Hippocampal synaptic plasticity during instrumental learning

present research examined the role of hippocampal NMDA-dependent synaptic potentiation on appetitive instrumental conditioning under a continuous reinforcement schedule. In the first experiment, low (.025 mg.kg) or moderate (.05 mg/kg) dosages of the NMDA receptor antagonist, MK801, failed to increase the number of training days required to reach acquisition criterion; number of training days required to reach criterion for extinction were also unaffected. In the second experiment, a higher dosage (.10 mg/kg) of MK801 or induction of long-term potentiation failed to alter the number of responses occurring during acquisition. These data suggest that hippocampal synaptic potentiation does not play a prominent role in instrumental learning with simple contingency conditions. It is suggested that hippocampal LTP reflects a perceptual process that contributes differentially to spatial cognition, classical and instrumental conditioning.     

Imaging brain plasticity during motor skill learning

The search for the neural substrates mediating the incremental acquisition of skilled motor behaviors has been the focus of a large body of animal and human studies in the past decade. Much less is known, however, with regard to the dynamic neural changes that occur in the motor system during the different phases of learning. In this paper, we review recent findings, mainly from our own work using fMRI, which suggest that: (i) the learning of sequential finger movements produces a slowly evolving reorganization within primary motor cortex (M1) over the course of weeks and (ii) this change in M1 follows more dynamic, rapid changes in the cerebellum, striatum, and other motor-related cortical areas over the course of days. We also briefly review neurophysiological and psychophysical evidence for the consolidation of motor skills, and we propose a working hypothesis of its underlying neural substrate in motor sequence learning.     

Hippocampal train stimulation modulates recall of fear extinction independently of prefrontal cortex synaptic plasticity and lesions

It has been shown that long-term potentiation (LTP) develops in the connection between the mediodorsal thalamus (MD) and the medial prefrontal cortex (mPFC) and between the hippocampus (HPC) and the mPFC following fear extinction, and correlates with extinction retention. However, recent lesion studies have shown that combined lesions of the MD and mPFC do not interfere with extinction learning and retention, while inactivation of the dorsal HPC disrupts fear extinction memory. Here we found in rats that immediate post-training HPC low-frequency stimulation (LFS) suppressed extinction-related LTP in the HPC-mPFC pathway and induced difficulties in extinction recall. HPC tetanus, applied several hours later, failed to re-establish mPFC LTP but facilitated recall of extinction. Delayed post-training HPC LFS also provoked mPFC depotentiation and difficulties with extinction recall. HPC tetanus abolished these two effects. We also found that damage to the mPFC induced fear return only in rats that received HPC LFS following extinction training. HPC tetanus also reversed this behavioral effect of HPC LFS in lesioned rats. These data suggest that the HPC interacts with the mPFC during fear extinction, but can modulate fear extinction independently of this interaction.     

The effect of deprivation level during noncontingent pairings and instrumental learning on subsequent instrumental performance

In Experiment 1, rats received either response-noncontingent pairings of a tone stimulus with food or response-contingent instrumental training during which only responses in the presence of the tone were reinforced. During this training rats were maintained at either 70 or 90% of their growth-adjusted predeprivation body weights. In a subsequent test phase, one-half of the subjects in each training condition were tested under either 70 or 90% body weight. Subjects which had received response-contingent instrumental training under 70% body weight responded significantly faster to presentations of the tone than did 90% body weight-trained subjects, regardless of test deprivation condition. There was no effect of the deprivation level in effect during response-noncontingent pairings. In Experiment 2, rats received noncontingent tone-reward pairings or nonpairings under either 70 or 90% body weight. In a later test phase under 90% body weight, instrumental responding to the tone was significantly faster for subjects which had received the tone-reward pairings. Deprivation level during the pairings again produced no effect. These results support two conclusions. First, the expectancy learning process appears to be relatively independent of deprivation conditions in effect when such learning takes place; and secondly, deprivation conditions in effect during instrumental learning affect the strength of S-R associative bonds formed.     

New insights into the regulation of synaptic plasticity from an unexpected place: Hippocampal area CA2

The search for molecules that restrict synaptic plasticity in the brain has focused primarily on sensory systems during early postnatal development, as critical periods for inducing plasticity in sensory regions are easily defined. The recent discovery that Schaffer collateral inputs to hippocampal area CA2 do not readily support canonical activity-dependent long-term potentiation (LTP) serves as a reminder that the capacity for synaptic modification is also regulated anatomically across different brain regions. Hippocampal CA2 shares features with other similarly "LTP-resistant" brain areas in that many of the genes linked to synaptic function and the associated proteins known to restrict synaptic plasticity are expressed there. Add to this a rich complement of receptors and signaling molecules permissive for induction of atypical forms of synaptic potentiation, and area CA2 becomes an ideal model system for studying specific modulators of brain plasticity. Additionally, recent evidence suggests that hippocampal CA2 is instrumental for certain forms of learning, memory, and social behavior, but the links between CA2-enriched molecules and putative CA2-dependent behaviors are only just beginning to be made. In this review, we offer a detailed look at what is currently known about the synaptic plasticity in this important, yet largely overlooked component of the hippocampus and consider how the study of CA2 may provide clues to understanding the molecular signals critical to the modulation of synaptic function in different brain regions and across different stages of development.     

The interaction between discriminative stimuli and outcomes during instrumental learning

Rats were trained on a biconditional discrimination in which the delivery of a food pellet stimulus signalled that pressing on one of two levers would be reinforced, whereas the delivery of a sucrose solution stimulus signalled that the reward was contingent on pressing the other lever. The outcome was the same food type as the discriminative stimulus in the congruent group but the other food type in the incongruent group. Both responses were rewarded with the same outcome in the same group. All the three groups learned the discrimination at statistically indistinguishable rates. Prefeeding one of the outcomes selectively reduced the associated response thereby demonstrating that responding was mediated by a representation of the outcome. Moreover, the outcome of one trial controlled responding on the next trial in accord with the stimulus function of the food type. These results are discussed in relation to the associative structures mediating the discriminative control of instrumental performance.     

Stimulus-outcome interactions during instrumental discrimination learning by rats and humans

The associative structure mediating goal-directed action was investigated using congruent and incongruent conditional discriminations. The stimulus was the same as the outcome in each component of the congruent discriminations, whereas the stimulus of one component of the incongruent discriminations was the same as the outcome of the other component. Humans, but not rats, learned the congruent discrimination more rapidly than the incongruent discrimination, a difference that the authors attribute to the fact that outcome-response associations caused response conflict in the incongruent discrimination. Moreover, responding was resistant to outcome devaluation following incongruent, but not congruent, training, suggesting that both humans and rats adopted a stimulus-response strategy to resolve the incongruent discrimination.     

Hippocampal inactivation enhances taste learning

Learning tasks are typically thought to be either hippocampal-dependent (impaired by hippocampal lesions) or hippocampal-independent (indifferent to hippocampal lesions). Here, we show that conditioned taste aversion (CTA) learning fits into neither of these categories. Rats were trained to avoid two taste stimuli, one novel and one familiar. Muscimol infused through surgically implanted intracranial cannulae temporarily inactivated the dorsal hippocampus during familiarization, subsequent CTA training, or both. As shown previously, hippocampal inactivation during familiarization enhanced the effect of that familiarization on learning (i.e., hippocampal inactivation enhanced latent inhibition of CTA); more novel and surprising, however, was the finding that hippocampal inactivation during training sessions strongly enhanced CTA learning itself. These phenomena were not caused by specific aspects of our infusion technique--muscimol infusions into the hippocampus during familiarization sessions did not cause CTAs, muscimol infusions into gustatory cortex caused the expected attenuation of CTA, and hippocampal inactivation caused the expected attenuation of spatial learning. Thus, we suggest that hippocampal memory processes interfere with the specific learning mechanisms underlying CTA, and more generally that multiple memory systems do not operate independently.     

Neuromodulation, development and synaptic plasticity.

We discuss parallels in the mechanisms underlying use-dependent synaptic plasticity during development and long-term potentiation (LTP) and long-term depression (LTD) in neocortical synapses. Neuromodulators, such as norepinephrine, serotonin, and acetylcholine have also been implicated in regulating both developmental plasticity and LTP/LTD. There are many potential levels of interaction between neuromodulators and plasticity. Ion channels are substrates for modulation in many cell types. We discuss examples of modulation of voltage-gated Ca2+ channels and Ca(2+)-dependent K+ channels and the consequences for neocortical pyramidal cell firing behaviour. At the time when developmental plasticity is most evident in rat cortex, the substrate for modulation is changing as the densities and relative proportions of various ion channels types are altered during ontogeny. We discuss examples of changes in K+ and Ca2+ channels and the consequence for modulation of neuronal activity.     

Individual differences in dopamine efflux in nucleus accumbens shell and core during instrumental learning

Combined activation of dopamine D1- and NMDA-glutamate receptors in the nucleus accumbens has been strongly implicated in instrumental learning, the process in which an individual learns that a specific action has a wanted outcome. To assess dopaminergic activity, we presented rats with two sessions (30 trials each) of a one-lever appetitive instrumental task and simultaneously measured dopamine efflux in the shell and core accumbens subareas using in vivo microdialysis. Dopamine efflux was increased during each session in all areas. The behavioral performance of the rats in the second session led us to divide them into a learning group (>90% correct trials) and a non-learning group. In the first session, the rats of the learning group showed significantly higher increases. The difference was most pronounced in the shell. In the second session, the dopamine increase was similar in both groups, although the learning groups now pressed the lever about three times more often and consequently obtained more rewards. We conclude that task-related activation of dopamine efflux is different between learning and non-learning rats only during the learning phase. These results support the pharmacological evidence that dopamine is of particular importance during the instrumental learning process.     

Irrelevant incentive learning during instrumental conditioning: The role of the drive-reinforcer and response-reinforcer relationships

Four experiments investigated the processes by which a motivationally-induced change in the value of the training reinforcer affects instrumental performance. Initially, thirsty rats were trained to lever press for either a sodium or non-sodium solution. In Experiment I sodium-trained rats responded faster in extinction following the induction of a sodium appetite, but not following either food or water deprivation. Thus, enhanced extinction performance depends upon the relevance of the training reinforcer to the test drive state. The remaining experiments examined the role of the instrumental contingency. Animals received response-contingent presentations of one solution alternated either within (Experiments II and III) or between sessions (Experiment IV) with non-contingent presentations of another solution. Neither procedure yielded convincing evidence that contingent sodium presentations generated more responding in extinction under a sodium appetite than did non-contingent sodium presentations. On the basis of these results, we argue that the instrumental contingency itself does not play a major role in this irrelevant incentive effect.     

Paleostriatal lesions and instrumental learning in the pigeon

In three experiments, pigeons with lesions of the paleostriatum (experimental subjects) and unoperated control birds were trained on tasks designed to assess their instrumental learning abilities. In Experiment 1, using an orthodox Skinner box, training was given on a variable interval (VI) followed by a fixed interval (FI) schedule of reinforcement and only non-significant differences between the groups emerged. Experiment 2 examined the performance of the same subjects on a VI schedule in which a response-contingent signal accompanied reinforcement. For control subjects the presence of the signal resulted in a low rate of response compared with that found in equivalent conditions with the signal omitted. Experimental subjects showed the same response rate when the signal was present as when it was absent. Experiment 3 employed naive subjects, and a Skinner box modified to facilitate key-pecking in total darkness. In this apparatus, experimental subjects showed a lowered response rate on a VI schedule. These tasks were analyzed in terms of the classical (stimulus-reinforcer) and instrumental (response-reinforcer) learning they involve. The results suggest that pigeons with paleostriatal lesions show a deficit in forming response-reinforcer associations, perhaps because the lesions reduce the salience of response-produced cues.     

Isoform specificity of protein kinase Cs in synaptic plasticity

Protein kinase Cs (PKCs) are implicated in many forms of synaptic plasticity. However, the specific isoform(s) of PKC that underlie(s) these events are often not known. We have used Aplysia as a model system in order to investigate the isoform specificity of PKC actions due to the presence of fewer isoforms and a large number of documented physiological roles for PKC in synaptic plasticity in this system. In particular, we have shown that distinct isoforms mediate distinct types of synaptic plasticity induced by the same neurotransmitter: The novel calcium-independent PKC Apl II is required for actions mediated by serotonin (5-HT) alone, while the classical calcium-dependent PKC Apl I is required for actions mediated when 5-HT is coupled to activity. We will discuss the reasons for PKC isoform specificity, assess the tools used to uncover isoform specificity, and discuss the implications of isoform specificity for understanding the roles of PKC in regulating synaptic plasticity.     

Neural functions of calcineurin in synaptic plasticity and memory

Major brain functions depend on neuronal processes that favor the plasticity of neuronal circuits while at the same time maintaining their stability. The mechanisms that regulate brain plasticity are complex and engage multiple cascades of molecular components that modulate synaptic efficacy. Protein kinases (PKs) and phosphatases (PPs) are among the most important of these components that act as positive and negative regulators of neuronal signaling and plasticity, respectively. In these cascades, the PP protein phosphatase 2B or calcineurin (CaN) is of particular interest because it is the only Ca(2+)-activated PP in the brain and a major regulator of key proteins essential for synaptic transmission and neuronal excitability. This review describes the primary properties of CaN and illustrates its functions and modes of action by focusing on several representative targets, in particular glutamate receptors, striatal enriched protein phosphatase (STEP), and neuromodulin (GAP43), and their functional significance for synaptic plasticity and memory.     

第二语言学习与脑可塑性

脑可塑性指人脑会因为环境刺激、认知需求和行为经验而产生功能或结构改变。近10年来的单双语者对比和语言训练研究结果表明, 不论儿童、青年或老年人, 第二语言学习和使用都能改变其脑运行模式并带来相应结构变化, 包括灰质(GM)体积和白质(WM)密度增加, 且长期持续的双语经验还能形成认知优势, 帮助抵制由老化导致的负面认知影响。基于脑可塑性概念及其研究证据, 从双语经验与语言训练两方面, 对比分析了长期和短期第二语言学习引起脑功能或结构变化及其内在机制, 并对未来相关研究进行了展望。     

Cortical plasticity associated with Braille learning

Blind subjects who learn to read Braille must acquire the ability to extract spatial information from subtle tactile stimuli. In order to accomplish this, neuroplastic changes appear to take place. During Braille learning, the sensorimotor cortical area devoted to the representation of the reading finger enlarges. This enlargement follows a two-step process that can be demonstrated with transcranial magnetic stimulation mapping and suggests initial unmasking of existing connections and eventual establishment of more stable structural changes. In addition, Braille learning appears to be associated with the recruitment of parts of the occipital, formerly `visual', cortex (V1 and V2) for tactile information processing. In blind, proficient Braille readers, the occipital cortex can be shown not only to be associated with tactile Braille reading but also to be critical for reading accuracy. Recent studies suggest the possibility of applying non-invasive neurophysiological techniques to guide and improve functional outcomes of these plastic changes. Such interventions might provide a means of accelerating functional adjustment to blindness.