The D2/D3-receptor antagonist tiapride impairs concurrent but not sequential taste aversion learning

Taste aversion learning (TAL) is a learning modality in which the animals reject a gustatory stimulus associated with the administration of noxious visceral substances. This learning can be established by concurrent or sequential procedures that involve different anatomical and functional mechanisms and may constitute distinct learning modalities. The dopaminergic system has been related to various learning processes and goal-directed behaviours. The present study examined the effect of the administration of tiapride, a D(2)/D(3) dopaminergic antagonist, on concurrent and sequential TAL. Results obtained showed that pre-treatment with tiapride blocks the acquisition of concurrent TAL but does not affect sequential TAL, including reversal learning tasks. These results demonstrate the involvement of the D(2)/D(3) dopaminergic receptors in the former but not the latter learning process. The dopaminergic system appears to participate in concurrent TAL, an "implicit" learning modality, but not in sequential TAL, which is considered a relational/explicit acquisition process.     

Neurophysiological and functional neuroanatomical coding of statistical and deterministic rule information during sequence learning

Humans are capable of acquiring multiple types of information presented in the same information stream. It has been suggested that at least two parallel learning processes are important during learning of sequential patterns—statistical learning and rule‐based learning. Yet, the neurophysiological underpinnings of these parallel learning processes are not fully understood. To differentiate between the simultaneous mechanisms at the single trial level, we apply a temporal EEG signal decomposition approach together with sLORETA source localization method to delineate whether distinct statistical and rule‐based learning codes can be distinguished in EEG data and can be related to distinct functional neuroanatomical structures. We demonstrate that concomitant but distinct aspects of information coded in the N2 time window play a role in these mechanisms: mismatch detection and response control underlie statistical learning and rule‐based learning, respectively, albeit with different levels of time‐sensitivity. Moreover, the effects of the two learning mechanisms in the different temporally decomposed clusters of neural activity also differed from each other in neural sources. Importantly, the right inferior frontal cortex (BA44) was specifically implicated in visuomotor statistical learning, confirming its role in the acquisition of transitional probabilities. In contrast, visuomotor rule‐based learning was associated with the prefrontal gyrus (BA6). The results show how simultaneous learning mechanisms operate at the neurophysiological level and are orchestrated by distinct prefrontal cortical areas. The current findings deepen our understanding on the mechanisms of how humans are capable of learning multiple types of information from the same stimulus stream in a parallel fashion.     

Socially acquired predator avoidance: is it just classical conditioning?

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.     

Dissociating hippocampal and striatal contributions to sequential prediction learning

Behavior may be generated on the basis of many different kinds of learned contingencies. For instance, responses could be guided by the direct association between a stimulus and response, or by sequential stimulus-stimulus relationships (as in model-based reinforcement learning or goal-directed actions). However, the neural architecture underlying sequential predictive learning is not well understood, in part because it is difficult to isolate its effect on choice behavior. To track such learning more directly, we examined reaction times (RTs) in a probabilistic sequential picture identification task in healthy individuals. We used computational learning models to isolate trial-by-trial effects of two distinct learning processes in behavior, and used these as signatures to analyse the separate neural substrates of each process. RTs were best explained via the combination of two delta rule learning processes with different learning rates. To examine neural manifestations of these learning processes, we used functional magnetic resonance imaging to seek correlates of time-series related to expectancy or surprise. We observed such correlates in two regions, hippocampus and striatum. By estimating the learning rates best explaining each signal, we verified that they were uniquely associated with one of the two distinct processes identified behaviorally. These differential correlates suggest that complementary anticipatory functions drive each region's effect on behavior. Our results provide novel insights as to the quantitative computational distinctions between medial temporal and basal ganglia learning networks and enable experiments that exploit trial-by-trial measurement of the unique contributions of both hippocampus and striatum to response behavior.     

Nucleus of the solitary tract and flavor aversion learning: relevance in concurrent but not sequential behavioral test

Theories relating the nucleus of the solitary tract to taste aversion learning (TAL) have received their main support from immunohistochemical research. In the present study, a behavioral analysis was performed on the effect of lesions of the intermediate nucleus of the solitary tract (iNST) on concurrent and sequential flavor aversion learning tasks. Bilateral lesions of the iNST impaired concurrent flavor learning, in which animals must discriminate between two simultaneously presented flavors paired with intragastric administration of a noxious or innocuous substance, respectively. However, the same iNST lesions did not interrupt the development of sequential flavor aversion learning, in which each flavor is offered individually on consecutive alternate days. These results behaviorally confirm the relevance of the nucleus of the solitary tract in TAL and suggest a functional dissociation between the neural systems underlying concurrent and sequential flavor aversion learning.     

The role of the external lateral parabrachial subnucleus in flavor preferences induced by predigested food administered intragastrically

A study was undertaken of the role of the external lateral parabrachial subnucleus (PBNLe) in flavor preferences induced by the intragastric administration of predigested/cephalic food. These preferences were developed using two different learning procedures, concurrent and sequential. In the concurrent procedure, two different-flavored stimuli were presented at the same time: one stimulus was paired with the simultaneous intragastric administration of partially digested food and the other with physiological saline. In the sequential learning procedure, the two stimuli were presented at alternate sessions. The results showed that PBNLe lesions blocked acquisition of concurrent learning but had no effect on the sequential procedure. In the latter case, both lesioned and control animals showed a strong preference for the gustatory stimulus paired with partially digested food. These results are interpreted in terms of a dual neurobiological system involved in the rewarding effects of visceral signals.     

Two forms of learning following training to a single odorant in Caenorhabditis elegans AWC neurons

The nematode Caenorhabditis elegans can adapt to both the AWC-sensed odorants benzaldehyde (Bnz) and isoamyl alcohol (IsoA) and can reciprocally cross-adapt. Yet we reveal that these four adaptation scenarios actually represent two distinct forms of learning: nonassociative habituation and associative learning by pairing with a starvation unconditioned stimulus. Training to the single odorant IsoA leads to both associative and nonassociative memory traces, which can be preferentially accessed by either a Bnz or IsoA retrieval stimulus, respectively. This represents the first demonstration in which the form of learning displayed after training to a single stimulus is a function of the retrieval stimulus used. Furthermore, these two forms of learning can be genetically double dissociated despite both forms occurring within the AWC primary sensory neuron. We find that associative learning requires the cGMP-dependent kinase egl-4 and insulin signaling, which acts downstream of egl-4. In contrast, nonassociative learning requires neither of these genes, but does require the TRPV channel osm-9, which is dispensable for associative learning. In addition, we find that the arrestin arr-1 is promiscuous between associative and nonassociative learning in mediating the adaptive response to the IsoA retrieval stimulus, suggesting that distinct forms of memory may nonetheless use common downstream effectors.     

Emotional and spatial learning in goldfish is dependent on different telencephalic pallial systems

In mammals, the amygdala and the hippocampus are involved in different aspects of learning. Whereas the amygdala complex is involved in emotional learning, the hippocampus plays a critical role in spatial and contextual learning. In fish, it has been suggested that the medial and lateral region of the telencephalic pallia might be the homologous neural structure to the mammalian amygdala and hippocampus, respectively. Although there is evidence of the implication of medial and lateral pallium in several learning processes, it remains unclear whether both pallial areas are involved distinctively in different learning processes. To address this issue, we examined the effect of selective ablation of the medial and lateral pallium on both two-way avoidance and reversal spatial learning in goldfish. The results showed that medial pallium lesions selectively impaired the two-way avoidance task. In contrast, lateral pallium ablations impaired the spatial task without affecting the avoidance performance. These results indicate that the medial and lateral pallia in fish are functionally different and necessary for emotional and spatial learning, respectively. Present data could support the hypothesis that a sketch of these regions of the limbic system, and their associated functions, were present in the common ancestor of fish and terrestrial vertebrates 400 million years ago.     

ACTH release during passive avoidance behavior

ACTH was measured by radioimmunoassay during learning and retention of a passive avoidance response. Electric footshock, used during the learning trial, appeared to be a weaker stimulus for ACTH release than was the retention test. Moreover high latency scores during retention were associated with high plasma ACTH levels, whereas shorter latencies were associated with lower levels. The results indicate that psychological mechanisms organizing behavioral coping are important in the response of the pituitary-adrenocortical system to stimuli which are related to a previous adversive experience.     

The path to memory is guided by strategy: distinct networks are engaged in associative encoding under visual and verbal strategy and influence memory performance in healthy and impaired individuals

Given the diversity of stimuli encountered in daily life, a variety of strategies must be used for learning new information. Relating and encoding visual and verbal stimuli into memory has been probed using various tasks and stimulus types. Engagement of specific subsequent memory and cortical processing regions depends on the stimulus modality of studied material; however, it remains unclear whether different encoding strategies similarly influence regional activity when stimulus type is held constant. In this study, participants encoded object pairs using a visual or verbal associative strategy during fMRI, and subsequent memory was assessed for pairs encoded under each strategy. Each strategy elicited distinct regional processing and subsequent memory effects: middle/superior frontal, lateral parietal, and lateral occipital for visually associated pairs and inferior frontal, medial frontal, and medial occipital for verbally associated pairs. This regional selectivity mimics the effects of stimulus modality, suggesting that cortical involvement in associative encoding is driven by strategy and not simply by stimulus type. The clinical relevance of these findings, probed in a patient with a recent aphasic stroke, suggest that training with strategies utilizing unaffected cortical regions might improve memory ability in patients with brain damage.     

6-Hydroxydopamine Lesions in the Rat Neostriatum Impair Sequential Learning in a Serial Reaction Time Task

Sequential behavior has been intensively investigated in humans using so-called serial reaction time tasks (SRTT), in which visual stimuli are either presented in a random or sequential order. Typically, when the stimulus presentation follows a previously learned sequential order, reaction times are decreased compared to random stimulus presentation and become partly automated. A vast amount of SRTT findings indicates that sequential learning and performance seem to be mediated amongst others by the basal ganglia—especially the striatum—and the neurotransmitter dopamine therein. In this study we used an operant rat version of the human four choice SRTT to investigate the effect of bilateral neostriatal dopamine lesions induced by 6-hydroxydopamine on sequential learning. The rats’ task was to respond rapidly to illuminated holes by nose-poking into them. During extensive training, the position of the illuminated hole followed a 12-item sequence. The outcome of this sequential training was also investigated in two tests, namely an interference test, where stimulus presentation switched between this sequential and a pseudo random order every five minutes, and a violation test, in which only one sequence item was eventually skipped. The neurotoxic lesions, which was placed before the start of training, led to the expected sub-total dopamine depletions (i.e. residual levels around 34–56% of controls), especially in the medial neostriatum. These lesions did not lead to general motor deficits in a catalepsy task, but moderate deficits in locomotion in an activity box, which largely recovered with time after lesion. In the SRTT, rats with lesions showed impaired learning, that is, less response accuracy and slower reaction times than the control group. During a subsequent test with alternating phases of sequential and random stimulus presentations, reaction times and accuracy of the control group were superior during sequential as compared to random stimulus phases. In the lesion group, only a moderate advantage in accuracy was observed. In the violation test, another outcome measure, the control group showed an expected increase in reaction times on the violated positions. By contrast, the lesion group showed no such increase, which indicates less automation of sequential behavior in these animals. For one, these findings support previous evidence in showing that neostriatal dopamine plays an important role for instrumental behavior, in general. Furthermore, and most importantly, they suggest that dopaminergic-striatal networks also play an important role in sequential behavior, especially its acquisition.     

A functional MRI protocol for localizing language comprehension in the human brain

We describe a functional magnetic resonance imaging (fMRI) protocol to separate activation of areas in the brain associated with language comprehension from sensory areas activated as a result of the presentation of the language stimulus, by comparing cortical activation patterns during the presentation of similar or the same language stimulus via two different sensory modalities (auditory and visual), and identifying the regions of activation that are common to both modalities. The protocol can be implemented on any MR scanner capable of functional imaging, and has proven valuable for the reliable identification of the lateralization and location of language centres in patients being considered for neurosurgical procedures. As well, the method has potential for the study of cortical processing of auditory speech and written language in healthy subjects and in subjects suffering from language disorders.     

Cortical control of complex sequential movement studied by functional neuroimaging techniques

Recent advances in functional neuroimaging techniques permit non-invasive visualization of the human brain functions. In the central mechanism for controlling complex sequential movement, several candidate brain regions have been suggested to participate in a different way by the previous studies. The motor executive areas including the bilateral primary sensorimotor area and supplementary motor area, appear to play an executive role in running motor sequences, regardless of their length, and increase their activity associated with implicit or procedural learning of motor sequence. In contrast, the fronto-parietal network including the bilateral premotor, prefrontal and posterior parietal cortices appears to be related to the length of sequence performed and increases its activity associated with explicit or declarative learning of motor sequence. Although these techniques provide useful information on human physiology and pathophysiology in various brain functions, in order to explore functional relevance of findings it is important to combine functional neuroimaging studies with other modalities of physiological techniques.     

A dissociation between visual and auditory hemi-inattention: Evidence from temporal order judgements

Patients with right hemisphere brain lesions often suffer from deficits in spatial attention that can be manifested in different sensory modalities. It has recently been claimed that a relationship (i.e., association) could exist between symptoms of hemi-inattention in different modalities, based on correlations between the results of visual and auditory clinical tests of neglect or extinction. However, it should be noted that the visual and auditory tasks varied greatly both in response type and level of sensitivity. Here, we have examined cross-modal associations in spatial attention deficits using a temporal order judgment task (TOJ) in which patients were required to identify which of two visual or auditory objects had appeared first. When compared to age and education matched control participants, the patients needed, on average, the contralesional stimulus to lead the ipsilesional stimulus to achieve the point of subjective simultaneity (PSS). No association between the degree of visual and auditory hemi-inattention was observed amongst the patients, suggesting that there is a certain degree of independence between the mechanisms subserving spatial attention across sensory modalities.     

Lesions of the lateral parabrachial nuclei disrupt aversion learning induced by electrical stimulation of the area postrema

The research about the neural basis of taste aversion learning (TAL) has pointed out the area postrema (AP) as a fundamental structure implied in the processing of certain toxic stimuli. Likewise, recent studies demonstrated that electric stimulation of the AP is an efficient substitute of the aversive stimulus. The lateral parabrachial nucleus (PBN1), one of the subnuclei of the parabrachial complex, is the main anatomic rostral connection of the AP. In the experiment presented here, we demonstrate that TAL induced by electric stimulation of the AP is interrupted when the PBN1 is lesioned, thus giving support to the functional role of this anatomic system (AP-PBNI) in the codification of aversive stimuli processed by the AP.     

Effects of stimulus parameters on seizure duration and ECS-induced retrograde amnesia

A selected electroconvulsive therapy stimulus dose can result from different combinations of pulse amplitude, pulse width, pulse frequency, and stimulus duration; however, the roles of these stimulus variables in the effects of the overall stimulus dose are not clearly understood. A series of studies on Wistar rats was therefore conducted to assess the effects of different stimulus compositions at constant stimulus charge. In the first two studies, two differently composed 60 mC charge unidirectional electroconvulsive shock (ECS) stimuli were administered once daily for 3 days, while in the third study three differently composed 120 mC charge unidirectional ECS stimuli were administered on a single occasion. At constant charge, a markedly longer stimulus duration was associated with ear burns and an approximately 12.5% longer seizure duration. At constant charge, however, different stimulus compositions were not associated with different degrees of impairment in two passive avoidance models of ECS-induced retrograde amnesia. These preliminary findings have implications for the choice of stimulus settings during dose titration and dose selection procedures. While the findings encourage further investigation, it appears that variations in stimulus duration are biologically significant, but minor variations in other stimulus elements may not influence the effects of electrically induced seizures very much.     

Hallmarks of a common forebrain vertebrate plan: specialized pallial areas for spatial, temporal and emotional memory in actinopterygian fish

In mammals and birds different pallial forebrain areas participate in separate memory systems. In particular, the hippocampal pallium is implicated in spatial memory and temporal attribute processing, whereas the amygdalar pallium is involved in emotional memory. Here we analyze the involvement of teleost fish lateral and medial pallia, proposed as homologous to the hippocampus and amygdala, respectively, in a variety of learning and memory tasks, such as spatial memory; reversal learning; delay or trace motor classical conditioning; heart rate, emotional classical conditioning; and two way active avoidance conditioning. Results show that the damage to the lateral pallium produces a profound deficit in spatial learning and memory in teleost fish. In addition, lateral pallium lesions produce a significant deficit in trace classical conditioning, whereas they have no significant effects on delay conditioning, or in heart rate conditioning. In contrast, medial pallium lesions disrupt emotional, heart rate conditioning and avoidance conditioning, but spare spatial memory and temporal stimulus processing. These data demonstrate a striking functional similarity between the medial and lateral pallia of teleost fish and the pallial amygdala and hippocampal pallium of land vertebrates, respectively. The reviewed evidence suggest that these two separate memory systems, the hippocampus-dependent spatial, relational or temporal memory system, and the amygdala based emotional memory system, could have appeared early during evolution, having conserved their functional identity through vertebrate phylogenesis.     

Noradrenaline involvement in the memory-enhancing effects of exposure to a complex rhythm stimulus following discriminated passive avoidance training in the young chick

Previous research in our laboratory has demonstrated a significant memory-enhancing effect of exposure to a complex rhythm stimulus following weakly-reinforced passive avoidance learning in chicks. The aim of this study was to explore whether noradrenaline mediates this process. Chicks were trained on a strongly-reinforced single-trial passive avoidance task involving discrimination between two coloured beads. Intracerebral administration of the protein synthesis blocker, anisomycin, revealed that a phase of memory formation sensitive to arousal levels was extended by approximately 35 min following exposure to the complex rhythm stimulus. Administration of 2,4-dinitrophenol showed that this extension occurred during phase B of intermediate-term memory. Finally, a higher dose of the beta-adrenergic receptor antagonist, propranolol, was required to inhibit long-term memory in the presence of the auditory stimulus than in its absence. These findings suggest that the memory-enhancing effects of the complex rhythm stimulus may be mediated by noradrenaline, possibly via an increase in physiological arousal.     

Action of PMA (phorbol myristate acetate), scopolamine, propranolol, and oxotremorine on memorization of an active or passive avoidance test

The role of various second messengers in the learning and retention of a passive or active avoidance has been investigated in mice. Scopolamine at 3 mg/kg i.p. inhibits muscarinic M1 and M2 receptors and thus acetylcholine activation of the phosphoinositide cycle. This results in amnesia of passive avoidance but has no effect on active avoidance learning. Oxotremorine at 0.05 mg/kg i.p., whose preferential M2 muscarinic action limits acetylcholine release and also inhibits adenylate cyclase activity, causes amnesia of the retention of a passive avoidance and antagonizes the learning of an active avoidance. DL-propranolol at 40 mg/kg i.p., which inhibits cAMP formation, does not affect retention of a passive avoidance but antagonizes that of an active avoidance. Similarly, phorbol myristate acetate a 0.1 mg/kg i.p., which activates protein kinase C, has no effect on the retention of a passive avoidance but antagonizes that of an active avoidance. The results tend to show a distinct role for cAMP-dependent protein kinase, which would participate in memorization processes of an active avoidance, and for protein kinase C, which would participate in that of a passive avoidance. The authors discuss the involvement of different neurophysiological mechanisms as a function of the type of behavior, depending on whether or not it is related to the control of environmental situations.