RESUMEN
The loss of midbrain dopaminergic (DA) neurons is the fundamental pathological feature of Parkinson's disease (PD). PD causes chronic pain in two-thirds of patients. Recent studies showed that the activation of the pedunculopontine tegmental nucleus (PPTg) can effectively relieve inflammatory pain and neuropathic pain. The PPTg is located in the pontomesencephalic tegmentum, a target of deep brain stimulation (DBS) treatment in PD, and is involved in motor control and sensory integration. To test whether the lesion of midbrain DA neurons induced pain hypersensitivity, and whether the chemogenetic activation of the PPTg could modulate the pain, the AAV-hM3Dq receptor was transfected and expressed into the PPTg neurons of 6-hydroxydopamine-lesioned mice. In this study, von Frey, open field, and adhesive tape removal tests were used to assess animals' pain sensitivity, locomotor activity, and sensorimotor function and somatosensory perception, respectively. Here, we found that the lesion of midbrain DA neurons induced a minor deficit in voluntary movement but did not affect sensorimotor function and somatosensory perception in the tape removal test. The results showed that lesion led to pain hypersensitivity, which could be alleviated both by levodopa and by the chemogenetic activation of the PPTg. Activating the PPTg may be a potential therapeutic strategy to relieve pain phenotypes in PD.
Asunto(s)
Neuronas Dopaminérgicas , Mesencéfalo , Núcleo Tegmental Pedunculopontino , Animales , Núcleo Tegmental Pedunculopontino/metabolismo , Neuronas Dopaminérgicas/metabolismo , Ratones , Mesencéfalo/metabolismo , Masculino , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/fisiopatología , Dolor/etiología , Dolor/metabolismo , Ratones Endogámicos C57BL , Estimulación Encefálica Profunda/métodos , Modelos Animales de Enfermedad , Levodopa/farmacología , OxidopaminaRESUMEN
The pedunculopontine tegmental nucleus of the brainstem (PPTg) has extensive interconnections and neuronal-behavioural correlates. It is implicated in movement control and sensorimotor integration. We investigated whether single neuron activity in freely moving rats is correlated with components of skilled forelimb movement, and whether individual neurons respond to both motor and sensory events. We found that individual PPTg neurons showed changes in firing rate at different times during the reach. This type of temporally specific modulation is like activity seen elsewhere in voluntary movement control circuits, such as the motor cortex, and suggests that PPTg neural activity is related to different specific events occurring during the reach. In particular, many neuronal modulations were time-locked to the end of the extension phase of the reach, when fine distal movements related to food grasping occur, indicating strong engagement of PPTg in this phase of skilled individual forelimb movements. In addition, some neurons showed brief periods of apparent oscillatory firing in the theta range at specific phases of the reach-to-grasp movement. When movement-related neurons were tested with tone stimuli, many also responded to this auditory input, allowing for sensorimotor integration at the cellular level. Together, these data extend the concept of the PPTg as an integrative structure in generation of complex movements, by showing that this function extends to the highly coordinated control of the forelimb during skilled reach to grasp movement, and that sensory and motor-related information converges on single neurons, allowing for direct integration at the cellular level.
Asunto(s)
Neuronas , Núcleo Tegmental Pedunculopontino , Ritmo Teta , Animales , Núcleo Tegmental Pedunculopontino/fisiología , Neuronas/fisiología , Ratas , Masculino , Ritmo Teta/fisiología , Movimiento/fisiología , Miembro Anterior/fisiología , Ratas Long-Evans , Potenciales de Acción/fisiología , Estimulación Acústica/métodosRESUMEN
Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance can become negatively reinforcing. Put differently, drug use can transform from a form of pleasure-seeking to a form of relief-seeking. Ventral tegmental area (VTA) GABA neurons form an anatomical point of divergence between two double dissociable pathways that have been shown to be functionally implicated and necessary for these respective motivations to seek drugs. The tegmental pedunculopontine nucleus (TPP) is necessary for opiate conditioned place preferences (CPP) in previously drug-naïve rats and mice, whereas dopaminergic (DA) transmission in the nucleus accumbens (NAc) is necessary for opiate CPP in opiate-dependent and withdrawn (ODW) rats and mice. Here, we show that this switch in functional anatomy is contingent upon the gap junction-forming protein, connexin-36 (Cx36), in VTA GABA neurons. Intra-VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug-naïve-like state wherein the TPP was necessary for opiate CPP and where opiate withdrawal aversions were lost. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons (GAD65-Cre;Cx36 fl(CFP)/fl(CFP)) exhibited a perpetual drug-naïve-like state wherein opiate CPP was always DA independent, and opiate withdrawal aversions were absent even in mice subjected to an opiate dependence and withdrawal induction protocol. Further, viral-mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to an ODW state wherein opiate CPP was DA dependent. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction.
Asunto(s)
Conexinas , Neuronas GABAérgicas , Proteína delta-6 de Union Comunicante , Uniones Comunicantes , Trastornos Relacionados con Opioides , Área Tegmental Ventral , Animales , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Conexinas/metabolismo , Conexinas/genética , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/efectos de los fármacos , Uniones Comunicantes/metabolismo , Uniones Comunicantes/efectos de los fármacos , Masculino , Ratas , Trastornos Relacionados con Opioides/metabolismo , Trastornos Relacionados con Opioides/fisiopatología , Mefloquina/farmacología , Ratones , Ratas Sprague-Dawley , Núcleo Tegmental Pedunculopontino/metabolismo , Núcleo Tegmental Pedunculopontino/efectos de los fármacosRESUMEN
BACKGROUND: The neural mechanisms underlying sevoflurane-induced loss of consciousness and recovery of consciousness after anaesthesia remain unknown. We investigated whether glutamatergic pedunculopontine tegmental nucleus (PPT) neurones are involved in the regulation of states of consciousness under sevoflurane anaesthesia. METHODS: In vivo fibre photometry combined with electroencephalography (EEG)/electromyography recording was used to record changes in the activity of glutamatergic PPT neurones under sevoflurane anaesthesia. Chemogenetic and cortical EEG recordings were used to explore their roles in the induction of and emergence from sevoflurane anaesthesia. Optogenetic methods combined with EEG recordings were used to explore the roles of glutamatergic PPT neurones and of the PPT-ventral tegmental area pathway in maintenance of anaesthesia. RESULTS: The population activity of glutamatergic PPT neurones was reduced before sevoflurane-induced loss of righting reflex and gradually recovered after return of righting reflex. Chemogenetic inhibition of glutamatergic PPT neurones accelerated induction of anaesthesia (hM4Di-CNO vs mCherry-CNO, 76 [17] vs 121 [27] s, P<0.0001) and delayed emergence from sevoflurane anaesthesia (278 [98] vs 145 [53] s, P<0.0001) but increased sevoflurane sensitivity. Optogenetic stimulation of glutamatergic PPT neurons or of the PPT-ventral tegmental area pathway promoted cortical activation and behavioural emergence during steady-state sevoflurane anaesthesia, reduced the depth of anaesthesia, and caused cortical arousal during sevoflurane-induced EEG burst suppression. CONCLUSIONS: Glutamatergic PPT neurones regulate induction and emergence of sevoflurane anaesthesia.
Asunto(s)
Núcleo Tegmental Pedunculopontino , Sevoflurano , Inconsciencia , Animales , Ratones , Electroencefalografía , Neuronas , Sevoflurano/farmacología , Inconsciencia/inducido químicamenteRESUMEN
Arrest of ongoing movements is an integral part of executing motor programs. Behavioral arrest may happen upon termination of a variety of goal-directed movements or as a global motor arrest either in the context of fear or in response to salient environmental cues. The neuronal circuits that bridge with the executive motor circuits to implement a global motor arrest are poorly understood. We report the discovery that the activation of glutamatergic Chx10-derived neurons in the pedunculopontine nucleus (PPN) in mice arrests all ongoing movements while simultaneously causing apnea and bradycardia. This global motor arrest has a pause-and-play pattern with an instantaneous interruption of movement followed by a short-latency continuation from where it was paused. Mice naturally perform arrest bouts with the same combination of motor and autonomic features. The Chx10-PPN-evoked arrest is different to ventrolateral periaqueductal gray-induced freezing. Our study defines a motor command that induces a global motor arrest, which may be recruited in response to salient environmental cues to allow for a preparatory or arousal state, and identifies a locomotor-opposing role for rostrally biased glutamatergic neurons in the PPN.
Asunto(s)
Neuronas , Núcleo Tegmental Pedunculopontino , Ratones , Animales , Neuronas/fisiología , Movimiento , Sustancia Gris Periacueductal/fisiología , Núcleo Tegmental Pedunculopontino/fisiologíaRESUMEN
Analyzing neuronal activities is essential to deciphering the function of neural circuits. In anesthetized rodents, simultaneous multisite recording of extracellular electrophysiological activity with defined electrical stimulation is a powerful tool to dissect reciprocal relationships between brain structures. Here, we present a protocol to simultaneously record from the subthalamic nucleus and substantia nigra pars reticulata while stimulating the pedunculopontine tegmental nucleus in anesthetized rats. This protocol describes the preparation of recording and stimulating electrodes, surgery setup, and detailed recording techniques. Basic post-recording data analysis methods are included as well. This protocol can be adapted to other brain areas of interest following the outlined procedures. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Assembly of recording and stimulating electrodes Basic Protocol 2: Implantation of recording and stimulating electrodes in an anesthetized rat Basic Protocol 3: Simultaneous recording from the STN and SNr with PPTg stimulation Basic Protocol 4: Histological verification of recording sites Basic Protocol 5: Analysis of electrophysiological data.
Asunto(s)
Núcleo Tegmental Pedunculopontino , Núcleo Subtalámico , Ratas , Animales , Sustancia Negra/fisiología , Estimulación Eléctrica , Núcleo Subtalámico/fisiología , Neuronas/fisiologíaRESUMEN
The pedunculopontine nucleus (PPN) is a small brainstem structure and has attracted attention as a potentially effective deep brain stimulation (DBS) target for the treatment of Parkinson's disease (PD). However, the in vivo location of PPN remains poorly described and barely visible on conventional structural magnetic resonance (MR) images due to a lack of high spatial resolution and tissue contrast. This study aims to delineate the PPN on a high-resolution (HR) atlas and investigate the visibility of the PPN in individual quantitative susceptibility mapping (QSM) images. We combine a recently constructed Montreal Neurological Institute (MNI) space unbiased QSM atlas (MuSus-100), with an implicit representation-based self-supervised image super-resolution (SR) technique to achieve an atlas with improved spatial resolution. Then guided by a myelin staining histology human brain atlas, we localize and delineate PPN on the atlas with improved resolution. Furthermore, we examine the feasibility of directly identifying the approximate PPN location on the 3.0-T individual QSM MR images. The proposed SR network produces atlas images with four times the higher spatial resolution (from 1 to 0.25 mm isotropic) without a training dataset. The SR process also reduces artifacts and keeps superb image contrast for further delineating small deep brain nuclei, such as PPN. Using the myelin staining histological atlas as guidance, we first identify and annotate the location of PPN on the T1-weighted (T1w)-QSM hybrid MR atlas with improved resolution in the MNI space. Then, we relocate and validate that the optimal targeting site for PPN-DBS is at the middle-to-caudal part of PPN on our atlas. Furthermore, we confirm that the PPN region can be identified in a set of individual QSM images of 10 patients with PD and 10 healthy young adults. The contrast ratios of the PPN to its adjacent structure, namely the medial lemniscus, on images of different modalities indicate that QSM substantially improves the visibility of the PPN both in the atlas and individual images. Our findings indicate that the proposed SR network is an efficient tool for small-size brain nucleus identification. HR QSM is promising for improving the visibility of the PPN. The PPN can be directly identified on the individual QSM images acquired at the 3.0-T MR scanners, facilitating a direct targeting of PPN for DBS surgery.
Asunto(s)
Estimulación Encefálica Profunda , Núcleo Tegmental Pedunculopontino , Adulto Joven , Humanos , Imagen por Resonancia Magnética/métodos , Núcleo Tegmental Pedunculopontino/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Mapeo Encefálico/métodos , Estimulación Encefálica Profunda/métodosRESUMEN
BACKGROUND: Axial symptoms of Parkinson's disease (PD) can be debilitating and are often refractory to conventional therapies such as dopamine replacement therapy and deep brain stimulation (DBS) of the subthalamic nuclei (STN). OBJECTIVE: Evaluate the efficacy of bilateral DBS of the pedunculopontine nucleus area (PPNa) and investigate structural and physiological correlates of clinical response. METHODS: A randomized, double-blind, cross-over clinical trial was employed to evaluate the efficacy of bilateral PPNa-DBS on axial symptoms. Lead positions and neuronal activity were evaluated with respect to clinical response. Connectomic cortical activation profiles were generated based on the volumes of tissue activated. RESULTS: PPNa-DBS modestly improved (pâ=â0.057) axial symptoms in the medication-off condition, with greatest positive effects on gait symptoms (pâ=â0.027). Electrode placements towards the anterior commissure (ρ=â0.912; pâ=â0.011) or foramen caecum (ρ=â0.853; pâ=â0.031), near the 50% mark of the ponto-mesencephalic junction, yielded better therapeutic responses. Recording trajectories of patients with better therapeutic responses (i.e., more anterior electrode placements) had neurons with lower firing-rates (pâ=â0.003) and higher burst indexes (pâ=â0.007). Structural connectomic profiles implicated activation of fibers of the posterior parietal lobule which is involved in orienting behavior and locomotion. CONCLUSION: Bilateral PPNa-DBS influenced gait symptoms in patients with PD. Anatomical and physiological information may aid in localization of a favorable stimulation target.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Tegmental Pedunculopontino , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/tratamiento farmacológico , Estimulación Encefálica Profunda/métodos , MarchaRESUMEN
The relationship between serotonin dysfunction and schizophrenia commenced with the discovery of the effects of lysergic acid diethylamide (LSD) that has high affinity for 5-HT2A receptors. Activation of these receptors produces perceptual and behavioural changes such as illusions, visual hallucinations and locomotor hyperactivity. Using prepulse inhibition (PPI) of the acoustic startle, which is impaired in schizophrenia,we aimed to investigate:i) the existence of a direct and potentially inhibitory neural pathway between the inferior colliculus (IC) and the pedunculopontine tegmental nucleus (PPTg) involved in the mediation of PPI responses by a neural tract tracing procedure;ii) if the microinjection of the 5-HT2A receptors agonist DOI in IC would activate neurons in this structure and in the PPTg by a c-Fos protein immunohistochemistry study;iii) whether the deficits in PPI responses, observed after the administration of DOI in the IC, could be prevented by the concomitant microinjection of the GABAA receptor antagonist bicuculline in the PPTg.Male Wistar rats were used in this study. An IC-PPTg reciprocated neuronal pathway was identified by neurotracing. The number of c-Fos labelled cells was lower in the DOI group in IC and PPTg, suggesting that this decrease could be due to the high levels of GABA in both structures. The concomitant microinjections of bicuculline in PPTg and DOI in IC prevented the PPI deficit observed after the IC microinjection of DOI. Our findings suggest that IC 5-HT2A receptors may be at least partially involved in the regulation of inhibitory pathways mediating PPI response in IC and PPTg structures.
Asunto(s)
Colículos Inferiores , Núcleo Tegmental Pedunculopontino , Ratas , Animales , Masculino , Inhibición Prepulso/fisiología , Reflejo de Sobresalto/fisiología , Receptores de GABA-A , Receptor de Serotonina 5-HT2A , Bicuculina/farmacología , Serotonina/farmacología , Ratas WistarRESUMEN
The pedunculopontine nucleus (PPN) is the major part of the mesencephalic locomotor region, involved in the control of gait and locomotion. The PPN contains glutamatergic, cholinergic, and GABAergic neurons that all make local connections, but also have long-range ascending and descending connections. While initially thought of as a region only involved in gait and locomotion, recent evidence is showing that this structure also participates in decision-making to initiate movement. Clinically, the PPN has been used as a target for deep brain stimulation to manage freezing of gait in late Parkinson's disease. In this review, we will discuss current thinking on the role of the PPN in locomotor control. We will focus on the cytoarchitecture and functional connectivity of the PPN in relationship to motor control.
Asunto(s)
Estimulación Encefálica Profunda , Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Núcleo Tegmental Pedunculopontino , Humanos , Enfermedad de Parkinson/terapia , Locomoción , MesencéfaloRESUMEN
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is standard care for severe motor symptoms of Parkinson's disease (PD). However, a challenge of DBS remains improving gait. Gait has been associated with the cholinergic system in the pedunculopontine nucleus (PPN). In this study, we investigated the effects of long-term intermittent bilateral STN-DBS on PPN cholinergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonian mouse model. Motor behavior, previously assessed by the automated Catwalk gait analysis, demonstrated a parkinsonian-like motor phenotype with static and dynamic gait impairments, which were reversed by STN-DBS. In this study, a subset of brains was further immunohistochemically processed for choline acetyltransferase (ChAT) and the neuronal activation marker c-Fos. MPTP treatment resulted in a significant reduction of PPN ChAT expressing neurons compared to saline treatment. STN-DBS did not alter the number of ChAT expressing neurons, nor the number of double-labelled PPN neurons for ChAT and c-Fos. Although STN-DBS improved gait in our model this was not associated with an altered expression or activation of PPN acetylcholine neurons. Motor and gait effects of STN-DBS are therefore less likely to be mediated by the STN-PPN connection and PPN cholinergic system.
Asunto(s)
Estimulación Encefálica Profunda , Núcleo Tegmental Pedunculopontino , Núcleo Subtalámico , Ratones , Animales , Estimulación Encefálica Profunda/métodos , Núcleo Tegmental Pedunculopontino/metabolismo , Neuronas Colinérgicas , Marcha , ColinérgicosRESUMEN
BACKGROUND: Deep brain stimulation (DBS) is commonly used to alleviate motor symptoms in several movement disorders. However, the procedure is invasive, and the technology has remained largely stagnant since its inception decades ago. Recently, we have shown that wireless nanoelectrodes may offer an alternative approach to conventional DBS. However, this method is still in its infancy, and more research is required to characterize its potential before it can be considered as an alternative to conventional DBS. OBJECTIVES: Herein, we aimed to investigate the effect of stimulation via magnetoelectric nanoelectrodes on primary neurotransmitter systems that have implications for DBS in movement disorders. METHODS: Mice were injected with either magnetoelectric nanoparticles (MENPs) or magnetostrictive nanoparticles (MSNPs, as a control) in the subthalamic nucleus (STN). Mice then underwent magnetic stimulation, and their motor behavior was assessed in the open field test. In addition, magnetic stimulation was applied before sacrifice and post-mortem brains were processed for immunohistochemistry (IHC) to assess the co-expression of c-Fos with either tyrosine hydroxylase (TH), tryptophan hydroxylase-2 (TPH2) or choline acetyltransferase (ChAT). RESULTS: Stimulated animals covered longer distances in the open field test when compared to controls. Moreover, we found a significant increase in c-Fos expression in the motor cortex (MC) and paraventricular region of the thalamus (PV-thalamus) after magnetoelectric stimulation. Stimulated animals showed fewer TPH2/c-Fos double-labeled cells in the dorsal raphe nucleus (DRN), as well as TH/c-Fos double-labeled cells in the ventral tegmental area (VTA), but not in the substantia nigra pars compacta (SNc). There was no significant difference in the number of ChAT/ c-Fos double-labeled cells in the pedunculopontine nucleus (PPN). CONCLUSIONS: Magnetoelectric DBS in mice enables selective modulation of deep brain areas and animal behavior. The measured behavioral responses are associated with changes in relevant neurotransmitter systems. These changes are somewhat similar to those observed in conventional DBS, suggesting that magnetoelectric DBS might be a suitable alternative.
Asunto(s)
Estimulación Encefálica Profunda , Trastornos del Movimiento , Núcleo Tegmental Pedunculopontino , Núcleo Subtalámico , Ratones , Animales , Núcleo Subtalámico/metabolismo , Estimulación Encefálica Profunda/métodos , Núcleo Tegmental Pedunculopontino/metabolismo , Tálamo/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: People commonly report positive changes following stressful experiences (perceived posttraumatic growth; PPTG), yet whether PPTG validly reflects positive changes remains unestablished. DESIGN AND METHODS: We tested the extent to which COVID-19 pandemic-related PPTG relates to positive changes in corresponding psychosocial resources in a national US sample participating in a five wave study (T1-T5), focusing here on T2-T5: ns = 712-860. We examined correlations between resource change (both latent and observed difference scores) and PPTG at each occasion and conducted structural equation models to separate occasion-specific and stable (traitlike) PPTG variance. We related changes in resources to occasion-specific and stable PPTG components. RESULTS: Associations between change scores and occasion-specific PPTG were sparse, providing limited evidence of PPTG validity. Associations between change scores and stable PPTG tended to be positive and stronger than associations for occasion-specific PPTG. DISCUSSION: Perceptions of growth were largely unrelated to experienced positive changes and thus appear to be largely illusory. However, a personality-like tendency to believe one grows from stressful experiences relates more strongly to actual resource growth. These results suggest that people are not accurate reporters of positive changes they experience and that interventions aimed at promoting post-traumatic growth may be premature.
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COVID-19 , Núcleo Tegmental Pedunculopontino , Crecimiento Psicológico Postraumático , Humanos , PandemiasRESUMEN
Parkinson's disease (PD) is a motor disorder resulting from degeneration of dopaminergic neurons of substantia nigra pars compacta (SNpc), with classical and non-classical symptoms such as respiratory instability. An important region for breathing control, the Pedunculopontine Tegmental Nucleus (PPTg), is composed of cholinergic, glutamatergic, and GABAergic neurons. We hypothesize that degenerated PPTg neurons in a PD model contribute to the blunted respiratory activity. Adult mice (40 males and 29 females) that express the fluorescent green protein in cholinergic, glutamatergic or GABAergic cells were used (Chat-cre Ai6, Vglut2-cre Ai6 and Vgat-cre Ai6) and received bilateral intrastriatal injections of vehicle or 6-hydroxydopamine (6-OHDA). Ten days later, the animals were exposed to hypercapnia or hypoxia to activate PPTg neurons. Vglut2-cre Ai6 animals also received retrograde tracer injections (cholera toxin b) into the retrotrapezoid nucleus (RTN) or preBötzinger Complex (preBötC) and anterograde tracer injections (AAV-mCherry) into the SNpc. In 6-OHDA-injected mice, there is a 77% reduction in the number of dopaminergic neurons in SNpc without changing the number of neurons in the PPTg. Hypercapnia activated fewer Vglut2 neurons in PD, and hypoxia did not activate PPTg neurons. PPTg neurons do not input RTN or preBötC regions but receive projections from SNpc. Although our results did not show a reduction in the number of glutamatergic neurons in PPTg, we observed a reduction in the number of neurons activated by hypercapnia in the PD animal model, suggesting that PPTg may participate in the hypercapnia ventilatory response.
Asunto(s)
Enfermedad de Parkinson , Núcleo Tegmental Pedunculopontino , Masculino , Ratones , Animales , Enfermedad de Parkinson/metabolismo , Oxidopamina , Hipercapnia/metabolismo , Neuronas Dopaminérgicas/metabolismo , Colinérgicos , Hipoxia/metabolismoRESUMEN
Free-water imaging can predict and monitor dopamine system degeneration in people with Parkinson's disease. It can also enhance the sensitivity of traditional diffusion tensor imaging (DTI) metrics for indexing neurodegeneration. However, these tools are yet to be applied to investigate cholinergic system degeneration in Parkinson's disease, which involves both the pedunculopontine nucleus and cholinergic basal forebrain. Free-water imaging, free-water-corrected DTI and volumetry were used to extract structural metrics from the cholinergic basal forebrain and pedunculopontine nucleus in 99 people with Parkinson's disease and 46 age-matched controls. Cognitive ability was tracked over 4.5 years. Pearson's partial correlations revealed that free-water-corrected DTI metrics in the pedunculopontine nucleus were associated with performance on cognitive tasks that required participants to make rapid choices (behavioural flexibility). Volumetric, free-water content and DTI metrics in the cholinergic basal forebrain were elevated in a sub-group of people with Parkinson's disease with evidence of cognitive impairment, and linear mixed modelling revealed that these metrics were differently associated with current and future changes to cognition. Free water and free-water-corrected DTI can index cholinergic degeneration that could enable stratification of patients in clinical trials of cholinergic interventions for cognitive decline. In addition, degeneration of the pedunculopontine nucleus impairs behavioural flexibility in Parkinson's disease, which may explain this region's role in increased risk of falls.
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Prosencéfalo Basal , Enfermedad de Parkinson , Núcleo Tegmental Pedunculopontino , Humanos , Enfermedad de Parkinson/complicaciones , Imagen de Difusión Tensora , Prosencéfalo Basal/diagnóstico por imagen , Colinérgicos , Agua , Neuronas ColinérgicasRESUMEN
Prior studies indicate more severe brainstem cholinergic deficits in Progressive Supranuclear Palsy (PSP) compared to Parkinson's disease (PD), but the extent and topography of subcortical deficits remains poorly understood. The objective of this study is to investigate differential cholinergic systems changes in progressive supranuclear palsy (PSP, n = 8) versus Parkinson's disease (PD, n = 107) and older controls (n = 19) using vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol (FEOBV) positron emission tomography (PET). A whole-brain voxel-based PET analysis using Statistical Parametric Mapping (SPM) software (SPM12) for inter-group comparisons using parametric [18F]-FEOBV DVR images. Voxel-based analyses showed lower FEOBV binding in the tectum, metathalamus, epithalamus, pulvinar, bilateral frontal opercula, anterior insulae, superior temporal pole, anterior cingulum, some striatal subregions, lower brainstem, and cerebellum in PSP versus PD (p < 0.05; false discovery rate-corrected). More severe and diffuse reductions were present in PSP vs controls. Higher frequency of midbrain cholinergic losses was seen in PSP compared to the PD participants using 5th percentile normative cut-off values (χ2 = 4.12, p < 0.05). When compared to PD, these findings suggested disease-specific cholinergic vulnerability in the tectum, striatal cholinergic interneurons, and projections from the pedunculopontine nucleus, medial vestibular nucleus, and the cholinergic forebrain in PSP.
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Enfermedad de Parkinson , Núcleo Tegmental Pedunculopontino , Parálisis Supranuclear Progresiva , Humanos , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Tomografía de Emisión de Positrones/métodos , Núcleo Tegmental Pedunculopontino/metabolismo , ColinérgicosRESUMEN
The subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and pedunculopontine tegmental nucleus (PPTg) are reciprocally connected brain regions that play significant roles in the motor control. However, the electrophysiological relationship among the STN, SNr, and PPTg remains controversial. The present study was designed to further explore the mutual electrophysiological relationship of these brain regions from the perspective of the PPTg-STN-SNr neural circuit. The neuronal activities in the STN and SNr were simultaneously recorded while the PPTg was stimulated in anesthetized rats. The activation of PPTg induced excitatory responses of both the STN and SNr neurons. Comparisons of excitation latencies between the STN and SNr were made to distinguish the excitation evoked from the PPTg-STN-SNr pathway. Additionally, two types of excitatory responses and various inhibitory responses with different latencies in the SNr were recorded. The SNr responses could also be classified into five different response categories, which might attribute to projections within different neural circuits. Neuronal recordings were analyzed in different electrophysiological features (i.e., interspike interval [ISI] mode, ISI asymmetry index, ISI coefficient of variance, firing rate, burst index, and trough peak duration), and different response patterns of neurons had their specific features in neuronal activities. These findings indicated the complex interactions among the STN, SNr, and PPTg electrophysiologically, and provided insights into exploring information transmission mechanisms underlying these circuits.
Asunto(s)
Porción Reticular de la Sustancia Negra , Núcleo Tegmental Pedunculopontino , Núcleo Subtalámico , Animales , Neuronas/fisiología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/metabolismoRESUMEN
Goal-directed locomotion requires control signals that propagate from higher order areas to regulate spinal mechanisms. The corticosubthalamic hyperdirect pathway offers a short route for cortical information to reach locomotor centers in the brainstem. We developed a task in which head-fixed mice run to a visual landmark and then stop and wait to collect the reward and examined the role of secondary motor cortex (M2) projections to the subthalamic nucleus (STN) in controlling locomotion. Our behavioral modeling, calcium imaging, and optogenetics manipulation results suggest that the M2-STN pathway can be recruited during visually guided locomotion to rapidly and precisely control the pedunculopontine nucleus (PPN) of the mesencephalic locomotor region through the basal ganglia. By capturing the physiological dynamics through a feedback control model and analyzing neuronal signals in M2, PPN, and STN, we find that the corticosubthalamic projections potentially control PPN activity by differentiating an M2 error signal to ensure fast input-output dynamics.