RESUMEN
Plants are a valuable source of information for pharmacological research and new drug discovery. The present study aimed to evaluate the neuroprotective potential of the leaves of the medicinal plant Sterculia setigera. In vitro, the effect of Sterculia setigera leaves dry hydroethanolic extract (SSE) was tested on cultured cerebellar granule neurons (CGN) survival when exposed to hydrogen peroxide (H2O2) or 6-hydroxydopamine (6-OHDA), using the viability probe fluorescein diacetate (FDA), a lactate dehydrogenase (LDH) activity assay, an immunocytochemical staining against Gap 43, and the quantification of the expression of genes involved in apoptosis, necrosis, or oxidative stress. In vivo, the effect of intraperitoneal (ip) injection of SSE was assessed on the developing brain of 8-day-old Wistar rats exposed to ethanol neurotoxicity by measuring caspase-3 activity on cerebellum homogenates, the expression of some genes in tissue extracts, the thickness of cerebellar cortical layers and motor coordination. In vitro, SSE protected CGN against H2O2 and 6-OHDA-induced cell death at a dose of 10 µg/mL, inhibited the expression of genes Casp3 and Bad, and upregulated the expression of Cat and Gpx7. In vivo, SSE significantly blocked the deleterious effect of ethanol by reducing the activity of caspase-3, inhibiting the expression of Bax and Tp53, preventing the reduction of the thickness of the internal granule cell layer of the cerebellar cortex, and restoring motor functions. Sterculia setigera exerts neuroactive functions as claimed by traditional medicine and should be a good candidate for the development of a neuroprotective treatment against neurodegenerative diseases.
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Muerte Celular , Etanol , Neuronas , Fármacos Neuroprotectores , Extractos Vegetales , Hojas de la Planta , Sterculia , Animales , Ratas , Caspasa 3/metabolismo , Etanol/administración & dosificación , Etanol/química , Etanol/toxicidad , Peróxido de Hidrógeno/toxicidad , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Oxidopamina/toxicidad , Ratas Wistar , Sterculia/química , Hojas de la Planta/química , Plantas Medicinales/química , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/patología , Lactato Deshidrogenasas/metabolismo , Proteína GAP-43/análisis , Apoptosis/genética , Estrés Oxidativo/genética , Cerebelo/citología , Cerebelo/efectos de los fármacos , Cerebelo/patología , Cerebelo/fisiología , Masculino , Femenino , Células Cultivadas , Muerte Celular/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Fitoquímicos/administración & dosificación , Fitoquímicos/análisis , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Extractos Vegetales/farmacología , Antioxidantes/análisis , Antioxidantes/química , Antioxidantes/farmacología , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Cromatografía Líquida con Espectrometría de Masas , Metabolismo SecundarioRESUMEN
BACKGROUND: Acupuncture involving the limb region may be effective for stroke rehabilitation clinically, but the visualised and explanatory evidence is limited. Our objectives were to assess the specific effects of acupuncture for ischaemic stroke (IS) patients with hemiparesis and investigate its therapy-driven modification in functional connectivity. METHODS: IS patients were randomly assigned (2:1) to receive 10 sessions of hand-foot 12 needles acupuncture (HA, n=30) or non-acupoint (NA) acupuncture (n=16), enrolling gender-matched and age-matched healthy controls (HCs, n=34). The clinical outcomes were the improved Fugl-Meyer Assessment scores including upper and lower extremity (ΔFM, ΔFM-UE, ΔFM-LE). The neuroimaging outcome was voxel-mirrored homotopic connectivity (VMHC). Static and dynamic functional connectivity (sFC, DFC) analyses were used to study the neuroplasticity reorganisation. RESULTS: 46 ISs (mean(SD) age, 59.37 (11.36) years) and 34 HCs (mean(SD) age, 52.88 (9.69) years) were included in the per-protocol analysis of clinical and neuroimaging. In clinical, ΔFM scores were 5.00 in HA group and 2.50 in NA group, with a dual correlation between ΔFM and ΔVMHC (angular: r=0.696, p=0.000; cerebellum: r=-0.716, p=0.000) fitting the linear regression model (R2=0.828). In neuroimaging, ISs demonstrated decreased VMHC in bilateral postcentral gyrus and cerebellum (Gaussian random field, GRF corrected, voxel p<0.001, cluster p<0.05), which fitted the logistic regression model (AUC=0.8413, accuracy=0.7500). Following acupuncture, VMHC in bilateral superior frontal gyrus orbital part was increased with cerebro-cerebellar changes, involving higher sFC between ipsilesional superior frontal gyrus orbital part and the contralesional orbitofrontal cortex as well as cerebellum (GRF corrected, voxel p<0.001, cluster p<0.05). The coefficient of variation of VMHC was decreased in bilateral posterior cingulate gyrus (PPC) locally (GRF corrected, voxel p<0.001, cluster p<0.05), with integration states transforming into segregation states overall (p<0.05). There was no acupuncture-related adverse event. CONCLUSIONS: The randomised clinical and neuroimaging trial demonstrated acupuncture could promote the motor recovery and modified cerebro-cerebellar VMHC via bilateral static and dynamic reorganisations for IS patients with hemiparesis.
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Terapia por Acupuntura , Cerebelo , Accidente Cerebrovascular Isquémico , Paresia , Recuperación de la Función , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Accidente Cerebrovascular Isquémico/fisiopatología , Accidente Cerebrovascular Isquémico/terapia , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/diagnóstico , Resultado del Tratamiento , Cerebelo/fisiopatología , Cerebelo/diagnóstico por imagen , Paresia/fisiopatología , Paresia/etiología , Paresia/terapia , Paresia/diagnóstico por imagen , Imagen por Resonancia Magnética , Cerebro/diagnóstico por imagen , Cerebro/fisiopatología , Plasticidad Neuronal , Adulto , Evaluación de la Discapacidad , Factores de Tiempo , Rehabilitación de Accidente Cerebrovascular , Estado FuncionalRESUMEN
INTRODUCTION: Connector hubs are specialized brain regions that connect multiple brain networks and therefore have the potential to affect the functions of multiple systems. This study aims to examine the involvement of connector hub regions in essential tremor. METHODS: We examined whole-brain functional connectivity alterations across multiple brain networks in 27 patients with essential tremor and 27 age- and sex-matched healthy controls to identify affected hub regions using a network metric called functional connectivity overlap ratio estimated from resting-state functional MRI. We also evaluated the relationships of affected hubs with cognitive and tremor scores in all patients and with motor function improvement scores in 15 patients who underwent postoperative follow-up evaluations after focused ultrasound thalamotomy. RESULTS: We have identified affected connector hubs in the cerebellum and thalamus. Specifically, the dentate nucleus in the cerebellum and the dorsomedial thalamus exhibited more extensive connections with the sensorimotor network in patients. Moreover, the connections of the thalamic pulvinar with the visual network were also significantly widespread in the patient group. The connections of these connector hub regions with cognitive networks were negatively associated (FDR q < 0.05) with cognitive, tremor, and motor function improvement scores. CONCLUSION: In patients with essential tremor, connector hub regions within the cerebellum and thalamus exhibited widespread functional connections with sensorimotor and visual networks, leading to alternative pathways outside the classical tremor axis. Their connections with cognitive networks also affect patients' cognitive function.
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Temblor Esencial , Humanos , Temblor Esencial/cirugía , Temblor , Imagen por Resonancia Magnética , Tálamo/diagnóstico por imagen , Tálamo/cirugía , Cerebelo/diagnóstico por imagen , CogniciónRESUMEN
Physical exercise is known to reduce anxiety, but the underlying brain mechanisms remain unclear. Here, we explore a hypothalamo-cerebello-amygdalar circuit that may mediate motor-dependent alleviation of anxiety. This three-neuron loop, in which the cerebellar dentate nucleus takes center stage, bridges the motor system with the emotional system. Subjecting animals to a constant rotarod engages glutamatergic cerebellar dentate neurons that drive PKCδ+ amygdalar neurons to elicit an anxiolytic effect. Moreover, challenging animals on an accelerated rather than a constant rotarod engages hypothalamic neurons that provide a superimposed anxiolytic effect via an orexinergic projection to the dentate neurons that activate the amygdala. Our findings reveal a cerebello-limbic pathway that may contribute to motor-triggered alleviation of anxiety and that may be optimally exploited during challenging physical exercise.
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Ansiolíticos , Animales , Ansiedad/metabolismo , Hipotálamo , Cerebelo , Trastornos de AnsiedadRESUMEN
BACKGROUND: Premature infants may suffer from high levels of bilirubin that could lead to neurotoxicity. Bilirubin has been shown to decrease L1-mediated ERK1/2 signaling, L1 phosphorylation, and L1 tyrosine 1176 dephosphorylation. Furthermore, bilirubin redistributes L1 into lipid rafts (LR) and decreases L1-mediated neurite outgrowth. We demonstrate that choline supplementation improves L1 function and signaling in the presence of bilirubin. METHODS: Cerebellar granule neurons (CGN) were cultured with and without supplemental choline, and the effects on L1 signaling and function were measured in the presence of bilirubin. L1 activation of ERK1/2, L1 phosphorylation and dephosphorylation were measured. L1 distribution in LR was quantified and neurite outgrowth of CGN was determined. RESULTS: Forty µM choline significantly reduced the effect of bilirubin on L1 activation of ERK1/2 by 220% (p = 0.04), and increased L1 triggered changes in tyrosine phosphorylation /dephosphorylation of L1 by 34% (p = 0.026) and 35% (p = 0.02) respectively. Choline ameliorated the redistribution of L1 in lipid rafts by 38% (p = 0.02) and increased L1-mediated mean neurite length by 11% (p = 0.04). CONCLUSION: Choline pretreatment of CGN significantly reduced the disruption of L1 function by bilirubin. The supplementation of pregnant women and preterm infants with choline may increase infant resilience to the effects of bilirubin. IMPACT: This article establishes choline as an intervention for the neurotoxic effects of bilirubin on lipid rafts. This article provides clear evidence toward establishing one intervention for bilirubin neurotoxicity, where little is understood. This article paves the way for future investigation into the mechanism of the ameliorative effect of choline on bilirubin neurotoxicity.
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Bilirrubina , Cerebelo , Colina , Neuronas , Bilirrubina/farmacología , Bilirrubina/metabolismo , Colina/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Cerebelo/efectos de los fármacos , Cerebelo/citología , Animales , Fosforilación , Células Cultivadas , Microdominios de Membrana/metabolismo , Microdominios de Membrana/efectos de los fármacos , Suplementos Dietéticos , Molécula L1 de Adhesión de Célula Nerviosa/metabolismo , Transducción de Señal/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Humanos , Neuritas/efectos de los fármacos , Neuritas/metabolismoRESUMEN
Dietary polyphenol consumption is associated with a wide range of neuroprotective effects by improving mitochondrial function and signaling. Consequently, the use of polyphenol supplementation has been investigated as an approach to prevent neurodevelopmental diseases during gestation; however, the data obtained are still very inconclusive, mostly because of the difficulty of choosing the correct doses and period of administration to properly prevent neurodegenerative diseases without undermining normal brain development. Thus, we aimed to evaluate the effect of naringin supplementation during the third week of gestation on mitochondrial health and signaling in the cerebellum of 21-day-old offspring. The offspring born to naringin-supplemented dams displayed higher mitochondrial mass, membrane potential, and superoxide content in the cerebellum without protein oxidative damage. Such alterations were associated with dynamin-related protein 1 (DRP1) and phosphorylated AKT (p-AKT) downregulation, whereas the sirtuin 3 (SIRT3) levels were strongly upregulated. Our findings suggest that high dietary polyphenol supplementation during gestation may reduce mitochondrial fission and affect mitochondrial dynamics even 3 weeks after delivery via SIRT3 and p-AKT. Although the offspring born to naringin dams did not present neurobehavioral defects, the mitochondrial alterations elicited by naringin may potentially interfere during neurodevelopment and need to be further investigated.
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Flavanonas , Sirtuina 3 , Ratas , Animales , Femenino , Embarazo , Ratas Wistar , Sirtuina 3/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Cerebelo/metabolismo , Suplementos Dietéticos , Mitocondrias/metabolismo , Polifenoles/metabolismoRESUMEN
BACKGROUND: Current pathophysiological models of Parkinson's disease (PD) assume a malfunctioning network being adjusted by the DBS signal. As various authors showed a main involvement of the cerebellum within this network, cerebello-cerebral fiber tracts are gaining special interest regarding the mediation of DBS effects. OBJECTIVES: The crossing and non-decussating fibers of the dentato-rubro-thalamic tract (c-DRTT/nd-DRTT) and the subthalamo-ponto-cerebellar tract (SPCT) are thought to build up an integrated network enabling a bidimensional communication between the cerebellum and the basal ganglia. The aim of this study was to investigate the influence of these tracts on clinical control of Parkinsonian tremor evoked by DBS. METHODS: We analyzed 120 electrode contacts from a cohort of 14 patients with tremor-dominant or equivalence-type PD having received bilateral STN-DBS. Probabilistic tractography was performed to depict the c-DRTT, nd-DRTT, and SPCT. Distance maps were calculated for the tracts and correlated to clinical tremor control for each electrode pole. RESULTS: A significant difference between "effective" and "less-effective" contacts was only found for the c-DRTT (p = 0.039), but not for the SPCT, nor the nd-DRTT. In logistic and linear regressions, significant results were also found for the c-DRTT only (pmodel logistic = 0.035, ptract logistic = 0,044; plinear = 0.027). CONCLUSIONS: We found a significant correlation between the distance of the DBS electrode pole to the c-DRTT and the clinical efficacy regarding tremor reduction. The c-DRTT might therefore play a major role in the mechanisms of alleviation of Parkinsonian tremor and could eventually serve as a possible DBS target for tremor-dominant PD in future.
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Estimulación Encefálica Profunda , Temblor Esencial , Enfermedad de Parkinson , Humanos , Temblor/etiología , Temblor/terapia , Estimulación Encefálica Profunda/métodos , Tálamo , Cerebelo/diagnóstico por imagen , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/terapiaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Cancer stands as one of the leading causes of death worldwide according to the World Health Organization (WHO), and it has led to approximately 10 million fatalities in 2020. Medicinal plants are still widely used and accepted form of treatment for most diseases including cancer in Ghana. This review presented Cryptolepis nigrescens (Wennberg) L. Joubert. and Bruyns., Prosopsis africana (Guill. and Perr.) Taub. and Pterygota macrocarpa K. Schum. as medicinal plants that are traditionally used to treat tumour growth, amongst other diseases, in the Ashanti region of Ghana. AIM OF REVIEW: This paper aims to present a comprehensive review on the botanical description, ecological distribution, ethnomedicinal uses, phytochemical composition and ethnopharmacological relevance of C. nigrescens, P. africana and P. macrocarpa. MATERIALS AND METHODS: The review covers works published between 1962 and 2023 from various countries. Published books, thesis, scientific and medical articles on C. nigrescens, P. africana and P. macrocarpa were collected from the following databases: 'Scopus', 'Science Direct', 'Medline', 'PubMed', 'Research Gate' 'Google Scholar, and 'Springer link' using the keywords. RESULTS: Phytochemical analysis of C. nigrescens, P. africana and P. macrocarpa revealed the presence of some prominent bioactive compounds such as convallatoxin, 7,3,4-trihydroxy-3-methoxyflavanone and dioxane, respectively. Plant extracts and isolated compounds of these medicinal plants exhibited a wide range of ethnopharmacological activities including antimicrobial, anti-inflammatory, antioxidant, analgesic, cytotoxic, antimalarial, antipyretic, haematinic, hepato-protective, aphrodisiac and antihypertensive properties. CONCLUSION: The present review on C. nigrescens , P.africana and P. macrocarpa provided a credible summary of the ethnopharmacological research conducted on these medicinal plants till date. The data also highligted the potential therapeutic profiles of these plants in Ghana that could serve as foundation for future studies. Additionally, the information significantly supported the traditional and commercial use of these plants among the people.
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Anomalías Múltiples , Anomalías del Ojo , Enfermedades Renales Quísticas , Neoplasias , Plantas Medicinales , Humanos , Animales , Cryptolepis , Ghana , Cerebelo , Anomalías del Ojo/tratamiento farmacológico , Enfermedades Renales Quísticas/tratamiento farmacológico , Retina , Etnofarmacología , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Fitoquímicos/farmacología , Fitoquímicos/uso terapéutico , Fitoquímicos/análisis , Neoplasias/tratamiento farmacológico , PterygotaRESUMEN
The brain controls nearly all bodily functions via spinal projecting neurons (SPNs) that carry command signals from the brain to the spinal cord. However, a comprehensive molecular characterization of brain-wide SPNs is still lacking. Here we transcriptionally profiled a total of 65,002 SPNs, identified 76 region-specific SPN types, and mapped these types into a companion atlas of the whole mouse brain1. This taxonomy reveals a three-component organization of SPNs: (1) molecularly homogeneous excitatory SPNs from the cortex, red nucleus and cerebellum with somatotopic spinal terminations suitable for point-to-point communication; (2) heterogeneous populations in the reticular formation with broad spinal termination patterns, suitable for relaying commands related to the activities of the entire spinal cord; and (3) modulatory neurons expressing slow-acting neurotransmitters and/or neuropeptides in the hypothalamus, midbrain and reticular formation for 'gain setting' of brain-spinal signals. In addition, this atlas revealed a LIM homeobox transcription factor code that parcellates the reticulospinal neurons into five molecularly distinct and spatially segregated populations. Finally, we found transcriptional signatures of a subset of SPNs with large soma size and correlated these with fast-firing electrophysiological properties. Together, this study establishes a comprehensive taxonomy of brain-wide SPNs and provides insight into the functional organization of SPNs in mediating brain control of bodily functions.
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Encéfalo , Perfilación de la Expresión Génica , Vías Nerviosas , Neuronas , Médula Espinal , Animales , Ratones , Hipotálamo , Neuronas/metabolismo , Neuropéptidos , Médula Espinal/citología , Médula Espinal/metabolismo , Encéfalo/citología , Encéfalo/metabolismo , Neurotransmisores , Mesencéfalo/citología , Formación Reticular/citología , Electrofisiología , Cerebelo/citología , Corteza Cerebral/citologíaRESUMEN
Ischemic heart disease is a fatal cardiovascular disease that irreversibly impairs the function of the heart, followed by reperfusion leading to a further increase in infarct size. Clinically, we call it myocardial ischemia-reperfusion injury (MIRI). A growing number of clinical observations and experimental studies have found electroacupuncture (EA) to be effective in alleviating MIRI. This study attempts to investigate whether glutamatergic neurons in fastigial nucleus (FN) of the cerebellum are involved in EA pretreatment to alleviate MIRI via sympathetic nerves, and the potential mechanisms of EA pretreatment process. A MIRI model was established by ligating the coronary artery of the left anterior descending branch of the heart for 30 minutes, followed by 2 hours of reperfusion. Multichannel physiological recordings, electrocardiogram, cardiac ultrasound, chemical genetics, enzyme-linked immunosorbent assay and immunofluorescence staining methods were combined to demonstrate that EA pretreatment inhibited neuronal firing and c-Fos expression in FN of the cerebellum and reduced cardiac sympathetic firing. Meanwhile, EA pretreatment significantly reduced cardiac ejection fraction (EF), shortening fraction (SF), percentage infarct area, decreased myocardial norepinephrine (NE), creatine kinase isoenzyme MB (CK-MB) concentrations, and improved MIRI-induced myocardial tissue morphology. The results were similar to the inhibition of glutamatergic neurons in FN. However, the activation of glutamatergic neurons in FN diminished the aforementioned effects of EA pretreatment. This study revealed that glutamatergic neurons in FN of the cerebellum is involved in EA pretreatment mediated sympathetic nervous and may be a potential mediator for improving MIRI.
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Electroacupuntura , Daño por Reperfusión Miocárdica , Humanos , Núcleos Cerebelosos , Cerebelo , InfartoRESUMEN
High salt intake increases inflammatory and oxidative stress responses and causes an imbalance of neurotransmitters involved in the pathogenesis of hypertension that is related to the onset of cerebral injury. Using natural compounds that target oxidative stress and neuroinflammation pathways remains a promising approach for treating neurological diseases. Barley (Hordeum vulgare L.) seeds are rich in protein, fiber, minerals, and phenolic compounds, that exhibit potent neuroprotective effects in various neurodegenerative diseases. Therefore, this work aimed to investigate the efficacy of barley ethanolic extract against a high salt diet (HSD)-induced cerebellum injury in hypertensive rats. Forty-eight Wistar rats were divided into six groups. Group (I) was the control. The second group, the HSD group, was fed a diet containing 8% NaCl. Groups II and III were fed an HSD and simultaneously treated with either amlodipine (1 mg /kg b.wt p.o) or barley extract (1000 mg /kg b.wt p.o) for five weeks. Groups IV and V were fed HSD for five weeks, then administered with either amlodipine or barley extract for another five weeks. The results revealed that barley treatment significantly reduced blood pressure and effectively reduced oxidative stress and inflammation in rat's cerebellum as indicated by higher GSH and nitric oxide levels and lower malondialdehyde, TNF-α, and IL-1ß levels. Additionally, barley restored the balance of neurotransmitters and improved cellular energy performance in the cerebellum of HSD-fed rats. These findings suggest that barley supplementation exerted protective effects against high salt-induced hypertension by an antioxidant, anti-inflammatory, and vasodilating effects and restoring neurochemical alterations.
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Hordeum , Hipertensión , Ratas , Animales , Cloruro de Sodio , Cloruro de Sodio Dietético , Enfermedades Neuroinflamatorias , Ratas Wistar , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Estrés Oxidativo , Amlodipino , Cerebelo , Etanol , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéuticoRESUMEN
BACKGROUND: Spatial patterns of brain functional connectivity can vary substantially at the individual level. Applying cortical surface-based approaches with individualized rather than group templates may accelerate the discovery of biological markers related to psychiatric disorders. We investigated cortico-subcortical networks from multi-cohort data in people with schizophrenia spectrum disorders (SSDs) and healthy controls (HC) using individualized connectivity profiles. METHODS: We utilized resting-state and anatomical MRI data from n = 406 participants (n = 203 SSD, n = 203 HC) from four cohorts. Functional timeseries were extracted from previously defined intrinsic network subregions of the striatum, thalamus, and cerebellum as well as 80 cortical regions of interest, representing six intrinsic networks using (1) volume-based approaches, (2) a surface-based group atlas approaches, and (3) Personalized Intrinsic Network Topography (PINT). RESULTS: The correlations between all cortical networks and the expected subregions of the striatum, cerebellum, and thalamus were increased using a surface-based approach (Cohen's D volume vs. surface 0.27-1.00, all p < 10-6 ) and further increased after PINT (Cohen's D surface vs. PINT 0.18-0.96, all p < 10-4 ). In SSD versus HC comparisons, we observed robust patterns of dysconnectivity that were strengthened using a surface-based approach and PINT (Number of differing pairwise-correlations: volume: 404, surface: 570, PINT: 628, FDR corrected). CONCLUSION: Surface-based and individualized approaches can more sensitively delineate cortical network dysconnectivity differences in people with SSDs. These robust patterns of dysconnectivity were visibly organized in accordance with the cortical hierarchy, as predicted by computational models.
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Corteza Cerebral , Neuroimagen Funcional , Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagen , Masculino , Femenino , Adulto , Corteza Cerebral/diagnóstico por imagen , Adolescente , Adulto Joven , Imagen por Resonancia Magnética , Descanso , Cuerpo Estriado/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Cerebelo/diagnóstico por imagenRESUMEN
Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous activity promotes seizures. Virus tracing identifies cerebellar and cerebral cortical afferents as robust contributors to the seizures. Of these inputs, only microinfusion of lidocaine into the cerebellar nuclei blocks seizure initiation. Our data reveal the VPM as a source of generalized convulsive seizures, with cerebellar input providing critical signals.
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Convulsiones , Núcleos Talámicos Ventrales , Ratones , Animales , Tálamo , Corteza Cerebral/fisiología , CerebeloRESUMEN
Diverse subpopulations of astrocytes tile different brain regions to accommodate local requirements of neurons and associated neuronal circuits. Nevertheless, molecular mechanisms governing astrocyte diversity remain mostly unknown. We explored the role of a zinc finger transcription factor Yin Yang 1 (YY1) that is expressed in astrocytes. We found that specific deletion of YY1 from astrocytes causes severe motor deficits in mice, induces Bergmann gliosis, and results in simultaneous loss of GFAP expression in velate and fibrous cerebellar astrocytes. Single cell RNA-seq analysis showed that YY1 exerts specific effects on gene expression in subpopulations of cerebellar astrocytes. We found that although YY1 is dispensable for the initial stages of astrocyte development, it regulates subtype-specific gene expression during astrocyte maturation. Moreover, YY1 is continuously needed to maintain mature astrocytes in the adult cerebellum. Our findings suggest that YY1 plays critical roles regulating cerebellar astrocyte maturation during development and maintaining a mature phenotype of astrocytes in the adult cerebellum.
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Astrocitos , Yin-Yang , Animales , Ratones , Astrocitos/metabolismo , Cerebelo/metabolismo , Neuronas/metabolismo , Factores de Transcripción/metabolismoRESUMEN
The thalamus is a critical relay center for neural pathways involving sensory, motor, and cognitive functions, including cortico-striato-thalamo-cortical and cortico-ponto-cerebello-thalamo-cortical loops. Despite the importance of these circuits, their development has been understudied. One way to investigate these pathways in human development in vivo is with functional connectivity MRI, yet few studies have examined thalamo-cortical and cerebello-cortical functional connectivity in development. Here, we used resting-state functional connectivity to measure functional connectivity in the thalamus and cerebellum with previously defined cortical functional networks in 2 separate data sets of children (7-12 years old) and adults (19-40 years old). In both data sets, we found stronger functional connectivity between the ventral thalamus and the somatomotor face cortical functional network in children compared with adults, extending previous cortico-striatal functional connectivity findings. In addition, there was more cortical network integration (i.e. strongest functional connectivity with multiple networks) in the thalamus in children than in adults. We found no developmental differences in cerebello-cortical functional connectivity. Together, these results suggest different maturation patterns in cortico-striato-thalamo-cortical and cortico-ponto-cerebellar-thalamo-cortical pathways.
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Cerebelo , Imagen por Resonancia Magnética , Adulto , Niño , Humanos , Adulto Joven , Cerebelo/diagnóstico por imagen , Vías Nerviosas/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Cuerpo EstriadoRESUMEN
Cerebral palsy (CP) is a syndrome characterized by a wide range of sensory and motor damage, associated with behavioral and cognitive deficits. The aim of the present study was to investigate the potential of a model of CP using a combination of perinatal anoxia and sensorimotor restriction of hind paws to replicate motor, behavioral and neural deficits. A total of 30 of male Wistar rats were divided into Control (C, n = 15), and CP (CP, n = 15) groups. The potential of the CP model was assessed by evaluating food intake, the behavioral satiety sequence, performance on the CatWalk and parallel bars, muscle strength, and locomotor activity. The weight of the encephalon, soleus, and extensor digitorum longus (EDL) muscles, and the activation of glial cells (microglia and astrocytes) were also measured. The CP animals showed delayed satiety, impaired locomotion on the CatWalk and open field test, reduced muscle strength, and reduced motor coordination. CP also reduced the weight of the soleus and muscles, brain weight, liver weight, and quantity of fat in various parts of the body. There was also found to be an increase in astrocyte and microglia activation in the cerebellum and hypothalamus (arcuate nucleus, ARC) of animals subjected to CP.
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Parálisis Cerebral , Embarazo , Femenino , Ratas , Animales , Masculino , Ratas Wistar , Parálisis Cerebral/complicaciones , Hipotálamo , Cerebelo , NeuroglíaRESUMEN
In addition to their core symptoms, most individuals with autism spectrum disorder (ASD) also experience motor impairments. These impairments are often linked to the cerebellum, which is the focus of the current study. Herein, we utilized a prenatal valproic acid (VPA)-induced rat model of autism and performed RNA sequencing in the cerebellum. Relative to control animals, the VPA-treated offspring demonstrated both abnormal motor coordination and impaired dendritic arborization of Purkinje cells (PCs). Concurrently, we observed a decrease in the cerebellar expression of retinoic acid (RA) synthesis enzymes (RDH10, ALDH1A1), metabolic enzyme (CYP26A2), and lower levels of RA, retinoic acid receptor α (RARα), and Cerebellin2 (CBLN2) in the VPA-treated offspring. However, RA supplementation ameliorated these deficits, restoring motor coordination, normalizing PCs dendritic arborization, and increasing the expression of RA, RARα, and CBLN2. Further, ChIP assays confirmed that RA supplementation enhanced RARα's binding capacity to CBLN2 promoters. Collectively, these findings highlight the therapeutic potential of RA for treating motor incoordination in VPA-induced autism, acting through the RARα-CBLN2 pathway.
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Trastorno del Espectro Autista , Trastorno Autístico , Efectos Tardíos de la Exposición Prenatal , Embarazo , Femenino , Ratas , Animales , Humanos , Ácido Valproico/efectos adversos , Trastorno Autístico/inducido químicamente , Trastorno Autístico/tratamiento farmacológico , Trastorno Autístico/metabolismo , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/metabolismo , Tretinoina/farmacología , Cerebelo/metabolismo , Ataxia/metabolismo , Suplementos Dietéticos , Efectos Tardíos de la Exposición Prenatal/metabolismo , Modelos Animales de EnfermedadRESUMEN
Humans and monkey studies showed that specific sectors of cerebellum and basal ganglia activate not only during execution but also during observation of hand actions. However, it is unknown whether, and how, these structures are engaged during the observation of actions performed by effectors different from the hand. To address this issue, in the present fMRI study, healthy human participants were required to execute or to observe grasping acts performed with different effectors, namely mouth, hand, and foot. As control, participants executed and observed simple movements performed with the same effectors. The results show that: (1) execution of goal-directed actions elicited somatotopically organized activations not only in the cerebral cortex but also in the cerebellum, basal ganglia, and thalamus; (2) action observation evoked cortical, cerebellar and subcortical activations, lacking a clear somatotopic organization; (3) in the territories displaying shared activations between execution and observation, a rough somatotopy could be revealed in both cortical, cerebellar and subcortical structures. The present study confirms previous findings that action observation, beyond the cerebral cortex, also activates specific sectors of cerebellum and subcortical structures and it shows, for the first time, that these latter are engaged not only during hand actions observation but also during the observation of mouth and foot actions. We suggest that each of the activated structures processes specific aspects of the observed action, such as performing internal simulation (cerebellum) or recruiting/inhibiting the overt execution of the observed action (basal ganglia and sensory-motor thalamus).
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Cerebelo , Mano , Humanos , Mano/fisiología , Cerebelo/diagnóstico por imagen , Cerebelo/fisiología , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/fisiología , Boca/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Tálamo/fisiologíaRESUMEN
This study aimed to delineate overlapping and distinctive functional connectivity in visual motor imagery, kinesthetic motor imagery, and motor execution of target-oriented grasping action of the right hand. Functional magnetic resonance imaging data were obtained from 18 right-handed healthy individuals during each condition. Seed-based connectivity and multi-voxel pattern analyses were employed after selecting seed regions with the left primary motor cortex and supplementary motor area. There was equivalent seed-based connectivity during the three conditions in the bilateral frontoparietal and temporal areas. When the seed region was the left primary motor cortex, increased connectivity was observed in the left cuneus and superior frontal area during visual and kinesthetic motor imageries, respectively, compared with that during motor execution. Multi-voxel pattern analyses revealed that each condition was differentiated by spatially distributed connectivity patterns of the left primary motor cortex within the right cerebellum VI, cerebellum crus II, and left lingual area. When the seed region was the left supplementary motor area, the connectivity patterns within the right putamen, thalamus, cerebellar areas IV-V, and left superior parietal lobule were significantly classified above chance level across the three conditions. The present findings improve our understanding of the spatial representation of functional connectivity and its specific patterns among motor imagery and motor execution. The strength and fine-grained connectivity patterns of the brain areas can discriminate between motor imagery and motor execution.
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Mapeo Encefálico , Encéfalo , Humanos , Mapeo Encefálico/métodos , Encéfalo/diagnóstico por imagen , Cerebelo , Mano , Lóbulo Parietal , Imagen por Resonancia MagnéticaRESUMEN
Very preterm infants show low levels of insulin-like growth factor-1 (IGF-1), which is associated with postnatal growth restriction and poor neurologic outcomes. It remains unknown whether supplemental IGF-1 may stimulate neurodevelopment in preterm neonates. Using cesarean-delivered preterm pigs as a model of preterm infants, we investigated the effects of supplemental IGF-1 on motor function and on regional and cellular brain development. Pigs were treated with 2.25 mg/kg/d recombinant human IGF-1/IGF binding protein-3 complex from birth until day 5 or 9 before the collection of brain samples for quantitative immunohistochemistry (IHC), RNA sequencing, and quantitative PCR analyses. Brain protein synthesis was measured using in vivo labeling with [2H5] phenylalanine. We showed that the IGF-1 receptor was widely distributed in the brain and largely coexisted with immature neurons. Region-specific quantification of IHC labeling showed that IGF-1 treatment promoted neuronal differentiation, increased subcortical myelination, and attenuated synaptogenesis in a region-dependent and time-dependent manner. The expression levels of genes involved in neuronal and oligodendrocyte maturation, and angiogenic and transport functions were altered, reflecting enhanced brain maturation in response to IGF-1 treatment. Cerebellar protein synthesis was increased by 19% at day 5 and 14% at day 9 after IGF-1 treatment. Treatment had no effect on Iba1+ microglia or regional brain weights and did not affect motor development or the expression of genes related to IGF-1 signaling. In conclusion, the data show that supplemental IGF-1 promotes brain maturation in newborn preterm pigs. The results provide further support for IGF-1 supplementation therapy in the early postnatal period in preterm infants.