Genetics and Pathogenesis of Dystonia

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2023, Номер 19(1), С. 99 - 131

Опубликована: Сен. 22, 2023

Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements postures caused involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic molecular insights have recently been gained. While they enable testing counseling, their translation into new therapies still limited. However, we are beginning to understand shared pathophysiological pathways mechanisms. It has become clear that dystonia results from dysfunctional network involving the basal ganglia, cerebellum, thalamus, cortex. On level, more than handful of, often intertwined, linked pathogenic variants in genes, including gene transcription during neurodevelopment (e.g.,

Язык: Английский

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Cerebellar control of fear learning via the cerebellar nuclei–Multiple pathways, multiple mechanisms?

Frontiers in Systems Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Май 9, 2023

Fear learning is mediated by a large network of brain structures and the understanding their roles interactions constantly progressing. There multitude anatomical behavioral evidence on interconnection cerebellar nuclei to other in fear network. Regarding nuclei, we focus coupling fastigial nucleus relation dentate ventral tegmental area. Many that receive direct projections from are playing role expression or extinction learning. We propose cerebellum, via its limbic system, acts as modulator learning, using prediction-error signaling regulation related thalamo-cortical oscillations.

Язык: Английский

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New clues for the role of cerebellum in schizophrenia and the associated cognitive impairment

Frontiers in Cellular Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Май 10, 2024

Schizophrenia (SZ) is a complex neuropsychiatric disorder associated with severe cognitive dysfunction. Although research has mainly focused on forebrain abnormalities, emerging results support the involvement of cerebellum in SZ physiopathology, particularly Cognitive Impairment Associated (CIAS). Besides its role motor learning and control, implicated cognition emotion. Recent suggests that structural functional changes are linked to deficits various domains including attention, working memory, decision-making. Moreover, cerebellar dysfunction related altered circuit activities connectivity brain regions processing. This review delves into CIAS. We initially consider major alterations CIAS, addressing impairments neurotransmitter systems, synaptic plasticity, connectivity. then focus recent findings showing several mechanisms also communication impaired. evidence implicates as key component circuits underpinning CIAS physiopathology. Further studies warranted might open new perspectives toward understanding physiopathology effective treatment these disorders.

Язык: Английский

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Reward signals in the motor cortex: from biology to neurotechnology

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 3, 2025

Over the past decade, research has shown that primary motor cortex (M1), brain's main output for movement, also responds to rewards. These reward signals may shape in its final stages, influencing movement invigoration and learning. In this Perspective, we highlight functional roles of M1 propose how they could guide advances neurotechnologies restoration, specifically brain-computer interfaces non-invasive brain stimulation. Understanding open new avenues enhancing control rehabilitation. The (M1) not only drives but authors discuss M1's transform like stimulation recovery.

Язык: Английский

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Cerebellar control of targeted tongue movements

The Journal of Physiology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 26, 2025

Abstract The cerebellum is critical for coordinating movements related to eating, drinking and swallowing, all of which require proper control the tongue. Cerebellar Purkinje cells can encode tongue movements, but it unclear how their simple spikes complex induce changes in shape that contribute goal‐directed movements. To study these relations, we recorded stimulated vermis hemispheres mice during spontaneous licking from a stationary or moving water spout. We found rhythmic with both spikes. Increased spike firing protrusion induces ipsiversive bending Unexpected target location trigger alter subsequent licks, adjusting trajectory. Furthermore, observed increased behavioural state at start end bouts. Using machine learning, confirmed alterations cell activity accompany licking, different often exerting heterogeneous encoding schemes. Our data highlight directional movement paramount cerebellar function modulation are complementary acquisition execution sensorimotor coordination. These results bring us closer understanding clinical implications disorders swallowing. image Key points When drinking, make directed towards source. fire rhythmically tune position source affects direction report also adjust right direction.

Язык: Английский

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Subtle changes in Purkinje cell firing in Purkinje cell-specific Dyt1 ΔGAG knock-in mice

Dystonia, Год журнала: 2025, Номер 4

Опубликована: Янв. 29, 2025

DYT1 dystonia is an inherited early-onset generalized characterized by sustained muscle contractions causing abnormal, repetitive movements or postures. Most patients have a heterozygous trinucleotide GAG deletion ( ΔGAG ) in DYT1/TOR1A, coding for torsinA. Dyt1 knock-in (KI) mice global KI show motor deficits and abnormal Purkinje cell firing. However, cell-specific conditional (Pcp2-KI) improved performance, reduced sensory-evoked brain activation the striatum midbrain, functional connectivity of with anterior medulla. Whether Pcp2-KI similar firing as mice, suggesting cell-autonomous effect causes unknown. We used acute cerebellar slice recording to address this issue. The exhibited no changes spontaneous intrinsic excitability compared control mice. While membrane properties were largely unchanged, resting potential was slightly hyperpolarized, which associated decreased baseline excitability. Our results suggest that not caused physiological elsewhere circuits. also contribute ongoing research how basal ganglia cerebellum interact influence normal states movement disorders.

Язык: Английский

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The effect of cerebellar TMS on error processing: A combined single-pulse TMS and ERP study

Imaging Neuroscience, Год журнала: 2024, Номер 2, С. 1 - 19

Опубликована: Янв. 16, 2024

Abstract The present study investigated temporal aspects of cerebellar contributions to the processing performance errors as indexed by error-related negativity (ERN) in response-locked event-related potential (ERP). We co-registered EEG and applied single-pulse transcranial magnetic stimulation (spTMS) left posterolateral cerebellum an extra-cerebellar control region (vertex) while healthy adult volunteers performed a Go/Nogo Flanker Task. In Go trials, TMS pulses were at four different time points, with shifts -100 ms, -50 0 or +50 ms relative individual error latency (IEL, i.e., ERN peak + median response time). These timings aggregated into early (-100 ms) late (0 for analysis. Nogo occurred 100 300 after stimulus onset. Mixed linear model analyses revealed that did not affect rates overall. No effects found times. As hypothesized, amplitudes decreased stimulation. significant differences positivity (Pe). Similar application probe cerebellar-brain inhibition motor domain, inhibitory tone cortex may have been disrupted pulses. Reduced output facilitated information selection, which is reflected ERN.

Язык: Английский

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The Role of the Human Cerebellum for Learning from and Processing of External Feedback in Non-Motor Learning: A Systematic Review

The Cerebellum, Год журнала: 2024, Номер 23(4), С. 1532 - 1551

Опубликована: Фев. 20, 2024

Abstract This review aimed to systematically identify and comprehensively the role of cerebellum in performance monitoring, focusing on learning from processing external feedback non-motor learning. While 1078 articles were screened for eligibility, ultimately 36 studies included which was delivered cognitive tasks referenced cerebellum. These patient populations with cerebellar damage healthy subjects applying neuroimaging. Learning patients different diseases heterogeneous, only about half all showing alterations. One study using EEG demonstrated that associated altered neural feedback. Studies assessing brain activity task-based fMRI or PET one resting-state functional imaging investigated connectivity changes following feedback-based participants revealed involvement particularly lateral posterior regions Cerebellar found at stages, e.g., during anticipation onset stimuli, substantiating cerebellum’s relevance aspects monitoring such as prediction. Future research will need further elucidate precisely how , where, when modulates prediction information, subregions are relevant, what extent alter these processes.

Язык: Английский

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Striosomes control dopamine via dual pathways paralleling canonical basal ganglia circuits

Current Biology, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Язык: Английский

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Histamine Modulation of the Basal Ganglia Circuitry in the Motor Symptoms of Parkinson's Disease

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(2)

Опубликована: Фев. 1, 2025

Parkinson's disease (PD) is characterized by dopaminergic system dysfunction that results from the degeneration of neurons in substantia nigra. However, studies suggest other neurotransmitters, especially histamine, may also play a role development PD. Numerous show histamine levels basal ganglia significantly change PD pathology, correlating with motor symptoms observed animal models Histamine activates H1R or H4R on microglia nigra, triggering an inflammatory response and promoting neuron degeneration. Additionally, modulates neuronal excitability firing activity (firing rate pattern) activating H1R, H2R, H3R nucleus, ultimately impacting normal behavior as well This review presents its receptor ligands nuclei, along downstream ion channels linked to receptors influence immune response, excitability, It highlights their effects connection symptoms. Investigating new targeting associated facilitate novel treatments for

Язык: Английский

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