Impaired Motor Skill Learning Research Articles

Balance Between Projecting Neuronal Populations of the Nucleus Accumbens Controls Social Behavior in Mice

BackgroundDeficient social interactions are a hallmark of major neuropsychiatric disorders, and accumulating evidence points to altered social reward and motivation as key underlying mechanisms of these pathologies. In the present study, we further explored the role of the balance of activity between D1 and D2 receptor–expressing striatal projection neurons (D1R- and D2R-SPNs) in the control of social behavior, challenging the hypothesis that excessive D2R-SPN activity, rather than deficient D1R-SPN activity, compromises social behavior. MethodsWe selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor–mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function, and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the nucleus accumbens (NAc) and pharmacological compounds repressing D2R-SPN. ResultsTargeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated motor skill learning, and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum. Ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior but impaired motor skill learning and decreased anxiety levels. Deletion of D2R-SPNs in the NAc produced motor stereotypies but facilitated social behavior and impaired motor skill learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and observed a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition. ConclusionsRepressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficits in neuropsychiatric disorders.

Synaptic and Genetic Bases of Impaired Motor Learning Associated with Modified Experience-Dependent Cortical Plasticity in Heterozygous Reeler Mutants.

Patients with neurodevelopmental disorders show impaired motor skill learning. It is unclear how the effect of genetic variation on synaptic function and transcriptome profile may underlie experience-dependent cortical plasticity, which supports the development of fine motor skills. RELN (reelin) is one of the genes implicated in neurodevelopmental psychiatric vulnerability. Heterozygous reeler mutant (HRM) mice displayed impairments in reach-to-grasp learning, accompanied by less extensive cortical map reorganization compared with wild-type mice, examined after 10days of training by intracortical microstimulation. Assessed by patch-clamp recordings after 3days of training, the training induced synaptic potentiation and increased glutamatergic-transmission of cortical layer III pyramidal neurons in wild-type mice. In contrast, the basal excitatory and inhibitory synaptic functions were depressed, affected both by presynaptic and postsynaptic impairments in HRM mice; and thus, no further training-induced synaptic plasticity occurred. HRM exhibited downregulations of cortical synaptophysin, immediate-early gene expressions, and gene enrichment, in response to 3days of training compared with trained wild-type mice, shown using quantitative reverse transcription polymerase chain reaction, immunohistochemisty, and RNA-sequencing. We demonstrated that motor learning impairments associated with modified experience-dependent cortical plasticity are at least partially attributed by the basal synaptic alternation as well as the aberrant early experience-induced gene enrichment in HRM.

1339-P: Peripheral RNA Biomarkers for Neurocognitive Impairment in the Mouse Models of Offspring from Mother with Diabetes

Diabetes during gestation negatively correlates with cognitive and behavioral functions of the child. To better understand the correlation, we aim at defining peripheral biomarkers of cognitive impairment in offspring from mother with diabetes (OMD). As the first step, we established mouse model of OMD. Six weeks old CD-1 female mice received intraperitoneal (i.p.) injection of streptozotocin (STZ) (150mg/kg). Following confirmation of diabetes 2 weeks post STZ injection, these animals were crossed with normal male to give OMD. The accelerated rotarod test was performed on OMD (n=26) and the control animals (n=30) at postnatal day 30-31. OMD shows impaired motor skill learning (p<0.05). From OMD and the control animals, three subtypes (T cell, B cell and monocytes) of white blood cells were sorted by using Flow cytometer for RNA sequencing. We performed both differential expression and splicing analyses. Interestingly, by comparing another mouse offspring model of fetal stress exposure, fetal alcohol spectrum disorders (FASD) model, offspring from dam received i.p. injections of 25% ethanol at 4.0 g/kg daily at embryonic day 16-17, that shows the same motor skill learning deficits, we found that common differential alternative splicing events between OMD and FASD. 13, 16, and 0 alternative splicing events are defined in T cell, B cell and monocytes respectively. In contrast, there are very few common differential gene expressions. Deep learning with those common alternative splicing biomarkers in T cell gave ∼0.8 accuracy in classification of good and poor learners. Collectively, these results demonstrate potential of the alternative splicing events as the biomarkers of cognitive impairment in OMD. Disclosure J. Sasaki: None. D. Dutta: None. K. Sugai: None. T. Sasaki: None. A. Bansal: None. S. Yamashita: None. M. Odawara: Speaker’s Bureau; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Company, Ltd., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Astellas Pharma Inc., AstraZeneca, Daiichi Sankyo, Eli Lilly Japan K.K., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi-Aventis, Sanwa Kagaku Kenkyusho, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. M. Torii: None. K. Hashimoto-Torii: None. Funding National Institutes of Health (UH2AA026106)

Impaired motor skill learning and altered seizure susceptibility in mice with loss or gain of function of the Kcnt1 gene encoding Slack (KNa1.1) Na+-activated K+ channels

Gain-of-function mutations in KCNT1, the gene encoding Slack (KNa1.1) channels, result in epilepsy of infancy with migrating focal seizures (EIMFS) and several other forms of epilepsy associated with severe intellectual disability. We have generated a mouse model of this condition by replacing the wild type gene with one encoding Kcnt1R455H, a cytoplasmic C-terminal mutation homologous to a human R474H variant that results in EIMFS. We compared behavior patterns and seizure activity in these mice with those of wild type mice and Kcnt1−/− mice. Complete loss of Kcnt1 produced deficits in open field behavior and motor skill learning. Although their thresholds for electrically and chemically induced seizures were similar to those of wild type animals, Kcnt1−/− mice were significantly protected from death after maximum electroshock-induced seizures. In contrast, homozygous Kcnt1R455H/R455H mice were embryonic lethal. Video-EEG monitoring of heterozygous Kcnt1+/R455H animals revealed persistent interictal spikes, spontaneous seizures and a substantially decreased threshold for pentylenetetrazole-induced seizures. Surprisingly, Kcnt1+/R455H mice were not impaired in tasks of exploratory behavior or procedural motor learning. These findings provide an animal model for EIMFS and suggest that Slack channels are required for the development of procedural learning and of pathways that link cortical seizures to other regions required for animal survival.

Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome

BackgroundFragile X syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, fragile X mental retardation protein. Fmr1 global knockout (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS. MethodsTaking advantage of the Cre-lox system, we generated and characterized mice in which fragile X mental retardation protein is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects. ResultsWe found that adult astrocyte-specific Fmr1 KO mice displayed increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. Although spine density was normal at 1 month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, fragile X mental retardation protein expression in only astrocytes was insufficient to rescue most spine or behavioral defects. ConclusionsOur work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice.

Motor-Skill Learning Is Dependent on Astrocytic Activity

Motor-skill learning induces changes in synaptic structure and function in the primary motor cortex through the involvement of a long-term potentiation- (LTP-) like mechanism. Although there is evidence that calcium-dependent release of gliotransmitters by astrocytes plays an important role in synaptic transmission and plasticity, the role of astrocytes in motor-skill learning is not known. To test the hypothesis that astrocytic activity is necessary for motor-skill learning, we perturbed astrocytic function using pharmacological and genetic approaches. We find that perturbation of astrocytes either by selectively attenuating IP3R2 mediated astrocyte Ca2+ signaling or using an astrocyte specific metabolic inhibitor fluorocitrate (FC) results in impaired motor-skill learning of a forelimb reaching-task in mice. Moreover, the learning impairment caused by blocking astrocytic activity using FC was rescued by administration of the gliotransmitter D-serine. The learning impairments are likely caused by impaired LTP as FC blocked LTP in slices and prevented motor-skill training-induced increases in synaptic AMPA-type glutamate receptor in vivo. These results support the conclusion that normal astrocytic Ca2+ signaling during a reaching task is necessary for motor-skill learning.

Altered Structural and Functional Synaptic Plasticity with Motor Skill Learning in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited intellectual disability. FXS results from a mutation that causes silencing of the FMR1 gene, which encodes the fragile X mental retardation protein. Patients with FXS exhibit a range of neurological deficits, including motor skill deficits. Here, we have investigated motor skill learning and its synaptic correlates in the fmr1 knock-out (KO) mouse. We find that fmr1 KO mice have impaired motor skill learning of a forelimb-reaching task, compared with their wild-type (WT) littermate controls. Electrophysiological recordings from the forelimb region of the primary motor cortex demonstrated reduced, training-induced synaptic strengthening in the trained hemisphere. Moreover, long-term potentiation (LTP) is impaired in the fmr1 KO mouse, and motor skill training does not occlude LTP as it does in the WT mice. Whereas motor skill training induces an increase of synaptic AMPA-type glutamate receptor subunit 1 (GluA1), there is a delay in GluA1 increase in the trained hemisphere of the fmr1 KO mice. Using transcranial in vivo multiphoton microscopy, we find that fmr1 KO mice have similar spine density but increased dendritic spine turnover compared with WT mice. Finally, we report that motor skill training-induced formation of dendritic spines is impaired in fmr1 KO mice. We conclude that FMRP plays a role in motor skill learning and that reduced functional and structural synaptic plasticity might underlie the behavioral deficit in the fmr1 KO mouse.

P 92. Effect of transcranial direct current stimulation (tDCS) on complex motor skill learning

Transcranial direct current stimulation (tDCS) applied over primary motor cortex (M1) has been shown to influence motor skill learning in a polarity-dependent manner. Most of the studies used simplified models of motor skill learning with particular emphasis on hand movements with sequential character. However, the effect of tDCS on complex multi-joint learning paradigms has so far not been investigated. The aim of the study was to investigate polarity-specific tDCS effects on motor skill learning and consolidation in a complex whole-body dynamic balance task (DBT). We hypothesized that tDCS over the supplementary motor area (SMA), a region that is known to be involved in the control of multi-joint whole-body movements, will result in polarity specific changes in DBT learning. In a parallel double-blinded design we applied 20 min of either anodal or cathodal tDCS over the supplementary motor area (SMA), while subjects performed a complex whole-body dynamic balancing task (DBT). A reference electrode was attached over the right forehead. For the DBT we used a discovery learning approach in which no information about the performance strategy was provided. Therefore, during the time course of DBT learning, subjects had to discover their optimal strategy to improve task performance. 20 min of anodal tDCS over SMA with a reference electrode (cathode) placed over the right forehead impaired motor skill learning of the DBT compared to sham. This effect was still present on the second day of training. Reversing the polarity (cathode over SMA, anode over right forehead) did not affect motor skill learning neither on the first nor on the second day of training. To better disentangle whether the impaired motor skill learning was due to a modulation of SMA or prefrontal regions, we performed an additional control experiment. Hence, we applied anodal tDCS over SMA together with a larger presumably more ineffective reference electrode (cathode) over the right forehead. Interestingly, this alternative tDCS electrode setup did not affect the outcome of DBT learning. Our results provide novel evidence, that a modulation of the prefrontal cortex by the cathodal (reference) tDCS electrode impairs complex multi-joint motor skill learning. We suggest that inhibition of higher cognitive processes (e.g. strategy finding, feedback processing) rather than excitation of SMA might explain our finding. Hence, future studies should take the positioning of the tDCS reference electrode into account when investigating complex motor skill learning.

Effect of transcranial direct current stimulation (tDCS) during complex whole body motor skill learning

The aim of the study was to investigate tDCS effects on motor skill learning in a complex whole body dynamic balance task (DBT). We hypothesized that tDCS over the supplementary motor area (SMA), a region that is known to be involved in the control of multi-joint whole body movements, will result in polarity specific changes in DBT learning. In a randomized sham-controlled, double-blinded parallel design, we applied 20min of tDCS over the supplementary motor area (SMA) and prefrontal cortex (PFC) while subjects performed a DBT. Anodal tDCS over SMA with the cathode placed over contralateral PFC impaired motor skill learning of the DBT compared to sham. This effect was still present on the second day of training. Reversing the polarity (cathode over SMA, anode over PFC) did not affect motor skill learning neither on the first nor on the second day of training. To better disentangle whether the impaired motor skill learning was due to a modulation of SMA or PFC, we performed an additional control experiment. Here, we applied anodal tDCS over SMA together with a larger and presumably more ineffective electrode (cathode) over PFC. Interestingly this alternative tDCS electrode setup did not affect the outcome of DBT learning. Our results provide novel evidence that a modulation of the (right) PFC seems to impair complex multi-joint motor skill learning. Hence, future studies should take the positioning of both tDCS electrodes into account when investigating complex motor skill learning.

GL.03 Molecular windows into speech and language disorders

People who carry rare heterozygous mutations disrupting the FOXP2 gene have problems mastering the complex sequences of mouth movements needed for speech, along with deficits in many aspects of expressive...

A28 Accumulation and aggregation of human mutant huntingtin and neuron atrophy in BAC-HD transgenic rat

Background and aimWe have previously generated and characterised in detail transgenic rats which express a fragment of mutant huntingtin (htt). This rat model mirrors many aspects of Huntington's disease (HD)...

The structure of innate vocalizations in Foxp2‐deficient mouse pups

Heterozygous mutations of the human FOXP2 gene are implicated in a severe speech and language disorder. Aetiological mutations of murine Foxp2 yield abnormal synaptic plasticity and impaired motor-skill learning in mutant mice, while knockdown of the avian orthologue in songbirds interferes with auditory-guided vocal learning. Here, we investigate influences of two distinct Foxp2 point mutations on vocalizations of 4-day-old mouse pups (Mus musculus). The R552H missense mutation is identical to that causing speech and language deficits in a large well-studied human family, while the S321X nonsense mutation represents a null allele that does not produce Foxp2 protein. We ask whether vocalizations, based solely on innate mechanisms of production, are affected by these alternative Foxp2 mutations. Sound recordings were taken in two different situations: isolation and distress, eliciting a range of call types, including broadband vocalizations of varying noise content, ultrasonic whistles and clicks. Sound production rates and several acoustic parameters showed that, despite absence of functional Foxp2, homozygous mutants could vocalize all types of sounds in a normal temporal pattern, but only at comparably low intensities. We suggest that altered vocal output of these homozygotes may be secondary to developmental delays and somatic weakness. Heterozygous mutants did not differ from wild-types in any of the measures that we studied (R552H) or in only a few (S321X), which were in the range of differences routinely observed for different mouse strains. Thus, Foxp2 is not essential for the innate production of emotional vocalizations with largely normal acoustic properties by mouse pups.

Impaired motor-skill learning, slowed reaction time, and elevated cerebrospinal-fluid quinolinic acid in a subgroup of HIV-infected individuals.

Impaired motor-skill learning, slowed reaction time, and elevated cerebrospinal-fluid quinolinic acid in a subgroup of HIV-infected individuals.

Impaired motor-skill learning, slowed reaction time, and elevated cerebrospinal-fluid quinolinic acid in a subgroup of HIV-infected individuals.

Impaired motor-skill learning, slowed reaction time, and elevated cerebrospinal-fluid quinolinic acid in a subgroup of HIV-infected individuals.