Music training is related to late ERP modulation and enhanced performance during Simon task but not Stroop task.

Increasing evidence suggests that music training correlates with better performance in tasks measuring executive function components including inhibitory control, working memory and selective attention. The Stroop and Simon tasks measure responses to congruent and incongruent information reflecting cognitive conflict resolution. However, there are more reports of a music-training advantage in the Simon than the Stroop task. Reports indicate that these tasks may differ in the timing of conflict resolution: the Stroop task might involve early sensory stage conflict resolution, while the Simon task may do so at a later motor output planning stage. We hypothesize that musical experience relates to conflict resolution at the late motor output stage rather than the early sensory stage. Behavioral responses, and event-related potentials (ERP) were measured in participants with varying musical experience during these tasks. It was hypothesized that musical experience correlates with better performance in the Simon but not the Stroop task, reflected in ERP components in the later stage of motor output processing in the Simon task. Participants were classified into high- and low-music training groups based on the Goldsmith Musical Sophistication Index. Electrical brain activity was recorded while they completed visual Stroop and Simon tasks. The high-music training group outperformed the low-music training group on the Simon, but not the Stroop task. Mean amplitude difference (incongruent-congruent trials) was greater for the high-music training group at N100 for midline central (Cz) and posterior (Pz) sites in the Simon task and midline central (Cz) and frontal (Fz) sites in the Stroop task, and at N450 at Cz and Pz in the Simon task. N450 difference peaks occurred earlier in the high-music training group at Pz. Differences between the groups at N100 indicate that music training may be related to better sensory discrimination. These differences were not related to better behavioral performance. Differences in N450 responses between the groups, particularly in regions encompassing the motor and parietal cortices, suggest a role of music training in action selection during response conflict situations. Overall, this supports the hypothesis that music training selectively enhances cognitive conflict resolution during late motor output planning stages.

Effects of acute and long-term mindfulness on neural activity and the conflict resolution component of attention.

Mindfulness practices have been linked to enhanced attention and conflict resolution abilities. While much research has focused on the long-term effects of mindfulness, the immediate impact of a single session has been less studied. This study recruited 20 experienced meditators and 20 novices and assigned them to a mindfulness or a control condition. They completed a Stroop Task to measure cognitive conflict resolution before and after the intervention, with brain activity monitored via functional near-infrared spectroscopy (fNIRS). Novices showed an age-related decline in conflict resolution ability, while experienced meditators didn't. Initially, both groups showed similar Stroop performance, but experienced meditators had greater brain activation in the left dorsolateral prefrontal cortex (DLPFC). Post-intervention, novices in the breath count task became more similar to experienced meditators in their neural activity during conflict resolution. Our findings indicate that long-term mindfulness experience may protect against age-related decline in cognitive conflict resolution speed, and may alter neural processing of cognitive conflict resolution.

Music Training, and the Ability of Musicians to Harmonize, Are Associated With Enhanced Planning and Problem-Solving.

Music training is associated with enhanced executive function but little is known about the extent to which harmonic aspects of musical training are associated with components of executive function. In the current study, an array of cognitive tests associated with one or more components of executive function, was administered to young adult musicians and non-musicians. To investigate how harmonic aspects of musical training relate to executive function, a test of the ability to compose a four-part harmony was developed and administered to musicians. We tested the working hypothesis that musicians would outperform non-musicians on measures of executive function, and that among musicians, the ability to harmonize would correlate positively with measures of executive function. Results indicate that musicians outperformed non-musicians on the Tower of London task, a measure of planning and problem-solving. Group differences were not detected on tasks more selective for inhibitory control, conflict resolution, or working memory. Among musicians, scores on the harmony assessment were positively correlated with performance of the Tower of London task. Taken together, the current results support a strong relationship between musicianship and planning and problem solving abilities, and indicate that the ability to harmonize is associated with components of executive function contributing to planning and problem solving.

Music Training, Working Memory, and Neural Oscillations: A Review.

This review focuses on reports that link music training to working memory and neural oscillations. Music training is increasingly associated with improvement in working memory, which is strongly related to both localized and distributed patterns of neural oscillations. Importantly, there is a small but growing number of reports of relationships between music training, working memory, and neural oscillations in adults. Taken together, these studies make important contributions to our understanding of the neural mechanisms that support effects of music training on behavioral measures of executive functions. In addition, they reveal gaps in our knowledge that hold promise for further investigation. The current review is divided into the main sections that follow: (1) discussion of behavioral measures of working memory, and effects of music training on working memory in adults; (2) relationships between music training and neural oscillations during temporal stages of working memory; (3) relationships between music training and working memory in children; (4) relationships between music training and working memory in older adults; and (5) effects of entrainment of neural oscillations on cognitive processing. We conclude that the study of neural oscillations is proving useful in elucidating the neural mechanisms of relationships between music training and the temporal stages of working memory. Moreover, a lifespan approach to these studies will likely reveal strategies to improve and maintain executive function during development and aging.

Phosphorylation of tyrosine receptor kinase B in the dorsal striatum and dorsal hippocampus is associated with response learning in a water plus maze.

The dorsal hippocampus and dorsal striatum have dissociable roles in learning and memory that are related to region-specific changes in proteins necessary for neuronal plasticity and memory formation. There is additional evidence that the hippocampus and striatum can interact during memory formation. Phosphorylation of tyrosine receptor kinase B is important for memory formation in the hippocampus, but whether or not it has a role in striatum-dependent learning, or in interactions between the hippocampus and striatum, has not been examined. In the present study, we tested the hypothesis that response training increases pTrkB in the dorsal striatum, but decreases pTrkB in dorsal hippocampus, due to an interaction between the systems during memory formation. Results show a significant decrease in pTrkB levels in the dorsal hippocampus of rats trained on the response task compared with swim controls. Response training did not increase pTrkB levels in the dorsal striatum. Positive correlations were found between response learning and the total area of cells expressing pTrkB in the dorsal striatum, while no correlations were found in swim controls. Our results partially support our hypothesis and indicate that response learning is associated with a decrease in hippocampal pTrkB, while phosphorylation of TrkB in the dorsal striatum remains constant. This indicates that suppression of hippocampal pTrkB during response learning may be involved in striatum-dependent memory formation. Additionally, our findings suggest that activation of TrkB in a sparse arrangement of cells may be associated with faster acquisition of a response task. (PsycINFO Database Record

Protein Phosphatase-1 Inhibitor-2 Is a Novel Memory Suppressor.

Reversible phosphorylation, a fundamental regulatory mechanism required for many biological processes including memory formation, is coordinated by the opposing actions of protein kinases and phosphatases. Type I protein phosphatase (PP1), in particular, has been shown to constrain learning and memory formation. However, how PP1 might be regulated in memory is still not clear. Our previous work has elucidated that PP1 inhibitor-2 (I-2) is an endogenous regulator of PP1 in hippocampal and cortical neurons (Hou et al., 2013). Contrary to expectation, our studies of contextual fear conditioning and novel object recognition in I-2 heterozygous mice suggest that I-2 is a memory suppressor. In addition, lentiviral knock-down of I-2 in the rat dorsal hippocampus facilitated memory for tasks dependent on the hippocampus. Our data indicate that I-2 suppresses memory formation, probably via negatively regulating the phosphorylation of cAMP/calcium response element-binding protein (CREB) at serine 133 and CREB-mediated gene expression in dorsal hippocampus. Surprisingly, the data from both biochemical and behavioral studies suggest that I-2, despite its assumed action as a PP1 inhibitor, is a positive regulator of PP1 function in memory formation. SIGNIFICANCE STATEMENT: We found that inhibitor-2 acts as a memory suppressor through its positive functional influence on type I protein phosphatase (PP1), likely resulting in negative regulation of cAMP/calcium response element-binding protein (CREB) and CREB-activated gene expression. Our studies thus provide an interesting example of a molecule with an in vivo function that is opposite to its in vitro function. PP1 plays critical roles in many essential physiological functions such as cell mitosis and glucose metabolism in addition to its known role in memory formation. PP1 pharmacological inhibitors would thus not be able to serve as good therapeutic reagents because of its many targets. However, identification of PP1 inhibitor-2 as a critical contributor to suppression of memory formation by PP1 may provide a novel therapeutic target for memory-related diseases.

Effects of lentivirus-mediated CREB expression in the dorsolateral striatum: memory enhancement and evidence for competitive and cooperative interactions with the hippocampus.

Neural systems specialized for memory may interact during memory formation or recall, and the results of interactions are important determinants of how systems control behavioral output. In two experiments, we used lentivirus-mediated expression of the transcription factor CREB (LV-CREB) to test if localized manipulations of cellular plasticity influence interactions between the hippocampus and dorsolateral striatum. In Experiment 1, we tested the hypothesis that infusion of LV-CREB in the dorsolateral striatum facilitates memory for response learning, and impairs memory for place learning. LV-CREB in the dorsolateral striatum had no effect on response learning, but impaired place memory; a finding consistent with competition between the striatum and hippocampus. In Experiment 2, we tested the hypothesis that infusion of LV-CREB in the dorsolateral striatum facilitates memory for cue learning, and impairs memory for contextual fear conditioning. LV-CREB in the dorsolateral striatum enhanced memory for cue learning and, in contrast to our prediction, also enhanced memory for contextual fear conditioning, consistent with a cooperative interaction between the striatum and hippocampus. Overall, the current experiments demonstrate that infusion of LV-CREB in the dorsolateral striatum (1) increases levels of CREB protein locally, (2) does not alter acquisition of place, response, cue, or contextual fear conditioning, (3) facilitates memory for cue learning and contextual fear conditioning, and (4) impairs memory for place learning. Taken together, the present results provide evidence that LV-CREB in the dorsolateral striatum can enhance memory formation and cause both competitive and cooperative interactions with the hippocampus.

Lentivirus-mediated chronic expression of dominant-negative CREB in the dorsal hippocampus impairs memory for place learning and contextual fear conditioning.

Extensive research has shown that the transcription factor CREB has an important role during memory formation. In the present study, we tested a new method for chronic, stable expression of a dominant-negative form of CREB (mCREB) in the dorsal hippocampus using lentiviral vectors. In specific, we tested whether lentivirus-mediated chronic expression of mutant CREB impairs memory for two hippocampus-dependent tasks - place training in the water maze and contextual fear conditioning. Two weeks following intra-hippocampal infusion, experimental (mCREB) and control (LacZ and saline) rats were trained for 30 trials in one session on a place task in a water plus-maze and tested for an additional 30 trials on day 2 and on day 7. On day 8, all rats were trained on a contextual fear conditioning task and tested 24h later. For place learning, there was no difference between treatment groups on day 1, indicating that treatment with the lentiviral vectors did not alter performance or acquisition of the task. In comparisons with controls, mCREB-treated rats were not significantly impaired on day 2, overall, but they showed significant impairment on day 7. Contextual fear memory was impaired in mCREB-infused rats in comparison with controls. At the end of the experiment, total CREB and phosphorylated CREB protein were measured by western blot. Levels of total CREB were increased by approximately 40% among mCREB-treated rats in comparisons with controls, whereas levels of pCREB did not differ between groups, suggesting that the treatment caused significant expression of mCREB. In addition, mCREB infused rats showed a significant reduction in the pCREB to CREB ratio in comparison with controls, suggesting that the memory deficit seen in mCREB rats is most likely due to disruption of gene regulation caused by expression of mutant CREB. Taken together, the present results show that lentivirus expressing mCREB can be used to effectively alter CREB function within the hippocampus and that the treatment impairs memory for hippocampus-dependent tasks.

The orbitofrontal cortex is not necessary for acquisition or remote recall of socially transmitted food preferences.

A role for prefrontal cortex has been proposed in systems consolidation of memory. The current study examined the effects of excitotoxic lesions of the orbitofrontal cortex (OFC) in rats on acquisition and remote recall of socially transmitted food preferences (STFP). Subjects received excitotoxic lesions of the OFC, and they were trained on two food preferences. They were tested 1h after the first training session to determine the effect of the lesion on acquisition. The following day, they were trained on a second preference and tested 10 days later to determine the effect of the lesion on remote recall. OFC lesions did not impair either STFP acquisition or remote recall in comparisons with sham-operated animals. In addition, a subset of animals underwent odor discrimination and reversal training. Consistent with previous reports, subjects with OFC lesions required more trials to reach criterion and made more errors during reversal training than did sham-operated animals. Taken together, the results of the present study indicate that the orbitofrontal cortex is not necessary for acquisition or systems consolidation of socially transmitted food preferences.

Transfection of mutant CREB in the striatum, but not the hippocampus, impairs long-term memory for response learning.

Extensive research has shown that the striatum is necessary for response learning. We reported previously that rats using a response strategy to solve a cross maze task showed sustained phosphorylation of striatal CREB [Colombo, P. J., Brightwell, J. J., & Countryman, R. A. (2003). Cognitive strategy-specific increases in phosphorylated cAMP response element-binding protein and c-Fos in the hippocampus and dorsal striatum. Journal of Neuroscience, 23(8), 3547-3554], a transcription factor implicated in long-term memory formation. In the current study, we used viral vector-mediated gene transfer to test the hypothesis that CREB function in the dorsolateral striatum is necessary for the formation of long-term memory for a response strategy. In addition, we tested the hypothesis that the striatum and the hippocampus interact in a cooperative or competitive manner during memory formation. CREB function was blocked in the dorsolateral striatum by overexpression of a mutant form of CREB in which Ser133 was replaced with Ala (HSV-mCREB). CREB function was increased or decreased in the dorsal hippocampus by overexpressing wild-type CREB (HSV-CREB) or mutant CREB. Rats were trained to make a consistent turning response in one session to a criterion of 9 out of 10 correct trials in a water version of the cross maze. Experimental subjects and controls were trained 3 days following infusion into the hippocampus or striatum and tested for memory of the strategy 6 days later. There were no significant differences between treatment groups in acquisition of the task. At test, controls showed significant savings whereas rats infused with HSV-mCREB in the striatum did not. Rats receiving intrahippocampal overexpression of HSV-CREB, HSV-mCREB, or vehicle all showed significant savings between training and test. The present results show that long-term memory of a response strategy requires CREB function in the dorsolateral striatum and is independent of CREB function in the dorsal hippocampus.

Time-courses of Fos expression in rat hippocampus and neocortex following acquisition and recall of a socially transmitted food preference.

The present study examined expression of the immediate-early gene, c-Fos, following acquisition, 48-h (recent) recall, and 1-week (remote) recall of a socially transmitted food preference (STFP) in multiple brain regions implicated in learning and memory. In comparisons with controls, trained Long-Evans rats had increased Fos immunoreactivity in the ventral hippocampus following acquisition and recent recall. In the parahippocampal cortices, Fos was increased in the lateral entorhinal cortex after acquisition. In the orbitofrontal cortex, increased Fos immunoreactivity was observed in the lateral orbital cortex following both recent and remote recall and in the ventral orbital cortex following remote recall, indicating a role for the orbitofrontal cortex in the remote recall of STFP memory. In contrast, in the medial prefrontal cortex, increased Fos-ir was found following acquisition in the prelimbic cortex and following recent recall in the prelimbic and infralimbic cortices. No differences in Fos expression were found between trained rats and controls in the dorsal hippocampus, posterior parietal cortex, or amygdala. The present findings support a time-limited role of the hippocampus in the acquisition and recall of STFP memory and implicate neocortical regions involved in STFP acquisition, recent, and remote recall.

Long-term memory for place learning is facilitated by expression of cAMP response element-binding protein in the dorsal hippocampus.

Extensive research has shown that the hippocampus is necessary for consolidation of long-term spatial memory in rodents. We reported previously that rats using a place strategy to solve a cross maze task showed sustained phosphorylation of hippocampus cyclic AMP response element-binding protein (CREB), a transcription factor implicated in long-term memory formation. In the current study, we used viral vector-mediated gene transfer to test the hypothesis that formation of long-term memory for place learning can be facilitated by increasing levels of CREB in the dorsal hippocampus. Three days after intrahippocampus infusion, experimental (HSV-CREB) and control (HSV-LacZ; saline) rats were trained during a single session on a place task in a water cross maze. Rats were tested for memory 5 d later. Rats in all groups showed short-term memory, and there were no significant differences among treatment groups during acquisition. However, only HSV-CREB-infused rats showed significant savings between training and test, while HSV-LacZ- and saline-treated rats did not. Quantitative Western blotting confirmed that levels of dorsal hippocampus CREB were increased during training in rats infused with HSV-CREB in comparisons with controls. The present results show that formation of long-term memory can be facilitated by increasing levels of hippocampus CREB protein.

NMDA receptors regulate developmental gap junction uncoupling via CREB signaling.

Signaling through gap junctions (electrical synapses) is important in the development of the mammalian central nervous system. Abundant between neurons during postnatal development, gap junction coupling subsequently decreases and remains low in the adult, confined to specific subsets of neurons. Here we report that developmental uncoupling of gap junctions in the rat hypothalamus in vivo and in vitro is associated with a decrease in connexin 36 (Cx36) protein expression. Both developmental gap junction uncoupling and Cx36 downregulation are prevented by the blockade of NMDA glutamate receptors, action potentials and the calcium-cyclic AMP response element binding protein (CREB), and are accelerated by CREB overexpression. Developmental gap junction uncoupling and Cx36 downregulation are not affected by blockade of non-NMDA glutamate receptors, and do not occur in hypothalamic neurons from NMDA receptor subunit 1 (NMDAR1) knockout mice. These results demonstrate that NMDA receptor activity contributes to the developmental uncoupling of gap junctions via CREB-dependent downregulation of Cx36.

Hippocampal c-fos is necessary for long-term memory of a socially transmitted food preference.

The present article examined the requirement of hippocampal c-Fos for learning a socially transmitted food preference (STFP). We reported previously that expression of the c-Fos protein is increased in the dorsal and ventral hippocampus of rats trained on the STFP (Countryman, Orlowski, Brightwell, Oskowitz, & Colombo, 2005). Pretraining intrahippocampal antisense to the immediate early gene c-fos was administered to adult male Long-Evans rats to determine if c-fos expression is necessary for either short- or long-term memory for STFP. Guide cannulae were implanted bilaterally into the dorsal hippocampus. Antisense oligodeoxynucleotides (ODNs) were administered unilaterally either 6.5, 8.5, 10.5, or 12.5 h prior to STFP training while either sense ODNs or saline were infused into the opposite hemisphere. Immunocytochemistry was performed, and cells showing c-Fos immunoreactivity (ir) were counted from the antisense-treated hemisphere and compared to cell counts from the control hemisphere. The results indicated significant suppression of learning-induced c-Fos protein at the 8.5 and 10.5 infusion-train intervals. Additional rats were implanted with cannulae into the dorsal and ventral hippocampus, and antisense ODNs, sense ODNs, or saline were administered bilaterally 8.5h prior to training. Rats were tested immediately and 14 days after training. Rats in all groups showed a significant preference for the demonstrated food at the short-term memory test. At the long-term memory test, however, rats infused with c-fos antisense showed no preference for the demonstrated food whereas rats infused with either sense or saline maintained their preference. The present findings suggest that c-fos is necessary for consolidation of non-spatial hippocampal-dependent memory.

Hippocampal overexpression of mutant creb blocks long-term, but not short-term memory for a socially transmitted food preference.

Phosphorylation of the transcription factor CREB on Ser133 is implicated in the establishment of long-term memory for hippocampus-dependent tasks, including spatial learning and contextual fear conditioning. We reported previously that training on a hippocampus-dependent social transmission of food preference (STFP) task increases CREB phosphorylation in the hippocampus of trained rats in comparisons with controls. In the current study, we tested the hypothesis that CREB function is necessary for long-term memory for STFP using herpes simplex viral (HSV) vector-mediated gene transfer. Rats received intrahippocampal infusions of HSV-mCREB (a mutant form of CREB, in which Ser133 has been replaced with Ala), HSV-LacZ, or saline, and were trained 3 d later. Rats were tested for food preference (demonstrated vs. novel foods) immediately (short-term test) and 11 d (long-term test) after training. Rats in all treatment groups showed a significant preference for the demonstrated food at the short-term memory test. At the long-term memory test, however, the percentage of demonstrated food eaten by mCREB-treated rats was significantly less than that eaten by the LacZ- or saline-treated rats. Quantitative Western blotting confirmed that mCREB-infused rats had significantly more hippocampal CREB protein than controls during training. The present results show that hippocampal CREB function is necessary for long-term, but not short-term memory for STFP.

CREB phosphorylation and c-Fos expression in the hippocampus of rats during acquisition and recall of a socially transmitted food preference.

In the present study, phosphorylation of cAMP-response element binding protein (pCREB) and expression of c-Fos were measured in the dorsal and ventral hippocampus, as well as in a control region, the retrosplenial cortex, of rats following acquisition and recall of a socially transmitted food preference (STFP). Behavioral analyses revealed that STFP-trained rats showed a stronger preference for the demonstrated food than did rats in social-control or odor-control conditions. Rats in a social + odor control condition displayed an intermediate preference that was not significantly different from either STFP-trained rats or the social- or odor-controls. Immunocytochemical analyses revealed increased pCREB-immunoreactivity (ir) in the ventral hippocampus of STFP-trained rats in comparisons with rats in all three control conditions and increased pCREB-ir in the dorsal hippocampus in comparisons with the social- and odor-control conditions. In contrast, c-Fos-ir was greater in the dorsal hippocampus of STFP-trained rats in comparisons with all three control conditions and greater in the ventral hippocampus than rats in the social- and odor-control conditions. Comparisons of pCREB-ir and c-Fos-ir were made also between STFP-trained rats and social-controls following either acquisition or a 48-h recall test. c-Fos-ir was greater in STFP-trained rats after both acquisition and recall, whereas pCREB was greater after recall only. There were no differences in either c-Fos-ir or pCREB-ir in comparisons between trained and control rats in the retrosplenial cortex. The current results indicate that the activity of transcription factors in the hippocampus is related to both acquisition and retention of a socially transmitted food preference.

Learning-induced activation of transcription factors among multiple memory systems.

Experimental evidence for multiple memory systems grew initially from reports that integrity of the medial temporal lobes is necessary for some, but not all, types of memory formation. A primary inference from many studies of multiple memory systems is that they operate independently during encoding, storage, and retrieval of information. An accumulation of recent evidence, however, suggests that multiple memory systems may interact under some conditions. At the cellular level of analysis, it is accepted widely that protein synthesis is necessary for the formation of long-term memory and recent efforts have focused on the mechanisms by which learning-induced gene transcription and translation are regulated. The present review examines learning-induced activation of transcription factors among multiple memory systems. The results indicate that studies of transcriptional regulation, in conjunction with other experimental approaches, can provide complementary lines of evidence to further understanding of the extent to which multiple memory systems are independent or interactive.