Pathogenesis of dystonia: is it of cerebellar or basal ganglia origin?

Dystonia is a disorder of motor programmes controlling semiautomatic movements or postures, with clinical features such as sensory trick, which suggests sensorimotor mismatch as the basis. Dystonia was originally classified as a basal ganglia disease. It is now regarded as a 'network' disorder including the cerebellum, but the exact pathogenesis being unknown. Rare autopsy studies have found pathology both in the striatum and the cerebellum, and functional disorganisation was reported in the somatosensory cortex in patients. Recent animal studies showed physiologically tight disynaptic connections between the cerebellum and the striatum. We review clinical evidence in light of this new functional interaction between the cerebellum and basal ganglia, and put forward a hypothesis that dystonia is a basal ganglia disorder that can be induced by aberrant afferent inputs from the cerebellum

Practice Makes Imperfect: Restorative Effects of Sleep on Motor Learning

Emerging evidence suggests that sleep plays a key role in procedural learning, particularly in the continued development of motor skill learning following initial acquisition. We argue that a detailed examination of the time course of performance across sleep on the finger-tapping task, established as the paradigm for studying the effect of sleep on motor learning, will help distinguish a restorative role of sleep in motor skill learning from a proactive one. Healthy subjects rehearsed for 12 trials and, following a night of sleep, were tested. Early training rapidly improved speed as well as accuracy on pre-sleep training. Additional rehearsal caused a marked slow-down in further improvement or partial reversal in performance to observed levels below theoretical upper limits derived on the basis of early pre-sleep rehearsal. This decrement in learning efficacy does not occur always, but if and only if it does, overnight sleep has an effect in fully or partly restoring the efficacy and actual performance to the optimal theoretically achieveable level. Our findings re-interpret the sleep-dependent memory enhancement in motor learning reported in the literature as a restoration of fatigued circuitry specialized for the skill. In providing restitution to the fatigued brain, sleep eliminates the rehearsal-induced synaptic fatigue of the circuitry specialized for the task and restores the benefit of early pre-sleep rehearsal. The present findings lend support to the notion that latent sleep-dependent enhancement of performance is a behavioral expression of the brain's restitution in sleep

Genome-Wide Identification of Bcl11b Gene Targets Reveals Role in Brain-Derived Neurotrophic Factor Signaling

B-cell leukemia/lymphoma 11B (Bcl11b) is a transcription factor showing predominant expression in the striatum. To date, there are no known gene targets of Bcl11b in the nervous system. Here, we define targets for Bcl11b in striatal cells by performing chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in combination with genome-wide expression profiling. Transcriptome-wide analysis revealed that 694 genes were significantly altered in striatal cells over-expressing Bcl11b, including genes showing striatal-enriched expression similar to Bcl11b. ChIP-seq analysis demonstrated that Bcl11b bound a mixture of coding and non-coding sequences that were within 10 kb of the transcription start site of an annotated gene. Integrating all ChIP-seq hits with the microarray expression data, 248 direct targets of Bcl11b were identified. Functional analysis on the integrated gene target list identified several zinc-finger encoding genes as Bcl11b targets, and further revealed a significant association of Bcl11b to brain-derived neurotrophic factor/neurotrophin signaling. Analysis of ChIP-seq binding regions revealed significant consensus DNA binding motifs for Bcl11b. These data implicate Bcl11b as a novel regulator of the BDNF signaling pathway, which is disrupted in many neurological disorders. Specific targeting of the Bcl11b-DNA interaction could represent a novel therapeutic approach to lowering BDNF signaling specifically in striatal cells

Neurobiology of rodent self-grooming and its value for translational neuroscience

Self-grooming is a complex innate behaviour with an evolutionarily conserved sequencing pattern and is one of the most frequently performed behavioural activities in rodents. In this Review, we discuss the neurobiology of rodent self-grooming, and we highlight studies of rodent models of neuropsychiatric disorders-including models of autism spectrum disorder and obsessive compulsive disorder-that have assessed self-grooming phenotypes. We suggest that rodent self-grooming may be a useful measure of repetitive behaviour in such models, and therefore of value to translational psychiatry. Assessment of rodent self-grooming may also be useful for understanding the neural circuits that are involved in complex sequential patterns of action.National Institutes of Health (U.S.) (Grant NS025529)National Institutes of Health (U.S.) (Grant HD028341)National Institutes of Health (U.S.) (Grant MH060379

Predicting Individuals' Learning Success from Patterns of Pre-Learning MRI Activity

Performance in most complex cognitive and psychomotor tasks improves with training, yet the extent of improvement varies among individuals. Is it possible to forecast the benefit that a person might reap from training? Several behavioral measures have been used to predict individual differences in task improvement, but their predictive power is limited. Here we show that individual differences in patterns of time-averaged T2*-weighted MRI images in the dorsal striatum recorded at the initial stage of training predict subsequent learning success in a complex video game with high accuracy. These predictions explained more than half of the variance in learning success among individuals, suggesting that individual differences in neuroanatomy or persistent physiology predict whether and to what extent people will benefit from training in a complex task. Surprisingly, predictions from white matter were highly accurate, while voxels in the gray matter of the dorsal striatum did not contain any information about future training success. Prediction accuracy was higher in the anterior than the posterior half of the dorsal striatum. The link between trainability and the time-averaged T2*-weighted signal in the dorsal striatum reaffirms the role of this part of the basal ganglia in learning and executive functions, such as task-switching and task coordination processes. The ability to predict who will benefit from training by using neuroimaging data collected in the early training phase may have far-reaching implications for the assessment of candidates for specific training programs as well as the study of populations that show deficiencies in learning new skills

Repeated Methamphetamine Administration Differentially Alters Fos Expression in Caudate-Putamen Patch and Matrix Compartments and Nucleus Accumbens

Background: The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase (‘‘sensitization’’) in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum—the so-called patch/striosome and matrix. Methodology/Principal Findings: In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens). Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but no

Sonic Hedgehog Is a Chemoattractant for Midbrain Dopaminergic Axons

Midbrain dopaminergic axons project from the substantia nigra (SN) and the ventral tegmental area (VTA) to rostral target tissues, including the striatum, pallidum, and hypothalamus. The axons from the medially located VTA project primarily to more medial target tissues in the forebrain, whereas the more lateral SN axons project to lateral targets including the dorsolateral striatum. This structural diversity underlies the distinct functions of these pathways. Although a number of guidance cues have been implicated in the formation of the distinct axonal projections of the SN and VTA, the molecular basis of their diversity remains unclear. Here we investigate the molecular basis of structural diversity in mDN axonal projections. We find that Sonic Hedgehog (Shh) is expressed at a choice point in the course of the rostral dopaminergic projections. Furthermore, in midbrain explants, dopaminergic projections are attracted to a Shh source. Finally, in mice in which Shh signaling is inactivated during late neuronal development, the most medial dopaminergic projections are deficient

Distribution of GABAergic Interneurons and Dopaminergic Cells in the Functional Territories of the Human Striatum

BACKGROUND: The afferent projections of the striatum (caudate nucleus and putamen) are segregated in three territories: associative, sensorimotor and limbic. Striatal interneurons are in part responsible for the integration of these different types of information. Among them, GABAergic interneurons are the most abundant, and can be sorted in three populations according to their content in the calcium binding proteins calretinin (CR), parvalbumin (PV) and calbindin (CB). Conversely, striatal dopaminergic cells (whose role as interneurons is still unclear) are scarce. This study aims to analyze the interneuron distribution in the striatal functional territories, as well as their organization regarding to the striosomal compartment. METHODOLOGY/PRINCIPAL FINDINGS: We used immunohistochemical methods to visualize CR, PV, CB and tyrosine hydroxylase (TH) positive striatal neurons. The interneuronal distribution was assessed by stereological methods applied to every striatal functional territory. Considering the four cell groups altogether, their density was higher in the associative (2120±91 cells/mm(3)) than in the sensorimotor (959±47 cells/mm(3)) or limbic (633±119 cells/mm(3)) territories. CB- and TH-immunoreactive(-ir) cells were distributed rather homogeneously in the three striatal territories. However, the density of CR and PV interneurons were more abundant in the associative and sensorimotor striatum, respectively. Regarding to their compartmental organization, CR-ir interneurons were frequently found in the border between compartments in the associative and sensorimotor territories, and CB-ir interneurons abounded at the striosome/matrix border in the sensorimotor domain. CONCLUSIONS/SIGNIFICANCE: The present study demonstrates that the architecture of the human striatum in terms of its interneuron composition varies in its three functional territories. Furthermore, our data highlight the importance of CR-ir striatal interneurons in the integration of associative information, and the selective role of PV-ir interneurons in the motor territory. On the other hand, the low density of dopaminergic cells casts doubts about their role in the normal human striatum

Motor Skill Learning, Retention, and Control Deficits in Parkinson's Disease

Parkinson's disease, which affects the basal ganglia, is known to lead to various impairments of motor control. Since the basal ganglia have also been shown to be involved in learning processes, motor learning has frequently been investigated in this group of patients. However, results are still inconsistent, mainly due to skill levels and time scales of testing. To bridge across the time scale problem, the present study examined de novo skill learning over a long series of practice sessions that comprised early and late learning stages as well as retention. 19 non-demented, medicated, mild to moderate patients with Parkinson's disease and 19 healthy age and gender matched participants practiced a novel throwing task over five days in a virtual environment where timing of release was a critical element. Six patients and seven control participants came to an additional long-term retention testing after seven to nine months. Changes in task performance were analyzed by a method that differentiates between three components of motor learning prominent in different stages of learning: Tolerance, Noise and Covariation. In addition, kinematic analysis related the influence of skill levels as affected by the specific motor control deficits in Parkinson patients to the process of learning. As a result, patients showed similar learning in early and late stages compared to the control subjects. Differences occurred in short-term retention tests; patients' performance constantly decreased after breaks arising from poorer release timing. However, patients were able to overcome the initial timing problems within the course of each practice session and could further improve their throwing performance. Thus, results demonstrate the intact ability to learn a novel motor skill in non-demented, medicated patients with Parkinson's disease and indicate confounding effects of motor control deficits on retention performance