Learning-induced Changes Research Articles

Perceptual Learning Improves Contrast Sensitivity of V1 Neurons in Cats

Perceptual learning has been documented in adult humans over a wide range of tasks. Although the often-observed specificity of learning is generally interpreted as evidence for training-induced plasticity in early cortical areas, physiological evidence for training-induced changes in early visual cortical areas is modest, despite reports of learning-induced changes of cortical activities in fMRI studies. To reveal the physiological bases of perceptual learning, we combined psychophysical measurements with extracellular single-unit recording under anesthetized preparations and examined the effects of training in grating orientation identification on both perceptual and neuronal contrast sensitivity functions of cats. We have found that training significantly improved perceptual contrast sensitivity of the cats to gratings with spatial frequencies near the "trained" spatial frequency, with stronger effects in the trained eye. Consistent with behavioral assessments, the mean contrast sensitivity of neurons recorded from V1 of the trained cats was significantly higher than that of neurons recorded from the untrained cats. Furthermore, in the trained cats, the contrast sensitivity of V1 neurons responding preferentially to stimuli presented via the trained eyes was significantly greater than that of neurons responding preferentially to stimuli presented via the "untrained" eyes. The effect was confined to the trained spatial frequencies. In both trained and untrained cats, the neuronal contrast sensitivity functions derived from the contrast sensitivity of the individual neurons were highly correlated with behaviorally determined perceptual contrast sensitivity functions. We suggest that training-induced neuronal contrast gain in area V1 underlies behaviorally determined perceptual contrast sensitivity improvements.

Persistence of Long-Term Memory Storage: New Insights into its Molecular Signatures in the Hippocampus and Related Structures

Although much is known about long-term memory (LTM) consolidation, what puts the "long" in LTM is the exclusive feature of persisting over time. However, until recently the molecular mechanisms underneath memory persistence had never been properly studied. In rats, the protein translation inhibitor anisomycin impaired memory persistence when injected into the dorsal hippocampus 12h after inhibitory avoidance (IA) training without affecting memory formation. Here, we also show learning-induced changes in hippocampal c-Fos, Homer 1a, Akt, CamKIIα, and ERK2 levels around 18-24h after IA training. Thus, memory persistence is associated with a late phase of plasticity-related protein synthesis in the hippocampus.

Balanced plasticity and stability of the electrical properties of a molluscan modulatory interneuron after classical conditioning: a computational study

The Cerebral Giant Cells (CGCs) are a pair of identified modulatory interneurons in the Central Nervous System of the pond snail Lymnaea stagnalis with an important role in the expression of both unconditioned and conditioned feeding behavior. Following single-trial food-reward classical conditioning, the membrane potential of the CGCs becomes persistently depolarized. This depolarization contributes to the conditioned response by facilitating sensory cell to command neuron synapses, which results in the activation of the feeding network by the conditioned stimulus. Despite the depolarization of the membrane potential, which enables the CGGs to play a key role in learning-induced network plasticity, there is no persistent change in the tonic firing rate or shape of the action potentials, allowing these neurons to retain their normal network function in feeding. In order to understand the ionic mechanisms of this novel combination of plasticity and stability of intrinsic electrical properties, we first constructed and validated a Hodgkin-Huxley-type model of the CGCs. We then used this model to elucidate how learning-induced changes in a somal persistent sodium and a delayed rectifier potassium current lead to a persistent depolarization of the CGCs whilst maintaining their firing rate. Including in the model an additional increase in the conductance of a high-voltage-activated calcium current allowed the spike amplitude and spike duration also to be maintained after conditioning. We conclude therefore that a balanced increase in three identified conductances is sufficient to explain the electrophysiological changes found in the CGCs after classical conditioning.

Searching for learning-dependent changes in the antennal lobe: simultaneous recording of neural activity and aversive olfactory learning in honeybees

Plasticity in the honeybee brain has been studied using the appetitive olfactory conditioning of the proboscis extension reflex, in which a bee learns the association between an odor and a sucrose reward. In this framework, coupling behavioral measurements of proboscis extension and invasive recordings of neural activity has been difficult because proboscis movements usually introduce brain movements that affect physiological preparations. Here we took advantage of a new conditioning protocol, the aversive olfactory conditioning of the sting extension reflex, which does not generate this problem. We achieved the first simultaneous recordings of conditioned sting extension responses and calcium imaging of antennal lobe activity, thus revealing on-line processing of olfactory information during conditioning trials. Based on behavioral output we distinguished learners and non-learners and analyzed possible learning-dependent changes in antennal lobe activity. We did not find differences between glomerular responses to the CS+ and the CS− in learners. Unexpectedly, we found that during conditioning trials non-learners exhibited a progressive decrease in physiological responses to odors, irrespective of their valence. This effect could neither be attributed to a fitness problem nor to abnormal dye bleaching. We discuss the absence of learning-induced changes in the antennal lobe of learners and the decrease in calcium responses found in non-learners. Further studies will have to extend the search for functional plasticity related to aversive learning to other brain areas and to look on a broader range of temporal scales.

A complementary systems account of word learning: neural and behavioural evidence.

In this paper we present a novel theory of the cognitive and neural processes by which adults learn new spoken words. This proposal builds on neurocomputational accounts of lexical processing and spoken word recognition and complementary learning systems (CLS) models of memory. We review evidence from behavioural studies of word learning that, consistent with the CLS account, show two stages of lexical acquisition: rapid initial familiarization followed by slow lexical consolidation. These stages map broadly onto two systems involved in different aspects of word learning: (i) rapid, initial acquisition supported by medial temporal and hippocampal learning, (ii) slower neocortical learning achieved by offline consolidation of previously acquired information. We review behavioural and neuroscientific evidence consistent with this account, including a meta-analysis of PET and functional Magnetic Resonance Imaging (fMRI) studies that contrast responses to spoken words and pseudowords. From this meta-analysis we derive predictions for the location and direction of cortical response changes following familiarization with pseudowords. This allows us to assess evidence for learning-induced changes that convert pseudoword responses into real word responses. Results provide unique support for the CLS account since hippocampal responses change during initial learning, whereas cortical responses to pseudowords only become word-like if overnight consolidation follows initial learning.

Short-term language experience shapes the plasticity of the visual word form area

Previous studies have identified a region in the left fusiform gyrus that responds selectively to visual words, termed the visual word form area (VWFA). Converging evidence from neuropsychological, electrophysiological, and functional neuroimaging studies suggests that the VWFA is wired up largely by long-term experience because it responds specifically to words and letter strings only in an orthography a subject knows. However, it is less clear whether the plasticity of the VWFA can be modulated by short-term language experience. Here, we used functional magnetic resonance imaging (fMRI) to address this question by examining whether the representation for novel stimuli could be constructed in the VWFA after a short-term language experience. In particular, we trained subjects to associate a set of novel stimuli with English letters. We found that VWFA response to the trained stimuli was significantly higher than that of untrained stimuli after 3 days of association training. This learning-induced change in neural activities was absent in other specialized cortical areas involved in face perception or in processing object shapes. Multivariate pattern analysis further revealed that the learning-induced representation engaged the same neural population underlying the representation for language forms constructed through long-term experience. Our study clearly illuminates that the plasticity of the VWFA can be shaped by short-term language experience, bridging the gap between short-term and long-term experiences in language learning.

Extinction of cued fear memory involves a distinct form of depotentiation at cortical input synapses onto the lateral amygdala

The amygdala is known to be a critical storage site of conditioned fear memory. Among the two major pathways to the lateral amygdala (LA), the cortical pathway is known to display a presynaptic long-term potentiation which is occluded with fear conditioning. Here we show that fear extinction results in a net depression of conditioning-induced potentiation at cortical input synapses onto the LA (C-LA synapses). Fear conditioning induced a significant potentiation of excitatory postsynaptic currents at C-LA synapses compared with naïve and unpaired controls, whereas extinction apparently reversed this potentiation. Paired-pulse low-frequency stimulation (pp-LFS) induced synaptic depression in the C-LA pathway of fear-conditioned rats, but not in naïve or unpaired controls, indicating that the pp-LFS-induced depression is specific to associative learning-induced changes (pp-LFS-induced depotentiation(ex vivo)). Importantly, extinction occluded pp-LFS-induced depotentiation(ex vivo), suggesting that extinction shares some mechanisms with the depotentiation. pp-LFS-induced depotentiation(ex vivo) required NMDA receptor (NMDAR) activity, consistent with a previous finding that blockade of amygdala NMDARs impaired fear extinction. In addition, pp-LFS-induced depotentiation(ex vivo) required activity of group II metabotropic glutamate receptors (mGluRs), known to be present at presynaptic terminals, but not AMPAR internalization, consistent with a presynaptic mechanism for pp-LFS-induced depotentiation(ex vivo). This result is in contrast with another form of ex vivo depotentiation in the thalamic pathway that requires both group I mGluR activity and AMPAR internalization. We thus suggest that extinction of conditioned fear involves a distinct form of depotentiation at C-LA synapses, which depends upon both NMDARs and group II mGluRs.

A novel extended Granger Causal Model approach demonstrates brain hemispheric differences during face recognition learning.

Two main approaches in exploring causal relationships in biological systems using time-series data are the application of Dynamic Causal model (DCM) and Granger Causal model (GCM). These have been extensively applied to brain imaging data and are also readily applicable to a wide range of temporal changes involving genes, proteins or metabolic pathways. However, these two approaches have always been considered to be radically different from each other and therefore used independently. Here we present a novel approach which is an extension of Granger Causal model and also shares the features of the bilinear approximation of Dynamic Causal model. We have first tested the efficacy of the extended GCM by applying it extensively in toy models in both time and frequency domains and then applied it to local field potential recording data collected from in vivo multi-electrode array experiments. We demonstrate face discrimination learning-induced changes in inter- and intra-hemispheric connectivity and in the hemispheric predominance of theta and gamma frequency oscillations in sheep inferotemporal cortex. The results provide the first evidence for connectivity changes between and within left and right inferotemporal cortexes as a result of face recognition learning.

The levo enantiomer of amphetamine increases memory consolidation and gene expression in the hippocampus without producing locomotor stimulation

Dextro-amphetamine enhances memory and other cognitive functions in animals and humans. The use of d-amphetamine as a memory enhancer, however, is limited by a robust stimulatory side-effect profile caused by release of dopamine. The levo enantiomer of amphetamine has been shown to be considerably less effective as a dopamine releaser and less potent in producing the stimulatory effects characteristic of d-amphetamine. In order to determine whether l-amphetamine and the structurally related compound, l-methamphetamine, retain cognitive-enhancing effects despite their lack of stimulatory activity, we administered the compounds to rats prior to activity monitoring experiments, and in different animals, immediately after training on inhibitory avoidance and object recognition tasks. Results demonstrated that l-amphetamine and l-methamphetamine did not increase locomotion and stereotypies beyond control levels, but did produce significant memory enhancement. In addition, l-amphetamine and l-methamphetamine alleviated scopolamine-induced amnesia in the inhibitory avoidance task. In all cases, these compounds produced an effect comparable to that of d-amphetamine, but required only one quarter of the d-amphetamine dose to produce the same effect size. We also found that l-amphetamine modulates learning-induced changes in hippocampal Arc/Arg3.1 protein synthesis that correlate with memory consolidation. These results suggest that l-amphetamine and l-methamphetamine are potent memory enhancers in rats and may ultimately be useful for treating memory disorders in humans.

Cortical mechanisms of sensory learning and object recognition

Learning about the world through our senses constrains our ability to recognise our surroundings. Experience shapes perception. What is the neural basis for object recognition and how are learning-induced changes in recognition manifested in neural populations? We consider first the location of neurons that appear to be critical for object recognition, before describing what is known about their function. Two complementary processes of object recognition are considered: discrimination among diagnostic object features and generalization across non-diagnostic features. Neural plasticity appears to underlie the development of discrimination and generalization for a given set of features, though tracking these changes directly over the course of learning has remained an elusive task.

Transient Spine Expansion and Learning-Induced Plasticity in Layer 1 Primary Motor Cortex

Experience-dependent regulation of synaptic strength in the horizontal connections in layer 1 of the primary motor cortex is likely to play an important role in motor learning. Dendritic spines, the primary sites of excitatory synapses in the brain, are known to change shape in response to various experimental stimuli. We used a rat motor learning model to examine connection strength via field recordings in slices and confocal imaging of labeled spines to explore changes induced solely by learning a simple motor task. We report that motor learning increases response size, while transiently occluding long-term potentiation (LTP) and increasing spine width in layer 1. This demonstrates learning-induced changes in behavior, synaptic responses, and structure in the same animal, suggesting that an LTP-like process in the motor cortex mediates the initial learning of a skilled task.

Imaging of an Early Memory Trace in theDrosophilaMushroom Body

Extensive molecular, genetic, and anatomical analyses have suggested that olfactory memory is stored in the mushroom body (MB), a higher-order olfactory center in the insect brain. The MB comprises three subtypes of neurons with axons that extend into different lobes. A recent functional imaging study has revealed a long-term memory trace manifested as an increase in the Ca(2+) activity in an axonal branch of a subtype of MB neurons. However, early memory traces in the MB remain elusive. We report here learning-induced changes in Ca(2+) activities during early memory formation in a different subtype of MB neurons. We used three independent in vivo and in vitro preparations, and all of them showed that Ca(2+) activities in the axonal branches of alpha'/beta' neurons in response to a conditioned olfactory stimulus became larger compared with one that was not conditioned. The changes were dependent on proper G-protein signaling in the MB. The importance of these changes in the Ca(2+) activity of alpha'/beta' neurons during early memory formation was further tested behaviorally by disrupting G-protein signaling in these neurons or blocking their synaptic outputs during the learning and memory process. Our results suggest that increased Ca(2+) activity in response to a conditioned olfactory stimulus may be a neural correlate of early memory in the MB.

Behavioral andIn VitroCorrelates of Compulsive-Like Food Seeking Induced by Operant Conditioning inAplysia

Motivated behaviors comprise appetitive actions whose occurrence results partly from an internally driven incentive to act. Such impulsive behavior can also be regulated by external rewarding stimuli that, through learning processes, can lead to accelerated and seemingly automatic, compulsive-like recurrences of the rewarded act. Here, we explored such behavioral plasticity in Aplysia by analyzing how appetitive reward stimulation in a form of operant conditioning can modify a goal-directed component of the animal's food-seeking behavior. In naive animals, protraction/retraction cycles of the tongue-like radula are expressed sporadically with highly variable interbite intervals. In contrast, animals that were previously given a food-reward stimulus in association with each spontaneous radula bite now expressed movement cycles with an elevated frequency and a stereotyped rhythmic organization. This rate increase and regularization, which was retained for several hours after training, depended on both the reward quality and its contingency because accelerated, stereotyped biting was not induced in animals that had previously received a less-palatable food stimulus or had been subjected to nonassociative reward stimulation. Neuronal correlates of these learning-induced changes were also expressed in the radula motor pattern-generating circuitry of isolated buccal ganglia. In such in vitro preparations, moreover, manipulation of the burst frequency of the bilateral motor pattern-initiating B63 interneurons indicated that the regularization of radula motor pattern generation in contingently trained animals occurred separately from an increase in cycle rate, thereby suggesting independent processes of network plasticity. These data therefore suggest that operant conditioning can induce compulsive-like actions in Aplysia feeding behavior and provide a substrate for a cellular analysis of the underlying mechanisms.

Learning-Induced Enduring Changes in Functional Connectivity among Prefrontal Cortical Neurons

Current thinking about how memories are stored in the brain has been profoundly influenced by Donald O. Hebb's cell assembly hypothesis, which posits that (1) learning produces a stable alteration in patterns of connectivity among repeatedly coactivated neurons, and (2) memory retrieval involves reactivation of those altered patterns of connectivity. However, learning-induced changes in connectivity that persist over long periods of time have not been clearly demonstrated. In the present study, two spatial navigation tasks and a long-term ensemble recording technique are used to describe long-lasting modifications in functional connectivity (FC) (defined as changes in synchronous firing) of prefrontal cortical neurons in behaving rats. Animals were initially trained to alternate visiting two spatial locations on a figure-8-shaped maze to obtain a reward (alternating task 1). Afterward, while continuing on task 1, animals were additionally trained to visit only one spatial location on the same maze to obtain a reward (unilateral task 2). Multiple single units were recorded while rats were undergoing acquisition, retention, and performance of both tasks. Our data indicate that correlated firing of prefrontal cortical neurons changed significantly in early phases of training when learning rate was maximal but became progressively smaller in later phases when learning reached asymptote. After animals became proficient, FC remained constant, although neuronal activities varied across two different tasks. The present finding of negatively accelerated changes in FC confirms associative learning theories and provides crucial neurophysiological evidence for Hebb's hypothesis.

Learning in the absence of experience-dependent regulation of NMDAR composition

Olfactory discrimination (OD) learning consists of two phases: an initial N-methyl-D-aspartate (NMDA) receptor-sensitive rule-learning phase, followed by an NMDA receptor (NMDAR)-insensitive pair-learning phase. The rule-learning phase is accompanied by changes in the composition and function of NMDARs at synapses in the piriform cortex, resulting in a high level of the NR2a subunit relative to NR2b. Here we show that the learning-induced changes in NMDAR composition in the adult piriform cortex are due to a decrease in the level of the NR2b subunit protein, rather than an increase in the level of NR2a. Chronic administration of an NMDAR open channel blocker during training delays OD learning and blocks learning-induced changes in NMDAR subunit composition. However, the animals still learn the OD task. Our data demonstrate that learning can occur in the absence of activity-dependent regulation of NMDAR composition, suggesting differences in the mechanism for long-term maintenance of NMDAR-dependent and NMDAR-independent learning.

The Cellular Mechanisms of Learning inAplysia:Of Blind Men and Elephants

Until recently, investigations of the neurobiological substrates of simple forms of learning and memory in the marine snail Aplysia have focused mostly on plastic changes that occur within the presynaptic sensory neurons. Here, I summarize the results of recent studies that indicate that exclusively presynaptic processes cannot account for simple forms of learning in Aplysia. In particular, I present evidence that postsynaptic mechanisms play a far more important role in nonassociative learning in Aplysia than has been appreciated before now. Moreover, I describe recent data that suggests the intriguing hypothesis that the persistent, learning-induced changes in Aplysia sensory neurons might depend critically on postsynaptic signals for their induction. Finally, I discuss the potential applicability of this hypothesis to learning-related synaptic plasticity in the mammalian brain.

Cortical rewiring and information storage.

Current thinking about long-term memory in the cortex is focused on changes in the strengths of connections between neurons. But ongoing structural plasticity in the adult brain, including synapse formation/elimination and remodelling of axons and dendrites, suggests that memory could also depend on learning-induced changes in the cortical 'wiring diagram'. Given that the cortex is sparsely connected, wiring plasticity could provide a substantial boost in storage capacity, although at a cost of more elaborate biological machinery and slower learning.

Reduction of single-neuron firing uncertainty by cortical ensembles during motor skill learning.

Motor skill learning is usually characterized by shortening of response time and performance of faster, more stereotypical movements. However, little is known about the changes in neural activity that underlie these behavioral changes. Here we used chronically implanted electrode arrays to record neuronal activity in the rat primary motor cortex (MI) as animals learned to execute movements in two directions. Strong modulation of MI single-neuron activity was observed while movement duration of the animal decreased. Despite many learning-induced changes, the precision with which single neurons fire did not improve with learning. Hence, prediction of movement direction from single neurons was bounded. In contrast, prediction of movement direction using neuronal ensembles improved significantly with learning, suggesting that, with practice, neuronal ensembles learn to overcome the uncertainty introduced by single-neuron stochastic activity.

Effects of training on neuronal activity and interactions in primary and higher visual cortices in the alert cat.

The effects of behavioral training on early visual representations have been elusive when assessed with firing rates. Learning-induced changes in performance, however, suggest that representations should encompass early cortical stages. Here, we address the question of whether training-induced effects are pertinent to neuronal activity outside the task proper, which is a requirement if subsequent perceptional processes should profit from training. To search for a neuronal signature of training effects beyond firing rates, we measured local field potentials, multiunit and isolated spike activity during passive viewing of previously learned stimulus response associations (S+ and S-) in areas 17/18 and 21a of two alert cats. Evoked potential responses as well as gamma oscillations even during the first 200 msec were found to be stronger for S+ in both areas. Most importantly, the later parts of the response (>200 msec) not only exhibit a highly significant difference in coherent gamma oscillations for S+ and S- both within and across areas, but are also characterized by a pronounced preference in firing rate for S+ in area 21a, whereas primary cortex shows a nonsignificant trend for weaker spike responses. From these results, we conclude that training-induced plasticity occurs in adult visual cortex for behaviorally relevant stimuli by changing primarily the temporal structure of neuronal activity at early stages of cortical processing, whereas later stages of cortical processing express the increased coherence of their input in elevated firing rates.

Long-term potentiation in visual cortical projections to the medial prefrontal cortex of the rat

In order to investigate neural mechanisms by which the prefrontal cortex adaptively modifies its activities based on past experience, we examined whether or not sensory cortical projections to the medial prefrontal cortex support long-term potentiation (LTP) in rats. Monosynaptic projections from the secondary visual cortex, mediomedial area (V2MM) to the infralimbic cortex were confirmed by orthodromic as well as antidromic activation of single units. High-frequency stimulation (50 Hz, 2 s) induced LTP (approximately 45% increase over the baseline) in the V2MM projection to the infralimbic cortex. LTP induction in this pathway was completely blocked by an injection (i.p.) of CPP, an N-methyl- d-aspartate receptor antagonist. LTP was also induced in the ventral hippocampal projection to the infralimbic cortex by the same high-frequency stimulation. The present results suggest that modification of synaptic weights of afferent sensory cortical projections is one mechanism underlying learning-induced changes in prefrontal cortical neural activities.