RESUMEN
The cerebral cortex has long been thought to be involved in the pathophysiology of motor symptoms of Parkinson's disease. The impaired cortical function is believed to be a direct and immediate effect of pathologically patterned basal ganglia output, mediated to the cerebral cortex by way of the ventral motor thalamus. However, recent studies in humans with Parkinson's disease and in animal models of the disease have provided strong evidence suggesting that the involvement of the cerebral cortex is much broader than merely serving as a passive conduit for subcortical disturbances. In the present review, we discuss Parkinson's disease-related changes in frontal cortical motor regions, focusing on neuropathology, plasticity, changes in neurotransmission, and altered network interactions. We will also examine recent studies exploring the cortical circuits as potential targets for neuromodulation to treat Parkinson's disease.
Asunto(s)
Corteza Motora , Enfermedad de Parkinson , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/patología , Humanos , Corteza Motora/fisiopatología , Animales , Plasticidad Neuronal/fisiología , Vías Nerviosas/fisiopatologíaRESUMEN
DYT1 dystonia is associated with decreased striatal dopamine release. In this study, we examined the possibility that ultrastructural changes of nigrostriatal dopamine terminals could contribute to this neurochemical imbalance using a serial block face/scanning electron microscope (SBF/SEM) and three-dimensional reconstruction to analyse striatal tyrosine hydroxylase-immunoreactive (TH-IR) terminals and their synapses in a DYT1(ΔE) knockin (DYT1-KI) mouse model of DYT1 dystonia. Furthermore, to study possible changes in vesicle packaging capacity of dopamine, we used transmission electron microscopy to assess the synaptic vesicle size in striatal dopamine terminals. Quantitative comparative analysis of 80 fully reconstructed TH-IR terminals in the WT and DYT1-KI mice indicate (1) no significant difference in the volume of TH-IR terminals; (2) no major change in the proportion of axo-spinous versus axo-dendritic synapses; (3) no significant change in the post-synaptic density (PSD) area of axo-dendritic synapses, while the PSDs of axo-spinous synapses were significantly smaller in DYT1-KI mice; (4) no significant change in the contact area between TH-IR terminals and dendritic shafts or spines, while the ratio of PSD area/contact area decreased significantly for both axo-dendritic and axo-spinous synapses in DYT1-KI mice; (5) no significant difference in the mitochondria volume; and (6) no significant difference in the synaptic vesicle area between the two groups. Altogether, these findings suggest that abnormal morphometric changes of nigrostriatal dopamine terminals and their post-synaptic targets are unlikely to be a major source of reduced striatal dopamine release in DYT1 dystonia.
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Distonía Muscular Deformante , Distonía , Ratones , Animales , Dopamina/análisis , Distonía/genética , Distonía Muscular Deformante/genética , Cuerpo Estriado/química , Sinapsis/ultraestructuraRESUMEN
BACKGROUND: Freezing of gait (FOG) is a major cause of falling in Parkinson's disease (PD) and can be responsive or unresponsive to levodopa. Pathophysiology is poorly understood. OBJECTIVE: To examine the link between noradrenergic systems, the development of FOG in PD and its responsiveness to levodopa. METHODS: We examined norepinephrine transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[α-(2-methoxyphenoxy)benzyl]morpholine) in 52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize PD patients as non-freezing (NO-FOG, N = 16), levodopa responsive freezing (OFF-FOG, N = 10), and levodopa-unresponsive freezing (ONOFF-FOG, N = 21), and also included a non-PD FOG group, primary progressive freezing of gait (PP-FOG, N = 5). RESULTS: Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P = 0.021) and regionally in the frontal lobe, left and right thalamus, temporal lobe, and locus coeruleus, with the strongest effect in right thalamus (P = 0.038). Additional regions examined in a post hoc secondary analysis including the left and right amygdalae confirmed the contrast between OFF-FOG and NO-FOG (P = 0.003). A linear regression analysis identified an association between reduced NET binding in the right thalamus and more severe New FOG Questionnaire (N-FOG-Q) score only in the OFF-FOG group (P = 0.022). CONCLUSION: This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.
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Trastornos Neurológicos de la Marcha , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/tratamiento farmacológico , Levodopa/uso terapéutico , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Trastornos Neurológicos de la Marcha/diagnóstico por imagen , Trastornos Neurológicos de la Marcha/tratamiento farmacológico , Trastornos Neurológicos de la Marcha/etiología , MarchaRESUMEN
Decreased cortical serotonergic and catecholaminergic innervation of the frontal cortex has been reported at early stages of Parkinson's disease (PD). However, the limited availability of animal models that exhibit these pathological features has hampered our understanding of the functional significance of these changes during the course of the disease. In the present study, we assessed longitudinal changes in cortical serotonin and catecholamine innervation in motor-symptomatic and asymptomatic monkeys chronically treated with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Densitometry and unbiased stereological techniques were used to quantify changes in serotonin and tyrosine hydroxylase (TH) immunoreactivity in frontal cortices of 3 control monkeys and 3 groups of MPTP-treated monkeys (motor-asymptomatic [N = 2], mild parkinsonian [N = 3], and moderate parkinsonian [N = 3]). Our findings revealed a significant decrease (P < 0.001) in serotonin innervation of motor (Areas 4 and 6), dorsolateral prefrontal (Areas 9 and 46), and limbic (Areas 24 and 25) cortical areas in motor-asymptomatic MPTP-treated monkeys. Both groups of symptomatic MPTP-treated animals displayed further serotonin denervation in these cortical regions (P < 0.0001). A significant loss of serotonin-positive dorsal raphe neurons was found in the moderate parkinsonian group. On the other hand, the intensity of cortical TH immunostaining was not significantly affected in motor asymptomatic MPTP-treated monkeys, but underwent a significant reduction in the moderate symptomatic group (P < 0.05). Our results indicate that chronic intoxication with MPTP induces early pathology in the corticopetal serotonergic system, which may contribute to early non-motor symptoms in PD.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Enfermedad de Parkinson , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Desnervación , Macaca mulatta , Serotonina , Tirosina 3-MonooxigenasaRESUMEN
The synaptic organization of thalamic inputs to motor cortices remains poorly understood in primates. Thus, we compared the regional and synaptic connections of vGluT2-positive thalamocortical glutamatergic terminals in the supplementary motor area (SMA) and the primary motor cortex (M1) between control and MPTP-treated parkinsonian monkeys. In controls, vGluT2-containing fibers and terminal-like profiles invaded layer II-III and Vb of M1 and SMA. A significant reduction of vGluT2 labeling was found in layer Vb, but not in layer II-III, of parkinsonian animals, suggesting a potential thalamic denervation of deep cortical layers in parkinsonism. There was a significant difference in the pattern of synaptic connectivity in layers II-III, but not in layer Vb, between M1 and SMA of control monkeys. However, this difference was abolished in parkinsonian animals. No major difference was found in the proportion of perforated versus macular post-synaptic densities at thalamocortical synapses between control and parkinsonian monkeys in both cortical regions, except for a slight increase in the prevalence of perforated axo-dendritic synapses in the SMA of parkinsonian monkeys. Our findings suggest that disruption of the thalamic innervation of M1 and SMA may underlie pathophysiological changes of the motor thalamocortical loop in the state of parkinsonism.
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Corteza Motora/ultraestructura , Trastornos Parkinsonianos/patología , Densidad Postsináptica/ultraestructura , Tálamo/ultraestructura , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Femenino , Macaca mulatta , Masculino , Vías Nerviosas/ultraestructura , Neurotoxinas , Proteína 2 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
The primate ventral motor thalamus contains a large number of GABAergic interneurons of poorly understood function and anatomical connectivity. Glutamatergic inputs to these cells arise predominantly from corticothalamic (in both basal ganglia- and cerebellar-receiving ventral motor thalamic territories; BGMT and CBMT, respectively) and cerebellothalamic terminals (in CBMT). In Parkinson's disease patients and animal models, neuronal activity is abnormal within both BGMT and CBMT. Historically, such motor thalamic dysregulation has been largely attributed to changes in inhibitory tone from the basal ganglia output nuclei, ignoring the potential role of other thalamic inputs in such processes, particularly within the CBMT, which is largely devoid of direct basal ganglia afferents. We have recently reported changes in the abundance and structural morphology of corticothalamic terminals in BGMT of parkinsonian monkeys. In this study, we assessed potential changes in the prevalence of cortical (vesicular glutamate transporter 1-positive, vGluT1-positive) and subcortical (vGluT2-positive) glutamatergic inputs in contact with GABAergic interneurons in BGMT and CBMT of MPTP-treated parkinsonian monkeys. Our findings revealed that interneurons represent a major target of both sets of glutamatergic terminals. In both BGMT and CBMT of control and parkinsonian monkeys, 29%-38% of total asymmetric axodendritic synapses (putative glutamatergic) were formed by vGluT1-positive terminals and 11%-17% of total vGluT1-positive terminals targeted dendrites of GABAergic interneurons. In CBMT, 16%-18% of asymmetric synaptic inputs on interneurons involved vGluT2-containing terminals. No major differences in the extent of glutamatergic innervation of thalamic GABAergic interneurons were found between control and parkinsonian monkeys.
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Interneuronas , Tálamo , Animales , Haplorrinos , Humanos , Neuronas , SinapsisRESUMEN
The uniqueness of neural processes between allocentric and egocentric spatial coding has been controversial. The distinctive paradigms used in previous studies for manipulating spatial coding could have attributed for the inconsistent results. This study was aimed to generate converging evidence from previous functional brain imaging experiments for collating neural substrates associated with these two types of spatial coding. An additional aim was to test whether test-taking processes would have influenced the results. We obtained coordinate-based functional neuroimaging data for 447 subjects and performed activation likelihood estimation (ALE) meta-analysis. Among the 28 experiments, the results indicate two common clusters of convergence. They were the right precuneus and the right superior frontal gyrus as parts of the parieto-frontal circuit. Between-type differences were in the parieto-occipital circuit, with allocentric showing convergence in the superior occipital gyrus (SOG) cluster compared with egocentric showing convergence in the middle occipital gyrus (MOG) cluster. Task-specific influences were only found in allocentric spatial coding. Spatial judgment-oriented tasks seem to increase the demands on manipulating spatial relationships among the visual objects, while spatial navigation tasks seem to increase the demands on maintaining object representations. Our findings address the theoretical controversies on spatial coding that both the allocentric and egocentric types are common in their processes mediated by the parieto-frontal network, while unique and additional processes in the allocentric type are mediated by the parieto-occipital network. The positive results on possible task-specific confound offer insights into the future design of spatial tasks for eliciting spatial coding processes.
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Percepción Espacial , Navegación Espacial , Humanos , Juicio , Orientación Espacial , Lóbulo ParietalRESUMEN
Impaired behavioral flexibility and repetitive behavior is a common phenotype in autism and other neuropsychiatric disorders, but the underlying synaptic mechanisms are poorly understood. The trans-synaptic glutamate delta (GluD)-Cerebellin 1-Neurexin complex, critical for synapse formation/maintenance, represents a vulnerable axis for neuropsychiatric diseases. We have previously found that GluD1 deletion results in reversal learning deficit and repetitive behavior. In this study, we show that selective ablation of GluD1 from the dorsal striatum impairs behavioral flexibility in a water T-maze task. We further found that striatal GluD1 is preferentially found in dendritic shafts, and more frequently associated with thalamic than cortical glutamatergic terminals suggesting localization to projections from the thalamic parafascicular nucleus (Pf). Conditional deletion of GluD1 from the striatum led to a selective loss of thalamic, but not cortical, terminals, and reduced glutamatergic neurotransmission. Optogenetic studies demonstrated functional changes at thalamostriatal synapses from the Pf, but no effect on the corticostriatal system, upon ablation of GluD1 in the dorsal striatum. These studies suggest a novel molecular mechanism by which genetic variations associated with neuropsychiatric disorders may impair behavioral flexibility, and reveal a unique principle by which GluD1 subunit regulates forebrain circuits.
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Conducta Animal/fisiología , Cuerpo Estriado/metabolismo , Receptores de Glutamato/metabolismo , Tálamo/metabolismo , Animales , Cuerpo Estriado/fisiología , Femenino , Masculino , Ratones , Neurogénesis/fisiología , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Tálamo/fisiopatologíaRESUMEN
Inflammation has been linked to the development of nonmotor symptoms in Parkinson's disease (PD), which greatly impact patients' quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. We report 5 cases of progressive parkinsonism in non-human primates to gain a broader understanding of MPTP-induced central and peripheral inflammatory dysfunction to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation. Monkeys were also evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Additionally, monkeys were treated with a novel TNF inhibitor XPro1595 (10 mg/kg, n = 3) or vehicle (n = 2) every three days starting 11 weeks after the initiation of MPTP to determine whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. The case studies revealed that earlier and robust [18F]FEPPA PET signals resulted in earlier and more severe parkinsonism, which was seen in male cases compared to female cases. Potential other sex differences were observed in circulating inflammation, microbiota diversity and their metabolites. Additional studies with larger group sizes of both sexes would enable confirmation and extension of these findings. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.
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Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Inflamación/metabolismo , Macaca mulatta , Microglía/metabolismo , Trastornos Parkinsonianos/fisiopatología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Anilidas , Animales , Conducta Animal , Cognición/fisiología , Progresión de la Enfermedad , Ácidos Grasos Volátiles/metabolismo , Femenino , Imagen por Resonancia Magnética , Masculino , Microglía/efectos de los fármacos , Microglía/patología , Neurotoxinas , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/microbiología , Tomografía de Emisión de Positrones , Piridinas , Inhibidores del Factor de Necrosis Tumoral/farmacología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Retrogradely-transducing viral vectors are versatile tools for anatomical and functional interrogations of neural circuits. These vectors can be applied in nonhuman primates (NHPs), powerful model species for neuroscientific studies with limited genetic tractability, but limited data are available regarding the tropism and transgene expression patterns of such viruses after injections in NHP brains. Consequently, NHP researchers must often rely on related data available from other species for experimental planning. To evaluate the suitability of rAAV2-retro in the NHP basal ganglia, we studied the transgene expression patterns at the light and electron microscope level after injections of rAAV2-retro vector encoding the opsin Jaws conjugated to a green fluorescent protein (GFP) in the putamen of rhesus macaques. For inter-species comparison, we injected the same vector in the rat dorsal striatum. In both species, GFP expression was observed in numerous cortical and subcortical regions with known striatal projections. However, important inter-species differences in pathway transduction were seen, including labeling of the intralaminar thalamostriatal projection in rats, but not monkeys. Electron microscopic ultrastructural observations within the basal ganglia revealed GFP labeling in both postsynaptic dendrites and presynaptic axonal terminals; the latter likely derived from anterograde transgene transport in neurons that project to the striatum, and from collaterals of these neurons. Our results suggest that certain neural pathways may be refractory to transduction by retrograde vectors in a species-specific manner, highlighting the need for caution when determining the suitability of a retrograde vector for NHP studies based solely on rodent data.
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Cuerpo Estriado , Electrones , Animales , Vectores Genéticos , Macaca mulatta , Ratas , TransgenesRESUMEN
Designer receptors exclusively activated by designer drugs (DREADDs) are extensively used to modulate neuronal activity in rodents, but their use in primates remains limited. An essential need that remains is the demonstration that DREADDs are efficiently expressed on the plasma membrane of primate neurons. To address this issue, electron microscopy immunogold was used to determine the subcellular localization of the AAV vector-induced DREADDs hM4Di and hM3Dq fused to different tags in various brain areas of rhesus monkeys and mice. When hM4Di was fused to mCherry, the immunogold labelling was mostly confined to the intracellular space, and poorly expressed at the plasma membrane in monkey dendrites. In contrast, the hM4Di-mCherry labelling was mostly localized to the dendritic plasma membrane in mouse neurons, suggesting species differences in the plasma membrane expression of these exogenous proteins. The lack of hM4Di plasma membrane expression may limit the functional effects of systemic administration of DREADD-actuators in monkey neurons. Removing the mCherry and fusing of hM4Di with the haemagglutinin (HA) tag resulted in strong neuronal plasma membrane immunogold labelling in both monkeys and mice neurons. Finally, hM3Dq-mCherry was expressed mostly at the plasma membrane in monkey neurons, indicating that the fusion of mCherry with hM3Dq does not hamper membrane incorporation of this specific DREADD. Our results suggest that the pattern of ultrastructural expression of DREADDs in monkey neurons depends on the DREADD/tag combination. Therefore, a preliminary characterization of plasma membrane expression of specific DREADD/tag combinations is recommended when using chemogenetic approaches in primates.
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Encéfalo/metabolismo , Membrana Celular/metabolismo , Neuronas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animales , Dendritas/metabolismo , Femenino , Macaca mulatta , Masculino , RatonesRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder clinically characterized by cardinal motor deficits including bradykinesia, tremor, rigidity and postural instability. Over the past decades, it has become clear that PD symptoms extend far beyond motor signs to include cognitive, autonomic and psychiatric impairments, most likely resulting from cortical and subcortical lesions of non-dopaminergic systems. In addition to nigrostriatal dopaminergic degeneration, pathological examination of PD brains, indeed, reveals widespread distribution of intracytoplasmic inclusions (Lewy bodies) and death of non-dopaminergic neurons in the brainstem and thalamus. For that past three decades, the MPTP-treated monkey has been recognized as the gold standard PD model because it displays some of the key behavioral and pathophysiological changes seen in PD patients. However, a common criticism raised by some authors about this model, and other neurotoxin-based models of PD, is the lack of neuronal loss beyond the nigrostriatal dopaminergic system. In this review, we argue that this assumption is largely incorrect and solely based on data from monkeys intoxicated with acute administration of MPTP. Work achieved in our laboratory and others strongly suggest that long-term chronic administration of MPTP leads to brain pathology beyond the dopaminergic system that displays close similarities to that seen in PD patients. This review critically examines these data and suggests that the chronically MPTP-treated nonhuman primate model may be suitable to study the pathophysiology and therapeutics of some non-motor features of PD.
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Cuerpo Estriado/patología , Neuronas Dopaminérgicas/patología , Degeneración Nerviosa/patología , Trastornos Parkinsonianos/patología , Sustancia Negra/patología , Animales , HaplorrinosRESUMEN
In Parkinson's disease (PD) patients and animal models of PD, the progressive degeneration of the nigrostriatal dopamine (DA) projection leads to two major changes in the morphology of striatal projection neurons (SPNs), i.e., a profound loss of dendritic spines and the remodeling of axospinous glutamatergic synapses. Striatal spine loss is an early event tightly associated with the extent of striatal DA denervation, but not the severity of parkinsonian motor symptoms, suggesting that striatal spine pruning might be a form of homeostatic plasticity that compensates for the loss of striatal DA innervation and the resulting dysregulation of corticostriatal glutamatergic transmission. On the other hand, the remodeling of axospinous corticostriatal and thalamostriatal glutamatergic synapses might represent a form of late maladaptive plasticity that underlies changes in the strength and plastic properties of these afferents and the resulting increased firing and bursting activity of striatal SPNs in the parkinsonian state. There is also evidence that these abnormal synaptic connections might contribute to the pathophysiology of L-DOPA-induced dyskinesia. Despite the significant advances made in this field over the last thirty years, many controversial issues remain about the striatal SPN subtypes affected, the role of spine changes in the altered activity of SPNs in the parkinsonisn state, and the importance of striatal spine plasticity in the pathophysiology of L-DOPA-induced dyskinesia. In this review, we will examine the current state of knowledge of these issues, discuss the limitations of the animal models used to address some of these questions, and assess the relevance of data from animal models to the human-diseased condition.
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Cuerpo Estriado/patología , Espinas Dendríticas/patología , Homeostasis/fisiología , Plasticidad Neuronal/fisiología , Enfermedad de Parkinson/patología , Animales , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Haplorrinos , Enfermedad de Parkinson/fisiopatologíaRESUMEN
The role of the corticothalamic projection in the ventral motor thalamus remains poorly understood. Therefore, we studied the electrophysiological responses of neurons in the basal ganglia and cerebellar receiving-territories of the motor thalamus (BGMT and CbMT, respectively) using optogenetic activation of corticothalamic projections in awake rhesus macaques. After injections of viral vectors carrying the excitatory opsins ChR2 or C1V1 into the primary motor and premotor cortices of two monkeys, we used optrodes to light activate opsin-expressing neurons in cortex or their terminals in the thalamus while simultaneously recording the extracellular activity of neurons in the vicinity of the stimulation sites. As expected, light activation of opsins in the cerebral cortex evoked robust, short-latency increases in firing of cortical neurons. In contrast, light stimulation of corticothalamic terminals induced small-amplitude, long-latency increases and/or decreases of activity in thalamic neurons. In postmortem material, opsins were found to be expressed in cell bodies and dendrites of cortical neurons and along their corticothalamic projections. At the electron microscopic level, opsin labeling was confined to unmyelinated preterminal axons and small terminals that formed asymmetric synapses with dendrites of projection neurons or GABAergic interneurons in BGMT and CbMT and with neurons in the reticular thalamic nucleus. The morphological features of the transfected terminals, along with the long latency and complex physiological responses of thalamic neurons to their activation, suggest a modulatory role of corticothalamic afferents upon the primate ventral motor thalamus. SIGNIFICANCE STATEMENT: This study provides the first analysis of the physiological effects of cortical inputs on the activity of neurons in the primate ventral motor thalamus using light activation of opsin-containing corticothalamic terminals in awake monkeys. We found that selective light activation of corticothalamic terminals in contact with distal dendrites of thalamocortical neurons and GABAergic interneurons elicits complex patterns of slowly developing excitatory and inhibitory effects in thalamic neurons of the basal ganglia- and cerebellar-receiving regions of the motor thalamus. Our observations suggest a modulatory (instead of a "driver") role of the corticothalamic system in the primate ventral motor thalamus.
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Potenciales de Acción/fisiología , Corteza Motora/fisiología , Neuronas Motoras/fisiología , Optogenética/métodos , Sinapsis/fisiología , Tálamo/fisiología , Animales , Estimulación Eléctrica/métodos , Macaca mulatta , Masculino , Vías Nerviosas/fisiología , VigiliaRESUMEN
There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DßH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At the electron microscopic level, some DßH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD.
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1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Intoxicación por MPTP/tratamiento farmacológico , Mesencéfalo/efectos de los fármacos , Núcleo Subtalámico/efectos de los fármacos , Animales , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Intoxicación por MPTP/patología , Macaca mulatta , Masculino , Mesencéfalo/fisiopatología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiopatología , Núcleo Subtalámico/fisiopatología , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiopatologíaRESUMEN
A role for the cerebellum in causing ataxia, a disorder characterized by uncoordinated movement, is widely accepted. Recent work has suggested that alterations in activity, connectivity, and structure of the cerebellum are also associated with dystonia, a neurological disorder characterized by abnormal and sustained muscle contractions often leading to abnormal maintained postures. In this manuscript, the authors discuss their views on how the cerebellum may play a role in dystonia. The following topics are discussed: The relationships between neuronal/network dysfunctions and motor abnormalities in rodent models of dystonia. Data about brain structure, cerebellar metabolism, cerebellar connections, and noninvasive cerebellar stimulation that support (or not) a role for the cerebellum in human dystonia. Connections between the cerebellum and motor cortical and sub-cortical structures that could support a role for the cerebellum in dystonia. Overall points of consensus include: Neuronal dysfunction originating in the cerebellum can drive dystonic movements in rodent model systems. Imaging and neurophysiological studies in humans suggest that the cerebellum plays a role in the pathophysiology of dystonia, but do not provide conclusive evidence that the cerebellum is the primary or sole neuroanatomical site of origin.
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Cerebelo/fisiopatología , Distonía/fisiopatología , Animales , Cerebelo/diagnóstico por imagen , Cerebelo/patología , Distonía/diagnóstico por imagen , Distonía/patología , Humanos , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/patología , Vías Nerviosas/fisiopatologíaRESUMEN
The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)-P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson's disease.
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Regulación del Desarrollo de la Expresión Génica/fisiología , Neuronas/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Núcleo Subtalámico/citología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Animales Recién Nacidos , Dendritas/metabolismo , Dendritas/ultraestructura , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/genética , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/ultraestructura , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Núcleo Subtalámico/crecimiento & desarrolloRESUMEN
N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamatergic receptors that have been implicated in learning, development, and neuropathological conditions. They are typically composed of GluN1 and GluN2A-D subunits. Whereas a great deal is known about the role of GluN2A- and GluN2B-containing NMDARs, much less is known about GluN2D-containing NMDARs. Here we explore the subunit composition of synaptic NMDARs on hippocampal interneurons. GluN2D mRNA was detected by single-cell PCR and in situ hybridization in diverse interneuron subtypes in the CA1 region of the hippocampus. The GluN2D subunit was detectable by immunoblotting and immunohistochemistry in all subfields of the hippocampus in young and adult mice. In whole-cell patch-clamp recordings from acute hippocampal slices, (+)-CIQ, the active enantiomer of the positive allosteric modulator CIQ, significantly enhanced the amplitude of the NMDAR component of miniature excitatory postsynaptic currents (mEPSCs) in CA1 interneurons but not in pyramidal cells. (+)-CIQ had no effect in slices from Grin2d-/- mice, suggesting that GluN2D-containing NMDARs participate in excitatory synaptic transmission onto hippocampal interneurons. The time course of the NMDAR component of the mEPSC was unaffected by (+)-CIQ potentiation and was not accelerated in slices from Grin2d-/- mice compared with wild-type, suggesting that GluN2D does not detectably slow the NMDAR EPSC time course at this age. (+)-CIQ increased the activity of CA1 interneurons as detected by the rate and net charge transfer of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal cells. These data provide evidence that interneurons contain synaptic NMDARs possessing a GluN2D subunit, which can influence interneuron function and signal processing.
Asunto(s)
Hipocampo/citología , Interneuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmisión Sináptica , Regulación Alostérica/efectos de los fármacos , Animales , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Interneuronas/efectos de los fármacos , Activación del Canal Iónico/efectos de los fármacos , Isoquinolinas/farmacología , Ratones Endogámicos C57BL , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de N-Metil-D-Aspartato/genética , Estereoisomerismo , Transmisión Sináptica/efectos de los fármacos , Factores de Tiempo , Xenopus laevisRESUMEN
Identification of reliable and robust biomarkers is crucial to enable early diagnosis of Parkinson disease (PD) and monitoring disease progression. While imperfect, the slow, chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced non-human primate animal model system of parkinsonism is an abundant source of pre-motor or early stage PD biomarker discovery. Here, we present a study of a MPTP rhesus monkey model of PD that utilizes complementary quantitative iTRAQ-based proteomic, glycoproteomics and phosphoproteomics approaches. We compared the glycoprotein, non-glycoprotein, and phosphoprotein profiles in the putamen of asymptomatic and symptomatic MPTP-treated monkeys as well as saline injected controls. We identified 86 glycoproteins, 163 non-glycoproteins, and 71 phosphoproteins differentially expressed in the MPTP-treated groups. Functional analysis of the data sets inferred the biological processes and pathways that link to neurodegeneration in PD and related disorders. Several potential biomarkers identified in this study have already been translated for their usefulness in PD diagnosis in human subjects and further validation investigations are currently under way. In addition to providing potential early PD biomarkers, this comprehensive quantitative proteomic study may also shed insights regarding the mechanisms underlying early PD development. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology.