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1.
Nat Commun ; 11(1): 4958, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009395

RESUMO

Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Regulação para Baixo , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Transtornos Parkinsonianos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Astrócitos/metabolismo , Membrana Celular/metabolismo , Modelos Animais de Doenças , Glutamato Descarboxilase/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Núcleo Accumbens/metabolismo
2.
Acta Neurol Scand ; 142(4): 385-391, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32914881

RESUMO

BACKGROUND: Idiopathic Parkinson's disease (PD) is characterized by clinical motor symptoms including hypokinesia, rigidity and tremor. In addition to the movement disorder, cognitive deficits are commonly described. In the present study, we applied FP-CIT SPECT to investigate the impact of nigrostriatal dopaminergic degeneration on cognitive function in PD patients. METHODS: Fifty-four PD patients underwent [123I]FP-CIT SPECT and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) testing. FP-CIT SPECT visualized the density of presynaptic dopamine transporters in both striata, each subdivided into a limbic, executive and sensorimotor subregion according to the atlas of Tziortzi et al (Cereb Cortex 24, 2014, 1165). CERAD testing quantified cognitive function. RESULTS: In the CERAD testing, PD patients exhibited deficits in the domains of semantic memory, attention, visuospatial function, non-verbal memory and executive function. After correction for multiple testing, the performance of the subtests Figure Recall and Trail-Making Test A correlated significantly with FP-CIT uptake into the ipsilateral executive subregion. The performance of the subtest Figure Saving correlated significantly with FP-CIT uptake into the contralateral executive subregion. CONCLUSIONS: The significant correlation between cognitive function and density of nigrostriatal dopamine transporters, as assessed by FP-CIT SPECT, indicate that striatal dopaminergic pathways-primarily the executive striatal subregion-are relevant to cognitive processing in PD.


Assuntos
Cognição , Corpo Estriado/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos , Corpo Estriado/metabolismo , Feminino , Humanos , Masculino , Doença de Parkinson/fisiopatologia , Tremor
3.
Proc Natl Acad Sci U S A ; 117(33): 20265-20273, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747555

RESUMO

Huntington disease (HD) is an ideal model for investigating selective neurodegeneration, as expanded polyQ repeats in the ubiquitously expressed huntingtin (HTT) cause the preferential neurodegeneration in the striatum of the HD patient brains. Here we report that adeno-associated virus (AAV) transduction-mediated depletion of Hap1, the first identified huntingtin-associated protein, in adult HD knock-in (KI) mouse brains leads to selective neuronal loss in the striatum. Further, Hap1 depletion-mediated neuronal loss via AAV transduction requires the presence of mutant HTT. Rhes, a GTPase that is enriched in the striatum and sumoylates mutant HTT to mediate neurotoxicity, binds more N-terminal HTT when Hap1 is deficient. Consistently, more soluble and sumoylated N-terminal HTT is presented in HD KI mouse striatum when HAP1 is absent. Our findings suggest that both Rhes and Hap1 as well as cellular stress contribute to the preferential neurodegeneration in HD, highlighting the involvement of multiple factors in selective neurodegeneration.


Assuntos
Corpo Estriado/patologia , Doença de Huntington/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/fisiologia , Optogenética , Animais , Corpo Estriado/metabolismo , Dependovirus , Regulação da Expressão Gênica , Doença de Huntington/genética , Lasers , Luz , Camundongos , Rede Nervosa , Proteínas do Tecido Nervoso/genética
4.
Nat Commun ; 11(1): 3996, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778725

RESUMO

Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Hipercinese/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Dopamina , Feminino , Hipercinese/induzido quimicamente , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Optogenética
5.
J Toxicol Sci ; 45(7): 391-399, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32612007

RESUMO

This study was aimed at examining propofol- (a known anesthetic) induced emotion-related behavioral disorders in mice, and exploring the possible molecular mechanisms. A total of 60 mice were divided into two groups: control and propofol group. Mice were injected with propofol (150 mg/kg, ip) at 8:00 a.m. (once a day, lasting for 30 days). During the 30 days, loss of righting reflex (LORR) and return of righting reflex (RORR) of mice were recorded every day. At the 1st (T1) and 30th (T2) day of drug discontinuance (T2), 15 mice of each group were selected to perform the open field test; then the mice underwent perfusion fixation, and the midbrain and corpus striatum were separated for immunofluorescence assay with anti-tyrosine hydroxylase (Th) and anti- dopamine transporter (DAT) antibodies. Results showed that after propofol injection, LORR and RORR increased and decreased, respectively. Long-term use of propofol resulted in decreased activities of mice (activity trajectory, line crossing, rearing time, scratching times and defecating frequency). Immunofluorescence assay showed long-term use of propofol induced decrease of Th and DAT. Collectively, our present work suggested long-term abuse of propofol induces neuropsychiatric function impairments, and the possible mechanisms are related to dopamine dyssynthesis via down-regulating tyrosine hydroxylase and dopamine transporter.


Assuntos
Anestésicos/toxicidade , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/patologia , Transtornos Mentais/induzido quimicamente , Propofol/toxicidade , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologia , Anestésicos/efeitos adversos , Animais , Neurônios Dopaminérgicos/metabolismo , Emoções/efeitos dos fármacos , Masculino , Transtornos Mentais/metabolismo , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Camundongos Endogâmicos C57BL , Propofol/efeitos adversos , Reflexo de Endireitamento/efeitos dos fármacos
6.
Life Sci ; 257: 118019, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32629002

RESUMO

Parkinson's disease (PD) is a disease of the human nervous system with an onset, in the sixth and seventh decades of the human life. Chiefly perceived as progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) with the ensued loss of dopamine in the striatum and the presence of Lewy bodies, consisting of α-synuclein agglomeration. In which the neuronal bridge between substantia nigra and striatum plays an advent role in the motor system. Dilapidation of these neurons results in dopamine depletion which in-turn makes hay to PD. Eventually, the etiology and pathogenesis of PD were still on a hike of dilemma. Traditional Chinese medicine (TCM), including Chinese herbal remedies, acupuncture, and manipulative therapies, is commonly used as an adjunctive therapy in different diseases, particularly neurological diseases, in Asian countries. Additionally, TCM might improve the prognoses and the quality of life of patients with PD because it induces less adverse drug reactions. The present review describes research on the various neuroprotective components and herbal extracts from herbal medicines in the context of addressing the effects of PD.


Assuntos
Medicina Tradicional Chinesa/métodos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Animais , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina , Neurônios Dopaminérgicos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Parte Compacta da Substância Negra/metabolismo , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
7.
BMC Neurol ; 20(1): 277, 2020 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-32652959

RESUMO

BACKGROUND: Dopamine transporter (DAT) imaging may enable clinicians to discriminate idiopathic normal pressure hydrocephalus (iNPH) from other parkinsonian disorders. However, a specific pattern of dopaminergic loss in DAT imaging of iNPH patients remains to be further elucidated. METHODS: In this preliminary study, 11 patients with iNPH in our hospital between March 2017 and February 2019 were finally enrolled. A diagnosis of iNPH was made according to the two established criteria. For visual analysis of DAT imaging, a striatum was divided into five domains. A semi-quantitative visual assessment was performed with a consensus between a nuclear medicine specialist and an experienced neurologist who were blinded to the clinical diagnosis. RESULTS: Striatal dopaminergic deficits were abnormal in 90.9% (10/11) of patients with iNPH. The degree of dopaminergic reduction was mild and heterogeneous. However, a tendency of preferential striatal DAT loss in the caudate nucleus (90.9%, 10/11) than in the putamen (72.7%, 8/11) was observed, whereas ventral portion (9.1%, 1/11) was relatively preserved. CONCLUSION: Striatal dopaminergic depletion might be mild and heterogeneous in patients with iNPH. These dopaminergic deficits were more common in the caudate nucleus than in the putamen, suggesting a pattern different from other degenerative parkinsonian disorders.


Assuntos
Corpo Estriado , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/metabolismo , Hidrocefalia de Pressão Normal , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Diagnóstico por Imagem , Humanos , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Hidrocefalia de Pressão Normal/metabolismo
8.
Neurology ; 95(3): e280-e290, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32616674

RESUMO

OBJECTIVE: To investigate whether the patterns of striatal dopamine depletion on dopamine transporter (DAT) scans could provide information on the long-term prognosis in Parkinson disease (PD). METHODS: We enrolled 205 drug-naive patients with early-stage PD, who underwent 18F-FP-CIT PET scans at initial assessment and received PD medications for 3 or more years. After quantifying the DAT availability in each striatal subregion, factor analysis was conducted to simplify the identification of striatal dopamine depletion patterns and to yield 4 striatal subregion factors. We assessed the effect of these factors on the development of levodopa-induced dyskinesia (LID), wearing-off, freezing of gait (FOG), and dementia during the follow-up period (6.84 ± 1.80 years). RESULTS: The 4 factors indicated which striatal subregions were relatively preserved: factor 1 (caudate), factor 2 (more-affected sensorimotor striatum), factor 3 (less-affected sensorimotor striatum), and factor 4 (anterior putamen). Cox regression analyses using the composite scores of these striatal subregion factors as covariates demonstrated that selective dopamine depletion in the sensorimotor striatum was associated with a higher risk for developing LID. Selective dopamine loss in the putamen, particularly in the anterior putamen, was associated with early development of wearing-off. Selective involvement of the anterior putamen was associated with a higher risk for dementia conversion. However, the patterns of striatal dopamine depletion did not affect the risk of FOG. CONCLUSIONS: These findings suggested that the patterns of striatal dopaminergic denervation, which were estimated by the equation derived from the factor analysis, have a prognostic implication in patients with early-stage PD.


Assuntos
Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Dopamina/metabolismo , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Tomografia por Emissão de Pósitrons/tendências , Idoso , Diagnóstico Precoce , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
9.
Proc Natl Acad Sci U S A ; 117(27): 15989-15999, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581130

RESUMO

Huntington disease (HD) is caused by an expansion mutation of the N-terminal polyglutamine of huntingtin (mHTT). mHTT is ubiquitously present, but it induces noticeable damage to the brain's striatum, thereby affecting motor, psychiatric, and cognitive functions. The striatal damage and progression of HD are associated with the inflammatory response; however, the underlying molecular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling revealed that the cGAS mRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. Moreover, the protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10) are increased in HD striatum. Depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy in HD cells. In contrast, reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Ribosome profiling also revealed that LC3A and LC3B, the two major autophagy initiators, show altered ribosome occupancy in HD cells. We also detected the presence of numerous micronuclei, which are known to induce cGAS, in the cytoplasm of neurons derived from human HD embryonic stem cells. Collectively, our results indicate that cGAS is up-regulated in HD and mediates inflammatory and autophagy responses. Thus, targeting the cGAS pathway may offer therapeutic benefits in HD.


Assuntos
Autofagia/fisiologia , Doença de Huntington/genética , Doença de Huntington/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Animais , Quimiocina CCL5/metabolismo , Quimiocina CXCL10/metabolismo , Corpo Estriado/metabolismo , Células-Tronco Embrionárias , Humanos , Proteína Huntingtina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Neostriado/metabolismo , Neurônios/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Transcriptoma , Regulação para Cima
10.
Mol Biol (Mosk) ; 54(2): 313-320, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392202

RESUMO

Striatal-enriched protein tyrosine phosphatase (STEP), which was initially identified in the striatum, is encoded by the Ptpn5 gene and is expressed in neurons of various structures of the brain. STEP is involved in regulating neuroplasticity, and its expression abnormalities are associated with human neurodegenerative disorders. The STEP inhibitor 8-trifluoromethyl-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (TC-2153) has been shown to affect the serotoninergic system of the brain. However, the influence of the serotoninergic system on the STEP regulation has not been studied yet. The aim of the study was to investigate how pharmacologically induced changes in the brain serotonin (5-HT) level affect Ptpn5 expression and STEP activity in adult male C57BL/6J mice. To modulate the 5-HT level in the brain, the 5-HT synthesis inhibitor p-chlorophenylalanine or 5-HT degradation inhibitor pargyline was administered intraperitoneally for three successive days. Changes in 5-HT concentration in the brain were assayed using high-performance liquid chromatography. The STEP activity was determined spectrophotometrically in the supernatant by the rate of p-nitrophenyl phosphate dephosphorylation in the absence and presence of the selective STEP inhibitor TC-2153. The Ptpn5 mRNA level was determined using quantitative RT-PCR. The Ptpn5 expression level in the striatum was three times higher than in the cortex and hippocampus. Both increases and decreases in brain 5-HT were for the first time associated with a decrease in Ptpn5 mRNA in the striatum. STEP activity in the striatum and cortex was significantly higher than in the hippocampus. However, p-chlorophenylalanine and pargyline did not affect the STEP activity in the brain structures tested. Thus, a new method was proposed to study the STEP activity in the brain and p-chlorophenylalanine and pargyline were shown to decrease Ptpn5 expression in the striatum in mice.


Assuntos
Alanina/análogos & derivados , Cloraminas/farmacologia , Corpo Estriado/metabolismo , Pargilina/farmacologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Alanina/farmacologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios , Serotonina
11.
PLoS One ; 15(5): e0226790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365120

RESUMO

Patients with DYT1 dystonia caused by the mutated TOR1A gene exhibit risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. It is unclear whether this behaviour can be linked to changes in cortico-striatal plasticity demonstrated in animal models which share the same TOR1A mutation. We hypothesised that we could reproduce the experimental risk taking behaviour using a model of the basal ganglia under conditions where cortico-striatal plasticity was abnormal. As dopamine exerts opposing effects on cortico-striatal plasticity via different receptors expressed on medium spiny neurons (MSN) of the direct (D1R dominant, dMSNs) and indirect (D2R dominant, iMSNs) pathways, we tested whether abnormalities in cortico-striatal plasticity in one or both of these pathways could explain the patient's behaviour. Our model could generate simulated behaviour indistinguishable from patients when cortico-striatal plasticity was abnormal in both dMSNs and iMSNs in opposite directions. The risk neutral behaviour of the patients was replicated when increased cortico-striatal long term potentiation in dMSN's was in combination with increased long term depression in iMSN's. This result is consistent with previous observations in rodent models of increased cortico-striatal plasticity at in dMSNs, but contrasts with the pattern reported in vitro of dopamine D2 receptor dependant increases in cortico-striatal LTP and loss of LTD at iMSNs. These results suggest that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 receptor dependant cortico-striatal plasticity that are not apparent in rodent models of this disease.


Assuntos
Dopamina/genética , Distonia Muscular Deformante/genética , Chaperonas Moleculares/genética , Receptores de Dopamina D2/genética , Animais , Gânglios da Base/metabolismo , Gânglios da Base/fisiologia , Comportamento Animal/fisiologia , Ciências Biocomportamentais , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopamina/metabolismo , Distonia Muscular Deformante/psicologia , Feminino , Humanos , Aprendizagem/fisiologia , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Rigidez Muscular/genética , Rigidez Muscular/patologia , Mutação/genética , Vias Neurais/metabolismo , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Reforço Psicológico , Assunção de Riscos , Roedores/genética , Roedores/fisiologia , Sinapses/genética
12.
Nat Commun ; 11(1): 2582, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444599

RESUMO

Polyglutamine expansion in proteins can cause selective neurodegeneration, although the mechanisms are not fully understood. In Huntington's disease (HD), proteolytic processing generates toxic N-terminal huntingtin (HTT) fragments that preferentially kill striatal neurons. Here, using CRISPR/Cas9 to truncate full-length mutant HTT in HD140Q knock-in (KI) mice, we show that exon 1 HTT is stably present in the brain, regardless of truncation sites in full-length HTT. This N-terminal HTT leads to similar HD-like phenotypes and age-dependent HTT accumulation in the striatum in different KI mice. We find that exon 1 HTT is constantly generated but its selective accumulation in the striatum is associated with the age-dependent expression of striatum-enriched HspBP1, a chaperone inhibitory protein. Our findings suggest that tissue-specific chaperone function contributes to the selective neuropathology in HD, and highlight the therapeutic potential in blocking generation of exon 1 HTT.


Assuntos
Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/etiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores Etários , Animais , Sistemas CRISPR-Cas , Núcleo Celular/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Éxons , Feminino , Técnicas de Introdução de Genes , Doença de Huntington/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Mutação , Fenótipo
13.
Nat Commun ; 11(1): 2555, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444624

RESUMO

Fetal alcohol exposure (FAE) is the leading preventable developmental cause of cognitive dysfunction. Even in the absence of binge drinking, alcohol consumption during pregnancy can leave offspring deficient. However, the mechanisms underlying these deficiencies are unknown. Using a mouse model of gestational ethanol exposure (GEE), we show increased instrumental lever-pressing and disruption of efficient habitual actions in adults, indicative of disrupted cognitive function. In vivo electrophysiology reveals disrupted action encoding in dorsolateral striatum (DLS) associated with altered habit learning. GEE mice exhibit decreased GABAergic transmission onto DLS projection neurons, including inputs from parvalbumin interneurons, and increased endocannabinoid tone. Chemogenetic activation of DLS parvalbumin interneurons reduces the elevated lever pressing of GEE mice. Pharmacologically increasing endocannabinoid tone mimics GEE effects on cognition and synaptic transmission. These findings show GEE induces long-lasting deficits in cognitive function that may contribute to human FAE, and identify potential mechanisms for future therapeutic targeting.


Assuntos
Corpo Estriado/fisiopatologia , Etanol/efeitos adversos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Cognição/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Etanol/metabolismo , Feminino , Desenvolvimento Fetal , Humanos , Masculino , Camundongos Endogâmicos C57BL , Linhagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia
14.
Nat Commun ; 11(1): 1957, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327644

RESUMO

Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.


Assuntos
Neostriado/citologia , Neurônios/fisiologia , Núcleo Accumbens/citologia , Receptores de Dopamina D2/metabolismo , Anfetamina/farmacologia , Animais , Biomarcadores/metabolismo , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopaminérgicos/farmacologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neostriado/metabolismo , Neostriado/fisiologia , Vias Neurais , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Receptores de Dopamina D2/genética
15.
J Neurosci ; 40(18): 3675-3691, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32238479

RESUMO

The transcription factor Nurr1 has been identified to be ectopically induced in the striatum of rodents expressing l-DOPA-induced dyskinesia (LID). In the present study, we sought to characterize Nurr1 as a causative factor in LID expression. We used rAAV2/5 to overexpress Nurr1 or GFP in the parkinsonian striatum of LID-resistant Lewis or LID-prone Fischer-344 (F344) male rats. In a second cohort, rats received the Nurr1 agonist amodiaquine (AQ) together with l-DOPA or ropinirole. All rats received a chronic DA agonist and were evaluated for LID severity. Finally, we performed single-unit recordings and dendritic spine analyses on striatal medium spiny neurons (MSNs) in drug-naïve rAAV-injected male parkinsonian rats. rAAV-GFP injected LID-resistant hemi-parkinsonian Lewis rats displayed mild LID and no induction of striatal Nurr1 despite receiving a high dose of l-DOPA. However, Lewis rats overexpressing Nurr1 developed severe LID. Nurr1 agonism with AQ exacerbated LID in F344 rats. We additionally determined that in l-DOPA-naïve rats striatal rAAV-Nurr1 overexpression (1) increased cortically-evoked firing in a subpopulation of identified striatonigral MSNs, and (2) altered spine density and thin-spine morphology on striatal MSNs; both phenomena mimicking changes seen in dyskinetic rats. Finally, we provide postmortem evidence of Nurr1 expression in striatal neurons of l-DOPA-treated PD patients. Our data demonstrate that ectopic induction of striatal Nurr1 is capable of inducing LID behavior and associated neuropathology, even in resistant subjects. These data support a direct role of Nurr1 in aberrant neuronal plasticity and LID induction, providing a potential novel target for therapeutic development.SIGNIFICANCE STATEMENT The transcription factor Nurr1 is ectopically induced in striatal neurons of rats exhibiting levodopa-induced dyskinesia [LID; a side-effect to dopamine replacement strategies in Parkinson's disease (PD)]. Here we asked whether Nurr1 is causing LID. Indeed, rAAV-mediated expression of Nurr1 in striatal neurons was sufficient to overcome LID-resistance, and Nurr1 agonism exacerbated LID severity in dyskinetic rats. Moreover, we found that expression of Nurr1 in l-DOPA naïve hemi-parkinsonian rats resulted in the formation of morphologic and electrophysiological signatures of maladaptive neuronal plasticity; a phenomenon associated with LID. Finally, we determined that ectopic Nurr1 expression can be found in the putamen of l-DOPA-treated PD patients. These data suggest that striatal Nurr1 is an important mediator of the formation of LID.


Assuntos
Corpo Estriado/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/toxicidade , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/biossíntese , Transtornos Parkinsonianos/metabolismo , Idoso , Animais , Corpo Estriado/efeitos dos fármacos , Discinesia Induzida por Medicamentos/patologia , Feminino , Humanos , Masculino , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Ratos Sprague-Dawley
16.
Neurology ; 94(15): e1605-e1613, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32161031

RESUMO

OBJECTIVE: Unilateral onset of parkinsonism due to nigrostriatal damage of the contralateral hemisphere is frequent in Parkinson disease (PD). There is evidence for a left-hemispheric bias of motor asymmetry in right-handed patients with PD indicating a hemispheric dominance. Isolated REM sleep behavior disorder (IRBD) constitutes the prodromal stage of PD and other synucleinopathies. To test the hypothesis that right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction, we evaluated this aspect using neuroimaging instruments. METHODS: In 167 right-handed patients with IRBD without parkinsonism, we evaluated in each hemisphere the integrity of the striatal dopaminergic terminals by dopamine transporter (DAT)-SPECT and the substantia nigra echogenicity by transcranial sonography. RESULTS: DAT-SPECT showed lower specific binding ratio (SBR) in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. The percentage of patients with lower SBR was greater in the left striatum and left caudate nucleus than in the right striatum and right caudate nucleus. In those who developed a synucleinopathy in <5 years from DAT-SPECT, there was a lower SBR in the left putamen and left caudate nucleus than in the right putamen and right caudate nucleus. Substantia nigra echogenic size was greater in the left than in the right side in patients with hyperechogenicity and among individuals who phenoconverted in <5 years from transcranial sonography. CONCLUSION: Right-handed patients with IRBD exhibit left-hemispheric predominance of subclinical nigrostriatal dysfunction. In premotor PD, the neurodegenerative process begins asymmetrically, initially impairing the nigrostriatal system of the dominant hemisphere.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/farmacologia , Dopamina/metabolismo , Doença de Parkinson/fisiopatologia , Transtorno do Comportamento do Sono REM/fisiopatologia , Adulto , Idoso , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Doença de Parkinson/metabolismo , Putamen/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/diagnóstico , Transtorno do Comportamento do Sono REM/metabolismo , Substância Negra/diagnóstico por imagem , Substância Negra/fisiopatologia , Ultrassonografia Doppler Transcraniana/métodos
17.
Science ; 367(6484): 1362-1366, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32193325

RESUMO

Stimulants such as methylphenidate are increasingly used for cognitive enhancement but precise mechanisms are unknown. We found that methylphenidate boosts willingness to expend cognitive effort by altering the benefit-to-cost ratio of cognitive work. Willingness to expend effort was greater for participants with higher striatal dopamine synthesis capacity, whereas methylphenidate and sulpiride, a selective D2 receptor antagonist, increased cognitive motivation more for participants with lower synthesis capacity. A sequential sampling model informed by momentary gaze revealed that decisions to expend effort are related to amplification of benefit-versus-cost information attended early in the decision process, whereas the effect of benefits is strengthened with higher synthesis capacity and by methylphenidate. These findings demonstrate that methylphenidate boosts the perceived benefits versus costs of cognitive effort by modulating striatal dopamine signaling.


Assuntos
Cognição/efeitos dos fármacos , Corpo Estriado/metabolismo , Dopamina/metabolismo , Metilfenidato/farmacologia , Motivação/efeitos dos fármacos , Sulpirida/farmacologia , Adolescente , Núcleo Caudado/metabolismo , Comportamento de Escolha , Tomada de Decisões , Dopamina/biossíntese , Antagonistas dos Receptores de Dopamina D2/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Feminino , Fixação Ocular , Humanos , Masculino , Memória , Recompensa , Movimentos Sacádicos , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
18.
Anat Sci Int ; 95(4): 429-439, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32200530

RESUMO

In Parkinson's disease (PD), physical therapy is one of the mainstays of supportive treatment modalities. This study focused on the neuroprotective effect of regular exercise on striatal calretinin positive interneurons in a rat model of PD. 6-hydroxydopamine (6-OHDA) was injected unilaterally into the medial forebrain bundle of Wistar rats. 6-OHDA lesioned (Parkinsonian) and unlesioned (control) rats were divided into sedentary and exercise groups. Exercise groups had daily swimming sessions for 30 min for 6 weeks. After 6-OHDA injections, an apomorphine-induced rotation test was performed (0.05 mg/kg, subcutaneous) at the 3rd and 6th weeks. At the end of the 6th week, brains were removed following transcardiac perfusion. The brain sections were stained immunohistochemically for tyrosine hydroxylase and calretinin reactivity. The number of rotations was significantly lower in Parkinsonian exercise group compared to Parkinsonian sedentary group at the 6th week (p = 0.024) and there was significant difference between Parkisonian sedentary groups at the 3rd and 6th weeks (p < 0.002). The calretinin positive interneurons significantly increased in the Parkinsonian exercise group compared to Parkinsonian sedentary group (p = 0.0003) and control exercise group (p < 0.0001). To conclude, the swimming exercise led to a striking increment of calretinin positive interneurons in the striatum of Parkinsonian rat. These findings indicated that the neuroprotective mechanism of exercise increased the number of striatal calretinin positive interneurons that might generate new approaches for the mechanism of neuroprotection. We concluded that striatal calretinin positive interneurons have an important role in the neuroprotective mechanisms of exercise in PD.


Assuntos
Calbindina 2/metabolismo , Corpo Estriado/metabolismo , Interneurônios/metabolismo , Neuroproteção/fisiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , Condicionamento Físico Animal/fisiologia , Natação/fisiologia , Animais , Modelos Animais de Doenças , Masculino , Oxidopamina , Ratos Wistar
19.
Neurobiol Aging ; 89: 12-23, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32143981

RESUMO

The nigrostriatal dopaminergic system (NDS) controls motor activity, and its impairment during type 2 diabetes (T2D) progression could increase Parkinson's disease risk in diabetics. If so, whether glycemia regulation prevents this impairment needs to be addressed. We investigated whether T2D impairs the NDS and whether dipeptidyl peptidase-4 inhibition (DPP-4i; a clinical strategy against T2D but also neuroprotective in animal models) prevents this effect, in middle-aged mice. Neither T2D (induced by 12 months of high-fat diet) nor aging (14 months) changed striatal dopamine content assessed by high-performance liquid chromatography. However, T2D reduced basal and amphetamine-stimulated striatal extracellular dopamine, assessed by microdialysis. Both the DPP-4i linagliptin and the sulfonylurea glimepiride (an antidiabetic comparator unrelated to DPP-4i) counteracted these effects. The functional T2D-induced effects did not correlate with NDS neuronal/glial alterations. However, aging itself affected striatal neurons/glia, and the glia effects were counteracted mainly by DPP-4i. These findings show NDS functional pathophysiology in T2D and suggest the preventive use of two unrelated anti-T2D drugs. Moreover, DPP-4i counteracted striatal age-related glial alterations suggesting striatal rejuvenation properties.


Assuntos
Envelhecimento/metabolismo , Corpo Estriado/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Dopamina/metabolismo , Linagliptina/farmacologia , Substância Negra/metabolismo , Compostos de Sulfonilureia/farmacologia , Animais , Diabetes Mellitus Tipo 2/complicações , Progressão da Doença , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Doença de Parkinson/etiologia , Doença de Parkinson/prevenção & controle , Risco
20.
Proc Natl Acad Sci U S A ; 117(13): 7418-7429, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32170006

RESUMO

The striatal complex of basal ganglia comprises two functionally distinct districts. The dorsal district controls motor and cognitive functions. The ventral district regulates the limbic function of motivation, reward, and emotion. The dorsoventral parcellation of the striatum also is of clinical importance as differential striatal pathophysiologies occur in Huntington's disease, Parkinson's disease, and drug addiction disorders. Despite these striking neurobiologic contrasts, it is largely unknown how the dorsal and ventral divisions of the striatum are set up. Here, we demonstrate that interactions between the two key transcription factors Nolz-1 and Dlx1/2 control the migratory paths of striatal neurons to the dorsal or ventral striatum. Moreover, these same transcription factors control the cell identity of striatal projection neurons in both the dorsal and the ventral striata including the D1-direct and D2-indirect pathways. We show that Nolz-1, through the I12b enhancer, represses Dlx1/2, allowing normal migration of striatal neurons to dorsal and ventral locations. We demonstrate that deletion, up-regulation, and down-regulation of Nolz-1 and Dlx1/2 can produce a striatal phenotype characterized by a withered dorsal striatum and an enlarged ventral striatum and that we can rescue this phenotype by manipulating the interactions between Nolz-1 and Dlx1/2 transcription factors. Our study indicates that the two-tier system of striatal complex is built by coupling of cell-type identity and migration and suggests that the fundamental basis for divisions of the striatum known to be differentially vulnerable at maturity is already encoded by the time embryonic striatal neurons begin their migrations into developing striata.


Assuntos
Gânglios da Base/citologia , Corpo Estriado/citologia , Estriado Ventral/citologia , Animais , Gânglios da Base/metabolismo , Diferenciação Celular , Corpo Estriado/metabolismo , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Interneurônios/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Estriado Ventral/metabolismo
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