Experience-dependent Neural Plasticity Research Articles

Rapid-acting antidepressant drugs modulate affective bias in rats.

How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we used an affective bias behavioral test in rats, based on an associative learning task, to investigate the effects of RAADs. To generate an affective bias, animals learned to associate two different digging substrates with a food reward in the presence or absence of an affective state manipulation. A choice between the two reward-associated digging substrates was used to quantify the affective bias generated. Acute treatment with the RAADs ketamine, scopolamine, or psilocybin selectively attenuated a negative affective bias in the affective bias test. Low, but not high, doses of ketamine and psilocybin reversed the valence of the negative affective bias 24 hours after RAAD treatment. Only treatment with psilocybin, but not ketamine or scopolamine, led to a positive affective bias that was dependent on new learning and memory formation. The relearning effects of ketamine were dependent on protein synthesis localized to the rat medial prefrontal cortex and could be modulated by cue reactivation, consistent with experience-dependent neural plasticity. These findings suggest a neuropsychological mechanism that may explain both the acute and sustained effects of RAADs, potentially linking their effects on neural plasticity with affective bias modulation in a rodent model.

Experience-dependent Tip60 nucleocytoplasmic transport is regulated by its NLS/NES sequences for neuroplasticity gene control

Nucleocytoplasmic transport (NCT) in neurons is critical for enabling proteins to enter the nucleus and regulate plasticity genes in response to environmental cues. Such experience-dependent (ED) neural plasticity is central for establishing memory formation and cognitive function and can influence the severity of neurodegenerative disorders like Alzheimer's disease (AD). ED neural plasticity is driven by histone acetylation (HA) mediated epigenetic mechanisms that regulate dynamic activity-dependent gene transcription profiles in response to neuronal stimulation. Yet, how histone acetyltransferases (HATs) respond to extracellular cues in the in vivo brain to drive HA-mediated activity-dependent gene control remains unclear. We previously demonstrated that extracellular stimulation of rat hippocampal neurons in vitro triggers Tip60 HAT nuclear import with concomitant synaptic gene induction. Here, we focus on investigating Tip60 HAT subcellular localization and NCT specifically in neuronal activity-dependent gene control by using the learning and memory mushroom body (MB) region of the Drosophila brain as a powerful in vivo cognitive model system. We used immunohistochemistry (IHC) to compare the subcellular localization of Tip60 HAT in the Drosophila brain under normal conditions and in response to stimulation of fly brain neurons in vivo either by genetically inducing potassium channels activation or by exposure to natural positive ED conditions. Furthermore, we found that both inducible and ED condition-mediated neural induction triggered Tip60 nuclear import with concomitant induction of previously identified Tip60 target genes and that Tip60 levels in both the nucleus and cytoplasm were significantly decreased in our well-characterized Drosophila AD model. Mutagenesis of a putative nuclear localization signal (NLS) sequence and nuclear export signal (NES) sequence that we identified in the Drosophila Tip60 protein revealed that both are functionally required for appropriate Tip60 subcellular localization. Our results support a model by which neuronal stimulation triggers Tip60 NCT via its NLS and NES sequences to promote induction of activity-dependent neuroplasticity gene transcription and that this process may be disrupted in AD.

Bimanual Movements and Chronic Stroke Rehabilitation: Looking Back and Looking Forward

Executing voluntary motor actions in the upper extremities after a stroke is frequently challenging and frustrating. Although spontaneous motor recovery can occur, reorganizing the activation of the primary motor cortex and supplementary motor area takes a considerable amount of time involving effective rehabilitation interventions. Based on motor control theory and experience-dependent neural plasticity, stroke protocols centered on bimanual movement coordination are generating considerable evidence in overcoming dysfunctional movements. Looking backward and forward in this comprehensive review, we discuss noteworthy upper extremity improvements reported in bimanual movement coordination studies including force generation. Importantly, the effectiveness of chronic stroke rehabilitation approaches that involve voluntary interlimb coordination principles look promising.

Seasonal changes in the hippocampal formation of hoarding and non-hoarding tits

The hippocampal formation (HF) processes spatial memories for cache locations in food-hoarding birds. Hoarding is a seasonal behavior, and seasonal changes in the HF have been described in some studies, but not in others. One potential reason is that birds may have been sampled during the seasonal hoarding peak in some studies, but not in others. In this study, we investigate the seasonal changes in hoarding and HF in willow tits (Poecile montanus). We compare this to seasonal changes in HF in a closely related non-hoarding bird, the great tit (Parus major). Willow tits near Oulu, Finland, show a seasonal hoarding peak in September and both HF volume and neuron number show a similar peak. HF neuronal density also increases in September, but then remains the same throughout winter. Unexpectedly, the great tit HF also changes seasonally, although in a different pattern: the great tit telencephalon increases in volume from July to August and decreases again in November. Great tit HF volume follows suit, but with a delay. Great tit HF neuron number and density also increase from August to September and stay high throughout winter. We hypothesize that seasonal changes in hoarding birds’ HF are driven by food-hoarding experience (e.g., the formation of thousands of memories). The seasonal changes in great tit brains may also be due to experience-dependent plasticity, responding to changes in the social and spatial environment. Large-scale experience-dependent neural plasticity is therefore probably not an adaptation of food-hoarding birds, but a general property of the avian HF and telencephalon.

Childhood Adversity and Affective Touch Perception: A Comparison of United Kingdom Care Leavers and Non-care Leavers.

In the United Kingdom, the most common reasons for a child to come under the care of social services are neglect and abuse. Such early childhood adversity is a risk factor for social-isolation and poor mental health in adulthood. Touch is a key channel for nurturing interactions, and previous studies have shown links between early somatosensory input, experience dependent neural plasticity, and later life emotional functioning. The aim of the present study was to test the relationship between childhood neglect/abuse and later life experiences, attitudes, and hedonic ratings of affective touch. Here, affective touch is defined as low force, dynamic touch which C-Tactile afferents (CTs) respond optimally to. We hypothesized that a childhood lacking in early nurturing tactile stimulation would be associated with reduced sensitivity to socially relevant affective touch in adulthood. To test this, 19 care leavers (average 9.32 ± 3.70 years in foster care) and 32 non-care leavers were recruited through opportunity sampling (mean age = 21.25 ± 1.74 years). Participants completed a range of psychophysical somatosensory tests. First, they rated the pleasantness of CT-optimal (3 cm/s) and non-CT-optimal (0.3 and 30 cm/s) stroking touch applied to their forearm, both robotically and by an experimenter. They also made vicarious ratings of the anticipated pleasantness of social tactile interactions depicted in a series of videos. Finally, they filled in the Childhood Trauma Questionnaire (CTQ) and the Touch Experiences and Attitudes Questionnaire (TEAQ). As expected, care leavers reported significantly higher levels of childhood trauma than the control group. They also reported significantly lower levels of positive childhood touch compared to non-care leavers, but their attitudes and experiences of current intimate and affiliative touch did not differ. Across all psychophysical tests, care leavers showed specific reduction in sensitivity to the affective value of CT targeted 3 cm/s touch. The results of this study support the hypothesis that a lack of nurturing touch in early developmental periods leads to blunted sensitivity to the specific social value of affective touch. Future research should investigate the neural and physiological mechanisms underlying the observed effect.

Pubertal Testosterone Programs Adult Behavioral Adaptations to Sexual Experience through Infralimbic Cortex ΔFosB.

Acquisition of social proficiency entails behavioral adaptations to social experience, including both behavioral flexibility and inhibition of behaviors inappropriate in specific social contexts. Here, we investigated the contributions of testosterone and ΔFosB, a transcription factor linked to experience-dependent neural plasticity, to the adolescent maturation of social proficiency in male-female social interactions. To determine whether pubertal testosterone organizes circuits underlying social proficiency, we first compared behavioral adaptations to sexual experience in male Syrian hamsters that were deprived of testosterone during puberty (prepubertal castration; NoT@P) to those of males deprived of testosterone for an equivalent period of time in adulthood (postpubertal castration; T@P). All males were given testosterone replacement in adulthood for two weeks before sexual behavior testing, where males were allowed to interact with a receptive female once per week for five consecutive weeks. T@P males showed the expected decrease in ectopic (mis-directed) mounts with sexual experience, whereas NoT@P males did not. In addition, sexual experience induced FosB gene products expression in the infralimbic cortex (IL) in T@P, but not NoT@P, males. Overexpression of ΔFosB via an adeno-associated viral (AAV) vector in the IL of NoT@P males prior to sexual behavior testing was sufficient to produce a behavioral phenotype similar to that of experienced T@P males. Finally, overexpression of ΔFosB in IL increased the density of immature spines on IL dendrites. Our findings provide evidence that social proficiency acquired through sexual experience is organized by pubertal testosterone through the regulation of ΔFosB in the IL, possibly through increasing synaptic lability.

Structural Variation of Chondroitin Sulfate Chains Contributes to the Molecular Heterogeneity of Perineuronal Nets.

Aggrecan, a chondroitin sulfate (CS) proteoglycan, forms lattice-like extracellular matrix structures called perineuronal nets (PNNs). Neocortical PNNs primarily ensheath parvalbumin-expressing inhibitory neurons (parvalbumin, PV cells) late in brain development. Emerging evidence indicates that PNNs promote the maturation of PV cells by enhancing the incorporation of homeobox protein Otx2 and regulating experience-dependent neural plasticity. Wisteria floribunda agglutinin (WFA), an N-acetylgalactosamine-specific plant lectin, binds to the CS chains of aggrecan and has been widely used to visualize PNNs. Although PNNs show substantial molecular heterogeneity, the importance of this heterogeneity in neural plasticity remains unknown. Here, in addition to WFA lectin, we used the two monoclonal antibodies Cat315 and Cat316, both of which recognize the glycan structures of aggrecan, to investigate the molecular heterogeneity of PNNs. WFA detected the highest number of PNNs in all cortical layers, whereas Cat315 and Cat316 labeled only a subset of PNNs. WFA+, Cat315+, and Cat316+ PNNs showed different laminar distributions in the adult visual cortex. WFA, Cat315 and Cat316 detected distinct, but partially overlapping, populations of PNNs. Based on the reactivities of these probes, we categorized PNNs into four groups. We found that two subpopulation of PNNs, one with higher and one with lower WFA-staining are differentially labeled by Cat316 and Cat315, respectively. CS chains recognized by Cat316 were diminished in mice deficient in an enzyme involved in the initiation of CS-biosynthesis. Furthermore, WFA+ and Cat316+ aggrecan were spatially segregated and formed microdomains in a single PNN. Otx2 co-localized with Cat316+ but not with WFA+ aggrecan in PNNs. Our results suggest that the heterogeneity of PNNs around PV cells may affect the functional maturation of these cells.

Experience-dependent neural plasticity, learning, and memory in the era of epitranscriptomics.

In this short review, we highlight recent findings in the emerging field of epitranscriptomic mechanisms and discuss their potential role in neural plasticity, learning and memory. These include the influence of RNA modifications on activity-induced RNA structure states, RNA editing and RNA localization, and how qualitative state changes in RNA increase the functional diversity and information-carrying capacity of RNA molecules. We predict that RNA modifications may be just as important for synaptic plasticity and memory as quantitative changes in transcript and protein abundance, but with the added advantage of not being required to signal back to the nucleus, and therefore better suited to be coordinated with the temporal dynamics of learning.

Arc restores juvenile plasticity in adult mouse visual cortex

The molecular basis for the decline in experience-dependent neural plasticity over age remains poorly understood. In visual cortex, the robust plasticity induced in juvenile mice by brief monocular deprivation during the critical period is abrogated by genetic deletion of Arc, an activity-dependent regulator of excitatory synaptic modification. Here, we report that augmenting Arc expression in adult mice prolongs juvenile-like plasticity in visual cortex, as assessed by recordings of ocular dominance (OD) plasticity in vivo. A distinguishing characteristic of juvenile OD plasticity is the weakening of deprived-eye responses, believed to be accounted for by the mechanisms of homosynaptic long-term depression (LTD). Accordingly, we also found increased LTD in visual cortex of adult mice with augmented Arc expression and impaired LTD in visual cortex of juvenile mice that lack Arc or have been treated in vivo with a protein synthesis inhibitor. Further, we found that although activity-dependent expression of Arc mRNA does not change with age, expression of Arc protein is maximal during the critical period and declines in adulthood. Finally, we show that acute augmentation of Arc expression in wild-type adult mouse visual cortex is sufficient to restore juvenile-like plasticity. Together, our findings suggest a unifying molecular explanation for the age- and activity-dependent modulation of synaptic sensitivity to deprivation.

Protracted and asynchronous accumulation of PSD95-family MAGUKs during maturation of nascent dendritic spines.

The formation and stabilization of new dendritic spines is a key component of the experience-dependent neural circuit plasticity that supports learning, but the molecular maturation of nascent spines remains largely unexplored. The PSD95-family of membrane-associated guanylate kinases (PSD-MAGUKs), most notably PSD95, has a demonstrated role in promoting spine stability. However, nascent spines contain low levels of PSD95, suggesting that other members of the PSD-MAGUK family might act to stabilize nascent spines in the early stages of spiny synapse formation. Here, we used GFP-fusion constructs to quantitatively define the molecular composition of new spines, focusing on the PSD-MAGUK family. We found that PSD95 levels in new spines were as low as those previously associated with rapid subsequent spine elimination, and new spines did not achieve mature levels of PSD95 until between 12 and 20 h following new spine identification. Surprisingly, we found that the PSD-MAGUKs PSD93, SAP97, and SAP102 were also substantially less enriched in new spines. However, they accumulated in new spines more quickly than PSD95: SAP102 enriched to mature levels within 3 h, SAP97 and PSD93 enriched gradually over the course of 6 h. Intriguingly, when we restricted our analysis to only those new spines that persisted, SAP97 was the only PSD-MAGUK already present at mature levels in persistent new spines when first identified. Our findings uncover a key structural difference between nascent and mature spines, and suggest a mechanism for the stabilization of nascent spines through the sequential arrival of PSD-MAGUKs. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1161-1174, 2017.

Automated Operant Conditioning in the Mouse Home Cage

Recent advances in neuroimaging and genetics have made mice an advantageous animal model for studying the neurophysiology of sensation, cognition, and locomotion. A key benefit of mice is that they provide a large population of test subjects for behavioral screening. Reflex-based assays of hearing in mice, such as the widely used acoustic startle response, are less accurate than operant conditioning in measuring auditory processing. To date, however, there are few cost-effective options for scalable operant conditioning systems. Here, we describe a new system for automated operant conditioning, the Psibox. It is assembled from low cost parts, designed to fit within typical commercial wire-top cages, and allows large numbers of mice to train independently in their home cages on positive reinforcement tasks. We found that groups of mice trained together learned to accurately detect sounds within 2 weeks of training. In addition, individual mice isolated from groups also showed good task performance. The Psibox facilitates high-throughput testing of sensory, motor, and cognitive skills in mice, and provides a readily available animal population for studies ranging from experience-dependent neural plasticity to rodent models of mental disorders.

Improving practice with integration of patient directed activity during inpatient rehabilitation

Background: Early initiation of rehabilitation following stroke promotes better long-term outcomes than delayed onset, emphasizing the importance of inpatient therapy. However, literature indicates that following stroke individuals in inpatient rehabilitation spend the majority of their day in their bedroom and inactive. Consequently, since amount of functional activity is posited to relate to outcomes, the current rehabilitation model needs to be challenged with innovative solutions to maximize recovery. Rationale: In an attempt to promote greater activity and higher doses of therapy during inpatient rehabilitation, we implemented the “Patient Directed Activity Program” to facilitate specific movement and improve outcomes for patients post stroke. Our interdisciplinary activity program was conceptualized on a theoretical model for stroke recovery and principles of experience-dependent neural plasticity. Main features: The “Patient Directed Activity Program” includes distinct activity stations designed to increase repetition, stimulation, attention, and activity of the affected upper extremities, lower extremities, and trunk. Each task-specific activity was easily graded to achieve moderate- to high-intensity. The activity program prescribed individuals up to three additional 30-minute bouts of activities daily that were to be completed independently, and in addition to standard of care. Clinical application: After implementing this program in our facility for one year as a quality improvement project, the intervention has been delivered as an Institutional Review Board approved randomized controlled trial (Clinical Trial #NCT02446197). Challenges with people and facilities have been overcome, resulting in a feasible program that can be delivered in an inpatient setting. High satisfaction has been reported by patients and clinicians.

Impaired acquisition of classically conditioned fear-potentiated startle reflexes in humans with focal bilateral basolateral amygdala damage

Based on studies in rodents, the basolateral amygdala (BLA) is considered a key site for experience-dependent neural plasticity underlying the acquisition of conditioned fear responses. In humans, very few studies exist of subjects with selective amygdala lesions and those studies have only implicated the amygdala more broadly leaving the role of amygdala sub-regions underexplored. We tested a rare sample of subjects (N = 4) with unprecedented focal bilateral BLA lesions due to a genetic condition called Urbach-Wiethe disease. In a classical delay fear conditioning experiment, these subjects showed impaired acquisition of conditioned fear relative to a group of matched control subjects (N = 10) as measured by fear-potentiation of the defensive eye-blink startle reflex. After the experiment, the BLA-damaged cases showed normal declarative memory of the conditioned association. Our findings provide new evidence that the human BLA is essential to drive fast classically conditioned defensive reflexes.

Maintenance of dominance status is necessary for resistance to social defeat stress in Syrian hamsters

Resilience is an active process that involves a discrete set of neural substrates and cellular mechanisms and enables individuals to avoid some of the negative consequences of extreme stress. We have previously shown that dominant individuals show less stress-induced changes in behavior compared to subordinates using a conditioned defeat model in male Syrian hamsters (Mesocricetus auratus). To rule out pre-existing differences between dominants and subordinates, we examined whether 14 days of dominance experience is required to reduce the conditioned defeat response and whether the development of conditioned defeat resistance correlates with defeat-induced neural activation in select brain regions. We paired hamsters in daily 5-min aggressive encounters for 1, 7, or 14 days and then exposed animals to 3, 5-min social defeat episodes. The next day animals received conditioned defeat testing which involved a 5-min social interaction test with a non-aggressive intruder. In separate animals brains were collected after social defeat for c-Fos immunohistochemistry. We found that 14-day dominants showed a decreased conditioned defeat response compared to 14-day subordinates and controls, while 1-day and 7-day dominants did not differ from their subordinate counterparts. Also, the duration of dominance relationship was associated with distinct patterns of defeat-induced neural activation such that only 14-day dominants showed elevated c-Fos immunoreactivity in the ventral medial prefrontal cortex, medial amygdala, and lateral portions of the ventral medial hypothalamus. Our data suggest that resistance to social stress develops during the maintenance of dominance relationships and is associated with experience-dependent neural plasticity in select brain regions.

Arc regulates experience-dependent persistent firing patterns in frontal cortex.

The brain encodes information about past experience in specific populations of neurons that communicate with one another by firing action potentials. Studies of experience-dependent neural plasticity have largely focused on individual synaptic changes in response to neuronal input. Indicative of the neuronal output transmitted to downstream neurons, persistent firing patterns are affected by prior experience in selective neuronal populations. However, little is known about the molecular and cellular mechanisms by which experience-related persistent firing patterns are regulated in specific neuronal populations. Using frontal cortical slices prepared from transgenic mice carrying a fluorescent reporter of Arc gene expression, this study investigates how behavioral experience and the activity-regulated Arc gene affect patterns of neuronal firing. We found that motor training increases Arc expression in subsets of excitatory neurons. Those neurons exhibit persistent firing in contrast to Arc-negative neurons from the same mice or neurons from the untrained mice. Furthermore, in mice carrying genetic deletion of Arc, the frontal cortical circuitry is still in place to initiate experience-dependent gene expression, but the level of persistent firing thereafter is diminished. Finally, our results showed that the emergence of persistent activity is associated with Arc-dependent changes in the function of NMDA-type glutamate receptors, rather than changes in AMPA-type receptors or membrane excitability. Our findings therefore reveal an Arc-dependent molecular pathway by which gene-experience interaction regulates the emergence of persistent firing patterns in specific neuronal populations.

Postsynaptic neural activity regulates neuronal addition in the adult avian song control system.

A striking feature of the nervous system is that it shows extensive plasticity of structure and function that allows animals to adjust to changes in their environment. Neural activity plays a key role in mediating experience-dependent neural plasticity and, thus, creates a link between the external environment, the nervous system, and behavior. One dramatic example of neural plasticity is ongoing neurogenesis in the adult brain. The role of neural activity in modulating neuronal addition, however, has not been well studied at the level of neural circuits. The avian song control system allows us to investigate how activity influences neuronal addition to a neural circuit that regulates song, a learned sensorimotor social behavior. In adult white-crowned sparrows, new neurons are added continually to the song nucleus HVC (proper name) and project their axons to its target nucleus, the robust nucleus of the arcopallium (RA). We report here that electrical activity in RA regulates neuronal addition to HVC. Decreasing neural activity in RA by intracerebral infusion of the GABAA receptor agonist muscimol decreased the number of new HVC neurons by 56%. Our results suggest that postsynaptic electrical activity influences the addition of new neurons into a functional neural circuit in adult birds.

Optimization of Cell Morphology Measurement via Single-Molecule Tracking PALM

In neurons, the shape of dendritic spines relates to synapse function, which is rapidly altered during experience-dependent neural plasticity. The small size of spines makes detailed measurement of their morphology in living cells best suited to super-resolution imaging techniques. The distribution of molecular positions mapped via live-cell Photoactivated Localization Microscopy (PALM) is a powerful approach, but molecular motion complicates this analysis and can degrade overall resolution of the morphological reconstruction. Nevertheless, the motion is of additional interest because tracking single molecules provides diffusion coefficients, bound fraction, and other key functional parameters. We used Monte Carlo simulations to examine features of single-molecule tracking of practical utility for the simultaneous determination of cell morphology. We find that the accuracy of determining both distance and angle of motion depend heavily on the precision with which molecules are localized. Strikingly, diffusion within a bounded region resulted in an inward bias of localizations away from the edges, inaccurately reflecting the region structure. This inward bias additionally resulted in a counterintuitive reduction of measured diffusion coefficient for fast-moving molecules; this effect was accentuated by the long camera exposures typically used in single-molecule tracking. Thus, accurate determination of cell morphology from rapidly moving molecules requires the use of short integration times within each image to minimize artifacts caused by motion during image acquisition. Sequential imaging of neuronal processes using excitation pulses of either 2 ms or 10 ms within imaging frames confirmed this: processes appeared erroneously thinner when imaged using the longer excitation pulse. Using this pulsed excitation approach, we show that PALM can be used to image spine and spine neck morphology in living neurons. These results clarify a number of issues involved in interpretation of single-molecule data in living cells and provide a method to minimize artifacts in single-molecule experiments.

Reflections of experience-expectant development in repair of the adult damaged brain.

Behavioral experience has long been known to influence functional outcome after brain injury, but only recently has its pervasive role in the reorganization of the adult brain after damage become appreciated. We briefly review findings from animal models on the role of experience in shaping neuronal events after stroke-like injury. Experience-dependent neural plasticity can be enhanced or impaired by brain damage, depending upon injury parameters and timing. The neuronal growth response to some experiences is heightened due to interactions with denervation-induced plasticity. This includes compensatory behavioral strategies developed in response to functional impairments. Early behavioral experiences can constrain later experience-dependent plasticity, leading to suboptimal functional outcome. Time dependencies and facets of neural growth patterns are reminiscent of experience-expectant processes that shape brain development. As with sensitive periods in brain development, this process may establish behavioral patterns early after brain injury which are relatively resistant to later change.

Cocaine increases phosphorylation of MeCP2 in the rat striatum in vivo: A differential role of NMDA receptors

Methyl CpG-binding protein-2 (MeCP2) is a transcriptional regulator that binds to methylated DNA at CpG sites and functions to silence DNA transcription. MeCP2 is subject to the phosphorylation modification at serine 421 (S421), which releases MeCP2 from DNA and thus facilitates gene expression. As a transcriptional repressor densely expressed in limbic reward circuits of adult mammalian brains, MeCP2 is recently emerging as a critical epigenetic factor in experience-dependent neural plasticity and psychostimulant addiction. In this study, we investigated the regulation of MeCP2 phosphorylation in the rat striatum by the psychostimulant cocaine in vivo. We found that acute systemic injection of cocaine increased MeCP2 phosphorylation at S421 in the rat striatum, including both the caudate putamen and the nucleus accumbens, while cocaine did not affect MeCP2 phosphorylation in the medial prefrontal cortex. The cocaine-stimulated MeCP2 phosphorylation in the nucleus accumbens was a rapid and transient event, as it was evident at 20min and returned to normal levels 3h after drug injection. The cocaine effect in the caudate putamen was however relatively delayed. Reliable induction of MeCP2 phosphorylation in this region was detected at 60min. Pretreatment with an N-methyl-d-aspartate (NMDA) glutamate receptor antagonist significantly reduced the cocaine-stimulated MeCP2 phosphorylation in the caudate putamen, although not in the nucleus accumbens. Our data support that MeCP2 is a sensitive target of psychostimulants. Its phosphorylation status is regulated by psychostimulant exposure. NMDA receptors play a region-specific role in linking cocaine to MeCP2 phosphorylation in striatal neurons in vivo.

Cross-domain Effects of Music and Language Experience on the Representation of Pitch in the Human Auditory Brainstem

Neural encoding of pitch in the auditory brainstem is known to be shaped by long-term experience with language or music, implying that early sensory processing is subject to experience-dependent neural plasticity. In language, pitch patterns consist of sequences of continuous, curvilinear contours; in music, pitch patterns consist of relatively discrete, stair-stepped sequences of notes. The primary aim was to determine the influence of domain-specific experience (language vs. music) on the encoding of pitch in the brainstem. Frequency-following responses were recorded from the brainstem in native Chinese, English amateur musicians, and English nonmusicians in response to iterated rippled noise homologues of a musical pitch interval (major third; M3) and a lexical tone (Mandarin tone 2; T2) from the music and language domains, respectively. Pitch-tracking accuracy (whole contour) and pitch strength (50 msec sections) were computed from the brainstem responses using autocorrelation algorithms. Pitch-tracking accuracy was higher in the Chinese and musicians than in the nonmusicians across domains. Pitch strength was more robust across sections in musicians than in nonmusicians regardless of domain. In contrast, the Chinese showed larger pitch strength, relative to nonmusicians, only in those sections of T2 with rapid changes in pitch. Interestingly, musicians exhibited greater pitch strength than the Chinese in one section of M3, corresponding to the onset of the second musical note, and two sections within T2, corresponding to a note along the diatonic musical scale. We infer that experience-dependent plasticity of brainstem responses is shaped by the relative saliency of acoustic dimensions underlying the pitch patterns associated with a particular domain.