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, Journal Year: 2021, Volume and Issue: 118(43)

Published: Oct. 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.

Language: Английский

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The Mesencephalic Locomotor Region: Beyond Locomotor Control

Frontiers in Neural Circuits, Journal Year: 2022, Volume and Issue: 16

Published: May 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.

Language: Английский

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A translational roadmap for transcranial magnetic and direct current stimulation in stroke rehabilitation: Consensus-based core recommendations from the third stroke recovery and rehabilitation roundtable

International Journal of Stroke, Journal Year: 2023, Volume and Issue: 19(2), P. 145 - 157

Published: Oct. 12, 2023

The purpose of this Third Stroke Recovery and Rehabilitation Roundtable (SRRR3) was to develop consensus recommendations address outstanding barriers for the translation preclinical clinical research using non-invasive brain stimulation (NIBS) techniques Transcranial Magnetic Stimulation (TMS) Direct Current (tDCS) provide a roadmap integration these into practice.

Language: Английский

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Dynamically Controlled Flight Altitudes in Robo-Pigeons via Locus Coeruleus Neurostimulation

Research, Journal Year: 2025, Volume and Issue: 8

Published: Jan. 1, 2025

Robo-pigeons, a novel class of hybrid robotic systems developed using brain-computer interface technology, hold marked promise for search and rescue missions due to their superior load-bearing capacity sustained flight performance. However, current research remains largely confined laboratory environments, precise control behavior, especially altitude regulation, in large-scale spatial range outdoors continues pose challenge. Herein, we focus on overcoming this limitation by electrical stimulation the locus coeruleus (LoC) nucleus regulate outdoor altitude. We investigated effects varying parameters, including frequency (SF), interstimulus interval (ISI), cycles (SC), robo-pigeons. The findings indicate that SF functions as pivotal switch controlling ascending descending modes Specifically, 60 Hz effectively induced an average 12.241 m with 87.72% success rate, while 80 resulted 15.655 90.52% rate. below 40 did not affect change, whereas over 100 caused unstable flights. number SC was directly correlated magnitude enabling quantitative behavior. Importantly, LoC had no significant direction. This study is first establish targeted variation parameters within can achieve robo-pigeons, providing new insights advancing animal-robot real-world applications.

Language: Английский

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Pedunculopontine-stimulation obstructs hippocampal theta rhythm and halts movement

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: May 23, 2025

While the movement of rodents can be paused by optogenetic stimulation a brainstem nucleus, pedunculopontine nucleus (PPN), it is unknown whether this response has functional purpose. The arrest appears conspicuously similar to fear-induced freezing behavior and could constitute general halting mechanism for without an emotional component. Further, unclear what extent brain activity affected evoked motor arrest. Here, we investigate phenomenon engaging distinct activity, hippocampal theta rhythm. rhythm prominent during locomotor absent under normal immobile situations, yet present vigilant states like freezing. Specifically, ask PPN-induced same effect on as if animal would perform volitional arrest, which results in disappearance rhythm, or cause continuation expected An alternative hypothesis that represents ongoing intention move rather than itself. To distinguish between these two possibilities, recorded before induced PPN rats. was associated with clear obstruction activity. timescale less 200 ms, Since fear behavioral are did not see stimulation, suggest occurs our experiments reveal does represent intention, but sensory-motor state.

Language: Английский

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Deep brain stimulation for locomotion in incomplete human spinal cord injury (DBS-SCI): protocol of a prospective one-armed multi-centre study

BMJ Open, Journal Year: 2021, Volume and Issue: 11(9), P. e047670 - e047670

Published: Sept. 1, 2021

Introduction Spinal cord injury (SCI) is a devastating condition with immediate impact on the individual’s health and quality of life. Major functional recovery reaches plateau 3–4 months after despite intensive rehabilitative training. To enhance training efficacy improve long-term outcomes, combination rehabilitation electrical modulation spinal brain has recently aroused scientific interest encouraging results. The mesencephalic locomotor region (MLR), an evolutionarily conserved brainstem command control centre, considered promising target for deep stimulation (DBS) in patients SCI. Experiments showed that MLR-DBS can induce locomotion rats white matter destructions >85%. Methods analysis In this prospective one-armed multi-centre study, we investigate safety, feasibility, therapeutic to enable severely affected, subchronic chronic American Injury Association Impairment Scale C order recovery. Patients undergo programme while being regularly followed up until 6 post-implantation. acquired data each timepoint are compared baseline primary endpoint performance 6-minute walking test. clinical trial protocol was written accordance Standard Protocol Items: Recommendations Interventional Trials checklist. Ethics dissemination This first in-man study investigates potential SCI patients. One patient already been implanted electrodes underwent MLR during locomotion. Based preliminary results which promise safety recruitment further currently ongoing. Ethical approval obtained from Committee Canton Zurich (case number BASEC 2016-01104) Swissmedic (10000316). Results will be published peer-reviewed journals presented at conferences. Trial registration NCT03053791 .

Language: Английский

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Cholinergic Modulation of Locomotor Circuits in Vertebrates

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(18), P. 10738 - 10738

Published: Sept. 14, 2022

Locomotion is a basic motor act essential for survival. Amongst other things, it allows animals to move in their environment seek food, escape predators, or mates reproduction. The neural mechanisms involved the control of locomotion have been examined many vertebrate species and clearer picture progressively emerging. muscle synergies responsible propulsion are generated by networks located spinal cord. In turn, descending supraspinal inputs starting, maintaining, stopping as well steering controlling speed. Several neurotransmitter systems play crucial role modulating activity during locomotion. For instance, cholinergic both at levels underlying focus present review. Much information gained on modulation was obtained from lamprey model. Nicotinic increase level excitation brainstem command neurons, reticulospinal neurons (RSNs), whereas muscarinic activate select group hindbrain that project RSNs boost excitation. Muscarinic also reduce transmission sensory brainstem, phenomenon could help sustaining goal directed cord, intrinsic strongly modulate interneurons motoneurons locomotor output. Altogether, review underlines importance vertebrates.

Language: Английский

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The Mesencephalic Locomotor Region: Multiple Cell Types, Multiple Behavioral Roles, and Multiple Implications for Disease

The Neuroscientist, Journal Year: 2022, Volume and Issue: 30(3), P. 347 - 366

Published: Dec. 28, 2022

The mesencephalic locomotor region (MLR) controls locomotion in vertebrates. In humans with Parkinson disease, deficits are increasingly associated decreased activity the MLR. This brainstem region, commonly considered to include cuneiform and pedunculopontine nuclei, has been explored as a target for deep brain stimulation improve function, but results variable, from modest promising. However, MLR is heterogeneous structure, identification of best cell type only beginning. Here, I review studies that uncovered role genetically defined types, highlight cells whose activation improves function animal models disease. promising types activate comprise some glutamatergic neurons caudal well cholinergic nucleus. Activation GABAergic should be avoided, since they stop or evoke bouts flanked numerous stops. also potential spinal cord injury, supranuclear palsy, primary progressive freezing gait, stroke. Better targeting achieved through optimized protocols, pharmacotherapy, development optogenetics human use.

Language: Английский

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Target Selection for Magnetic Resonance‐Guided Focused Ultrasound in the Treatment of Parkinson's Disease

Journal of Magnetic Resonance Imaging, Journal Year: 2022, Volume and Issue: 56(1), P. 35 - 44

Published: Jan. 26, 2022

Parkinson's disease (PD) is a common, progressive, and incurable neurodegenerative disease. Pharmacological treatment the first‐line therapy for PD, including carbidopa–levodopa, dopamine agonists. However, some patients respond poorly to medication. For these patients, functional neurosurgical an important option. Magnetic resonance‐guided focused ultrasound (MRgFUS) novel, minimally invasive surgical option refractory drugs. Currently, several anatomical structures can be targeted by MRgFUS in of PD. there no uniform standard target selection. This review summarizes clinical studies on focusing relationship between different targets relieved symptoms, help clinicians determine ideal therapeutic individual patients. Evidence Level 5 Technical Efficacy Stage 4

Language: Английский

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Deep brain stimulation of the Cuneiform nucleus for levodopa-resistant freezing of gait in Parkinson’s disease: study protocol for a prospective, pilot trial

Pilot and Feasibility Studies, Journal Year: 2021, Volume and Issue: 7(1)

Published: June 2, 2021

Abstract Background Freezing of gait (FOG) is a particularly debilitating motor deficit seen in subset Parkinson’s disease (PD) patients that poorly responsive to standard levodopa therapy or deep brain stimulation (DBS) established PD targets such as the subthalamic nucleus and globus pallidus interna. The proposal DBS target midbrain, known pedunculopontine (PPN) address FOG, was based on its observed pathology hypothesized involvement locomotor control part mesencephalic region, functionally defined area midbrain elicits locomotion both intact animals decerebrate animal preparations with electrical stimulation. Initial reports PPN were met much enthusiasm; however, subsequent studies produced mixed results, recent meta-analysis results have been far less convincing than initially expected. A closer review extensive region (MLR) preclinical literature, including optogenetics studies, strongly suggests closely related cuneiform (CnF), just dorsal PPN, may be superior promote initiation. Methods We will conduct prospective, open-label, single-arm pilot study assess safety feasibility CnF levodopa-refractory FOG. Four receive assessments without during 6-month follow-up. Discussion This paper presents design rationale for investigating novel dysfunction, targeting considerations. intended support future larger scale clinical trials this target. Trial registration ClinicalTrials.gov identifier: NCT04218526 (registered January 6, 2020)

Language: Английский

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