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1.
Autophagy ; : 1-3, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35482760

RESUMO

Inhibition of chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation for intracellular proteins, may contribute to pathogenesis in neurodegenerative diseases including Parkinson disease (PD). Pathogenic variants of PD-related proteins that reside in the cytosol, including SNCA/alpha-synuclein, LRRK2 (leucine rich repeat kinase 2), UCHL1 (ubiquitin Cterminal hydrolase 1) and VPS35 (VPS35 retromer complex component), exert inhibitory effects on CMA. Decreased CMA activity has also been reported in sporadic PD patients, consistent with an association between CMA inhibition and PD. We have now reported the first example of CMA dysfunction caused by a non-cytosolic PD-related protein, GBA/ß-glucocerebrosidase, the most common genetic risk factor for PD, which uncovers a new role for CMA in endoplasmic reticulum (ER) quality control.

2.
ACS Chem Neurosci ; 13(8): 1251-1262, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35400149

RESUMO

Optical imaging of changes in the membrane potential of living cells can be achieved by means of fluorescent voltage-sensitive dyes (VSDs). A particularly challenging task is to efficiently deliver these highly lipophilic probes to specific neuronal subpopulations in brain tissue. We have tackled this task by designing a solubilizing, hydrophilic polymer platform that carries a high-affinity ligand for a membrane protein marker of interest and a fluorescent VSD. Here, we disclose an improved design of polymer-supported probes for chemical, nongenetic targeting of voltage sensors to axons natively expressing the dopamine transporter in ex vivo mouse brain tissue. We first show that for negatively charged rhodol VSDs functioning on the photoinduced electron transfer principle, poly(ethylene glycol) as a carrier enables targeting with higher selectivity than the polysaccharide dextran in HEK cell culture. In the same experimental setting, we also demonstrate that incorporation of an azetidine ring into the rhodol chromophore substantially increases the brightness and voltage sensitivity of the respective VSD. We show that the superior properties of the optimized sensor are transferable to recording of electrically evoked activity from dopaminergic axons in mouse striatal slices after averaging of multiple trials. Finally, we suggest the next milestones for the field to achieve single-scan recordings with nongenetically targeted VSDs in native brain tissue.


Assuntos
Neurônios Dopaminérgicos , Corantes Fluorescentes , Animais , Corantes Fluorescentes/química , Potenciais da Membrana/fisiologia , Camundongos , Polímeros , Xantonas
3.
NPJ Parkinsons Dis ; 8(1): 50, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35459867

RESUMO

In addition to the well-known degeneration of midbrain dopaminergic neurons, enteric neurons can also be affected in neurodegenerative disorders such as Parkinson's disease (PD). Dopaminergic neurons have recently been identified in the enteric nervous system (ENS). While ENS dopaminergic neurons have been shown to degenerate in genetic mouse models of PD, analyses of their survival in enteric biopsies of PD patients have provided inconsistent results to date. In this context, this review seeks to highlight the distinctive and shared factors and properties that control the evolution of these two sets of dopaminergic neurons from neuronal precursors to aging neurons. Although their cellular sources and developmental times of origin differ, midbrain and ENS dopaminergic neurons express many transcription factors in common and their respective environments express similar neurotrophic molecules. For example, Foxa2 and Sox6 are expressed by both populations to promote the specification, differentiation, and long-term maintenance of the dopaminergic phenotype. Both populations exhibit sustained patterns of excitability that drive intrinsic vulnerability over time. In disorders such as PD, colon biopsies have revealed aggregation of alpha-synuclein in the submucosal plexus where dopaminergic neurons reside and lack blood barrier protection. Thus, these enteric neurons may be more susceptible to neurotoxic insults and aggregation of α-synuclein that spreads from gut to midbrain. Under sustained stress, inefficient autophagy leads to neurodegeneration, GI motility dysfunction, and PD symptoms. Recent findings suggest that novel neurotrophic factors such as CDNF have the potential to be used as neuroprotective agents to prevent and treat ENS symptoms of PD.

4.
J Parkinsons Dis ; 2022 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-35253783

RESUMO

Patients with Parkinson's disease (PD) and other synucleinopathies often exhibit autoimmune features, including CD4+ and some CD8+ T lymphocytes that recognize epitopes derived from alpha-synuclein. While neurons have long been considered to not present antigens, recent data indicate that they can be induced to do so, particularly in response to interferons and other forms of stress. Here, we review literature on neuronal antigen presentation and its potential role in PD. Although direct evidence for CD8+ T cell-mediated neuronal death is lacking in PD, neuronal antigen presentation appears central to the pathology of Rasmussen's encephalitis, a pediatric neurological disorder driven by cytotoxic T cell infiltration and neuroinflammation. Emerging data suggest that T cells enter the brain in PD and other synucleinopathies, where the majority of neuromelanin-containing substantia nigra and locus coeruleus neurons express MHC Class I molecules. In cell culture, CD8+ T cell recognition of antigen:MHC Class I complexes on neuronal membranes leads to cytotoxic responses and neuronal cell death. Recent animal models suggest the possibility of T cell autoreactivity to mitochondrial antigens in PD. It remains unclear if neuronal antigen presentation plays a role in PD or other neurodegenerative disorders, and efforts are underway to better elucidate the potential impact of autoimmune responses on neurodegeneration.

5.
NPJ Parkinsons Dis ; 8(1): 30, 2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35314697

RESUMO

Parkinson's disease (PD) is a multi-stage neurodegenerative disorder with largely unknown etiology. Recent findings have identified PD-associated autoimmune features including roles for T cells. To further characterize the role of T cells in PD, we performed RNA sequencing on PBMC and peripheral CD4 and CD8 memory T cell subsets derived from PD patients and age-matched healthy controls. When the groups were stratified by their T cell responsiveness to alpha-synuclein (α-syn) as a proxy for an ongoing inflammatory autoimmune response, the study revealed a broad differential gene expression profile in memory T cell subsets and a specific PD associated gene signature. We identified significant enrichment of transcriptomic signatures previously associated with PD, including for oxidative stress, phosphorylation, autophagy of mitochondria, cholesterol metabolism and inflammation, and the chemokine signaling proteins CX3CR1, CCR5, and CCR1. In addition, we identified genes in these peripheral cells that have previously been shown to be involved in PD pathogenesis and expressed in neurons, such as LRRK2, LAMP3, and aquaporin. Together, these findings suggest that features of circulating T cells with α-syn-specific responses in PD patients provide insights into the interactive processes that occur during PD pathogenesis and suggest potential intervention targets.

6.
Sci Adv ; 8(6): eabm6393, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35138901

RESUMO

The most common genetic risk factors for Parkinson's disease (PD) are a set of heterozygous mutant (MT) alleles of the GBA1 gene that encodes ß-glucocerebrosidase (GCase), an enzyme normally trafficked through the ER/Golgi apparatus to the lysosomal lumen. We found that half of the GCase in lysosomes from postmortem human GBA-PD brains was present on the lysosomal surface and that this mislocalization depends on a pentapeptide motif in GCase used to target cytosolic protein for degradation by chaperone-mediated autophagy (CMA). MT GCase at the lysosomal surface inhibits CMA, causing accumulation of CMA substrates including α-synuclein. Single-cell transcriptional analysis and proteomics of brains from GBA-PD patients confirmed reduced CMA activity and proteome changes comparable to those in CMA-deficient mouse brain. Loss of the MT GCase CMA motif rescued primary substantia nigra dopaminergic neurons from MT GCase-induced neuronal death. We conclude that MT GBA1 alleles block CMA function and produce α-synuclein accumulation.


Assuntos
Autofagia Mediada por Chaperonas , Doença de Parkinson , Animais , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Camundongos , Mutação , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , alfa-Sinucleína/genética
7.
Elife ; 112022 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-35098924

RESUMO

Dopaminergic neurons modulate neural circuits and behaviors via dopamine (DA) release from expansive, long range axonal projections. The elaborate cytoarchitecture of these neurons is embedded within complex brain tissue, making it difficult to access the neuronal proteome using conventional methods. Here, we demonstrate APEX2 proximity labeling within genetically targeted neurons in the mouse brain, enabling subcellular proteomics with cell-type specificity. By combining APEX2 biotinylation with mass spectrometry, we mapped the somatodendritic and axonal proteomes of midbrain dopaminergic neurons. Our dataset reveals the proteomic architecture underlying proteostasis, axonal metabolism, and neurotransmission in these neurons. We find that most proteins encoded by DA neuron-enriched genes are localized within striatal dopaminergic axons, including ion channels with previously undescribed axonal localization. These proteomic datasets provide a resource for neuronal cell biology, and this approach can be readily adapted for study of other neural cell types.


Assuntos
Encéfalo/citologia , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Neurônios Dopaminérgicos/metabolismo , Endonucleases/metabolismo , Enzimas Multifuncionais/metabolismo , Proteômica , Animais , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/genética , Endonucleases/genética , Feminino , Masculino , Camundongos , Enzimas Multifuncionais/genética , Sinaptossomos/metabolismo
8.
Handb Clin Neurol ; 184: 439-455, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35034753

RESUMO

The notion that autoimmune responses to α-synuclein may be involved in the pathogenesis of this disorder stems from reports that mutations in α-synuclein or certain alleles of the major histocompatibility complex (MHC) are associated with the disease and that dopaminergic and norepinephrinergic neurons in the midbrain can present antigenic epitopes. Here, we discuss recent evidence that a defined set of peptides derived from α-synuclein act as antigenic epitopes displayed by specific MHC alleles and drive helper and cytotoxic T cell responses in patients with PD. Moreover, phosphorylated α-synuclein may activate T cell responses in a less restricted manner in PD. While the roles for the acquired immune system in disease pathogenesis remain unknown, preclinical animal models and in vitro studies indicate that T cells may interact with neurons and exert effects related to neuronal death and neuroprotection. These findings suggest that therapeutics that target T cells and ameliorate the incidence or disease severity of inflammatory bowel disorders or CNS autoimmune diseases such as multiple sclerosis may be useful in PD.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Animais , Dopamina , Humanos , Neurônios , Doença de Parkinson/genética , Linfócitos T
9.
Cell Rep ; 38(2): 110208, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35021090

RESUMO

Midbrain dopaminergic (mDA) neurons exhibit extensive dendritic and axonal arborizations, but local protein synthesis is not characterized in these neurons. Here, we investigate messenger RNA (mRNA) localization and translation in mDA neuronal axons and dendrites, both of which release dopamine (DA). Using highly sensitive ribosome-bound RNA sequencing and imaging approaches, we find no evidence for mRNA translation in mDA axons. In contrast, mDA neuronal dendrites in the substantia nigra pars reticulata (SNr) contain ribosomes and mRNAs encoding the major components of DA synthesis, release, and reuptake machinery. Surprisingly, we also observe dendritic localization of mRNAs encoding synaptic vesicle-related proteins, including those involved in exocytic fusion. Our results are consistent with a role for local translation in the regulation of DA release from dendrites, but not from axons. Our translatome data define a molecular signature of sparse mDA neurons in the SNr, including the enrichment of Atp2a3/SERCA3, an atypical ER calcium pump.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Biossíntese de Proteínas/fisiologia , RNA Mensageiro/metabolismo , Animais , Axônios/metabolismo , Dendritos/metabolismo , Dopamina/metabolismo , Feminino , Masculino , Mesencéfalo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Biossíntese de Proteínas/genética , RNA Mensageiro/genética , Ribossomos/metabolismo , Análise de Sequência de RNA/métodos , Substância Negra/metabolismo
10.
FEBS J ; 289(8): 2263-2281, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33977645

RESUMO

The synaptic pathways in the striatum are central to basal ganglia functions including motor control, learning and organization, action selection, acquisition of motor skills, cognitive function, and emotion. Here, we review the role of the striatum and its connections in motor learning and performance. The development of new techniques to record neuronal activity and animal models of motor disorders using neurotoxin, pharmacological, and genetic manipulations are revealing pathways that underlie motor performance and motor learning, as well as how they are altered by pathophysiological mechanisms. We discuss approaches that can be used to analyze complex motor skills, particularly in rodents, and identify specific questions central to understanding how striatal circuits mediate motor learning.


Assuntos
Gânglios da Base , Corpo Estriado , Animais , Gânglios da Base/fisiologia , Corpo Estriado/fisiologia
11.
ACS Chem Neurosci ; 12(24): 4546-4553, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34817175

RESUMO

Myriad neuropsychiatric disorders are due to dopamine dysfunction. However, understanding these disorders is limited by our ability to measure dopamine storage and release. Fluorescent false neurotransmitters (FFNs), small-molecule dyes that co-transit through the synaptic vesicle cycle, have allowed us to image dopamine in cell culture and acute brain slice, but in vivo microscopy is constrained by the biopenetrance of light. Here, we adapt FFNs into magnetic resonance false neurotransmitters (MFNs). The design principles guiding MFNs are (1) the molecule is a valid false neurotransmitter and (2) it has a 19F-substituent near a pH-sensing functional group, which (3) has pKa close to 6 so that the probe within vesicles is protonated. We demonstrate that MFN103 meets these criteria. While a magnetic resonance spectroscopy (MRS) signal was too low for measurement in vivo with the current technology, in principle, MFNs can quantify neurotransmitters within and without synaptic vesicles, which may underlie noninvasive in vivo analysis of dopamine neurotransmission.


Assuntos
Dopamina , Vesículas Sinápticas , Corantes Fluorescentes , Espectroscopia de Ressonância Magnética , Neurotransmissores , Transmissão Sináptica
12.
J Phys Chem A ; 125(35): 7616-7624, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34459589

RESUMO

A quantum chemical study of the nitroxide exchange reaction is presented. Inspired by the recent use of this reaction in the synthesis of dynamic covalent polymer networks, we studied the influence of substituents and solvents on the Gibbs free energy, which plays a crucial role for both the reversibility of the reaction and the extent of product formation. We provide accurate benchmark values based on CCSD(T) and COSMO-RS theory for a series of structural modifications and make suggestions for improving the molecular building blocks used so far.

13.
Genes (Basel) ; 12(8)2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-34440340

RESUMO

α-Synuclein (α-Syn) is a small cytosolic protein associated with a range of cellular compartments, including synaptic vesicles, the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes. In addition to its physiological role in regulating presynaptic function, the protein plays a central role in both sporadic and familial Parkinson's disease (PD) via a gain-of-function mechanism. Because of this, several recent strategies propose to decrease α-Syn levels in PD patients. While these therapies may offer breakthroughs in PD management, the normal functions of α-Syn and potential side effects of its depletion require careful evaluation. Here, we review recent evidence on physiological and pathological roles of α-Syn in regulating activity-dependent signal transduction and gene expression pathways that play fundamental role in synaptic plasticity.


Assuntos
Expressão Gênica/fisiologia , alfa-Sinucleína/genética , Humanos , Plasticidade Neuronal/fisiologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Transdução de Sinais/fisiologia
14.
Neurobiol Dis ; 158: 105473, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34371144

RESUMO

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.


Assuntos
Dendritos , Fatores de Troca do Nucleotídeo Guanina/genética , Neostriado/fisiopatologia , Plasticidade Neuronal , Sistema Nervoso Parassimpático/fisiopatologia , Sinapses , Animais , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/fisiopatologia , Doenças dos Gânglios da Base/psicologia , Estimulantes do Sistema Nervoso Central/farmacologia , Potenciais Pós-Sinápticos Excitadores/genética , Hipercinese/genética , Hipercinese/psicologia , Potenciação de Longa Duração , Masculino , Camundongos , Camundongos Knockout , Atividade Motora , Polimorfismo de Nucleotídeo Único , Receptor Muscarínico M1/genética , Receptor Muscarínico M1/fisiologia , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/psicologia
15.
NPJ Parkinsons Dis ; 7(1): 65, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312398

RESUMO

With the advent of the genetic era in Parkinson's disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects >10 million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein's varied roles, as they are known today; and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD.

16.
Cell Chem Biol ; 28(6): 748-764, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33894160

RESUMO

Dopamine is a modulatory neurotransmitter involved in learning, motor functions, and reward. Many neuropsychiatric disorders, including Parkinson's disease, autism, and schizophrenia, are associated with imbalances or dysfunction in the dopaminergic system. Yet, our understanding of these pervasive public health issues is limited by our ability to effectively image dopamine in humans, which has long been a goal for chemists and neuroscientists. The last two decades have witnessed the development of many molecules used to trace dopamine. We review the small molecules, nanoparticles, and protein sensors used with fluorescent microscopy/photometry, MRI, and PET that shape dopamine research today. None of these tools observe dopamine itself, but instead harness the biology of the dopamine system-its synthetic and metabolic pathways, synaptic vesicle cycle, and receptors-in elegant ways. Their advantages and weaknesses are covered here, along with recent examples and the chemistry and biology that allow them to function.


Assuntos
Dopamina/metabolismo , Dopamina/análise , Humanos , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo
17.
Cell ; 184(10): 2696-2714.e25, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33891876

RESUMO

Components of the proteostasis network malfunction in aging, and reduced protein quality control in neurons has been proposed to promote neurodegeneration. Here, we investigate the role of chaperone-mediated autophagy (CMA), a selective autophagy shown to degrade neurodegeneration-related proteins, in neuronal proteostasis. Using mouse models with systemic and neuronal-specific CMA blockage, we demonstrate that loss of neuronal CMA leads to altered neuronal function, selective changes in the neuronal metastable proteome, and proteotoxicity, all reminiscent of brain aging. Imposing CMA loss on a mouse model of Alzheimer's disease (AD) has synergistic negative effects on the proteome at risk of aggregation, thus increasing neuronal disease vulnerability and accelerating disease progression. Conversely, chemical enhancement of CMA ameliorates pathology in two different AD experimental mouse models. We conclude that functional CMA is essential for neuronal proteostasis through the maintenance of a subset of the proteome with a higher risk of misfolding than the general proteome.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Autofagia Mediada por Chaperonas/fisiologia , Neurônios/metabolismo , Proteostase , Envelhecimento/patologia , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Caseína Quinase I/genética , Autofagia Mediada por Chaperonas/genética , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Neurônios/patologia , Proteoma
18.
J Neurosci ; 41(16): 3597-3609, 2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33664134

RESUMO

Dynamic changes in motor abilities and motivated behaviors occur during the juvenile and adolescent periods. The striatum is a subcortical nucleus critical to action selection, motor learning, and reward processing. Its tonically active cholinergic interneuron (ChI) is an integral regulator of the synaptic activity of other striatal neurons, as well as afferent axonal projections of midbrain dopamine (DA) neurons; however, little is known about its development. Here, we report that ChI spontaneous activity increases during postnatal development of male and female mice, concomitant with a decreased afterhyperpolarization (AHP). We characterized the postnatal development of four currents that contribute to the spontaneous firing rate of ChIs, including ISK, IA, Ih, and INaP We demonstrated that the developmental increase in INaP drives increased ChI firing rates during the postnatal period and can be reversed by the INaP inhibitor, ranolazine. We next addressed whether immature cholinergic signaling may lead to functional differences in DA release during the juvenile period. In the adult striatum, nicotinic acetylcholine receptors (nAChRs) prevent linear summation of DA release in response to trains of high-frequency stimuli. We show that, in contrast, during the second postnatal week, DA release linearly sums with trains of high-frequency stimuli. Consistently, nAChR antagonists exert little effect on dopamine release at postnatal day (P)10, but enhance the summation of evoked DA release in mice older than postnatal day P28. Together, these results reveal that postnatal maturation of ChI activity is due primarily to enhanced INaP and identify an interaction between developing cholinergic signaling and DA neurotransmission in the juvenile striatum.SIGNIFICANCE STATEMENT Motor skills and motivated behavior develop rapidly in juvenile rodents. Recent work has highlighted processes that contribute to the postnatal maturation of striatal principal neurons during development. The functional development of the striatal cholinergic interneuron (ChI), however, has been unexplored. In this study, we tracked the ontogeny of ChI activity and cellular morphology, as well as the developmental trajectory of specific conductances that contribute to the activity of these cells. We further report a link between cholinergic signaling and dopamine (DA) release, revealing a change in the frequency-dependence of DA release during the early postnatal period that is mediated by cholinergic signaling. This study provides evidence that striatal microcircuits are dynamic during the postnatal period and that they undergo coordinated maturation.


Assuntos
Envelhecimento/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Interneurônios/fisiologia , Neostriado/crescimento & desenvolvimento , Neostriado/metabolismo , Sistema Nervoso Parassimpático/crescimento & desenvolvimento , Potenciais de Ação/fisiologia , Animais , Dendritos/metabolismo , Dendritos/ultraestrutura , Fenômenos Eletrofisiológicos , Feminino , Canais Iônicos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ranolazina/farmacologia , Receptores Nicotínicos/metabolismo , Transmissão Sináptica/fisiologia
19.
Front Cell Neurosci ; 15: 634493, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664651

RESUMO

The ability to identify and avoid environmental stimuli that signal danger is essential to survival. Our understanding of how the brain encodes aversive behaviors has been primarily focused on roles for the amygdala, hippocampus (HIPP), prefrontal cortex, ventral midbrain, and ventral striatum. Relatively little attention has been paid to contributions from the dorsal striatum (DS) to aversive learning, despite its well-established role in stimulus-response learning. Here, we review studies exploring the role of DS in aversive learning, including different roles for the dorsomedial and dorsolateral striatum in Pavlovian fear conditioning as well as innate and inhibitory avoidance (IA) behaviors. We outline how future investigation might determine specific contributions from DS subregions, cell types, and connections that contribute to aversive behavior.

20.
Hum Immunol ; 82(3): 155-161, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33583639

RESUMO

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to neuronal death in the brain and spinal cord. Over the last decades, evidence has emerged regarding the functional diversity of astrocytes, microglia, and T cells in the central nervous system (CNS), and the role of neuroinflammation in ALS. In this review, we summarize current knowledge regarding neuroinflammation in ALS, both at the level of specific molecular pathways and potential cellular pathways as well as outline questions about the immune mechanisms involved in ALS pathogenesis.


Assuntos
Esclerose Amiotrófica Lateral/imunologia , Encéfalo/patologia , Neuroglia/imunologia , Neurônios/patologia , Medula Espinal/patologia , Linfócitos T/imunologia , Animais , Autoimunidade , Humanos , Imunidade Celular , Inflamação Neurogênica , Transdução de Sinais
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