Learning-induced Neuroplasticity Research Articles

Activity-dependent transcriptional programs in memory regulate motor recovery after stroke

Stroke causes death of brain tissue leading to long-term deficits. Behavioral evidence from neurorehabilitative therapies suggest learning-induced neuroplasticity can lead to beneficial outcomes. However, molecular and cellular mechanisms that link learning and stroke recovery are unknown. We show that in a mouse model of stroke, which exhibits enhanced recovery of function due to genetic perturbations of learning and memory genes, animals display activity-dependent transcriptional programs that are normally active during formation or storage of new memories. The expression of neuronal activity-dependent genes are predictive of recovery and occupy a molecular latent space unique to motor recovery. With motor recovery, networks of activity-dependent genes are co-expressed with their transcription factor targets forming gene regulatory networks that support activity-dependent transcription, that are normally diminished after stroke. Neuronal activity-dependent changes at the circuit level are influenced by interactions with microglia. At the molecular level, we show that enrichment of activity-dependent programs in neurons lead to transcriptional changes in microglia where they differentially interact to support intercellular signaling pathways for axon guidance, growth and synaptogenesis. Together, these studies identify activity-dependent transcriptional programs as a fundamental mechanism for neural repair post-stroke.

Enhanced intrinsic functional connectivity in the visual system of visual artist: Implications for creativity.

This study sought to elucidate the cognitive traits of visual artists (VAs) from the perspective of visual creativity and the visual system (i.e., the most fundamental neural correlate). We examined the local and long-distance intrinsic functional connectivity (FC) of the visual system to unravel changes in brain traits among VAs. Twenty-seven university students majoring in visual arts and 27 non-artist controls were enrolled. VAs presented enhanced local FC in the right superior parietal lobule, right precuneus, left inferior temporal gyrus (ITG), left superior parietal lobule, left angular gyrus, and left middle occipital gyrus. VAs also presented enhanced FC with the ITG that targeted the visual area (occipital gyrus and cuneus), which appears to be associated with visual creativity. The visual creativity of VAs was correlated with strength of intrinsic functional connectivity in the visual system. Learning-induced neuroplasticity as a trait change observed in VAs can be attributed to the macroscopic consolidation of consociated neural circuits that are engaged over long-term training in the visual arts and aesthetic experience. The consolidated network can be regarded as virtuoso-specific neural fingerprint.

Memory Specific to Temporal Features of Sound Is Formed by Cue-Selective Enhancements in Temporal Coding Enabled by Inhibition of an Epigenetic Regulator

Recent investigation of memory-related functions in the auditory system have capitalized on the use of memory-modulating molecules to probe the relationship between memory and substrates of memory in auditory system coding. For example, epigenetic mechanisms, which regulate gene expression necessary for memory consolidation, are powerful modulators of learning-induced neuroplasticity and long-term memory (LTM) formation. Inhibition of the epigenetic regulator histone deacetylase 3 (HDAC3) promotes LTM, which is highly specific for spectral features of sound. The present work demonstrates for the first time that HDAC3 inhibition also enables memory for temporal features of sound. Adult male rats trained in an amplitude modulation (AM) rate discrimination task and treated with a selective inhibitor of HDAC3 formed memory that was highly specific to the AM rate paired with reward. Sound-specific memory revealed behaviorally was associated with a signal-specific enhancement in temporal coding in the auditory system; stronger phase locking that was specific to the rewarded AM rate was revealed in both the surface-recorded frequency following response and auditory cortical multiunit activity in rats treated with the HDAC3 inhibitor. Furthermore, HDAC3 inhibition increased trial-to-trial cortical response consistency (relative to naive and trained vehicle-treated rats), which generalized across different AM rates. Stronger signal-specific phase locking correlated with individual behavioral differences in memory specificity for the AM signal. These findings support that epigenetic mechanisms regulate activity-dependent processes that enhance discriminability of sensory cues encoded into LTM in both spectral and temporal domains, which may be important for remembering spectrotemporal features of sounds, for example, as in human voices and speech.SIGNIFICANCE STATEMENTEpigenetic mechanisms have recently been implicated in memory and information processing. Here, we use a pharmacological inhibitor of HDAC3 in a sensory model of learning to reveal the ability of HDAC3 to enable precise memory for amplitude-modulated sound cues. In so doing, we uncover neural substrates for memory's specificity for temporal sound cues. Memory specificity was supported by auditory cortical changes in temporal coding, including greater response consistency and stronger phase locking. HDAC3 appears to regulate effects across domains that determine specific cue saliency for behavior. Thus, epigenetic players may gate how sensory information is stored in long-term memory and can be leveraged to reveal the neural substrates of sensory details stored in memory.

Motor Skill Learning-Induced Functional Plasticity in the Primary Somatosensory Cortex: A Comparison Between Young and Older Adults

While in young adults (YAs) the underlying neural mechanisms of motor learning are well-studied, studies on the involvement of the somatosensory system during motor skill learning in older adults (OAs) remain sparse. Therefore, the aim of the present study was to investigate motor learning-induced neuroplasticity in the primary somatosensory cortex (S1) in YAs and OAs. Somatosensory evoked potentials (SEPs) were used to quantify somatosensory activation prior and immediately after motor skill learning in 20 right-handed healthy YAs (age range: 19–35 years) and OAs (age range: 57–76 years). Participants underwent a single session of a 30-min co-contraction task of the abductor pollicis brevis (APB) and deltoid muscle. To assess the effect of motor learning, muscle onset asynchrony (MOA) between the onsets of the contractions of both muscles was measured using electromyography monitoring. In both groups, MOA shortened significantly during motor learning, with YAs showing bigger reductions. No changes were found in SEP amplitudes after motor learning in both groups. However, a correlation analysis revealed an association between baseline SEP amplitudes of the N20/P25 and N30 SEP component and the motor learning slope in YAs such that higher amplitudes are related to higher learning. Hence, the present findings suggest that SEP amplitudes might serve as a predictor of individual motor learning success, at least in YAs. Additionally, our results suggest that OAs are still capable of learning complex motor tasks, showing the importance of motor training in higher age to remain an active part of our society as a prevention for care dependency.

Seasonal changes of perineuronal nets and song learning in adult canaries (Serinus canaria)

Songbirds learn their song during a sensitive period of development associated with enhanced neural plasticity. In addition, in open-ended learners such as canaries, a sensitive period for sensorimotor vocal learning reopens each year in the fall and leads to song modifications between successive breeding seasons. The variability observed in song production across seasons in adult canaries correlates with seasonal fluctuations of testosterone concentrations and with morphological changes in nuclei of the song control system (SCS). The sensitive periods for song learning during ontogeny and then again in adulthood could be controlled by the development of perineuronal nets (PNN) around parvalbumin-expressing interneurones (PV) which limits learning-induced neuroplasticity. However, this relationship has never been investigated in the context of adult vocal learning in adult songbirds. Here we explored PNN and PV expression in the SCS of adult male Fife Fancy canaries in relation to the seasonal variations of their singing behaviour. We found a clear pattern of seasonal variation in testosterone concentrations and song production. Furthermore, PNN expression was significantly higher in two specific song control nuclei, the robust nucleus of the arcopallium (RA) and the Area X of the basal ganglia, during the breeding season and during the later stages of sensorimotor song development compared to birds in an earlier stage of sensorimotor development during the fall. These data provide the first evidence that changes in PNN expression could represent a mechanism regulating the closing-reopening of sensitive periods for vocal learning across seasons in adult songbirds.

Neural correlates of sound-learning experiences in the auditory system: Translational candidates for hearing rehabilitation

A major disconnect between traditional auditory perception research and recent neuroscience is the high propensity in the auditory system for neuroplasticity. Altered processing of reward-associated sound stimuli can contribute to adaptive behavior, such as hearing, listening, and attending appropriately to sound cues. I will the present work from animal models of learning-induced neuroplasticity in the cortical and subcortical auditory system. The data show how receptive fields and tonotopic maps in primary auditory cortex (A1) as well as the auditory brainstem response (ABR) can change when adult animals trained by pairing a tone with the availability to obtain reward alters sound coding in the auditory system. Over the course of conditioning, increases and reductions, respectively, in ABR amplitude and peak latencies predict how well animals can pick out the learned sound-frequency acoustic cue from other frequencies following conditioning. Furthermore, receptive fields in A1 have narrower tuning for a remembered sound frequency—and only in animals who successfully remember that frequency over others assessed by behavioral test. Therefore, learned sounds are preferentially processed over novel and distractor sounds following conditioning. Significant behavioral preferences for learned tones may be due, in part, to the observed changes in auditory processing across the auditory system.

Distributed neural systems for musical time processing

My talk will feature recent MEG and EEG studies for examining time processing, and, together with other findings, discuss how distributed neural systems for musical time work together in managing top-down and bottom-up prediction, ensemble coordination, and learning-induced neuroplasticity. It has been long known that passive listening of metronome-like isochronous stimuli involves auditory cortices for simple prediction of the stimulus interval and detection of changes. Recently, however, more studies are aimed at capturing natural neural dynamics that encode or predict time without such "perturbation" approach. We show that in addition to auditory cortices, various motor-related brain areas contribute to neural oscillatory power modulations in listening to isochronous stimulus, and that beta-band frequency of this modulation may explain benefits of auditory-sensorimotor training in clinical populations with movement impairments. Moreover, modulation patterns can encode stimulus intervals, metric hierarchies in perception and imagery, as well as anticipation of upcoming tempo change (e.g., accelerando and ritardando). Listening paradigm is also used to show neuroplastic changes in naïve subjects after short-term piano training in the reward-related systems. Of further interest is frontal lobe's contribution to musical ensemble coordination sensitive to player's role asymmetry and agency (e.g., human vs. computer).

Association between increased serum d-serine and cognitive gains induced by intensive cognitive training in schizophrenia

Neuroscience-guided cognitive training induces significant improvement in cognition in schizophrenia subjects, but the biological mechanisms associated with these changes are unknown. In animals, intensive cognitive activity induces increased brain levels of the NMDA-receptor co-agonist d-serine, a molecular system that plays a role in learning-induced neuroplasticity and that may be hypoactive in schizophrenia. Here, we investigated whether training-induced gains in cognition were associated with increases in serum d-serine in outpatients with schizophrenia. Ninety patients with schizophrenia and 53 healthy controls were assessed on baseline serum d-serine, l-serine, and glycine. Schizophrenia subjects performed neurocognitive tests and were assigned to 50 h of either cognitive training of auditory processing systems (N = 47) or a computer games control condition (N = 43), followed by reassessment of cognition and serum amino acids. At study entry, the mean serum d-serine level was significantly lower in schizophrenia subjects vs. healthy subjects, while the glycine levels were significantly higher. There were no significant changes in these measures at a group level after the intervention. However, in the active training group, increased d-serine was significantly and positively correlated with improvements in global cognition and in Verbal Learning. No such associations were observed in the computer games control subjects, and no such associations were found for glycine. d-Serine may be involved in the neurophysiologic changes induced by cognitive training in schizophrenia. Pharmacologic strategies that target d-serine co-agonism of NMDA-receptor functioning may provide a mechanism for enhancing the behavioral effects of intensive cognitive training.

Neuroscience-informed computer-assisted cognitive training in schizophrenia.

Schizophrenia is a heterogeneous psychiatric syndrome characterized by psychosis. It is also a neurodevelopmental disorder. In the earliest phases of the illness, at-risk individuals exhibit subtle, nonspecific symptoms, including cognitive dysfunction and progressive brain volumetric loss. Generally, schizophrenia is characterized by abnormal/inefficient neural system operations and neural oscillatory activity, as well as functional disconnectivity across frontal-temporo parietal and frontal-subcortical networks; it thus may best be described as a widespread neural oscillatory connectomopathy. Despite earlier views of schizophrenia as an inevitably progressive neurodegenerative disease, emerging evidence indicates that endogenous neuroplastic capacity is retained. An active area of research is directed at understanding how best to harness this learning-induced neuroplasticity to enhance neural system functioning, improve cognition, and prevent-and possibly even reverse-disease progression. In this review, we present an overview of results from the most widely used computer-assisted cognitive-training programs in schizophrenia, contrasting a broad neuropsychological rehabilitation approach with a targeted cognitive-training approach. We then review studies on the neurobiological effects of these two training methods. Finally, we discuss future directions with a focus on the "oscillatory connectome" as a key area of investigation for developing the most precise and scientifically informed treatment approaches for this illness.

Associative learning and sensory neuroplasticity: how does it happen and what is it good for?

Historically, the body's sensory systems have been presumed to provide the brain with raw information about the external environment, which the brain must interpret to select a behavioral response. Consequently, studies of the neurobiology of learning and memory have focused on circuitry that interfaces between sensory inputs and behavioral outputs, such as the amygdala and cerebellum. However, evidence is accumulating that some forms of learning can in fact drive stimulus-specific changes very early in sensory systems, including not only primary sensory cortices but also precortical structures and even the peripheral sensory organs themselves. This review synthesizes evidence across sensory modalities to report emerging themes, including the systems’ flexibility to emphasize different aspects of a sensory stimulus depending on its predictive features and ability of different forms of learning to produce similar plasticity in sensory structures. Potential functions of this learning-induced neuroplasticity are discussed in relation to the challenges faced by sensory systems in changing environments, and evidence for absolute changes in sensory ability is considered. We also emphasize that this plasticity may serve important nonsensory functions, including balancing metabolic load, regulating attentional focus, and facilitating downstream neuroplasticity.

When Top-Down Meets Bottom-Up: Auditory Training Enhances Verbal Memory in Schizophrenia

A critical research priority for our field is to develop treatments that enhance cognitive functioning in schizophrenia and thereby attenuate the functional losses associated with the illness. In this article, we describe such a treatment method that is grounded in emerging research on the widespread sensory processing impairments of schizophrenia, as described elsewhere in this special issue. We first present the rationale for this treatment approach, which consists of cognitive training exercises that make use of principles derived from the past 2 decades of basic science research in learning-induced neuroplasticity; these exercises explicitly target not only the higher order or "top-down" processes of cognition but also the content building blocks of accurate and efficient sensory representations to simultaneously achieve "bottom-up" remediation. We then summarize our experience to date and briefly review our behavioral and serum biomarker findings from a randomized controlled trial of this method in outpatients with long-term symptoms of schizophrenia. Finally, we present promising early psychophysiological evidence that supports the hypothesis that this cognitive training method induces changes in aspects of impaired bottom-up sensory processing in schizophrenia. We conclude with the observation that neuroplasticity-based cognitive training brings patients closer to physiological patterns seen in healthy participants, suggesting that it changes the brain in an adaptive manner in schizophrenia.

Using Neuroplasticity-Based Auditory Training to Improve Verbal Memory in Schizophrenia

Impaired verbal memory in schizophrenia is a key rate-limiting factor for functional outcome, does not respond to currently available medications, and shows only modest improvement after conventional behavioral remediation. The authors investigated an innovative approach to the remediation of verbal memory in schizophrenia, based on principles derived from the basic neuroscience of learning-induced neuroplasticity. The authors report interim findings in this ongoing study. Fifty-five clinically stable schizophrenia subjects were randomly assigned to either 50 hours of computerized auditory training or a control condition using computer games. Those receiving auditory training engaged in daily computerized exercises that placed implicit, increasing demands on auditory perception through progressively more difficult auditory-verbal working memory and verbal learning tasks. Relative to the control group, subjects who received active training showed significant gains in global cognition, verbal working memory, and verbal learning and memory. They also showed reliable and significant improvement in auditory psychophysical performance; this improvement was significantly correlated with gains in verbal working memory and global cognition. Intensive training in early auditory processes and auditory-verbal learning results in substantial gains in verbal cognitive processes relevant to psychosocial functioning in schizophrenia. These gains may be due to a training method that addresses the early perceptual impairments in the illness, that exploits intact mechanisms of repetitive practice in schizophrenia, and that uses an intensive, adaptive training approach.