Brainstem Circuits for Locomotion

Annual Review of Neuroscience, Год журнала: 2022, Номер 45(1), С. 63 - 85

Опубликована: Янв. 5, 2022

Locomotion is a universal motor behavior that expressed as the output of many integrated brain functions. organized at several levels nervous system, with brainstem circuits acting gate between areas regulating innate, emotional, or motivational locomotion and executive spinal circuits. Here we review recent advances on involved in controlling locomotion. We describe how delineated command govern start, speed, stop, steering also discuss these pathways interface cord diverse important for context-specific selection A recurrent theme need to establish functional connectome from Finally, point unresolved issues concerning function locomotor control.

Язык: Английский

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Basal ganglia–spinal cord pathway that commands locomotor gait asymmetries in mice

Nature Neuroscience, Год журнала: 2024, Номер 27(4), С. 716 - 727

Опубликована: Фев. 12, 2024

Abstract The basal ganglia are essential for executing motor actions. How the engage spinal networks has remained elusive. Medullary Chx10 gigantocellular (Gi) neurons required turning gait programs, suggesting that gaits organized by executed via this descending pathway. Performing deep brainstem recordings of Gi Ca 2+ activity in adult mice, we show striatal projection initiate a dominant crossed pathway to on contralateral side. Using intersectional viral tracing and cell-type-specific modulation, uncover principal ganglia–spinal cord locomotor asymmetries mice: → pontine reticular nucleus, oral part (PnO) cord. Modulating restricted PnO restores competence upon damage, dysfunction may contribute debilitating deficits observed Parkinson’s disease. Our results reveal stratified circuit architecture underlying critical program.

Язык: Английский

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Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic

Trends in Pharmacological Sciences, Год журнала: 2022, Номер 43(12), С. 1098 - 1112

Опубликована: Окт. 20, 2022

Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation peripheral mAChRs were not available at that time. The discovery specific targeted ligands and combination treatments reduce engagement have advanced potential as effective psychotic disorders. This review provides perspectives on background identification antipsychotics, advances preclinical understanding targets, current state under active clinical development schizophrenia.

Язык: Английский

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Optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus controls locomotion in a mouse model of Parkinson’s disease

Proceedings of the National Academy of Sciences, Год журнала: 2021, Номер 118(43)

Опубликована: Окт. 20, 2021

In Parkinson's disease (PD), the loss of midbrain dopaminergic cells results in severe locomotor deficits, such as gait freezing and akinesia. Growing evidence indicates that these deficits can be attributed to decreased activity mesencephalic region (MLR), a brainstem controlling locomotion. Clinicians are exploring deep brain stimulation MLR treatment option improve function. The variable, from modest promising. However, within MLR, clinicians have targeted pedunculopontine nucleus exclusively, while leaving cuneiform unexplored. To our knowledge, effects never been determined parkinsonian conditions any animal model. Here, we addressed this issue mouse model PD, based on bilateral striatal injection 6-hydroxydopamine, which damaged nigrostriatal pathway activity. We show selective optogenetic glutamatergic neurons mice expressing channelrhodopsin Cre-dependent manner Vglut2-positive (Vglut2-ChR2-EYFP mice) increased number initiations, time spent locomotion, controlled speed. Using learning-based movement analysis, found limb kinematics optogenetic-evoked locomotion pathological were largely similar those recorded intact animals. Our work identifies potentially clinically relevant target conditions. study should open avenues develop using stimulation, pharmacotherapy, or optogenetics.

Язык: Английский

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Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Янв. 26, 2022

Abstract The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control initiation and maintenance. These motor actions are deficient in Parkinson’s disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Being downstream of the ganglia, PPN may be suitable target for ameliorating parkinsonian symptoms. Here, we use vivo cell-type specific activation to restore function two mouse models parkinsonism made by acute pharmacological blockage dopamine transmission. With combination chemo- opto-genetics, show excitation caudal can normalize otherwise severe deficit PD, whereas targeting local GABAergic population only leads recovery slow locomotion. rescue driven independent activity nearby promoting Cuneiform neurons. Our observations point as potential neuromodulatory restoration PD.

Язык: Английский

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The Mesencephalic Locomotor Region: Beyond Locomotor Control

Frontiers in Neural Circuits, Год журнала: 2022, Номер 16

Опубликована: Май 9, 2022

The mesencephalic locomotor region (MLR) was discovered several decades ago in the cat. It functionally defined based on ability of low threshold electrical stimuli within a comprising cuneiform and pedunculopontine nucleus to evoke locomotion. Since then, similar regions have been found diverse vertebrate species, including lamprey, skate, rodent, pig, monkey, human. MLR, while often viewed under lens locomotion, is involved processes involving autonomic nervous system, respiratory state-dependent activation motor systems. This review will discuss that comprises MLR examine their respective connectomes from both an anatomical functional angle. From perspective, primes cardiovascular systems before activity occurs. Inputs variety higher structures, direct outputs monoaminergic nuclei, allow be able respond appropriately These effects are roughly divided into escape exploratory behavior, also can reinforce selection these behaviors through projections adjacent structures such as periaqueductal gray or limbic cortical regions. Findings rat, mouse, cat discussed highlight similarities differences among species.

Язык: Английский

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Pedunculopontine Chx10+ neurons control global motor arrest in mice

Nature Neuroscience, Год журнала: 2023, Номер 26(9), С. 1516 - 1528

Опубликована: Июль 27, 2023

Abstract Arrest of ongoing movements is an integral part executing motor programs. Behavioral arrest may happen upon termination a variety goal-directed or as global either in the context fear response to salient environmental cues. The neuronal circuits that bridge with executive implement are poorly understood. We report discovery activation glutamatergic Chx10-derived neurons pedunculopontine nucleus (PPN) mice arrests all while simultaneously causing apnea and bradycardia. This has pause-and-play pattern instantaneous interruption movement followed by short-latency continuation from where it was paused. Mice naturally perform bouts same combination autonomic features. Chx10-PPN-evoked different ventrolateral periaqueductal gray-induced freezing. Our study defines command induces arrest, which be recruited cues allow for preparatory arousal state, identifies locomotor-opposing role rostrally biased PPN.

Язык: Английский

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Re-examining the pathobiological basis of gait dysfunction in Parkinson’s disease

Trends in Neurosciences, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Freezing of Gait in Parkinson’s Disease: Invasive and Noninvasive Neuromodulation

Neuromodulation Technology at the Neural Interface, Год журнала: 2020, Номер 24(5), С. 829 - 842

Опубликована: Дек. 26, 2020

Язык: Английский

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The PPN and motor control: Preclinical studies to deep brain stimulation for Parkinson’s disease

Frontiers in Neural Circuits, Год журнала: 2023, Номер 17

Опубликована: Фев. 28, 2023

The pedunculopontine nucleus (PPN) is the major part of mesencephalic locomotor region, involved in control gait and locomotion. PPN contains glutamatergic, cholinergic, GABAergic neurons that all make local connections, but also have long-range ascending descending connections. While initially thought as a region only locomotion, recent evidence showing this structure participates decision-making to initiate movement. Clinically, has been used target for deep brain stimulation manage freezing late Parkinson’s disease. In review, we will discuss current thinking on role control. We focus cytoarchitecture functional connectivity relationship motor

Язык: Английский

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