RESUMEN
INTRODUCTION: Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD). METHODS: We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (α-syn), phosphorylated-α-synuclein (pα-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure. RESULTS: Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine. CONCLUSIONS: These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.
Asunto(s)
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Enfermedad de Parkinson , Animales , Femenino , Masculino , alfa-Sinucleína/metabolismo , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de la radiación , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Porcinos , Tirosina 3-Monooxigenasa/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Nearly one billion people worldwide suffer from obsessive-compulsive behaviors1,2, yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive-compulsive behaviors as maladaptive habit learning3,4, which may be associated with abnormal beta-gamma neurophysiology of the orbitofrontal-striatal circuitry during reward processing5,6. We target the orbitofrontal cortex with alternating current, personalized to the intrinsic beta-gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward- but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive-compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive-compulsive symptoms. The results contribute to neurophysiological theories of reward, learning and obsessive-compulsive behavior, suggest a unifying functional role of rhythms in the beta-gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders.
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Cuerpo Estriado/diagnóstico por imagen , Trastorno Obsesivo Compulsivo/terapia , Corteza Prefrontal/diagnóstico por imagen , Estimulación Eléctrica Transcutánea del Nervio , Adulto , Mapeo Encefálico , Conducta Compulsiva/diagnóstico por imagen , Conducta Compulsiva/fisiopatología , Conducta Compulsiva/terapia , Cuerpo Estriado/fisiopatología , Cuerpo Estriado/efectos de la radiación , Femenino , Humanos , Masculino , Trastorno Obsesivo Compulsivo/diagnóstico por imagen , Trastorno Obsesivo Compulsivo/fisiopatología , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/efectos de la radiaciónRESUMEN
Huntington's disease (HD) is a neurological disorder characterized by motor disturbances. HD pathology is most prominent in the striatum, the central hub of the basal ganglia. The cerebral cortex is the main striatal afferent, and progressive cortico-striatal disconnection characterizes HD. We mapped striatal network dysfunction in HD mice to ultimately modulate the activity of a specific cortico-striatal circuit to ameliorate motor symptoms and recover synaptic plasticity. Multimodal MRI in vivo indicates cortico-striatal and thalamo-striatal functional network deficits and reduced glutamate/glutamine ratio in the striatum of HD mice. Moreover, optogenetically-induced glutamate release from M2 cortex terminals in the dorsolateral striatum (DLS) was undetectable in HD mice and striatal neurons show blunted electrophysiological responses. Remarkably, repeated M2-DLS optogenetic stimulation normalized motor behavior in HD mice and evoked a sustained increase of synaptic plasticity. Overall, these results reveal that selective stimulation of the M2-DLS pathway can become an effective therapeutic strategy in HD.
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Corteza Cerebral , Cuerpo Estriado , Estimulación Eléctrica , Enfermedad de Huntington/fisiopatología , Animales , Corteza Cerebral/citología , Corteza Cerebral/fisiología , Corteza Cerebral/efectos de la radiación , Cuerpo Estriado/citología , Cuerpo Estriado/fisiología , Cuerpo Estriado/efectos de la radiación , Ácido Glutámico/metabolismo , Ratones , Actividad Motora/fisiología , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Neuronas/fisiología , OptogenéticaRESUMEN
Focused ultrasound-enhanced intranasal (IN + FUS) delivery is a noninvasive approach that utilizes the olfactory pathway to administer pharmacological agents directly to the brain, allowing for a more homogenous distribution in targeted locations compared to IN delivery alone. However, whether such a strategy has therapeutic values, especially in neurodegenerative disorders such as Parkinson's disease (PD), remains to be established. Herein, we evaluated whether the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine catalysis, could be enhanced by IN + FUS delivery of brain-derived neurotrophic factor (BDNF) in a toxin-based PD mouse model. Mice were put on the subacute dosing regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), producing bilateral degeneration of the nigrostriatal pathway consistent with early-stage PD. MPTP mice then received BDNF intranasally followed by multiple unilateral FUS-induced blood-brain barrier (BBB) openings in the left basal ganglia for three consecutive weeks. Subsequently, mice were survived for two months and were evaluated morphologically and behaviorally to determine the integrity of their nigrostriatal dopaminergic pathways. Mice receiving IN + FUS had significantly increased TH immunoreactivity in the treated hemisphere compared to the untreated hemisphere while mice receiving only FUS-induced BBB opening or no treatment at all did not show any differences. Additionally, behavioral changes were only observed in the IN + FUS treated mice, indicating improved motor control function in the treated hemisphere. These findings demonstrate the robustness of the method and potential of IN + FUS for the delivery of bioactive factors for treatment of neurodegenerative disorder.
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Factor Neurotrófico Derivado del Encéfalo/farmacología , Dopamina/genética , Enfermedad de Parkinson Secundaria/terapia , Enfermedad de Parkinson/terapia , Tirosina 3-Monooxigenasa/genética , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Administración Intranasal , Animales , Ganglios Basales/efectos de los fármacos , Ganglios Basales/patología , Ganglios Basales/efectos de la radiación , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/efectos de la radiación , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/efectos de la radiación , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/efectos de la radiación , Modelos Animales de Enfermedad , Dopamina/biosíntesis , Humanos , Ratones , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/genética , Enfermedad de Parkinson Secundaria/patología , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/efectos de los fármacos , Sustancia Negra/efectos de la radiación , Ondas UltrasónicasRESUMEN
Prefrontal dysfunction is a common feature of brain diseases such as schizophrenia and contributes to deficits in executive functions, including working memory, attention, flexibility, inhibitory control, and timing of behaviors. Currently, few interventions improve prefrontal function. Here, we tested whether stimulating the axons of prefrontal neurons in the striatum could compensate for deficits in temporal processing related to prefrontal dysfunction. We used an interval-timing task that requires working memory for temporal rules and attention to the passage of time. Our previous work showed that inactivation of the medial frontal cortex (MFC) impairs interval timing and attenuates ramping activity, a key form of temporal processing in the dorsomedial striatum (DMS). We found that 20-Hz optogenetic stimulation of MFC axon terminals increased curvature of time-response histograms and improved interval-timing behavior. Furthermore, optogenetic stimulation of terminals modulated time-related ramping of medium spiny neurons in the striatum. These data suggest that corticostriatal stimulation can compensate for deficits caused by MFC inactivation and they imply that frontostriatal projections are sufficient for controlling responses in time.
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Axones/fisiología , Encefalopatías/fisiopatología , Neuronas/efectos de la radiación , Esquizofrenia/fisiopatología , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de la radiación , Animales , Axones/efectos de la radiación , Cuerpo Estriado/fisiopatología , Cuerpo Estriado/efectos de la radiación , Modelos Animales de Enfermedad , Estimulación Eléctrica , Función Ejecutiva/efectos de la radiación , Lóbulo Frontal/fisiopatología , Lóbulo Frontal/efectos de la radiación , Humanos , Masculino , Memoria a Corto Plazo/fisiología , Memoria a Corto Plazo/efectos de la radiación , Neuronas/patología , Optogenética/métodos , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/efectos de la radiación , Ratas , Tiempo de Reacción/fisiología , Tiempo de Reacción/efectos de la radiación , Esquizofrenia/diagnóstico por imagenRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of protein inclusions and the loss of dopaminergic neurons. Abnormal mitochondrial homeostasis is thought to be important for the pathogenesis of PD. Transcranial direct current stimulation (tDCS), a noninvasive brain stimulation technique, constitutes a promising approach for promoting recovery of various neurological conditions. However, little is known about its mechanism of action. The present study elucidated the neuroprotective effects of tDCS on the mitochondrial quality control pathway in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. We used the MPTP-induced neurotoxicity in vivo model. Mice were stimulated for 5 consecutive days with MPTP treatment. After observation of behavioral alteration using the rotarod test, mice were sacrificed for the measurement of the PD- and mitochondrial quality control-related protein levels in the substantia nigra. tDCS improved the behavioral alterations and changes in tyrosine hydroxylase levels in MPTP-treated mice. Furthermore, tDCS attenuated mitochondrial damage, as indicated by diminished mitochondrial swelling and mitochondrial glutamate dehydrogenase activity in the MPTP-induced PD mouse model. MPTP significantly increased mitophagy and decreased mitochondrial biogenesis-related proteins. These changes were attenuated by tDCS. Furthermore, MPTP significantly increased fission-related protein dynamin-related protein 1 with no effect on fusion-related protein mitofusin-2, and tDCS attenuated these changes. Our findings demonstrated the neuroprotective effect of anodal tDCS on the MPTP-induced neurotoxic mouse model through suppressing excessive mitophagy and balancing mitochondrial dynamics. The neuroprotective effect of anodal tDCS with modulation of mitochondrial dynamics provides a new therapeutic strategy for the treatment of PD.
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Intoxicación por MPTP/prevención & control , Dinámicas Mitocondriales/efectos de la radiación , Estimulación Transcraneal de Corriente Directa , Adenosina Trifosfato/análisis , Animales , Cuerpo Estriado/química , Cuerpo Estriado/efectos de la radiación , Cuerpo Estriado/ultraestructura , Electrodos , GTP Fosfohidrolasas/análisis , Glutamato Deshidrogenasa/análisis , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/terapia , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/enzimología , Mitofagia/efectos de la radiación , Proteínas del Tejido Nervioso/análisis , Biogénesis de Organelos , Prueba de Desempeño de Rotación con Aceleración Constante , Sustancia Negra/química , Sustancia Negra/efectos de la radiación , Sustancia Negra/ultraestructura , Tirosina 3-Monooxigenasa/análisisRESUMEN
Concern is growing about possible neuronal effects of human exposure to radiofrequency electromagnetic fields because of the increasing usage of cell phones and the close proximity of these devices to the brain when in use. We found that exposure to a radiofrequency electromagnetic field (RF-EMF) of 835 MHz (4.0 W/kg specific absorption rate [SAR] for 5 h/day for 12 weeks) affects striatal neurons in C57BL/6 mice. The number of synaptic vesicles (SVs) in striatal presynaptic boutons was significantly decreased after RF-EMF exposure. The expression levels of synapsin I and II were also significantly decreased in the striatum of the RF-EMF-exposed group. RF-EMF exposure led to a reduction in dopamine concentration in the striatum and also to a decrease in the expression of tyrosine hydroxylase in striatal neurons. Furthermore, in behavioral tests, exposure to RF-EMF impeded the recovery of locomotor activities after repeated treatments with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results suggest that the observed decrease in dopamine concentration in the striatum was caused by both a reduction in the number of dopaminergic neurons and a decline in the number of SVs. The decreased dopamine neuron numbers and concentration seen after RF-EMF exposure would have caused the difficult recovery after MPTP treatment. In summary, our results strongly suggest that exposing the brain to RF-EMF can decrease the number of SVs and dopaminergic neurons in the striatum. These primary changes impair the recovery of locomotor activities following MPTP damage to the striatum.
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Cuerpo Estriado/efectos de la radiación , Campos Electromagnéticos/efectos adversos , Ondas de Radio/efectos adversos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Animales , Teléfono Celular , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Sustancia Gris/metabolismo , Sustancia Gris/efectos de la radiación , Masculino , Ratones , Ratones Endogámicos C57BL , Neostriado/metabolismo , Neostriado/efectos de la radiación , Neuronas/metabolismo , Neuronas/efectos de la radiación , Vesículas Sinápticas/efectos de la radiaciónRESUMEN
Despite the numerous benefits of microwave applications in our daily life, microwaves were associated with diverse neurological complaints such as headaches and impaired sleep patterns, and changes in the electroencephalogram (EEG). To which extent microwaves influence the brain function remains unclear. This exploratory study assessed the behavior and neurochemistry in mice immediately or 4weeks after a 6-day exposure to low-intensity 10-GHz microwaves with an amplitude modulation (AM) of 2 or 8Hz. These modulation frequencies of 2 and 8Hz are situated within the delta and theta-alpha frequency bands in the EEG spectrum and are associated with sleep and active behavior, respectively. During these experiments, the specific absorbance rate was 0.3W/kg increasing the brain temperature with 0.23°C. For the first time, exposing mice to 8-Hz AM significantly reduced locomotor activity in an open field immediately after exposure which normalized after 4weeks. This in contrast to 2-Hz AM which didn't induce significant changes in locomotor activity immediately and 4weeks after exposure. Despite this difference in motor behavior, no significant changes in striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels and DOPAC/DA turnover nor in cortical glutamate (GLU) concentrations were detected. In all cases, no effects on motor coordination on a rotarod, spatial working memory, anxiety nor depressive-like behavior were observed. The outcome of this study indicates that exposing mice to low-intensity 8-Hz AM microwaves can alter the locomotor activity in contrast to 2-Hz AM which did not affect the tested behaviors.
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Cuerpo Estriado/efectos de la radiación , Locomoción/efectos de la radiación , Microondas , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Conducta Animal/efectos de la radiación , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Electroencefalografía , Ácido Glutámico/metabolismo , Masculino , RatonesRESUMEN
Effect of ionizing radiation on the brain affects neuronal, glial, and endothelial cell population and lead to significant morphological, metabolic, and functional deficits. In the present study we investigated a dose- and time-dependent correlation between radiation-induced metabolic and histopathological changes. Adult male Wistar rats received a total dose of 35Gy delivered in 7 fractions (dose 5Gy per fraction) once per week in the same weekday during 7 consecutive weeks. Proton magnetic resonance spectroscopy (1H MRS), histochemistry, immunohistochemistry and confocal microscopy were used to determine whether radiation-induced alteration of the brain metabolites correlates with appropriate histopathological changes of neurogenesis and glial cell response in 2 neurogenic regions: the hippocampal dentate gyrus (DG) and the subventricular zone-olfactory bulb axis (SVZ-OB axis). Evaluation of the brain metabolites 18-19 weeks after irradiation performed by 1H MRS revealed a significant decrease in the total N-acetylaspartate to total creatine (tNAA/tCr) ratio in the striatum and OB. A significant decline of gamma-aminobutyric acid to tCr (GABA/tCr) ratio was seen in the OB and hippocampus. MR revealed absence of gross inflammatory or necrotic lesions in these regions. Image analysis of the brain sections 18-21 weeks after the exposure showed a radiation-induced increase of neurodegeneration, inhibition of neurogenesis and strong resemblance to the reactive astrogliosis. Results showed that fractionated whole-brain irradiation led to the changes in neurotransmission and to the loss of neuronal viability in vivo. Metabolic changes were closely associated with histopathological findings, i.e. initiation of neuronal cell death, inhibition of neurogenesis and strong response of astrocytes indicated development of late radiation-induced changes.
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Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/efectos de la radiación , Animales , Astrocitos/efectos de la radiación , Peso Corporal/efectos de la radiación , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Cuerpo Estriado/efectos de la radiación , Proteínas de Dominio Doblecortina , Hipocampo/metabolismo , Hipocampo/patología , Hipocampo/efectos de la radiación , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Neurogénesis/efectos de la radiación , Neuronas/efectos de la radiación , Neuropéptidos/metabolismo , Bulbo Olfatorio/metabolismo , Bulbo Olfatorio/patología , Bulbo Olfatorio/efectos de la radiación , Tamaño de los Órganos/efectos de la radiación , Espectroscopía de Protones por Resonancia Magnética , Ratas WistarRESUMEN
Although noradrenaline and adrenaline are some of the most important neurotransmitters in the central nervous system, the effects of noradrenergic/adrenergic modulation on the striatum have not been determined. In order to explore the effects of adrenergic receptor (AR) agonists on the striatal firing patterns, we used optogenetic methods which can induce continuous firings. We employed transgenic rats expressing channelrhodopsin-2 (ChR2) in neurons. The medium spiny neuron showed a slow rising depolarization during the 1-s long optogenetic striatal photostimulation and a residual potential with 8.6-s half-life decay after the photostimulation. As a result of the residual potential, five repetitive 1-sec long photostimulations with 20-s onset intervals cumulatively increased the number of spikes. This 'firing increment', possibly relating to the timing control function of the striatum, was used to evaluate the AR modulation. The ß-AR agonist isoproterenol decreased the firing increment between the 1st and 5th stimulation cycles, while the α1-AR agonist phenylephrine enhanced the firing increment. Isoproterenol and adrenaline increased the early phase (0-0.5s of the photostimulation) firing response. This adrenergic modulation was inhibited by the ß-antagonist propranolol. Conversely, phenylephrine and noradrenaline reduced the early phase response. ß-ARs and α1-ARs work in opposition controlling the striatal firing initiation and the firing increment.
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Potenciales de Acción , Cuerpo Estriado/metabolismo , Receptores Adrenérgicos/metabolismo , Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Channelrhodopsins , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/efectos de la radiación , Epinefrina/farmacología , Isoproterenol/farmacología , Luz , Fenilefrina/farmacología , Propranolol/farmacología , Ratas Transgénicas , Ratas WistarRESUMEN
Bright-light interventions have successfully been used to reduce depression symptoms in patients with seasonal affective disorder, a depressive disorder most frequently occurring during seasons with reduced daylight availability. Yet, little is known about how light exposure impacts human brain function, for instance on risk taking, a process affected in depressive disorders. Here we examined the modulatory effects of bright-light exposure on brain activity during a risk-taking task. Thirty-two healthy male volunteers living in the greater Copenhagen area received 3weeks of bright-light intervention during the winter season. Adopting a double-blinded dose-response design, bright-light was applied for 30minutes continuously every morning. The individual dose varied between 100 and 11.000lx. Whole-brain functional MRI was performed before and after bright-light intervention to probe how the intervention modifies risk-taking related neural activity during a two-choice gambling task. We also assessed whether inter-individual differences in the serotonin transporter-linked polymorphic region (5-HTTLPR) genotype influenced the effects of bright-light intervention on risk processing. Bright-light intervention led to a dose-dependent increase in risk-taking in the LA/LA group relative to the non-LA/LA group. Further, bright-light intervention enhanced risk-related activity in ventral striatum and head of caudate nucleus in proportion with the individual bright-light dose. The augmentation effect of light exposure on striatal risk processing was not influenced by the 5-HTTLPR-genotype. This study provides novel evidence that in healthy non-depressive individuals bright-light intervention increases striatal processing to risk in a dose-dependent fashion. The findings provide converging evidence that risk processing is sensitive to bright-light exposure during winter.
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Conducta de Elección/fisiología , Conducta de Elección/efectos de la radiación , Cuerpo Estriado/fisiología , Cuerpo Estriado/efectos de la radiación , Luz , Iluminación/métodos , Asunción de Riesgos , Adaptación Fisiológica/fisiología , Adaptación Fisiológica/efectos de la radiación , Adolescente , Adulto , Mapeo Encefálico , Relación Dosis-Respuesta en la Radiación , Humanos , Masculino , Persona de Mediana Edad , Estimulación Luminosa/métodos , Dosis de Radiación , Adulto JovenRESUMEN
Converging lines of evidence indicate that near-infrared light treatment, also known as photobiomodulation (PBM), may exert beneficial effects and protect against cellular toxicity and degeneration in several animal models of human pathologies, including neurodegenerative disorders. In the present study, we report that chronic PMB treatment mitigates dopaminergic loss induced by unilateral overexpression of human α-synuclein (α-syn) in the substantia nigra of an AAV-based rat genetic model of Parkinson's disease (PD). In this model, daily exposure of both sides of the rat's head to 808-nm near-infrared light for 28 consecutive days alleviated α-syn-induced motor impairment, as assessed using the cylinder test. This treatment also significantly reduced dopaminergic neuronal loss in the injected substantia nigra and preserved dopaminergic fibers in the ipsilateral striatum. These beneficial effects were sustained for at least 6 weeks after discontinuing the treatment. Together, our data point to PBM as a possible therapeutic strategy for the treatment of PD and other related synucleinopathies.
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Neuronas Dopaminérgicas/efectos de la radiación , Terapia por Luz de Baja Intensidad , Enfermedad de Parkinson/radioterapia , Sustancia Negra/efectos de la radiación , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Cuerpo Estriado/efectos de la radiación , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Ratas Sprague-Dawley , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The present study was undertaken to investigate the pretreatment effects of standardized Ginkgo biloba extract (EGb761(®)) and low-dose whole-body γ-irradiation on the neurological dysfunction in the reserpine model of PD. Male Wistar rats were pretreated orally with EGb761 or fractionated low-dose whole-body γ-irradiation or their combination, then subjected to intraperitoneal injection of reserpine (5 mg/kg body weight) 24 h after the final dose of EGb761 or radiation. Reserpine injection resulted in the depletion of striatal dopamine (DA) level, increased catalepsy score, increased oxidative stress indicated via depletion of glutathione (GSH), increased malondialdehyde (MDA) and iron levels, decreased DA metabolites metabolizing enzymes; indicated by inhibition by glutathione-S-transferase, and nicotinamide adenine dinucleotide phosphate (NADPH)-quinone oxidoreductase (NQO) activities, mitochondrial dysfunction; indicated by declined complex I activity, and adenosine triphosphate (ATP) level and increased apoptosis; indicated by decreased mitochondrial B cell lymphoma-2 (Bcl-2) protein level and by transmission electron microscope. EGb761 and low-dose γ-radiation ameliorated the reserpine-induced state of oxidative stress, mitochondrial dysfunction, and apoptosis in brain. It can be concluded that EGb761, a widely used herbal medicine and low dose of γ-irradiation have protective effects for combating Parkinsonism possibly via replenishment of GSH levels.
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Cuerpo Estriado/efectos de la radiación , Suplementos Dietéticos , Neuronas/efectos de la radiación , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/prevención & control , Extractos Vegetales/uso terapéutico , Irradiación Corporal Total , Animales , Antiparkinsonianos/uso terapéutico , Apoptosis/efectos de la radiación , Conducta Animal/efectos de la radiación , Química Encefálica/efectos de la radiación , Catalepsia/etiología , Catalepsia/prevención & control , Terapia Combinada , Cuerpo Estriado/metabolismo , Cuerpo Estriado/ultraestructura , Modelos Animales de Enfermedad , Rayos gamma/uso terapéutico , Ginkgo biloba , Masculino , Neuronas/metabolismo , Neuronas/ultraestructura , Estrés Oxidativo/efectos de la radiación , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Proyectos Piloto , Distribución Aleatoria , Ratas Wistar , ReserpinaRESUMEN
Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.
Asunto(s)
Infarto de la Arteria Cerebral Media/fisiopatología , Infarto de la Arteria Cerebral Media/terapia , Terapia por Láser/métodos , Estimulación Luminosa/métodos , Recuperación de la Función/fisiología , Animales , Proteínas Bacterianas/genética , Conducta Animal/fisiología , Circulación Cerebrovascular/fisiología , Circulación Cerebrovascular/efectos de la radiación , Channelrhodopsins , Cuerpo Estriado/fisiología , Cuerpo Estriado/efectos de la radiación , Modelos Animales de Enfermedad , Proteína GAP-43/genética , Halorrodopsinas/fisiología , Luz , Proteínas Luminiscentes/genética , Masculino , Ratones , Ratones Transgénicos , Corteza Motora/fisiopatología , Corteza Motora/efectos de la radiación , Factor de Crecimiento Nervioso/genética , Plasticidad Neuronal/fisiología , Plasticidad Neuronal/efectos de la radiación , Fibras Ópticas , Recuperación de la Función/efectos de la radiación , Corteza Somatosensorial/fisiología , Corteza Somatosensorial/efectos de la radiaciónRESUMEN
The direct effects of electro-acupuncture (EA) on the dopaminergic neurotransmitter system in Parkinson's disease (PD) patients remain elusive. In the present study, 0, 2 or 100Hz EA was applied to acupoints Sanyinjiao (SP6), Yanglingquan (GB34) and Zusanli (ST36) in a rat model unilaterally lesioned by 6-hydroxydopamine. Rotational behavior tests were performed and the animals were then decapitated. Levels of striatal dopamine (DA), dopamine transporter, and D1- and D2-like DA receptors were subsequently evaluated. EA at 100 Hz was shown to significantly enhance survival of dopaminergic neurons in the substantia nigra (52.10 ± 11.41% of the level on the non-lesioned rats vs. 21.22 ± 5.52% in the non-EA group, P<0.05) and reduce motor deficits (207.80 ± 31.14 vs. 476.11 ± 68.80 turns/30 min, P<0.05), whereas it only slightly restored the 6-hydroxydopamine-induced loss of striatal DA (P>0.05 vs. the non-EA group). There was a 253.78% increase in dopamine transporter protein expression in the striatum in the 100 Hz EA group (P<0.05 vs. the non-EA group). Moreover, high frequency EA induced increases in striatal D1-like receptor mRNA and protein levels of 81.88% and 62.62%, respectively (P<0.001 and P<0.05 vs. the non-EA group). However, the D2-like DA receptor up-regulation observed in the non-EA group was suppressed in high frequency group (P>0.05 vs. the sham operation group). These findings suggest that high-frequency EA might work by acting on presynaptic dopamine transporter and postsynaptic dopamine receptors simultaneously to achieve a therapeutic effect in PD patients and models. This might shed some light on the mechanism by which EA affects the DA neurotransmitter system.
Asunto(s)
Terapia por Acupuntura , Cuerpo Estriado/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Regulación de la Expresión Génica , Síndromes de Neurotoxicidad/terapia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Puntos de Acupuntura , Análisis de Varianza , Animales , Apomorfina , Fenómenos Biofísicos/efectos de los fármacos , Fenómenos Biofísicos/fisiología , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Cuerpo Estriado/efectos de la radiación , Modelos Animales de Enfermedad , Dopamina/metabolismo , Agonistas de Dopamina , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Regulación de la Expresión Génica/efectos de la radiación , Masculino , Trastornos del Movimiento/etiología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Síndromes de Neurotoxicidad/complicaciones , Síndromes de Neurotoxicidad/etiología , Oxidopamina/toxicidad , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/genética , Receptores de Dopamina D2/genética , Simpaticolíticos/toxicidadRESUMEN
Ethanol (EtOH) potentiates the locomotor effects of 3,4-methylenedioxymetamphetamine (MDMA) in rats. This potentiation might involve pharmacokinetic and/or pharmacodynamic mechanisms. We explored whether the latter could be local. Using a slice superfusion approach, we assessed the effects of MDMA (0.3, 3microm) and/or EtOH (2mm) on the spontaneous outflow and electrically evoked release of serotonin (5-HT), dopamine (DA) and acetylcholine (ACh) in the striatum, and for comparison, on 5-HT release in hippocampal and neocortical tissue. MDMA and less effectively EtOH, augmented the outflow of 5-HT in all regions. The electrically evoked 5-HT release was increased by MDMA at 3microm in striatal slices only. With nomifensine throughout, EtOH significantly potentiated the 0.3microm MDMA-induced outflow of 5-HT, but only in striatal slices. EtOH or MDMA also enhanced the spontaneous outflow of DA, but MDMA reduced the electrically evoked DA release. With fluvoxamine throughout superfusion, EtOH potentiated the effect of MDMA on the spontaneous outflow of DA. Finally, 3microm MDMA diminished the electrically evoked release of ACh, an effect involving several receptors (D2, 5-HT2, NMDA, nicotinic, NK1), with some interactions with EtOH. Among other results, we show for the first time a local synergistic interaction of EtOH and MDMA on the spontaneous outflow of striatal DA and 5-HT, which could be relevant to the EtOH-induced potentiation of hyperlocomotion in MDMA-treated rats. These data do not preclude the contribution of other pharmacodynamic and/or pharmacokinetic mechanisms in vivo but support the hypothesis that EtOH may affect the abuse liability of MDMA.
Asunto(s)
Acetilcolina/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Etanol/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Serotoninérgicos/farmacología , Serotonina/metabolismo , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de la radiación , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Estimulación Eléctrica/métodos , Técnicas In Vitro , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Long-Evans , Tritio/metabolismoRESUMEN
We demonstrated that exposure to extremely low frequency magnetic fields (ELF-MF) enhanced dopamine levels in the rat striatum. To extend our understanding, we examined the role of dopaminergic receptors in ELF-MF-induced behavioral changes. Exposure to ELF-MF (2.4 mT, 1 h/day, for one or seven days) enhanced locomotor activity in a time-dependent manner. This hyperlocomotor activity paralleled an increase in c-Fos-like immunoreactivity (c-Fos-IR). Pretreatment with SCH23390, a dopaminergic D(1)-like receptor antagonist, but not with sulpiride, a dopaminergic D(2)-like receptor antagonist, inhibited ELF-MF-induced increased locomotor activity and c-Fos-IR. Thus, our results suggest that ELF-MF-induced behavioral responses are, at least in part, mediated by activation of dopamine D(1)-like receptors.
Asunto(s)
Conducta Animal/efectos de la radiación , Campos Electromagnéticos , Actividad Motora/efectos de la radiación , Receptores de Dopamina D1/metabolismo , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Western Blotting , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de la radiación , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta en la Radiación , Interpretación de Imagen Asistida por Computador/métodos , Inmunoquímica , Ratones , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efectos de la radiación , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ondas de Radio , Sulpirida/farmacología , Factores de TiempoRESUMEN
Conflicting reports exist concerning the effect aspartame (APM, l-aspartyl-l-phenylalanine methyl ester) has upon brain biogenic amines. In the following study, in vivo voltammetry was utilized to measure evoked extracellular dopamine (DA) levels in the striatum of rats in order to assess APM's effect. Time-course experiments revealed a significant decline in evoked extracellular DA levels within 1h of a single systemic dose (500mg/kg i.p.) when compared to vehicle-injected controls. The effect was frequency dependent and showed a significant decrease utilizing high frequency stimulation parameters (50 and 60Hz). In order to further determine APM's potential to alter evoked extracellular DA levels, extended stimulation periods were employed to deplete releasable stores both before and after APM administration in intact and 6-OHDA partially lesioned animals. The extended stimulation periods were applied at 60Hz for 2,5,10 and 20s durations. APM decreased DA levels under these conditions in both intact and 6-OHDA partially lesioned animals by an average of 34% and 51%, respectively. Kinetic analysis performed on frequency series indicated that the diminished DA levels corresponded to a significant reduction in DA release. These findings suggest that APM has a relatively potent effect of decreasing evoked extracellular DA levels when administered systemically under the conditions specified.
Asunto(s)
Aspartame/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Líquido Extracelular/efectos de los fármacos , Edulcorantes/farmacología , Análisis de Varianza , Animales , Lesiones Encefálicas/inducido químicamente , Lesiones Encefálicas/metabolismo , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/patología , Cuerpo Estriado/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica/métodos , Electroquímica/métodos , Líquido Extracelular/efectos de la radiación , Masculino , Oxidopamina , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Acetylcholine may help set the dynamics within neural systems to facilitate the learning of new information. Neural models have shown that if new information is encoded at the same time as retrieval of existing information that is already stored, the memories will interfere with each other. Structures such as the hippocampus have a distinct laminar organization of inputs that allows this hypothesis to be tested. In region CA1 of the rat (Sprague Dawley) hippocampus, the cholinergic agonist carbachol (CCh) suppresses transmission in stratum radiatum (SR), at synapses of the Schaffer collateral projection from CA3, while having lesser effects in stratum lacunosum-moleculare (SLM), the perforant path projection from entorhinal cortex (Hasselmo and Schnell, 1994). The current research extends support of this selectivity by demonstrating laminar effects in region CA3. CCh caused significantly greater suppression in SR than in SLM at low concentrations, while the difference in suppression was not significant at higher concentrations. Differences in paired-pulse facilitation suggest presynaptic inhibition substantially contributes to the suppression and is highly concentration and stratum dependent. This selective suppression of the recurrent excitation would be appropriate to set CA3 dynamics to prevent runaway modification of the synapses of excitatory recurrent collaterals by reducing the influence of previously stored associations and allowing incoming information from the perforant path to have a predominant influence on neural activity.
Asunto(s)
Acetilcolina/farmacología , Ácido Glutámico/farmacología , Hipocampo/citología , Inhibición Neural/efectos de los fármacos , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Animales , Cuerpo Estriado/fisiología , Cuerpo Estriado/efectos de la radiación , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Estimulación Eléctrica/métodos , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/efectos de la radiación , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Masculino , Inhibición Neural/fisiología , Vía Perforante/efectos de los fármacos , Vía Perforante/fisiología , Vía Perforante/efectos de la radiación , Ratas , Ratas Sprague-Dawley , Sinapsis/efectos de la radiación , Transmisión Sináptica/efectos de la radiaciónRESUMEN
Electrophysiological studies have demonstrated that dopaminergic neurons burst fire during certain aspects of reward-related behavior; however, the correlation between dopamine release and cell firing is unclear. When complex stimulation patterns that mimic intracranial self-stimulation were employed, dopamine release was shown to exhibit facilitated as well as depressive components (Montague et al. 2004). Understanding the biological mechanisms underlying these variations in dopamine release is necessary to unravel the correlation between unit activity and neurotransmitter release. The dopamine autoreceptor provides negative feedback to dopamine release, inhibiting release on the time scale of a few seconds. Therefore, we investigated this D(2) receptor to see whether it is one of the biological mechanisms responsible for the history-dependent modulation of dopamine release. Striatal dopamine release in anesthetized rats was evoked with stimulus trains that were designed to promote the variability of dopamine release. Consistent with the well established D(2)-mediated autoinhibition, the short-term depressive component of dopamine release was blocked by raclopride, a D(2) antagonist, and enhanced by quinpirole, a D(2)-receptor agonist. Surprisingly, these same drugs exerted a similar effect on the short-term facilitated component: a decrease with raclopride and an increase with quinpirole. These data demonstrate that the commanding control exerted by dopamine autoreceptors over short-term neuroadaptation of dopamine release involves both inhibitory and paradoxically, facilitatory components.