Role of the serotonin 5-HT(2A) receptor in learning

This study reviews the role of the serotonin 5-HT2A receptor in learning as measured by the acquisition of the rabbit's classically conditioning nictitating membrane response, a component of the eyeblink response. Agonists at the 5-HT2A receptor including LSD (d-lysergic acid diethylamide) enhanced associative learning at doses that produce cognitive effects in humans. Some antagonists such as BOL (d-bromolysergic acid diethylamide), LY53,857, and ketanserin acted as neutral antagonists in that they had no effect on learning, whereas others (MDL11,939, ritanserin, and mianserin) acted as inverse agonists in that they retarded learning through an action at the 5-HT2A receptor. These results were placed in the context of what is known concerning the anatomical distribution and electrophysiological effects of 5-HT2A receptor activation in frontal cortex and hippocampus, as well as the role of cortical 5-HT2A receptors in schizophrenia. It was concluded that the 5-HT2A receptor demonstrates constitutive activity, and that variations in this activity can produce profound alterations in cognitive states.     

Rapid visual learning in the rat: Effects at the 5-HT 1a receptor subtype

The 5-hydroxytryptamine 1a (5-HT 1a ) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; 0.15 mg/kg) impaired rats' rapid visual learning on a computerized maze. This treatment also increased decision time (DT) but the learning impairment was not necessarily a side-effect of slower responding because, in this task, responses made at long DT are more accurate than those at short DT. The selective 5-HT 1a receptor antagonist WAY-100635 (0.3 mg/kg) was itself without effect on accuracy, but was effective in reversing effects of 8-OH-DPAT (on both accuracy and DT). Within problems (i.e., over the 40-60 trials of a single discrimination), performance was reduced by treatment with 8-OH-DPAT at all stages of learning. We conclude that this effect is mediated through the 5-HT 1a receptor site (rather than through some other serotonergic receptor site or non-specific mechanism) as it was reversible by treatment with WAY-100635. Although it could still arise from behaviourally non-specific effects, the performance deficit finds its best account in terms of the psychological processes necessary to visual learning. Its reversal with WAY-100635 offers support to the hypothesis that 5-HT 1a receptor antagonists could improve cognitive function, under conditions of pre-existing impairment due to overactive serotonergic inhibition, as is thought to occur in Alzheimer's disease.     

Spatial learning in the 5-HT1B receptor knockout mouse: selective facilitation/impairment depending on the cognitive demand

Age-related memory decline is associated with a combined dysfunction of the cholinergic and serotonergic systems in the hippocampus and frontal cortex, in particular. The 5-HT1B receptor occupies strategic cellular and subcellular locations in these structures, where it plays a role in the modulation of ACh release. In an attempt to characterize the contribution of this receptor to memory functions, 5-HT1B receptor knockout (KO) mice were submitted to various behavioral paradigms carried out in the same experimental context (water maze), which were aimed at exposing mice to various levels of memory demand. 5-HT1BKO mice exhibited a facilitation in the acquisition of a hippocampal-dependent spatial reference memory task in the Morris water maze. This facilitation was selective of task difficulty, showing thus that the genetic inactivation of the 5-HT1B receptor is associated with facilitation when the complexity of the task is increased, and reveals a protective effect on age-related hippocampal-dependent memory decline. Young-adult and aged KO and wild-type (WT) mice were equally able to learn a delayed spatial matching-to-sample working memory task in a radial-arm water maze with short (0 or 5 min) delays. However, 5-HT1BKO mice, only, exhibited a selective memory impairment at intermediate and long (15, 30, and 60 min) delays. Treatment by scopolamine induced the same pattern of performance in wild type as did the mutation for short (5 min, no impairment) and long (60 min, impairment) delays. Taken together, these studies revealed a beneficial effect of the mutation on the acquisition of a spatial reference memory task, but a deleterious effect on a working memory task for long delays. This 5-HT1BKO mouse story highlights the problem of the potential existence of "global memory enhancers."     

Centre-embedded structures are a by-product of associative learning and working memory constraints: evidence from baboons (Papio Papio)

Influential theories have claimed that the ability for recursion forms the computational core of human language faculty distinguishing our communication system from that of other animals (Hauser, Chomsky, & Fitch, 2002). In the present study, we consider an alternative view on recursion by studying the contribution of associative and working memory processes. After an intensive paired-associate training with visual shapes, we observed that baboons spontaneously ordered their responses in keeping with a recursive, centre-embedded structure. This result suggests that the human ability for recursion might partly if not entirely originate from fundamental processing constraints already present in nonhuman primates and that the critical distinction between animal communication and human language should more likely be found in working memory capacities than in an ability to produce recursive structures per se.     

Enhanced retention in the passive-avoidance task by 5-HT(1A) receptor blockade is not associated with increased activity of the central nucleus of the amygdala

The effect of blockade of 5-HT1A receptors was investigated on (1). retention in a mildly aversive passive-avoidance task, and (2). spontaneous single-unit activity of central nucleus of the amygdala (CeA) neurons, a brain site implicated in modulation of retention. Systemic administration of the selective 5-HT1A antagonist NAN-190 immediately after training markedly-and dose-dependently-facilitated retention in the passive-avoidance task; enhanced retention was time-dependent and was not attributable to variations in wattages of shock received by animals. Systemic administration of NAN-190 had mixed effects on spontaneous single-unit activity of CeA neurons recorded extracellularly in vivo; microiontophoretic application of 5-HT, in contrast, consistently and potently suppressed CeA activity. The present findings-that 5-HT1A receptor blockade by NAN-190 (1). enhances retention in the passive-avoidance task, and (2). does not consistently increase spontaneous neuronal activity of the CeA-provide evidence that a serotonergic system tonically inhibits modulation of retention in the passive-avoidance task through activation of the 5-HT1A receptor subtype at brain sites located outside the CeA.     

Mitral cell beta1 and 5-HT2A receptor colocalization and cAMP coregulation: a new model of norepinephrine-induced learning in the olfactory bulb

In the present study we assess a new model for classical conditioning of odor preference learning in rat pups. In preference learning beta(1)-adrenoceptors activated by the locus coeruleus mediate the unconditioned stimulus, whereas olfactory nerve input mediates the conditioned stimulus, odor. Serotonin (5-HT) depletion prevents odor learning, with 5-HT(2A/2C) agonists correcting the deficit. Our new model proposes that the interaction of noradrenergic and serotonergic input with odor occurs in the mitral cells of the olfactory bulb through activation of cyclic adenosine monophosphate (cAMP). Here, using selective antibodies and immunofluorescence examined with confocal microscopy, we demonstrate that beta(1)-adrenoceptors and 5-HT(2A) receptors colocalize primarily on mitral cells. Using a cAMP assay and cAMP immunocytochemistry, we find that beta-adrenoceptor activation by isoproterenol, at learning-effective and higher doses, significantly increases bulbar cAMP, as does stroking. As predicted by our model, the cAMP increases are localized to mitral cells. 5-HT depletion of the olfactory bulb does not affect basal levels of cAMP but prevents isoproterenol-induced cAMP elevation. These results support the model. We suggest the mitral-cell cAMP cascade converges with a Ca(2+) pathway activated by odor to recruit CREB phosphorylation and memory-associated changes in the olfactory bulb. The dose-related increase in cAMP with isoproterenol implies a critical cAMP window because the highest dose of isoproterenol does not produce learning.     

Assessing the interplay between fear and learning in mice exposed to a live rat in a spatial memory task (MWM)

In this study we tested the hypothesis that fear might facilitate learning when experienced contextually to the task. To this purpose, learning and memory performance of CD-1 mice in a Morris Water Maze (MWM) was assessed in the presence of a live predator (rat). Results indicate that a live predator induced specific predatory-avoidance responses, such as diving behavior and thigmotaxis. The rat-exposed group showed the most adaptive strategy, balancing anti-predator behavior and escape responses, while the rat pre-exposed group showed impairment in the initial phases of the acquisition. The probe trial revealed distinct swimming patterns but equal memory abilities in the different groups. Overall, this procedure represents a novel and easy test to assess the effects of stressful stimuli, contextually to spatial learning and memory performance, in mice.     

AMPA/kainate, NMDA, and dopamine D1 receptor function in the nucleus accumbens core: a context-limited role in the encoding and consolidation of instrumental memory

Neural integration of glutamate- and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of learning (acquisition or consolidation) these receptors are recruited, nor is it known what role AMPA/kainate receptors have in these processes. Here we show that pre-trial intra-NAc core administration of the NMDA, AMPA/KA, and D1 receptor antagonists AP-5 (1 microg/0.5 microL), LY293558 (0.01 or 0.1 microg/0.5 microL), and SCH23390 (1 microg/0.5 microL), respectively, impaired acquisition of a lever-pressing response, whereas post-trial administration left memory consolidation unaffected. An analysis of the microstructure of behavior while rats were under the influence of these drugs revealed that glutamatergic and dopaminergic signals contribute differentially to critical aspects of the initial, randomly emitted behaviors that enable reinforcement learning. Thus, glutamate and dopamine receptors are activated in a time-limited fashion-only being required while the animals are actively engaged in the learning context.     

Dissociable learning processes,associative theory,and testimonial reviews: A comment on Smith and Church (2018)

Psychonomic Bulletin & Review - Smith and Church (Psychonomic Bulletin & Review, 25, 1565–1584 2018) present a “testimonial” review of dissociable learning processes...     

Constant capacity in an immediate serial-recall task: a logical sequel to Miller (1956)

We assessed a hypothesis that working memory capacity should include a constant number of separate mental units, or chunks (cf. Miller, 1956). Because of the practical difficulty of measuring chunks, this hypothesis has not been tested previously, despite wide attention to Miller's article. We used a training procedure to manipulate the strength of associations between pairs of words to be included in an immediate serial-recall task. Although the amount of training on associations clearly increased the availability of two-item chunks and therefore the number of items correct in list recall, the number of total chunks recalled (singletons plus two-word chunks) appeared to remain approximately constant across association strengths, supporting a hypothesis of constant capacity.     

A variant on promoter of the cannabinoid receptor 1 gene (CNR1) moderates the effect of valence on working memory

Cannabinoid receptor 1 gene (CNR1) variants have been related to affective information processing and, in particular, to stress release. Here, we aimed to examine whether the endocannabinoid system via CNR1 signaling modulates affective working memory, the memory system that transiently maintains and manipulates emotionally charged material. We focused on rs2180619 (A?>?G) polymorphism and examined genotype data collected from 231 healthy females. Analyses showed how a general positivity bias in working memory (i.e., better memory for positive words) emerged as task strings lengthened only in carriers of the major allele (AA/AG). Differently, GG carriers showed better memory for affective items in general (i.e., positive and negative words). These findings are some of the first to directly highlight the role of variant on promoter of the CNR1 gene in affective working memory and to evidence a differentiation among CNR1 genotypes in terms of larger difficulties in disengaging from negative stimuli in GG carriers.     

The genetic versus pharmacological invalidation of the cannabinoid CB(1) receptor results in differential effects on 'non-associative' memory and forebrain monoamine concentrations in mice

The endocannabinoid CB(1) receptor has been implicated in the inhibitory control of learning and memory. In the present experiment, we compared the behavioral response of CB(1) receptor knockout mice (CB(1)R(-/-)) with animals administered CB(1) receptor antagonist/inverse agonist SR141716A (rimonabant; 3 mg/kg IP, 30 min pre-trial) in terms of acquisition and retention of a habituation task and changes in cerebral monoamines. The results can be summarized as follows: (i) the acute and chronic invalidation of the CB(1) receptor resulted in an increase of behavioral habituation during the first exposure to an open field, indicative of enhanced acquisition of the task; (ii) CB(1)R(-/-) mice, but not rimonabant-treated animals, showed enhanced retention of the habituation task when re-tested 48 h and 1 week subsequent to the first exposure to the open field, respectively; (iii) the facilitation of retention of the habituation task in CB(1)R(-/-) mice was accompanied by a selective and site-specific increase in serotonin activity in hippocampus; and (iv) rimonabant-treated animals displayed 'antidepressant-like' neurochemical alterations of cerebral monoamines, that is, most parameters of monoaminergic activity were increased especially in dorsal striatum and hippocampus. Taken together, the present findings demonstrate that the genetic disruption of the CB(1) receptor gene can cause an improvement of behavioral habituation, which is considered to represent a form of 'non-associative' learning. Furthermore, our data support the assumption of a rimonabant-sensitive cannabinoid receptive site that is different from the 'classical' CB(1) receptor and which, under physiological conditions, might be involved in the inhibitory control of the acquisition but not retention of non-associative learning tasks.     

Acquisition, retention, and recall of memory after injection of RS67333, a 5-HT(4) receptor agonist, into the nucleus basalis magnocellularis of the rat

The serotonin 5-HT4 subtype receptor is predominantly localized into anatomical structures linked to memory and cognition. A few experimental studies report that the acute systemic administration of selective 5-HT4 agonists has ameliorative effects on memory performance, and that these effects are reversed by contemporary administration of 5-HT4 receptor antagonists. To verify whether this procognitive action occurs via the activation of the cholinergic nucleus basalis magnocellularis (NBM)-cortical pathways, we examined the effects of RS67333, a selective partial agonist of the 5-HT4 receptor, on rat performance in a place recognition task upon local administration of the drug into the NBM area. The intra-NBM administration of RS67333 enhances the acquisition (200-500 ng/0.5 microL) and the consolidation (40-200 ng/0.5 microL) of the place recognition memory. These effects are reversed by pretreatment with the selective 5-HT4 receptor antagonist RS39604 (300 ng/0.5 microL). Conversely, the recall of memory is not affected by the 5-HT4 agonist. Our results indicate that 5-HT4 receptors located within the NBM may play a role in spatial memory and that the procognitive effect of RS67333 is due, at least in part, to the potentiation of the activity of cholinergic NBM-cortical pathways.     

How experts' adaptations to representative task demands account for the expertise effect in memory recall: comment on Vicente and Wang (1998)

K. A. Ericsson and W. Kintsch's (1995) theoretical framework of long-term working memory (LTWM) accounts for how experts acquire encoding and retrieval mechanisms to adapt to real-time demands of working memory during representative interactions with their natural environments. The transfer of the same LTWM mechanisms is shown to account for the expertise effect in unrepresentative "contrived" memory tests. Therefore, K. J. Vicente and J. H. Wang's (1998) critique of the generalizability of the LTWM framework is rejected. Their proposed refutation of LTWM accounts is found to be based on misrepresented facts. The process-based framework of LTWM is shown to be superior to their product theory because it can explain interactions of the expertise effect in "contrived" recall under several testing conditions differing in presentation rate, instructions, and memory procedures.     

Working memory and behavioral inhibition in children with attention-deficit/hyperactivity disorder (ADHD): an examination of varied central executive demands,construct overlap,and task impurity

The stop-signal paradigm is the premier metric of behavioral inhibition in contemporary attention-deficit/hyperactivity disorder (ADHD) research. The stop-signal paradigm’s choice-reaction time component, however, arguably places greater demands on working memory processes (e.g., controlled-focused attention) relative to alternative inhibition metrics (i.e., go/no-go (GNG) tasks), and consequently obscures conclusions about inhibition and working memory deficits in affected children. The current study, therefore, aimed to determine whether shared variance between stop-signal behavioral inhibition and working memory performance in children with ADHD reflects overlap between the working memory and inhibition constructs or insufficient specificity of the stop-signal paradigm. Fifty-five children (8–12 years) with and without ADHD were administered established phonological (PH) and visuospatial (VS) working memory measures, as well as stop-signal and GNG tasks that vary with respect to demands on controlled-focused attention. Although working memory and GNG performance each uniquely predicted children’s inattention, stop-signal task performance was not a significant predictor of unique variance in inattention, above and beyond variance associated with working memory. Collectively, these findings suggest that performance on the stop-signal task, compared to the GNG task, is confounded by greater demands associated with working memory and consequently reflects an impure estimate of the inhibition construct.     

Hand preference and its flexibility according to the position of the object: a study in cercopithecines examining spontaneous behaviour and an experimental task (the Bishop QHP task)

The extant literature on manual laterality in non-human primates is inconclusive, plagued by inconsistent or contradictory findings and by disturbing methodological issues (e.g. uncontrolled influential factors, comparability issues). The present study examined hand preference and its flexibility in 15 red-capped mangabeys (C. t. torquatus) and 13 Campbell's monkeys (C. c. campbelli), two species that differ in their degree of arboreality. We investigated the influence of the spatial position of the object on hand preference for reaching. We considered spontaneous behaviour (reaching for food during daily feeding) and an experimental task: the QHP task. The QHP is a task that is used in humans. This is a simple reaching task that involves high spatial constraints on hand use. In our study, the subject had to reach for items that were placed on a semi-circle in front of it on five positions, including in the centre position, in the ipsilateral space and in the contralateral space. We assessed hand preference for reaching in front (baseline condition), and we examined how this preference changed when reaching in lateral positions. For reaching in front, about half of the subjects were lateralized and no group-level bias occurred, for both spontaneous and experimental conditions. When considering reaching in the lateral positions, we observed that the position of the object influenced hand use: individuals used the hand that was closest to the object. The results are discussed in relation to previous findings in humans and in non-human primates and regarding theories on handedness and flexibility of hand preference.     

Aggression is suppressed by acute stress but induced by chronic stress: Immobilization effects on aggression, hormones, and cortical 5-HT1B/ striatal dopamine D2 receptor density

Although it has been established by a number of investigators that a variety of stressors are associated with the induction of aggressive behavior, two specific issues remain unanswered. First, it is unclear whether the contexts surrounding stressors (e.g., stressor length and chance of winning over opponents) change outcomes regarding aggressive behavior. Second, if a relationship exists between stress and aggressive behavior, altered levels of stress-related hormone (e.g., corticosterone [CORT]), as well as aggression-related biomarkers (e.g., testosterone [T], density of prefronto-cortical 5-HT(1B) receptor and striatal dopamine D(2) receptor [D2r]) may contribute to changes in aggressive behavior. Thus, we examined how immobilization (with a 1-, 5-, or 10-day exposure) would impact (1) a longitudinal course of aggression toward different-sized opponents, (2) levels of CORT and T, and (3) densities of 5-HT(1B) receptor (5-HT1Br) in the prefrontal cortex (PFC) and D2r in the striatum. It was found that, regardless of small or large opponents, a single 2-h exposure to immobilization reduced aggressive behavior (stress-suppressed aggression) over time, whereas repeated (10-day) exposure to immobilization escalated aggressive behavior (stress-induced aggression). These stress effects persisted up to 1 week of recovery from immobilization stress. Moreover, immobilized rats demonstrated elevated levels of T, but not CORT, as compared with controls. Finally, acute immobilization altered D2r densities in the shell of the nucleus accumbens, and chronic immobilization changed 5-HT1Br in the PFC, including the downregulation of 5-HT1Br densities in the right prelimbic and orbitolateral cortices. The potential relationships among stress, aggression, and 5-HT1Br/D2r roles are discussed.     

Separate Digits tests: A brief history,a literature review,and a reexamination of the factor structure of the test of memory and learning (TOMAL)

Following a brief history of Digit Span, a review of 27 articles, selected from 76, addresses the question of whether to scale Digits Forward and Backward separately. The review begins with studies involving Digits Forward, followed in turn by studies of Digits Backward and of both subtests. Finally, the loadings of four TOMAL subtests, Digits Forward and Backward and Letters Forward and Backward, undergo examination in the context of two, three, and four factor promax solutions, with corresponding varimax solutions provided for comparison. The analysis leads to several conclusions. Though Digits Forward and Backward show similarities, they load differently in the three and four factor solutions; Digits Backward also displays a spatial element, and perhaps a transformative element, not apparent in Digits Forward. Moreover, the differences between the two measures have important neurologic and diagnostic implications.