Stimulus-response Learning Research Articles

The Enigmatic Persistence of Anorexia Nervosa

In this review, based on recent advances in cognitive neuroscience, the author presents a formulation in which the marked persistence of anorexia nervosa can be usefully understood as a well-ingrained maladaptive habit. The author reviewed the relevant literature on the development and course of anorexia nervosa and interpreted critical features in light of developments in cognitive neuroscience. Anorexia nervosa is a well characterized disorder with remarkable persistence both across history and among affected individuals. Food restriction, the salient behavioral feature of the disorder, often begins innocently but gradually takes on a life of its own. Over time, it becomes highly entrenched and resistant to change through either psychological or pharmacological treatment. Cognitive neuroscience has described two related but distinct processes that underlie the acquisition of new patterns of behavior, namely, action-outcome and stimulus-response learning. It is likely that both processes are engaged in the development of anorexia nervosa and that stimulus-response learning (that is, habit formation) is critical to the persistence of the dieting behavior. The formulation of the dieting behavior characteristic of anorexia nervosa as a well-entrenched habit provides a basis for understanding the striking persistence of this disorder. This model helps explain the resistance of anorexia nervosa to interventions that have established efficacy in related disorders and implies that addressing the dieting behavior is critical, especially early in the course of the illness, before it has become ingrained.

Biological sex influences learning strategy preference and muscarinic receptor binding in specific brain regions of prepubertal rats

According to the theory of multiple memory systems, specific brain regions interact to determine how the locations of goals are learned when rodents navigate a spatial environment. A number of factors influence the type of strategy used by rodents to remember the location of a given goal in space, including the biological sex of the learner. We recently found that prior to puberty male rats preferred a striatum-dependent stimulus-response strategy over a hippocampus-dependent place strategy when solving a dual-solution task, while age-matched females showed no strategy preference. Because the cholinergic system has been implicated in learning strategy and is known to be sexually dimorphic prior to puberty, we explored the relationship between learning strategy and muscarinic receptor binding in specific brain regions of prepubertal males and female rats. We confirmed our previous finding that at 28 days of age a significantly higher proportion of prepubertal males preferred a stimulus-response learning strategy than a place strategy to solve a dual-solution visible platform water maze task. Equal proportions of prepubertal females preferred stimulus-response or place strategies. Profiles of muscarinic receptor binding as assessed by autoradiography varied according to strategy preference. Regardless of biological sex, prepubertal rats that preferred stimulus-response strategy exhibited lower ratios of muscarinic receptor binding in the hippocampus relative to the dorsolateral striatum compared to rats that preferred place strategy. Importantly, much of the variance in this ratio was related to differences in the ventral hippocampus to a greater extent than the dorsal hippocampus. The ratios of muscarinic receptors in the hippocampus relative to the basolateral amygdala also were lower in rats that preferred stimulus-response strategy over place strategy. Results confirm that learning strategy preference varies with biological sex in prepubertal rats with males biased toward a stimulus-response strategy, and that stimulus-response strategy is associated with lower ratios of muscarinic binding in the hippocampus relative to either the striatum or amygdala.

Stress and estrous cycle affect strategy but not performance of female C57BL/6J mice

Stress induces a switch in learning strategies of male C57BL/6J mice from predominantly spatial to more stimulus–response learning. To study generalization of these findings over sex, we investigated female C57BL/6J mice at three phases of the estrous cycle under non stress and acute (10min) restraint stress conditions. On a circular hole board (CHB) task, about half of the naive female mice used spatial and stimulus–response strategies to solve the task. Under stress, female mice favored spatial over stimulus–response strategies, with 100% of female mice in the estrus phase. Performance expressed as latency to solve the task is only improved in stressed female mice in the estrus phase. We conclude that the use of learning strategies is influenced by sex and this difference between sexes is aggravated by acute stress.

Maximizing reflexivity and praxis by recognizing and counteracting the constraints imposed by stimulus-response learning

The Task Force on Educating for Excellence in the MPA Degree acknowledged the essential role of active learning when it advocated the use of pedagogical strategies such as classroom exercises and collaborative projects with agencies. The extent to which these strategies foster reflexivity and praxis is limited by stimulus-response learning, i.e., students deciphering what the instructor wants and producing the appropriate responses/materials. To measure the students' preferences for stimulus-response learning, the authors developed a questionnaire that was distributed to students enrolled in MPA courses at a mid-western university. The findings suggest the students' strong preference for stimulus-response learning arises from a fixation on maximizing grades within the allotted time for studies. Given this finding, a program's success in cultivating reflexivity and praxis is impacted by the adoption of strategies that counteract the preference for stimulus-response learning and thereby encourage students to become more self-directed. Several of these strategies are discussed in the paper's final section.

Simultaneous Glucocorticoid and Noradrenergic Activity Disrupts the Neural Basis of Goal-Directed Action in the Human Brain

Stress promotes a shift from goal-directed action-outcome learning toward habitual stimulus-response learning. This shift is mediated by an interaction of noradrenergic activity and glucocorticoid stress hormones. In the present experiment, we examined the neural correlates of the stress (hormone)-induced shift from goal-directed to habit learning in the human brain. Healthy participants were administered hydrocortisone, the α2-adrenoceptor antagonist yohimbine, or both before they were trained in two instrumental actions leading to two distinct food rewards. After training, one of the rewards was devalued by feeding participants to satiety on that food. Finally, participants were presented the two instrumental actions in extinction. We collected functional magnetic resonance images both during instrumental training and during extinction testing. Our behavioral data confirmed that the simultaneous administration of hydrocortisone and yohimbine renders instrumental behavior insensitive to the outcome devaluation (and thus habitual), whereas hydrocortisone or yohimbine alone have no such effect. At the neural level, the combined administration of hydrocortisone and yohimbine reduced the sensitivity of the orbitofrontal and medial prefrontal cortex to changes in outcome value. Brain areas that have been previously implicated in habit learning were not modulated by hydrocortisone and yohimbine. These findings suggest that concurrent glucocorticoid and noradrenergic activity disrupts the neural bases of goal-directed action and thus renders behavior habitual.

Impaired Generalization of Associative Learning in Patients with Alcohol Dependence After Intermediate-term Abstinence

We used an associative learning task in order to investigate cognitive dysfunctions in alcohol dependence. This test is suitable for the assessment of stimulus-response learning and memory generalization (acquired equivalence), which is related to medial temporal lobe functioning. Twenty patients with alcohol dependence (abstinence: >6 months) and 20 matched healthy controls participated in the study. In the task, antecedent stimuli were cartoon faces (girl, boy, man and woman) and consequent stimuli were color cartoon fishes. The task was to learn face-fish associations using feedback. In the transfer phase, the fish-face pairs were generalized to new associations. There was no significant difference between patients and controls during the acquisition phase of fish-face associations. In the transfer phase, patients were impaired relative to controls. We found no association between task performance and intelligence quotient. These results suggest that abstinent patients with alcohol dependence show marked dysfunctions in the generalization of associations, which may indicate the dysfunction of the medial temporal lobe.

Generalization of value in reinforcement learning by humans

Research in decision-making has focused on the role of dopamine and its striatal targets in guiding choices via learned stimulus-reward or stimulus-response associations, behavior that is well described by reinforcement learning theories. However, basic reinforcement learning is relatively limited in scope and does not explain how learning about stimulus regularities or relations may guide decision-making. A candidate mechanism for this type of learning comes from the domain of memory, which has highlighted a role for the hippocampus in learning of stimulus-stimulus relations, typically dissociated from the role of the striatum in stimulus-response learning. Here, we used functional magnetic resonance imaging and computational model-based analyses to examine the joint contributions of these mechanisms to reinforcement learning. Humans performed a reinforcement learning task with added relational structure, modeled after tasks used to isolate hippocampal contributions to memory. On each trial participants chose one of four options, but the reward probabilities for pairs of options were correlated across trials. This (uninstructed) relationship between pairs of options potentially enabled an observer to learn about option values based on experience with the other options and to generalize across them. We observed blood oxygen level-dependent (BOLD) activity related to learning in the striatum and also in the hippocampus. By comparing a basic reinforcement learning model to one augmented to allow feedback to generalize between correlated options, we tested whether choice behavior and BOLD activity were influenced by the opportunity to generalize across correlated options. Although such generalization goes beyond standard computational accounts of reinforcement learning and striatal BOLD, both choices and striatal BOLD activity were better explained by the augmented model. Consistent with the hypothesized role for the hippocampus in this generalization, functional connectivity between the ventral striatum and hippocampus was modulated, across participants, by the ability of the augmented model to capture participants' choice. Our results thus point toward an interactive model in which striatal reinforcement learning systems may employ relational representations typically associated with the hippocampus.

Priming and stimulus–response learning in perceptual classification tasks

Participants often respond more quickly and more accurately to a repeated stimulus compared to a non-repeated one, a phenomenon known as repetition priming. In semantic classification tasks priming appears to be largely attributable to the learning of stimulus–decision and stimulus–response associations, which allow participants to bypass many of the processes engaged during initial stimulus analysis. The current study tested whether stimulus–response learning plays a similarly dominant role in priming that occurs in perceptual classification tasks. Unfamiliar objects were used as stimuli to reduce the influence of semantic processes on priming and the task switched for all test trials to eliminate stimulus–decision learning. The results showed across-task priming as measured by reaction time facilitation and improved accuracy when the response remained the same during the encoding and test phases. When the response switched, similar levels of reaction time facilitation were observed, but priming as measured by accuracy was significantly reduced and no longer significant. These findings indicate that stimulus–response learning contributes to priming in perceptual classification tasks, but does not play a dominant role. Significant stimulus-level learning that is independent of the task and response also occurs and likely indexes facilitated perceptual processing of the objects.

Dorsal Striatum and Its Limbic Connectivity Mediate Abnormal Anticipatory Reward Processing in Obesity

Obesity is characterized by an imbalance in the brain circuits promoting reward seeking and those governing cognitive control. Here we show that the dorsal caudate nucleus and its connections with amygdala, insula and prefrontal cortex contribute to abnormal reward processing in obesity. We measured regional brain glucose uptake in morbidly obese (n = 19) and normal weighted (n = 16) subjects with 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) positron emission tomography (PET) during euglycemic hyperinsulinemia and with functional magnetic resonance imaging (fMRI) while anticipatory food reward was induced by repeated presentations of appetizing and bland food pictures. First, we found that glucose uptake rate in the dorsal caudate nucleus was higher in obese than in normal-weight subjects. Second, obese subjects showed increased hemodynamic responses in the caudate nucleus while viewing appetizing versus bland foods in fMRI. The caudate also showed elevated task-related functional connectivity with amygdala and insula in the obese versus normal-weight subjects. Finally, obese subjects had smaller responses to appetizing versus bland foods in the dorsolateral and orbitofrontal cortices than did normal-weight subjects, and failure to activate the dorsolateral prefrontal cortex was correlated with high glucose metabolism in the dorsal caudate nucleus. These findings suggest that enhanced sensitivity to external food cues in obesity may involve abnormal stimulus-response learning and incentive motivation subserved by the dorsal caudate nucleus, which in turn may be due to abnormally high input from the amygdala and insula and dysfunctional inhibitory control by the frontal cortical regions. These functional changes in the responsiveness and interconnectivity of the reward circuit could be a critical mechanism to explain overeating in obesity.

Sequence Learning Under Uncertainty in Children: Self-Reflection vs. Self-Assertion

We know that stochastic feedback impairs children’s associative stimulus–response (S–R) learning (Crone et al., 2004a; Eppinger et al., 2009), but the impact of stochastic feedback on sequence learning that involves deductive reasoning has not been not tested so far. In the current study, 8- to 11-year-old children (N = 171) learned a sequence of four left and right button presses, LLRR, RRLL, LRLR, RLRL, LRRL, and RLLR, which needed to be deduced from feedback because no directional cues were given. One group of children experienced consistent feedback only (deterministic feedback, 100% correct). In this condition, green feedback on the screen indicated that the children had been right when they were right, and red feedback indicated that the children had been wrong when they were wrong. Another group of children experienced inconsistent feedback (stochastic feedback, 85% correct, 15% false), where in some trials, green feedback on the screen could signal that children were right when in fact they were wrong, and red feedback could indicate that they were wrong when in fact they had been right. Independently of age, children’s sequence learning in the stochastic condition was initially much lower than in the deterministic condition, but increased gradually and improved with practice. Responses toward positive vs. negative feedback varied with age. Children were increasingly able to understand that they could have been wrong when feedback indicated they were right (self-reflection), but they remained unable to understand that they could have been right when feedback indicated they were wrong (self-assertion).

Stimulus/Response Learning in Masked Congruency Priming of Faces: Evidence for Covert Mental Classifications?

Reaction times for categorization of a probe face according to its sex or fame were contrasted as a function of whether the category of a preceding, sandwich-masked prime face was congruent or incongruent. Prime awareness was measured by the ability to later categorize the primes, and this was close to chance and typically uncorrelated with priming. When prime faces were never presented as visible probes within a test, priming was not reliable; when prime faces were also seen as probes, priming was only reliable if visible and masked presentation of faces were interleaved (not simply if primes had been visible in a previous session). In the latter case, priming was independent of experimentally induced face-response or face-category contingencies, ruling out any simple form of stimulus-response learning. We conclude that the reliable masked congruency priming reflects bindings between stimuli and multiple, abstract classifications that can be generated both overtly and covertly.

Learning to cope with stress: psychobiological mechanisms of stress resilience

Stress is the main non-genetic source of psychopathology. Therefore, the identification of neurobiological bases of resilience, the resistance to pathological outcomes of stress, is a most relevant topic of research. It is an accepted view that resilient individuals are those who do not develop helplessness, or other depression-like phenotypes, following a history of stress. In the present review, we discuss the phenotypic differences between mice of the inbred C57BL/6J and DBA/2J strains that could be associated with the strain-specific resistance to helplessness observable in DBA/2J mice. The reviewed results support the hypothesis that resilience to stress-promoted helplessness develops through interactions between a specific genetic makeup and a history of stress, and is associated with an active coping style, a bias toward the use of stimulus-response learning, and specific adaptive changes of mesoaccumbens dopamine transmission under stress. Finally, evidence that compulsivity represents a side effect of the neuroadaptive processes fostering resistance to develop depressive-like phenotypes under stress is discussed.

Reliance on habits at the expense of goal-directed control following dopamine precursor depletion.

RationaleDopamine is well known to play an important role in learning and motivation. Recent animal studies have implicated dopamine in the reinforcement of stimulus–response habits, as well as in flexible, goal-directed action. However, the role of dopamine in human action control is still not well understood.ObjectivesWe present the first investigation of the effect of reducing dopamine function in healthy volunteers on the balance between habitual and goal-directed action control.MethodsThe dietary intervention of acute dietary phenylalanine and tyrosine depletion (APTD) was adopted to study the effects of reduced global dopamine function on action control. Participants were randomly assigned to either the APTD or placebo group (ns = 14) to allow for a between-subjects comparison of performance on a novel three-stage experimental paradigm. In the initial learning phase, participants learned to respond to different stimuli in order to gain rewarding outcomes. Subsequently, an outcome-devaluation test and a slips-of-action test were conducted to assess whether participants were able to flexibly adjust their behaviour to changes in the desirability of the outcomes.ResultsAPTD did not prevent stimulus–response learning, nor did we find evidence for impaired response–outcome learning in the subsequent outcome-devaluation test. However, when goal-directed and habitual systems competed for control in the slips-of-action test, APTD tipped the balance towards habitual control. These findings were restricted to female volunteers.ConclusionsWe provide direct evidence that the balance between goal-directed and habitual control in humans is dopamine dependent. The results are discussed in light of gender differences in dopamine function and psychopathologies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2563-2) contains supplementary material, which is available to authorized users.

Repetition learning of vibrotactile temporal sequences: An fMRI study in blind and sighted individuals

The present fMRI study examined cortical activity to repeated vibrotactile sequences in 11 early blind and 11 sighted participants. All participants performed with > 90% accuracy and showed practice induced improvement with faster reaction times in identifying matched and unmatched vibrotactile sequences. In blind only, occipital/temporal and parietal/somatosensory cortices showed practice induced reductions in positive BOLD amplitudes that possibly reflected repetition induced learning effects. The significant findings in occipital cortex of the blind indicated that perceptual processing of tactile inputs in visually deprived cortex is dynamic as response amplitudes changed with practice. Thus, stimulus processing became more efficient. It was hypothesized that the changes in occipital cortex of the blind reflected life-long skill in processing somatosensory inputs. Both groups showed activity reductions with practice in mid/posterior ventrolateral prefrontal cortex. These activity reductions suggested common stimulus–response learning associations for vibrotactile sequences in mid/posterior ventrolateral prefrontal cortex.

Just Do It: Action-Dependent Learning Allows Sensory Prediction

Sensory-motor learning is commonly considered as a mapping process, whereby sensory information is transformed into the motor commands that drive actions. However, this directional mapping, from inputs to outputs, is part of a loop; sensory stimuli cause actions and vice versa. Here, we explore whether actions affect the understanding of the sensory input that they cause. Using a visuo-motor task in humans, we demonstrate two types of learning-related behavioral effects. Stimulus-dependent effects reflect stimulus-response learning, while action-dependent effects reflect a distinct learning component, allowing the brain to predict the forthcoming sensory outcome of actions. Together, the stimulus-dependent and the action-dependent learning components allow the brain to construct a complete internal representation of the sensory-motor loop.

Early iron deficiency enhances stimulus-response learning of adult rats in the context of competing spatial information

Iron deficiency early in life results in neurocognitive deficits that persist into adulthood despite iron treatment. The hippocampus is particularly vulnerable to iron deficiency during the fetal and neonatal periods as evidenced by poorer hippocampus-mediated spatial recognition learning. However, the extent to which early iron deficiency alters interactions between hippocampus-based and extra-hippocampus based learning systems remains undetermined. The present study used an ambiguous maze-learning task to examine the learning process in iron sufficient young adult rats that had recovered from iron deficiency in the fetal and neonatal period. Animals were presented with a stimulus response-learning task in the context of spatial information; a procedure designed to elicit competition between dorsal striatum- and hippocampus-based systems respectively. Formerly iron deficient adult rats showed enhanced stimulus-response learning in the context of competing spatial/distal cue information, a finding suggestive of reduced hippocampal functional influence. The study provides evidence that early iron deficiency alters how different learning systems develop and ultimately interact in adulthood. The potential unbalancing of activity among major memory systems during early life has been postulated by others as a relevant factor underlying the developmental origins of certain psychiatric disorders.

Dorsal hippocampal lesions boost performance in the rat sequential reaction time task

It is commonly accepted that the hippocampus plays a major role in declarative memory across species and that it is of particular relevance for spatial memory in rodents. However, the interplay between hippocampal function and nondeclarative memory systems, such as procedural stimulus-response (S-R) or sequential learning, is less clear: depending on task requirements, an interaction, dissociation or interference between hippocampal function and other memory systems may occur. This study was conducted to investigate the influence of dorsal ibotenic hippocampal lesions on learning and performance of sequential behavior in a rat version of the serial reaction time task (SRTT). Magnetic resonance imaging (MRI) analyses of the lesions revealed a bilateral volume reduction of ≈ 46% (histological analyses: ≈ 59%) of the total hippocampus. They were largely confined to its dorsal part and led to an expected spatial memory deficits in an object place recognition test as compared to healthy controls, even though sham lesions had the same effect. Our earlier studies on sequential learning had revealed substantial impairments in case of dorsal striatal dopaminergic lesions. In the present study, however, hippocampal lesioned animals unexpectedly showed superior performance throughout SRTT testing and training as compared to controls, which resulted in a higher degree of subsequent automated sequential behavior. Thus, our data reveal the infrequent case where hippocampal lesions lead to long-term improvements in test performance of a type of rather complex procedural behavior. One possible explanation for this effect is that hippocampal activity in rodents can interfere with other memory systems during the acquisition of procedural tasks with very low spatial requirements, as used here. Alternative explanations for the observed superior SRTT performance in lesioned animals, such as hyperactivity or increased exploratory drive are also topic of the discussion.

GL.01 Dopamine in health and disease

The original synthesis of dopamine in the laboratories of H.E. Dale in South London, followed some 50 years later by the seminal mapping of the mesencephalic dopamine (DA) pathways into...

P8 Functional contributions of basal ganglia pathways to stimulus-response learning in normal functioning and Parkinson’s Disease: A computational model

P8 Functional contributions of basal ganglia pathways to stimulus-response learning in normal functioning and Parkinson’s Disease: A computational model

Evidence for a virtual human analog of a rodent relational memory task: A study of aging and fMRI in young adults

A radial maze concurrent spatial discrimination learning paradigm consisting of two stages was previously designed to assess the flexibility property of relational memory in mice, as a model of human declarative memory. Aged mice and young adult mice with damage to the hippocampus, learned accurately Stage 1 of the task which required them to learn a constant reward location in a specific set of arms (i.e., learning phase). In contrast, they were impaired relative to healthy young adult mice in a second stage when faced with rearrangements of the same arms (i.e., flexibility probes). This mnemonic inflexibility in Stage 2 is thought to derive from insufficient relational processing by the hippocampus during initial learning (Stage 1) which favors stimulus-response learning, a form of procedural learning. This was proposed as a model of the selective declarative and relational memory decline classically described in elderly people. As a first step to examine the validity of this model, we adapted this protocol to humans using a virtual radial-maze. (1) We showed that performance in the flexibility probes in young and older adults positively correlated with performance in a wayfinding task, suggesting that our paradigm assesses relational memory. (2) We demonstrated that older healthy participants displayed a deficit in the performance of the flexibility probes (Stage 2), similar to the one previously seen in aged mice. This was associated with a decline in the wayfinding task. (3) Our fMRI data in young adults confirmed that hippocampal activation during early discrimination learning in Stage 1 correlated with memory flexibility in Stage 2, whereas caudate nucleus activation in Stage 1 negatively correlated with subsequent flexibility. By enabling relational memory assessment in mice and humans, our radial-maze paradigm provides a valuable tool for translational research.