubMed

Sada, Haruki; Shimomura, Manabu; Hinoi, Takao; Egi, Hiroyuki; Kawaguchi, Koji; Yano, Takuya; Niitsu, Hiroaki; Saitou, Yasufumi; Sawada, Hiroyuki; Miguchi, Masashi; Adachi, Tomohiro; Ohdan, Hideki

2015-03-26

The standard operation for colitic cancer in ulcerative colitis (UC) is restorative proctocolectomy; however, sporadic colorectal cancer (CRC) can coincidentally arise in patients with UC and the optimal procedure remains controversial. Therefore, it is crucial to preoperatively determine whether the CRC in UC is a sporadic or colitic cancer. We report a case of avoiding proctocolectomy for sporadic CRC in a patient with UC based on preoperative diagnosis involving p53 immunostaining. A 73-year-old man with CRC in UC had undergone sigmoid colectomy with lymphadenectomy because of the submucosal deep invasion pathologically after endoscopic mucosal resection. The cancer was diagnosed sporadic cancer preoperatively not only based on the endoscopic, clinical, and histological patterns but also that the colon epithelium was unlikely to develop dysplasia as the circumference and unaffected UC mucosa did not detect p53 protein overexpression. Recent reports have shown that the immunohistochemical detection of p53 protein overexpression can be useful for a differential diagnosis and as a predictor of dysplasia and colitic cancer. The analysis of p53 mutation status based on immunostaining of p53 protein expression in the unaffected UC mucosa can be useful for the decision regarding a surgical procedure for CRC in patients with UC.

[Expression and clinical significance of 5hmC in bladder urothelial carcinoma].

PubMed

Li, Jie; Xu, Yuqiao; Zhang, Zhiwen; Zhang, Ming; Zhang, Zhekai; Zhang, Feng; Li, Qing

2016-02-01

To investigate the expression of 5-hydroxymethylcytosine (5hmC) in bladder urothelial carcinoma (UC) and its clinical significance. The expression of 5hmC in 21 cases of UC tissues and pericarcinous urinary tract epithelium was detected by immunohistochemical staining. Then the expression of 5hmC in the surgical resection of UC tissues in 92 cases was also surveyed. Non parametric U Mann-Whitney test was used to analyze the correlation between 5hmC expression and clinical data. Single factor survival analysis was performed by Kaplan-Meier test. The expression of 5hmC in normal urinary tract epithelium and UC tissues was significantly different, but there was no significant difference in the expression of 5hmC between low and high grades of UC tissues as well as between different TNM grades. Kaplan-Meier single factor survival analysis showed that there was no significant correlation between the 5hmC expression level and the survival rate or the recurrence-free survival of UC patients. The expression level of 5hmC in UC tissues is significantly lower than that in pericarcinous urinary tract epithelium. There is no correlation between the 5hmC expression and the progression, prognosis and recurrence of UC.

Professional charges not reimbursed to dentists in the U.S.: evidence from Medical Expenditure Panel Survey, 1996.

PubMed

Chattopadhyay, A; Slade, G D; Caplan, D J

2009-12-01

This cross-sectional study examined professional charges not paid to dentists. This analysis used logistic regression in SUDAAN examining the 1996 MEPS data from 12,931 adults. Among people incurring dental care charges, 13.6% had more than $50 of unpaid charge (UC). The percapita UC was $53.30. Total UC was higher for highest income group [45.4% of total] compared to lowest income group [26.0%]. The percapita UC of $76.70 for low income group was significantly greater than for high income group ($47.80, P < 0.01). More Medicaid recipients (52% vs. non-recipients: 12%) incurred at least $50 in UC (P < 0.01). Adjusted odds of incurring UC were greater for those employed (OR = 1.3, 95% CI: 1.0-1.7), and for those with private insurance (OR: 1.5, CI: 1.3-1.9). Number of dental procedure types modified the association between Medicaid recipient and UC (OR = 13.6 for Medicaid recipients undergoing multiple procedure types; OR: 2.3 for Medicaid non-recipients with multiple procedure types; OR: 1.9 for Medicaid recipients receiving single dental procedure. Having private insurance, being unemployed and being Medicaid insured undergoing multiple procedure were strongest predictors of UC.

Golimumab in unresponsive ulcerative colitis

PubMed Central

Lippert, Elisabeth; Müller, Martina; Ott, Claudia

2014-01-01

Ulcerative colitis (UC) is a chronic inflammation mainly affecting the colon mucosa. It predominantly occurs in younger patients. Until recently, the main goals in the treatment of UC were to temper the symptoms, such as diarrhea, pain, and weight loss, by using mesalazine and steroids. With newer medications, such as immunomodulators (thiopurines) and the biologics providing blockade of tumor necrosis factor (TNF), the goals of the therapy in UC have changed to long-term remission and mucosal healing. The first available anti-TNF therapy in UC included infusion therapy with infliximab every few weeks. In 2012, subcutaneously administered adalimumab gained approval for the treatment of UC in Germany. In patients with a mild disease, therapy with mesalazine, orally or topically, can be sufficient. In patients with moderate to severe disease, therapy with azathioprine or anti-TNF is often required to reach disease control; however, this is only efficient in about two-thirds of patients. Some patients either show no response or a lost response while on treatment. So, further medical options are warranted in the treatment of UC. With golimumab, a new approach in the treatment of mild to moderate UC recently became available in Germany and is a promising new option in the therapy regimen for patients with UC. PMID:24904202

Antilaminaribioside and antichitobioside antibodies in inflammatory bowel disease.

PubMed

Rejchrt, S; Drahosová, M; Kopácová, M; Cyrany, J; Douda, T; Pintér, M; Bures, J

2008-01-01

Testing antilaminaribioside (ALCA) and antichitobioside (ACCA) antibodies in 89 Crohn's disease (CD), 31 ulcerative colitis (UC) and 50 controls, mean values were 38.6 and 53.0 ELISA units for CD, 34.0 and 32.6 for UC, 34.5 and 36.4 for controls, respectively. There was no significant difference of ALCA values between CD and UC (p = 0.401), CD and control subjects (p = 0.698) or UC and controls (p = 0.898). ACCA were significantly higher in CD compared with UC (p = 0.011) but not with the controls (p = 0.095). No significant difference of ACCA values between UC and controls (p = 0.107) was found. ALCA and ACCA values significantly correlated in CD (r = 0.548, p < 10(-4)) and UC (r = 0.885, p < 10(-4)) but not in controls (r = 0.153, p = 0.287). The positive predictive value for CD was only 20 (ALCA) and 8 % (ACCA), the negative ones (to exclude CD) 25 (ALCA) and 86 % (ACCA). Small and/or large bowel involvement or disease type (i.e. stenosing, perforating or inflammatory) of CD did not differ in the two values. The idea that ALCA and ACCA may be useful either to differentiate between CD, UC and healthy subjects or to stratify CD was not confirmed.

Role of classical conditioning in learning gastrointestinal symptoms

PubMed Central

Stockhorst, Ursula; Enck, Paul; Klosterhalfen, Sibylle

2007-01-01

Nausea and/or vomiting are aversive gastrointestinal (GI) symptoms. Nausea and vomiting manifest unconditionally after a nauseogenic experience. However, there is correlative, quasiexperimental and experimental evidence that nausea and vomiting can also be learned via classical (Pavlovian) conditioning and might occur in anticipation of the nauseogenic event. Classical conditioning of nausea can develop with chemotherapy in cancer patients. Initially, nausea and vomiting occur during and after the administration of cytotoxic drugs (post-treatment nausea and vomiting) as unconditioned responses (UR). In addition, 20%-30% of cancer patients receiving chemotherapy report these side effects, despite antiemetic medication, when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea (AN) and/or anticipatory vomiting (ANV) and are explained by classical conditioning. Moreover, there is recent evidence for the assumption that post-chemotherapy nausea is at least partly influenced by learning. After summarizing the relevant assumptions of the conditioning model, revealing that a context can become a conditioned stimulus (CS), the present paper summarizes data that nausea and/or vomiting is acquired by classical conditioning and, consequently, may be alleviated by conditioning techniques. Our own research has focussed on two aspects and is emphasized here. First, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion-sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea and associated endocrine and immunological responses is summarized. Results from the rotation-induced motion sickness model showed that gender is an important moderator variable to be considered in further studies. This paper concludes with a review of the application of the demonstrated conditioning principles as interventions to ameliorate distressing AN/ANV in cancer patients undergoing chemotherapy, which is the second focus of our work. PMID:17659689

Role of classical conditioning in learning gastrointestinal symptoms.

PubMed

Stockhorst, Ursula; Enck, Paul; Klosterhalfen, Sibylle

2007-07-07

Nausea and/or vomiting are aversive gastrointestinal (GI) symptoms. Nausea and vomiting manifest unconditionally after a nauseogenic experience. However, there is correlative, quasiexperimental and experimental evidence that nausea and vomiting can also be learned via classical (Pavlovian) conditioning and might occur in anticipation of the nauseogenic event. Classical conditioning of nausea can develop with chemotherapy in cancer patients. Initially, nausea and vomiting occur during and after the administration of cytotoxic drugs (post-treatment nausea and vomiting) as unconditioned responses (UR). In addition, 20%-30% of cancer patients receiving chemotherapy report these side effects, despite antiemetic medication, when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea (AN) and/or anticipatory vomiting (ANV) and are explained by classical conditioning. Moreover, there is recent evidence for the assumption that post-chemotherapy nausea is at least partly influenced by learning. After summarizing the relevant assumptions of the conditioning model, revealing that a context can become a conditioned stimulus (CS), the present paper summarizes data that nausea and/or vomiting is acquired by classical conditioning and, consequently, may be alleviated by conditioning techniques. Our own research has focussed on two aspects and is emphasized here. First, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion-sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea and associated endocrine and immunological responses is summarized. Results from the rotation-induced motion sickness model showed that gender is an important moderator variable to be considered in further studies. This paper concludes with a review of the application of the demonstrated conditioning principles as interventions to ameliorate distressing AN/ANV in cancer patients undergoing chemotherapy, which is the second focus of our work.

Ionic liquid dependence of triplet-sensitized photon upconversion.

PubMed

Murakami, Yoichi; Ito, Toshiyuki; Kawai, Akio

2014-12-11

Photon upconversion (UC) is a technology used to convert wasted lower energy photons to usable higher energy photons. Triplet-sensitized UC based on the triplet-triplet annihilation (TTA) of organic molecules has recently received attention because of its applicability to noncoherent sunlight. Among the various media proposed for this UC, ionic liquids (ILs) are practically advantageous because of their nonvolatility and nonflammability. However, from previous studies, the efficiency of UC (ΦUC) has been found to depend on the ILs employed. In this article, systematic investigations were carried out on samples made using more than 10 kinds of ILs, all of which were purified before sample fabrication to enhance data reliability. Several clear tendencies were found, and they were all related to the viscosity of the ILs. We also found that the magnitude of their solvatochromic shifts did not correlate to these trends. These results show that the dynamic aspects of the molecules influence the kinetics that govern the magnitude of ΦUC. Along with related discussions and interpretations, these results should provide a guideline toward increasing the ΦUC.

Intelligent Agents as a Basis for Natural Language Interfaces

DTIC Science & Technology

1988-01-01

language analysis component of UC, which produces a semantic representa tion of the input. This representation is in the form of a KODIAK network (see...Appendix A). Next, UC’s Concretion Mechanism performs concretion inferences ([Wilensky, 1983] and [Norvig, 1983]) based on the semantic network...The first step in UC’s processing is done by UC’s parser/understander component which produces a KODIAK semantic network representa tion of

Clonal Evolution of Chemotherapy-resistant Urothelial Carcinoma

PubMed Central

Faltas, Bishoy M.; Prandi, Davide; Tagawa, Scott T.; Molina, Ana M.; Nanus, David M.; Sternberg, Cora; Rosenberg, Jonathan; Mosquera, Juan Miguel; Robinson, Brian; Elemento, Olivier; Sboner, Andrea; Beltran, Himisha; Demichelis, Francesca; Rubin, Mark A.

2017-01-01

Chemotherapy-resistant urothelial carcinoma (UC) has no uniformly curative therapy. Understanding how selective pressure from chemotherapy directs UC’s evolution and shapes its clonal architecture is a central biological question with clinical implications. To address this question, we performed whole-exome sequencing and clonality analysis of 72 UCs including 16 matched sets of primary and advanced tumors prospectively collected before and after chemotherapy. Our analysis provided several insights: (i) chemotherapy-treated UC is characterized by intra-patient mutational heterogeneity and the majority of mutations are not shared, (ii) both branching evolution and metastatic spread are very early events in the natural history of UC; (iii) chemotherapy-treated UC is enriched with clonal mutations involving L1-cell adhesion molecule (L1CAM) and integrin signaling pathways; (iv) APOBEC induced-mutagenesis is clonally-enriched in chemotherapy-treated UC and continues to shape UC’s evolution throughout its lifetime. PMID:27749842

Huangqin-Tang and Ingredients in Modulating the Pathogenesis of Ulcerative Colitis.

PubMed

Wang, Chunyan; Tang, Xudong; Zhang, Li

2017-01-01

Ulcerative colitis (UC) is the most common inflammatory bowel disease worldwide. Current therapies in UC cause limitations, and herb medicine provides an important choice for UC treatment. Huangqin-Tang (HQT) is a well-known classical traditional Chinese herbal formula and has been used in China for thousands of years. A large number of pharmacological studies demonstrated HQT and its ingredients to be effective in treating UC. Though the therapeutic effect has been evaluated, comprehensive up-to-date reviews in this field are not yet available. Here we aim to review our current understanding of HQT and its ingredients in treating UC and how the agents modulate the main pathogenesis of the disease, including the intestinal environment, immune imbalance, inflammatory pathways, and oxidative stress. The summary on this issue may provide better understanding of HQT and its ingredients in treating UC and possibly help in promoting its clinical application.

The effects of muscle contraction and recombinant osteocalcin on insulin sensitivity ex vivo.

PubMed

Levinger, I; Lin, X; Zhang, X; Brennan-Speranza, T C; Volpato, B; Hayes, A; Jerums, G; Seeman, E; McConell, G

2016-02-01

We tested whether GPRC6A, the putative receptor of undercarboxylated osteocalcin (ucOC), is present in mouse muscle and whether ucOC increases insulin sensitivity following ex vivo muscle contraction. GPPRC6A is expressed in mouse muscle and in the mouse myotubes from a cell line. ucOC potentiated the effect of ex vivo contraction on insulin sensitivity. Acute exercise increases skeletal muscle insulin sensitivity. In humans, exercise increases circulating ucOC, a hormone that increases insulin sensitivity in rodents. We tested whether GPRC6A, the putative receptor of ucOC, is present in mouse muscle and whether recombinant ucOC increases insulin sensitivity in both C2C12 myotubes and whole mouse muscle following ex vivo muscle contraction. Glucose uptake was examined in C2C12 myotubes that express GPRC6A following treatment with insulin alone or with insulin and increasing ucOC concentrations (0.3, 3, 10 and 30 ng/ml). In addition, glucose uptake, phosphorylated (p-)AKT and p-AS160 were examined ex vivo in extensor digitorum longus (EDL) dissected from C57BL/6J wild-type mice, at rest, following insulin alone, after muscle contraction followed by insulin and after muscle contraction followed by recombinant ucOC then insulin exposure. We observed protein expression of the likely receptor for ucOC, GPRC6A, in whole muscle sections and differentiated mouse myotubes. We observed reduced GPRC6A expression following siRNA transfection. ucOC significantly increased insulin-stimulated glucose uptake dose-dependently up to 10 ng/ml, in differentiated mouse C2C12 myotubes. Insulin increased EDL glucose uptake (∼30 %, p < 0.05) and p-AKT and p-AKT/AKT compared with rest (all p < 0.05). Contraction prior to insulin increased muscle glucose uptake (∼25 %, p < 0.05), p-AKT, p-AKT/AKT, p-AS160 and p-AS160/AS160 compared with contraction alone (all p < 0.05). ucOC after contraction increased insulin-stimulated muscle glucose uptake (∼12 % p < 0.05) and p-AS160 (<0.05) more than contraction plus insulin alone but without effect on p-AKT. In the absence of insulin and/or of contraction, ucOC had no significant effect on muscle glucose uptake. GPRC6A, the likely receptor of osteocalcin (OC), is expressed in mouse muscle. ucOC treatment augments insulin-stimulated skeletal muscle glucose uptake in C2C12 myotubes and following ex vivo muscle contraction. ucOC may partly account for the insulin sensitizing effect of exercise.