RESUMO
Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.
Assuntos
Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Morte Celular , Dendritos/metabolismo , Dendritos/patologia , Modelos Animais de Doenças , Progressão da Doença , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Levodopa/farmacologia , Levodopa/uso terapêutico , Masculino , Camundongos , Destreza Motora/efeitos dos fármacos , NADH Desidrogenase/deficiência , NADH Desidrogenase/genética , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Fenótipo , Substância Negra/citologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismoRESUMO
Although mammalian retinal ganglion cells (RGCs) normally cannot regenerate axons nor survive after optic nerve injury, this failure is partially reversed by inducing sterile inflammation in the eye. Infiltrative myeloid cells express the axogenic protein oncomodulin (Ocm) but additional, as-yet-unidentified, factors are also required. We show here that infiltrative macrophages express stromal cellderived factor 1 (SDF1, CXCL12), which plays a central role in this regard. Among many growth factors tested in culture, only SDF1 enhances Ocm activity, an effect mediated through intracellular cyclic AMP (cAMP) elevation and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) activation. SDF1 deficiency in myeloid cells (CXCL12flx/flxLysM-Cre−/+ mice) or deletion of the SDF1 receptor CXCR4 in RGCs (intraocular AAV2-Cre in CXCR4flx/flx mice) or SDF1 antagonist AMD3100 greatly suppresses inflammation-induced regeneration and decreases RGC survival to baseline levels. Conversely, SDF1 induces optic nerve regeneration and RGC survival, and, when combined with Ocm/cAMP, SDF1 increases axon regeneration to levels similar to those induced by intraocular inflammation. In contrast to deletion of phosphatase and tensin homolog (Pten), which promotes regeneration selectively from αRGCs, SDF1 promotes regeneration from non-αRGCs and enables the latter cells to respond robustly to Pten deletion; however, SDF1 surprisingly diminishes the response of αRGCs to Pten deletion. When combined with inflammation and Pten deletion, SDF1 enables many RGCs to regenerate axons the entire length of the optic nerve. Thus, SDF1 complements the effects of Ocm in mediating inflammation-induced regeneration and enables different RGC subtypes to respond to Pten deletion.
Assuntos
Traumatismos do Nervo Óptico , Células Ganglionares da Retina , Axônios/metabolismo , Quimiocina CXCL12/genética , Monócitos/metabolismo , Regeneração Nervosa/fisiologia , Traumatismos do Nervo Óptico/genética , Traumatismos do Nervo Óptico/metabolismo , PTEN Fosfo-Hidrolase/genética , Células Ganglionares da Retina/fisiologiaRESUMO
Heightened aggressive behavior is considered as one of the central symptoms of many neuropsychiatric disorders including autism, schizophrenia, and dementia. The consequences of aggression pose a heavy burden on patients and their families and clinicians. Unfortunately, we have limited treatment options for aggression and lack mechanistic insight into the causes of aggression needed to inform new efforts in drug discovery and development. Levels of proinflammatory cytokines in the periphery or cerebrospinal fluid were previously reported to correlate with aggressive traits in humans. However, it is still unknown whether cytokines affect brain circuits to modulate aggression. Here, we examined the functional role of interleukin 1ß (IL-1ß) in mediating individual differences in aggression using a resident-intruder mouse model. We found that nonaggressive mice exhibit higher levels of IL-1ß in the dorsal raphe nucleus (DRN), the major source of forebrain serotonin (5-HT), compared to aggressive mice. We then examined the effect of pharmacological antagonism and viral-mediated gene knockdown of the receptors for IL-1 within the DRN and found that both treatments consistently increased aggressive behavior of male mice. Aggressive mice also exhibited higher c-Fos expression in 5-HT neurons in the DRN compared to nonaggressive mice. In line with these findings, deletion of IL-1 receptor in the DRN enhanced c-Fos expression in 5-HT neurons during aggressive encounters, suggesting that modulation of 5-HT neuronal activity by IL-1ß signaling in the DRN controls expression of aggressive behavior.
Assuntos
Agressão , Núcleo Dorsal da Rafe , Interleucina-1beta , Serotonina , Agressão/fisiologia , Animais , Núcleo Dorsal da Rafe/metabolismo , Humanos , Individualidade , Interleucina-1beta/metabolismo , Masculino , Camundongos , Serotonina/metabolismoRESUMO
PURPOSE OF REVIEW: To summarize the current state of art of gene therapy for Parkinson's disease. RECENT FINDINGS: Introduction of the gene for glutamic acid decarboxylase (GAD) into the subthalamic nucleus was successful in a randomized, double-blind clinical trial and recent data from PET imaging identified novel brain networks underlying both sham surgery and therapeutic responses in treated participants. Two other approaches use viral vectors to increase dopamine transmission in the striatum. Both strategies are being studied in active trials and have recently reported promising responses in human participants. New strategies in Parkinson's disease are focused upon targeting the underlying pathogenesis in those with genetic defects thought to be the cause of disease. Finally, noninvasive focused ultrasound is currently being tested for lesioning in Parkinson's disease patients, but this same technology can be used to transiently open the blood-brain barrier, raising the potential for noninvasive delivery of gene therapy vectors to specific brain targets. SUMMARY: Parkinson's disease gene therapy has moved from purely animal research three decades ago, to initial human studies two decades ago to many applications moving into late stage trials, currently. Recent successes and promising new technology should only accelerate the advance of gene therapy into active clinical practice.
Assuntos
Terapia Genética/métodos , Doença de Parkinson/terapia , Núcleo Subtalâmico/fisiopatologia , Animais , Barreira Hematoencefálica , Corpo Estriado/fisiopatologia , Vetores Genéticos , Humanos , Neuroimagem , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Tomografia por Emissão de Pósitrons , Ultrassonografia de IntervençãoRESUMO
Little is known about the molecular similarities and differences between neurons in the ventral (vSt) and dorsal striatum (dSt) and their physiological implications. In the vSt, serotonin [5-Hydroxytryptamine (5-HT)] modulates mood control and pleasure response, whereas in the dSt, 5-HT regulates motor behavior. Here we show that, in mice, 5-HT depolarizes cholinergic interneurons (ChIs) of the dSt whereas hyperpolarizing ChIs from the vSt by acting on different 5-HT receptor isoforms. In the vSt, 5-HT1A (a postsynaptic receptor) and 5-HT1B (a presynaptic receptor) are highly expressed, and synergistically inhibit the excitability of ChIs. The inhibitory modulation by 5-HT1B, but not that by 5-HT1A, is mediated by p11, a protein associated with major depressive disorder. Specific deletion of 5-HT1B from cholinergic neurons results in impaired inhibition of ACh release in the vSt and in anhedonic-like behavior.
Assuntos
Neurônios Colinérgicos/metabolismo , Neostriado/citologia , Serotonina/metabolismo , Acetilcolina/metabolismo , Animais , Comportamento Animal , Deleção de Genes , Interneurônios/citologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Serotonina/metabolismoRESUMO
The reduced movement repertoire of Parkinson's disease (PD) is mainly due to degeneration of nigrostriatal dopamine neurons. Restoration of dopamine transmission by levodopa (L-DOPA) relieves motor symptoms of PD but often causes disabling dyskinesias. Subchronic L-DOPA increases levels of adaptor protein p11 (S100A10) in dopaminoceptive neurons of the striatum. Using experimental mouse models of Parkinsonism, we report here that global p11 knockout (KO) mice develop fewer jaw tremors in response to tacrine. Following L-DOPA, global p11KO mice show reduced therapeutic responses on rotational motor sensitization, but also develop less dyskinetic side effects. Studies using conditional p11KO mice reveal that distinct cell populations mediate these therapeutic and side effects. Selective deletion of p11 in cholinergic acetyltransferase (ChAT) neurons reduces tacrine-induced tremor. Mice lacking p11 in dopamine D2R-containing neurons have a reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit tremor and rotational responses toward L-DOPA, but develop less dyskinesia. Moreover, coadministration of rapamycin with L-DOPA counteracts L-DOPA-induced dyskinesias in wild-type mice, but not in mice lacking p11 in D1R-containing neurons. 6-OHDA lesioning causes an increase of evoked striatal glutamate release in wild type, but not in global p11KO mice, indicating that altered glutamate neurotransmission could contribute to the reduced L-DOPA responsivity. These data demonstrate that p11 located in ChAT or D2R-containing neurons is involved in regulating therapeutic actions in experimental PD, whereas p11 in D1R-containing neurons underlies the development of L-DOPA-induced dyskinesias.
Assuntos
Anexina A2/fisiologia , Discinesias/fisiopatologia , Levodopa/uso terapêutico , Transtornos Parkinsonianos/tratamento farmacológico , Proteínas S100/fisiologia , Animais , Camundongos , Camundongos KnockoutRESUMO
Complications of dopamine replacement for Parkinson's disease (PD) can limit therapeutic options, leading to interest in identifying novel pathways that can be exploited to improve treatment. p11 (S100A10) is a cellular scaffold protein that binds to and potentiates the activity of various ion channels and neurotransmitter receptors. We have previously reported that p11 can influence ventral striatal function in models of depression and drug addiction, and thus we hypothesized that dorsal striatal p11 might mediate motor function and drug responses in parkinsonian mice. To focally inhibit p11 expression in the dorsal striatum, we injected an adeno-associated virus (AAV) vector producing a short hairpin RNA (AAV.sh.p11). This intervention reduced the impairment in motor function on forced tasks, such as rotarod and treadmill tests, caused by substantia nigra lesioning in mice. Measures of spontaneous movement and gait in an open-field test declined as expected in control lesioned mice, whereas AAV.sh.p11 mice remained at or near normal baseline. Mice with unilateral lesions were then challenged with l-dopa (levodopa) and various dopamine receptor agonists, and resulting rotational behaviors were significantly reduced after ipsilateral inhibition of dorsal striatal p11 expression. Finally, p11 knockdown in the dorsal striatum dramatically reduced l-dopa-induced abnormal involuntary movements compared with control mice. These data indicate that focal inhibition of p11 action in the dorsal striatum could be a promising PD therapeutic target to improve motor function while reducing l-dopa-induced dyskinesias.
Assuntos
Anexina A2/genética , Corpo Estriado/fisiologia , Discinesias/fisiopatologia , Terapia Genética , Atividade Motora , Transtornos Parkinsonianos/fisiopatologia , Proteínas S100/genética , Animais , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/terapiaRESUMO
BACKGROUND: Magnetic resonance imaging-guided focused ultrasound thalamotomy is approved by the U.S. Food and Drug Administration for treatment of essential tremor. Although this incisionless technology creates an ablative lesion, it potentially avoids serious complications of open stereotactic surgery. OBJECTIVE: To determine the safety profile of magnetic resonance imaging-guided focused ultrasound unilateral thalamotomy for essential tremor, including frequency, and severity of adverse events, including serious adverse events. METHODS: Analysis of safety data for magnetic resonance imaging-guided focused ultrasound thalamotomy (186 patients, five studies). RESULTS: Procedure-related serious adverse events were very infrequent (1.6%), without intracerebral hemorrhages or infections. Adverse events were usually transient and were commonly rated as mild (79%) and rarely severe (1%). As previously reported, abnormalities in sensation and balance were the commonest thalamotomy-related adverse events. CONCLUSION: The overall safety profile of magnetic resonance imaging-guided focused ultrasound thalamotomy supports its role as a new option for patients with medically refractory essential tremor. © 2018 International Parkinson and Movement Disorder Society.
Assuntos
Tremor Essencial , Imageamento por Ressonância Magnética , Doenças do Sistema Nervoso/etiologia , Complicações Pós-Operatórias/etiologia , Tálamo/diagnóstico por imagem , Tálamo/cirurgia , Ultrassonografia de Intervenção , Adulto , Estudos de Coortes , Tremor Essencial/diagnóstico por imagem , Tremor Essencial/cirurgia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Estados UnidosRESUMO
Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951-971.
Assuntos
Artefatos , Meios de Contraste , Aumento da Imagem/métodos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Metais , HumanosRESUMO
Recurrent axon collaterals are a major means of communication between spiny projection neurons (SPNs) in the striatum and profoundly affect the function of the basal ganglia. However, little is known about the molecular and cellular mechanisms that underlie this communication. We show that intrastriatal nitric oxide (NO) signaling elevates the expression of the vesicular GABA transporter (VGAT) within recurrent collaterals of SPNs. Down-regulation of striatal NO signaling resulted in an attenuation of GABAergic signaling in SPN local collaterals, down-regulation of VGAT expression in local processes of SPNs, and impaired motor behavior. PKG1 and cAMP response element-binding protein are involved in the signal transduction that transcriptionally regulates VGAT by NO. These data suggest that transcriptional control of the vesicular GABA transporter by NO regulates GABA transmission and action selection.
Assuntos
Gânglios da Base/metabolismo , Guanilato Ciclase/química , Neurônios/metabolismo , Óxido Nítrico/química , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/química , Animais , Axônios/metabolismo , AMP Cíclico/metabolismo , Dopamina/metabolismo , Eletrofisiologia , Retroalimentação Fisiológica , Feminino , Proteínas de Fluorescência Verde/metabolismo , Levodopa/química , Masculino , Camundongos , Plasticidade Neuronal , Oxidopamina/química , Transdução de Sinais , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismoRESUMO
Phosphatase and Tensin homolog deleted on chromosome 10 (PTEN) is a dual lipid-protein phosphatase known primarily as a growth preventing tumor suppressor. PTEN is also expressed in neurons, and pathways modulated by PTEN can influence neuronal function. Here we report a novel function of PTEN as a regulator of striatal dopamine signaling in a model of Parkinson's disease (PD). Blocking PTEN expression with an adeno-associated virus (AAV) vector expressing a small hairpin RNA (shRNA) resulted in reduced responses of cultured striatal neurons to dopamine, which appeared to be largely due to reduction in D2 receptor activation. Co-expression of shRNA-resistant wild-type and mutant forms of PTEN indicated that the lipid-phosphatase activity was essential for this effect. In both normal and Parkinsonian rats, inhibition of striatal PTEN in vivo resulted in motor dysfunction and impaired responses to dopamine, particularly D2 receptor agonists. Expression of PTEN mutants confirmed the lipid-phosphatase activity as critical, while co-expression of a dominant-negative form of Akt overcame the PTEN shRNA effect. These results identify PTEN as a key mediator of striatal responses to dopamine, and suggest that drugs designed to potentiate PTEN expression or activity, such as cancer chemotherapeutics, may also be useful for improving striatal responses to dopamine in conditions of dopamine depletion such as PD. This also suggests that strategies which increase Akt or decrease PTEN expression or function, such as growth factors to prevent neuronal death, may have a paradoxical effect on neurological functioning by inhibiting striatal responses to dopamine.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Atividade Motora/fisiologia , Neurônios/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Transtornos Parkinsonianos/fisiopatologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Células Cultivadas , Corpo Estriado/efeitos dos fármacos , Dependovirus , Agonistas de Dopamina/farmacologia , Vetores Genéticos , Masculino , Atividade Motora/efeitos dos fármacos , Mutação , Neurônios/efeitos dos fármacos , PTEN Fosfo-Hidrolase/genética , Transtornos Parkinsonianos/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno , Ratos Sprague-Dawley , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismoRESUMO
Malignant gliomas represent one of the most aggressive forms of cancer, displaying high mortality rates and limited treatment options. Specific subpopulations of cells residing in the tumor niche with stem-like characteristics have been postulated to initiate and maintain neoplasticity while resisting conventional therapies. The study presented here aims to define the role of glycogen synthase kinase 3 beta (GSK3b) in patient-derived glioblastoma (GBM) stem-like cell (GSC) proliferation, apoptosis and invasion. To evaluate the potential role of GSK3b in GBM, protein profiles from 68 GBM patients and 20 normal brain samples were analyzed for EGFR-mediated PI3kinase/Akt and GSK3b signaling molecules including protein phosphatase 2A (PP2A). To better understand the function of GSK3b in GBM, GSCs were isolated from GBM patient samples. Blocking GSK3b phosphorylation at Serine 9 attenuated cell proliferation while concomitantly stimulating apoptosis through activation of Caspase-3 in patient-derived GSCs. Increasing GSK3b protein content resulted in the inhibition of cell proliferation, colony formation and stimulated programmed cell death. Depleting GSK3b in GSCs down regulated PP2A. Furthermore, knocking down PP2A or blocking its activity by okadaic acid inactivated GSK3b by increasing GSK3b phosphorylation at Serine 9. Our data suggests that GSK3b may function as a regulator of apoptosis and tumorigenesis in GSCs. Therapeutic approaches targeting GSK3b in glioblastoma stem-like cells may be a useful addition to our current therapeutic armamentarium.
Assuntos
Neoplasias Encefálicas/fisiopatologia , Encéfalo/fisiopatologia , Receptores ErbB/metabolismo , Glioblastoma/fisiopatologia , Quinase 3 da Glicogênio Sintase/metabolismo , Proteína Fosfatase 2/metabolismo , Apoptose/fisiologia , Carcinogênese , Caspase 3/metabolismo , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Glicogênio Sintase Quinase 3 beta , Humanos , Células-Tronco Neoplásicas/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
There is increasing interest among functional neurosurgeons in the potential for novel therapies to impact upon diseases beyond movement disorders and pain. A target of increasing interest is the nucleus accumbens (NAc), which has long been studied as a key brain region mediating a variety of behaviors, including reward and satisfaction. As such, focal modulation of the biology of the NAc with deep brain stimulation or novel biological therapies such as gene therapy or cell transplantation could have a major impact upon disorders such as depression and drug addiction. In order to both develop appropriate therapies and then deliver them in an effective fashion, a thorough understanding of the biology, physiology, and anatomy of the NAc is critical. Here, we review the existing literature regarding several areas critical to the development of new therapies, including the known pharmacology, physiology, and connectivity of the NAc, as well as evidence supporting the potential for various NAc surgical therapies in animal models. We then review the relevant anatomy of the NAc, with particular attention to the surgical anatomy, imaging, and targeting necessary to facilitate a proper localization and delivery of new agents to this region. The NAc is a fascinating and potentially rich target for stereotactic neurosurgical intervention, and analysis of existing information regarding all aspects of this structure should help potentiate therapeutic advances and reduce complications from future studies of neurosurgical intervention in this region for a variety of disorders. © 2015 S. Karger AG, Basel.
RESUMO
A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.
Assuntos
Anexina A2/metabolismo , Depressão/fisiopatologia , Interneurônios/metabolismo , Núcleo Accumbens/metabolismo , Proteínas S100/metabolismo , Acetilcolina/metabolismo , Animais , Antidepressivos/farmacologia , Comportamento Animal , Depressão/metabolismo , Imuno-Histoquímica/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Chaperonas Moleculares/metabolismo , Neurônios/metabolismo , Neurotransmissores/metabolismo , Fenótipo , Receptores Colinérgicos/metabolismoRESUMO
The comorbidity of depression and cocaine addiction suggests shared mechanisms and anatomical pathways. Specifically, the limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders. P11 (S100A10) is a promising target for manipulating depression and addiction in mice. We summarized the recent genetic and viral strategies used to determine how the titration of p11 levels within the NAc affects hedonic behavior and cocaine reward learning in mice. In particular, p11 in the ChAT+ cells or DRD1+ MSN of the NAc, controls depressive-like behavior or cocaine reward, respectively. Treatments to counter maladaptation of p11 levels in the NAc could provide novel therapeutic opportunities for depression and cocaine addiction in humans.
Assuntos
Anexina A2/fisiologia , Depressão/epidemiologia , Transtorno Depressivo/epidemiologia , Proteínas do Tecido Nervoso/fisiologia , Núcleo Accumbens/fisiopatologia , Proteínas S100/fisiologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Anedonia/efeitos dos fármacos , Anedonia/fisiologia , Animais , Anexina A2/deficiência , Anexina A2/genética , Comportamento Apetitivo/fisiologia , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/fisiologia , Cocaína/farmacologia , Cocaína/toxicidade , Comorbidade , Depressão/fisiopatologia , Depressão/terapia , Transtorno Depressivo/fisiopatologia , Transtorno Depressivo/terapia , Modelos Animais de Doenças , Terapia Genética , Vetores Genéticos/uso terapêutico , Humanos , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurotransmissores/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Optogenética , Prazer/fisiologia , Prevalência , Transporte Proteico/efeitos dos fármacos , Interferência de RNA , Receptores de Neurotransmissores/efeitos dos fármacos , Receptores de Neurotransmissores/metabolismo , Recompensa , Proteínas S100/deficiência , Proteínas S100/genética , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/terapiaRESUMO
Cognitive impairments are a common feature of synucleinopathies such as Parkinson's Disease Dementia and Dementia with Lewy Bodies. These pathologies are characterized by accumulation of Lewy bodies and Lewy neurites as well as neuronal cell death. Alpha-synuclein is the main proteinaceous component of Lewy bodies and Lewy neurites. To model these pathologies in vivo, toxins that selectively target certain neuronal populations or different means of inducing alpha-synuclein aggregation can be used. Alpha-synuclein accumulation can be induced by genetic manipulation, viral vector overexpression or the use of preformed fibrils of alpha-synuclein. In this review, we summarize the cognitive impairments associated with different models of synucleinopathies and relevance to observations in human diseases.
RESUMO
BACKGROUND AND PURPOSE: The purpose of this study is to evaluate the feasibility of using 3-dimensional (3D) ultra-short echo time (UTE) radial imaging method for measurement of the permeability of the blood-brain barrier (BBB) to gadolinium-based contrast agent. In this study, we propose to use the golden-angle radial sparse parallel (GRASP) method with 3D center-out trajectories for UTE, hence named as 3D UTE-GRASP. We first examined the feasibility of using 3D UTE-GRASP dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) for differentiating subtle BBB disruptions induced by focused ultrasound (FUS). Then, we examined the BBB permeability changes in Alzheimer's disease (AD) pathology using Alzheimer's disease transgenic mice (5xFAD) at different ages. METHODS: For FUS experiments, we used four Sprague Dawley rats at similar ages where we compared BBB permeability of each rat receiving the FUS sonication with different acoustic power (0.4-1.0 MPa). For AD transgenic mice experiments, we included three 5xFAD mice (6, 12, and 16 months old) and three wild-type mice (4, 8, and 12 months old). RESULTS: The result from FUS experiments showed a progressive increase in BBB permeability with increase of acoustic power (p < .05), demonstrating the sensitivity of DCE-MRI method for detecting subtle changes in BBB disruption. Our AD transgenic mice experiments suggest an early BBB disruption in 5xFAD mice, which is further impaired with aging. CONCLUSION: The results in this study substantiate the feasibility of using the proposed 3D UTE-GRASP method for detecting subtle BBB permeability changes expected in neurodegenerative diseases, such as AD.
Assuntos
Doença de Alzheimer , Barreira Hematoencefálica , Meios de Contraste , Estudos de Viabilidade , Imageamento por Ressonância Magnética , Camundongos Transgênicos , Ratos Sprague-Dawley , Barreira Hematoencefálica/diagnóstico por imagem , Animais , Camundongos , Imageamento por Ressonância Magnética/métodos , Ratos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Permeabilidade Capilar/fisiologia , Imageamento Tridimensional/métodosRESUMO
Importance: Unilateral magnetic resonance-guided focused ultrasound ablation of ventralis intermedius nucleus of the thalamus for essential tremor reduces tremor on 1 side, but untreated contralateral or midline symptoms remain limiting for some patients. Historically, bilateral lesioning produced unacceptable risks and was supplanted by deep brain stimulation; increasing acceptance of unilateral focused ultrasound lesioning has led to interest in a bilateral option. Objective: To evaluate the safety and efficacy of staged, bilateral focused ultrasound thalamotomy. Design, Setting, and Participants: This prospective, open-label, multicenter trial treated patients with essential tremor from July 2020 to October 2021, with a 12-month follow-up, at 7 US academic medical centers. Of 62 enrolled patients who had undergone unilateral focused ultrasound thalamotomy at least 9 months prior to enrollment, 11 were excluded and 51 were treated. Eligibility criteria included patient age (22 years and older), medication refractory, tremor severity (Clinical Rating Scale for Tremor [CRST] part A score ≥2 for postural or kinetic tremor), and functional disability (CRST part C score ≥2 in any category). Intervention: A focused ultrasound system interfaced with magnetic resonance imaging allowed real-time alignment of thermography maps with anatomy. Subthreshold sonications allowed target interrogation for efficacy and off-target effects before creating an ablation. Main Outcomes and Measures: Tremor/motor score (CRST parts A and B) at 3 months for the treated side after treatment was the primary outcome measure, and secondary assessments for efficacy and safety continued to 12 months. Results: The mean (SD) population age was 73 (13.9) years, and 44 participants (86.3%) were male. The mean (SD) tremor/motor score improved from 17.4 (5.4; 95% CI, 15.9-18.9) to 6.4 (5.3; 95% CI, 4.9 to 7.9) at 3 months (66% improvement in CRST parts A and B scores; 95% CI, 59.8-72.2; P < .001). There was significant improvement in mean (SD) postural tremor (from 2.5 [0.8]; 95% CI, 2.3 to 2.7 to 0.6 [0.9]; 95% CI, 0.3 to 0.8; P < .001) and mean (SD) disability score (from 10.3 [4.7]; 95% CI, 9.0-11.6 to 2.2 [2.8]; 95% CI, 1.4-2.9; P < .001). Twelve participants developed mild (study-defined) ataxia, which persisted in 6 participants at 12 months. Adverse events (159 of 188 [85%] mild, 25 of 188 [13%] moderate, and 1 severe urinary tract infection) reported most commonly included numbness/tingling (n = 17 total; n = 8 at 12 months), dysarthria (n = 15 total; n = 7 at 12 months), ataxia (n = 12 total; n = 6 at 12 months), unsteadiness/imbalance (n = 10 total; n = 0 at 12 months), and taste disturbance (n = 7 total; n = 3 at 12 months). Speech difficulty, including phonation, articulation, and dysphagia, were generally mild (rated as not clinically significant, no participants with worsening in all 3 measures) and transient. Conclusions and Relevance: Staged, bilateral focused ultrasound thalamotomy significantly reduced tremor severity and functional disability scores. Adverse events for speech, swallowing, and ataxia were mostly mild and transient. Trial Registration: ClinicalTrials.gov Identifier NCT04112381.
RESUMO
Parkinson's disease (PD) is characterized by progressive motor as well as less recognized non-motor symptoms that arise often years before motor manifestation, including sleep and gastrointestinal disturbances. Despite the heavy burden on the patient's quality of life, these non-motor manifestations are poorly understood. To elucidate the temporal dynamics of the disease, we employed a mouse model involving injection of alpha-synuclein (αSyn) pre-formed fibrils (PFF) in the duodenum and antrum as a gut-brain model of Parkinsonism. Using anatomical mapping of αSyn-PFF propagation and behavioral and physiological characterizations, we unveil a correlation between post-injection time the temporal dynamics of αSyn propagation and non-motor/motor manifestations of the disease. We highlight the concurrent presence of αSyn aggregates in key brain regions, expressing acetylcholine or dopamine, involved in sleep duration, wakefulness, and particularly REM-associated atonia corresponding to REM behavioral disorder-like symptoms. This study presents a novel and in-depth exploration into the multifaceted nature of PD, unraveling the complex connections between α-synucleinopathies, gut-brain connectivity, and the emergence of non-motor phenotypes.