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1.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31588354

RESUMO

The latest animal neurophysiology has revealed that the dopamine reward prediction error signal drives neuronal learning in addition to behavioral learning and reflects subjective reward representations beyond explicit contingency. The signal complies with formal economic concepts and functions in real-world consumer choice and social interaction. An early response component is influenced by physical impact, reward environment, and novelty but does not fully code prediction error. Some dopamine neurons are activated by aversive stimuli, which may reflect physical stimulus impact or true aversiveness, but they do not seem to code general negative value or aversive prediction error. The reward prediction error signal is complemented by distinct, heterogeneous, smaller and slower changes reflecting sensory and motor contributors to behavioral activation, such as substantial movement (as opposed to precise motor control), reward expectation, spatial choice, vigor, and motivation. The different dopamine signals seem to defy a simple unifying concept and should be distinguished to better understand phasic dopamine functions.


Assuntos
Dopamina/fisiologia , Neurônios Dopaminérgicos/fisiologia , Recompensa , Animais , Aprendizagem , Motivação
2.
Nat Commun ; 10(1): 3097, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308381

RESUMO

Dopaminergic neurons in the brain of the Drosophila larva play a key role in mediating reward information to the mushroom bodies during appetitive olfactory learning and memory. Using optogenetic activation of Kenyon cells we provide evidence that recurrent signaling exists between Kenyon cells and dopaminergic neurons of the primary protocerebral anterior (pPAM) cluster. Optogenetic activation of Kenyon cells paired with odor stimulation is sufficient to induce appetitive memory. Simultaneous impairment of the dopaminergic pPAM neurons abolishes appetitive memory expression. Thus, we argue that dopaminergic pPAM neurons mediate reward information to the Kenyon cells, and in turn receive feedback from Kenyon cells. We further show that this feedback signaling is dependent on short neuropeptide F, but not on acetylcholine known to be important for odor-shock memories in adult flies. Our data suggest that recurrent signaling routes within the larval mushroom body circuitry may represent a mechanism subserving memory stabilization.


Assuntos
Encéfalo/fisiologia , Neurônios Dopaminérgicos/fisiologia , Drosophila melanogaster/fisiologia , Memória/fisiologia , Corpos Pedunculados/fisiologia , Recompensa , Acetilcolina/metabolismo , Animais , Apetite/fisiologia , Encéfalo/citologia , Condicionamento Clássico , Retroalimentação Fisiológica , Larva , Modelos Psicológicos , Corpos Pedunculados/citologia , Vias Neurais/fisiologia , Neuropeptídeos/metabolismo , Odorantes , Percepção Olfatória/fisiologia , Optogenética
3.
Life Sci ; 232: 116575, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211999

RESUMO

AIMS: Maternal smoking is considered a risk factor for childhood obesity. In a rat model of tobacco exposure during breastfeeding, we previously reported hyperphagia, overweight, increased visceral fat and hyperleptinemia in adult female offspring. Obesity and eating disorders are associated with impairment in the endocannabinoid (EC) and dopaminergic (DA) systems. Considering that women are prone to eating disorders, we hypothesize that adult female Wistar rats that were exposed to cigarette smoke (CS) during the suckling period would develop EC and DA systems deregulation, possibly explaining the eating disorder in this model. MATERIAL AND METHODS: To mimic maternal smoking, from postnatal day 3 to 21, dams and offspring were exposed to a smoking machine, 4×/day/1 h (CS group). Control animals were exposed to ambient air. Offspring were evaluated at 26 weeks of age. KEY FINDINGS: Concerning the EC system, the CS group had increased expression of diacylglycerol lipase (DAGL) in the lateral hypothalamus (LH) and decreased in the liver. In the visceral adipose tissue, the EC receptor (CB1r) was decreased. Regarding the DA system, the CS group showed higher dopamine transporter (DAT) protein expression in the prefrontal cortex (PFC) and lower DA receptor (D2r) in the arcuate nucleus (ARC). We also assessed the hypothalamic leptin signaling, which was shown to be unchanged. CS offspring showed decreased plasma 17ß-estradiol. SIGNIFICANCE: Neonatal CS exposure induces changes in some biomarkers of the EC and DA systems, which can partially explain the hyperphagia observed in female rats.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Endocanabinoides/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Animais Recém-Nascidos , Fumar Cigarros , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Endocanabinoides/fisiologia , Feminino , Região Hipotalâmica Lateral/efeitos dos fármacos , Região Hipotalâmica Lateral/metabolismo , Hipotálamo/metabolismo , Lactação/efeitos dos fármacos , Leptina/metabolismo , Lipase Lipoproteica/efeitos dos fármacos , Exposição Materna/efeitos adversos , Obesidade/etiologia , Obesidade/metabolismo , Ratos , Ratos Wistar , Receptores de Canabinoides/efeitos dos fármacos , Fumar , Tabaco
4.
Neuron ; 103(3): 432-444.e3, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31221559

RESUMO

Subtypes of nucleus accumbens medium spiny neurons (MSNs) promote dichotomous outcomes in motivated behaviors. However, recent reports indicate enhancing activity of either nucleus accumbens (NAc) core MSN subtype augments reward, suggesting coincident MSN activity may underlie this outcome. Here, we report a collateral excitation mechanism in which high-frequency, NAc core dopamine 1 (D1)-MSN activation causes long-lasting potentiation of excitatory transmission (LLP) on dopamine receptor 2 (D2)-MSNs. Our mechanistic investigation demonstrates that this form of plasticity requires release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. We also reveal that D2-MSN LLP requires muscarinic 1 receptor activation, intracellular calcium signaling, and GluR2-lacking AMPAR insertion. This study uncovers a mechanism for shaping NAc core activity through the transfer of excitatory information from D1-MSNs to D2-MSNs and may provide a means for altering goal-directed behavior through coordinated MSN activity.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Potenciação de Longa Duração/fisiologia , Núcleo Accumbens/fisiologia , Substância P/metabolismo , Potenciais de Ação/fisiologia , Animais , Aprepitanto/farmacologia , Sinalização do Cálcio/fisiologia , Neurônios Colinérgicos/fisiologia , Neurônios Dopaminérgicos/efeitos da radiação , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Motivação , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Núcleo Accumbens/citologia , Estimulação Luminosa , Piperidinas/farmacologia , Receptor Muscarínico M1/fisiologia , Receptores de AMPA/fisiologia , Receptores de Dopamina D1/análise , Receptores de Dopamina D2/análise , Receptores da Neurocinina-1/fisiologia
5.
PLoS Comput Biol ; 15(5): e1006998, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060045

RESUMO

Cortico-basal-ganglia-thalamic (CBGT) networks are critical for adaptive decision-making, yet how changes to circuit-level properties impact cognitive algorithms remains unclear. Here we explore how dopaminergic plasticity at corticostriatal synapses alters competition between striatal pathways, impacting the evidence accumulation process during decision-making. Spike-timing dependent plasticity simulations showed that dopaminergic feedback based on rewards modified the ratio of direct and indirect corticostriatal weights within opposing action channels. Using the learned weight ratios in a full spiking CBGT network model, we simulated neural dynamics and decision outcomes in a reward-driven decision task and fit them with a drift diffusion model. Fits revealed that the rate of evidence accumulation varied with inter-channel differences in direct pathway activity while boundary height varied with overall indirect pathway activity. This multi-level modeling approach demonstrates how complementary learning and decision computations can emerge from corticostriatal plasticity.


Assuntos
Tomada de Decisões/fisiologia , Neurônios Dopaminérgicos/fisiologia , Rede Nervosa/fisiologia , Animais , Gânglios da Base , Corpo Estriado , Retroalimentação , Humanos , Aprendizagem , Modelos Neurológicos , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Reforço (Psicologia) , Recompensa , Sinapses/fisiologia , Tálamo
6.
BMC Biol ; 17(1): 30, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30967153

RESUMO

BACKGROUND: Epigenetic mechanisms play fundamental roles in brain function and behavior and stressors such as social isolation can alter animal behavior via epigenetic mechanisms. However, due to cellular heterogeneity, identifying cell-type-specific epigenetic changes in the brain is challenging. Here, we report the first use of a modified isolation of nuclei tagged in specific cell type (INTACT) method in behavioral epigenetics of Drosophila melanogaster, a method we call mini-INTACT. RESULTS: Using ChIP-seq on mini-INTACT purified dopaminergic nuclei, we identified epigenetic signatures in socially isolated and socially enriched Drosophila males. Social experience altered the epigenetic landscape in clusters of genes involved in transcription and neural function. Some of these alterations could be predicted by expression changes of four transcription factors and the prevalence of their binding sites in several clusters. These transcription factors were previously identified as activity-regulated genes, and their knockdown in dopaminergic neurons reduced the effects of social experience on sleep. CONCLUSIONS: Our work enables the use of Drosophila as a model for cell-type-specific behavioral epigenetics and establishes that social environment shifts the epigenetic landscape in dopaminergic neurons. Four activity-related transcription factors are required in dopaminergic neurons for the effects of social environment on sleep.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Drosophila melanogaster/genética , Epigênese Genética/genética , Genética Comportamental/métodos , Meio Social , Animais , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Epigenômica/métodos , Masculino , Modelos Animais , Sono/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
7.
EBioMedicine ; 42: 225-237, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952618

RESUMO

BACKGROUND: We have recently reported that activation of cannabinoid type 2 receptors (CB2Rs) reduces dopamine (DA) neuron excitability in mouse ventral tegmental area (VTA). Here, we elucidate the underlying mechanisms. METHODS: Patch-clamp recordings were performed in mouse VTA slices and dissociated single VTA DA neurons. FINDINGS: Using cell-attached recording in VTA slices, bath-application of CB2R agonists (JWH133 or five other CB2R agonists) significantly reduced VTA DA neuron action potential (AP) firing rate. Under the patch-clamp whole-cell recording model, JWH133 (10 µM) mildly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) but not miniature inhibitory postsynaptic currents (mIPSCs). JWH133 also did not alter evoked EPSCs or IPSCs. In freshly dissociated VTA DA neurons, JWH133 reduced AP firing rate, delayed AP initiation and enhanced AP after-hyperpolarization. In voltage-clamp recordings, JWH133 (1 µM) enhanced M-type K+ currents and this effect was absent in CB2-/- mice and abolished by co-administration of a selective CB2R antagonist (10 µM, AM630). CB2R-mediated inhibition in VTA DA neuron firing can be mimicked by M-current opener (10 µM retigabine) and blocked by M-current blocker (30 µM XE991). In addition, enhancement of neuronal cAMP by forskolin (10 µM) reduced M-current and increased DA neuron firing rate. Finally, pharmacological block of synaptic transmission by NBQX (10 µM), D-APV (50 µM) and picrotoxin (100 µM) in VTA slices failed to prevent CB2R-mediated inhibition, while intracellular infusion of guanosine 5'-O-2-thiodiphosphate (600 µM, GDP-ß-S) through recording electrode to block postsynaptic G-protein function prevented JWH133-induced reduction in AP firing. INTERPRETATION: Our results suggest that CB2Rs modulate VTA DA neuron excitability mainly through an intrinsic mechanism, including a CB2R-mediated reduction of intracellular cAMP, and in turn enhancement of M-type K+ currents. FUND: This research was supported by the Barrow Neuroscience Foundation, the BNI-BMS Seed Fund, and CNSF (81771437).


Assuntos
Neurônios Dopaminérgicos/fisiologia , Receptor CB2 de Canabinoide/metabolismo , Área Tegmentar Ventral/metabolismo , Potenciais de Ação , Animais , Potenciais Evocados , Masculino , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/genética , Transdução de Sinais , Transmissão Sináptica
8.
Neurosci Biobehav Rev ; 100: 237-249, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851282

RESUMO

The detection and processing of novelty plays a critical role in memory function. Despite this, relatively little is known about how novelty influences memory in Alzheimer's disease (AD). This review sought to address whether AD patients are still sensitive to novelty; whether novelty triggers memory processes as is observed in healthy subjects; and whether it is possible to promote novelty to enhance memory at the different stages of AD. The studies reviewed showed that novelty processing is mostly impaired in AD patients, whereas it can be preserved under some conditions in MCI, particularly when cognitive demands are otherwise low. We further identify outstanding questions that should be addressed in the near future in order to more robustly establish the fate of novelty processing and detection in the course of AD. Doing so would allow to improve current models of memory impairment in AD, leading to a more comprehensive view of the sources of memory decline and could lead to neuropsychological and/or pharmaceutical rehabilitation programs.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Encéfalo/fisiopatologia , Comportamento Exploratório , Memória/fisiologia , Atenção/fisiologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Dopamina/fisiologia , Neurônios Dopaminérgicos/fisiologia , Humanos , Testes Neuropsicológicos
9.
Front Neural Circuits ; 13: 11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30858799

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease associated with progressive and inexorable loss of dopaminergic cells in Substantia Nigra pars compacta (SNc). Although many mechanisms have been suggested, a decisive root cause of this cell loss is unknown. A couple of the proposed mechanisms, however, show potential for the development of a novel line of PD therapeutics. One of these mechanisms is the peculiar metabolic vulnerability of SNc cells compared to other dopaminergic clusters; the other is the SubThalamic Nucleus (STN)-induced excitotoxicity in SNc. To investigate the latter hypothesis computationally, we developed a spiking neuron network-model of SNc-STN-GPe system. In the model, prolonged stimulation of SNc cells by an overactive STN leads to an increase in 'stress' variable; when the stress in a SNc neuron exceeds a stress threshold, the neuron dies. The model shows that the interaction between SNc and STN involves a positive-feedback due to which, an initial loss of SNc cells that crosses a threshold causes a runaway-effect, leading to an inexorable loss of SNc cells, strongly resembling the process of neurodegeneration. The model further suggests a link between the two aforementioned mechanisms of SNc cell loss. Our simulation results show that the excitotoxic cause of SNc cell loss might initiate by weak-excitotoxicity mediated by energy deficit, followed by strong-excitotoxicity, mediated by a disinhibited STN. A variety of conventional therapies were simulated to test their efficacy in slowing down SNc cell loss. Among them, glutamate inhibition, dopamine restoration, subthalamotomy and deep brain stimulation showed superior neuroprotective-effects in the proposed model.


Assuntos
Simulação por Computador , Neurônios Dopaminérgicos/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Glutâmico/toxicidade , Modelos Neurológicos , Doença de Parkinson/patologia , Neurônios Dopaminérgicos/fisiologia , Humanos
10.
Cell Tissue Res ; 377(1): 59-71, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30848354

RESUMO

Depression is one of the most prevalent psychiatric diseases, affecting the quality of life of millions of people. Ventral tegmental area (VTA) dopaminergic (DA) neurons are notably involved in evaluating the emotional and motivational value of a stimulus, in detecting reward prediction errors, in motivated learning, or in the propensity to initiate or withhold an action. DA neurons are thus involved in psychopathologies associated with perturbations of emotional and motivational states, such as depression. In this review, we focus on adaptations/alterations of the VTA, particularly of the VTA DA neurons, in the three most frequently used animal models of depression: learned helplessness, chronic mild stress and chronic social defeat.


Assuntos
Transtorno Depressivo Maior/fisiopatologia , Neurônios Dopaminérgicos/fisiologia , Área Tegmentar Ventral/fisiopatologia , Animais , Monoaminas Biogênicas/farmacologia , Monoaminas Biogênicas/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Masculino , Camundongos , Proteína Oncogênica v-akt/metabolismo , Canais de Potássio/metabolismo , Ratos , Estresse Psicológico , Área Tegmentar Ventral/efeitos dos fármacos
11.
Proc Natl Acad Sci U S A ; 116(12): 5765-5774, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30842285

RESUMO

Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene represent a cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, D620N, is considered pathogenic based upon its segregation with disease in multiple families with PD. At present, the mechanism(s) by which familial VPS35 mutations precipitate neurodegeneration in PD are poorly understood. Here, we employ a germline D620N VPS35 knockin (KI) mouse model of PD to formally establish the age-related pathogenic effects of the D620N mutation at physiological expression levels. Our data demonstrate that a heterozygous or homozygous D620N mutation is sufficient to reproduce key neuropathological hallmarks of PD as indicated by the progressive degeneration of nigrostriatal pathway dopaminergic neurons and widespread axonal pathology. Unexpectedly, endogenous D620N VPS35 expression induces robust tau-positive somatodendritic pathology throughout the brain as indicated by abnormal hyperphosphorylated and conformation-specific tau, which may represent an important and early feature of mutant VPS35-induced neurodegeneration in PD. In contrast, we find no evidence for α-synuclein-positive neuropathology in aged VPS35 KI mice, a hallmark of Lewy body pathology in PD. D620N VPS35 expression also fails to modify the lethal neurodegenerative phenotype of human A53T-α-synuclein transgenic mice. Finally, by crossing VPS35 KI and null mice, our data demonstrate that a single D620N VPS35 allele is sufficient for survival and early maintenance of dopaminergic neurons, indicating that the D620N VPS35 protein is fully functional. Our data raise the tantalizing possibility of a pathogenic interplay between mutant VPS35 and tau for inducing neurodegeneration in PD.


Assuntos
Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/fisiologia , Proteínas tau/metabolismo , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Técnicas de Introdução de Genes , Masculino , Camundongos , Mutação , Doenças do Sistema Nervoso/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Neuropatologia , Doença de Parkinson/genética , Transporte Proteico , alfa-Sinucleína/metabolismo , Proteínas tau/fisiologia
12.
Res Vet Sci ; 124: 149-157, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901667

RESUMO

Ivermectin is a human and veterinary antiparasitic drug which is one of the most widely used in the world. Studies from our group have revealed several behavioral and neurochemical impairments induced by therapeutic doses of ivermectin in adult rats. However, the effects on juveniles remain unknown. Ivermectin has been prescribed for juvenile humans, pets and farm animals, which still show remarkable development and postnatal maturation and may be more susceptible to drug interventions. Hence, we studied the behavioral and neurochemical effects of two therapeutical doses (0.2 and 1.0 mg/kg) of ivermectin in juvenile rats. As it is underestimated in prescriptions, the stress factor was also studied. Ivermectin 1.0 mg/kg induced hyperlocomotion in juvenile rats. Association of 1.0 mg/kg ivermectin with stress induced hypolocomotion in rats. Ivermectin 1.0 mg/kg whether or not associated with stress exacerbated socialization of rats. Ivermectin did not induce anxiety-like behavior neither affected corticosterone levels of juvenile rats. The motor/exploratory behavioral findings induced by association of ivermectin and stress seem to be triggered after the increase in the striatal serotonergic system activity. Association of ivermectin with stress increased striatal dopamine levels, which increased (excessive) social play behavior. Our results suggest a review of the prescribed dose of ivermectin for juvenile humans and pets. Moreover, the stress factor should be considered for ivermectin medical prescriptions, since it may exacerbate behavioral and neurochemical disturbances.


Assuntos
Antiparasitários/toxicidade , Ivermectina/toxicidade , Atividade Motora/efeitos dos fármacos , Comportamento Social , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Masculino , Ratos , Ratos Wistar , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Estresse Fisiológico/efeitos dos fármacos
13.
Artigo em Inglês | MEDLINE | ID: mdl-30774584

RESUMO

Dopaminergic and serotonergic neurons modulate and control processes ranging from reward signaling to regulation of motor outputs. Further, dysfunction of these neurons is involved in both degenerative and psychiatric disorders. Elucidating the roles of these neurons has been greatly facilitated by bacterial artificial chromosome (BAC) transgenic mouse lines expressing channelrhodopsin to readily enable cell-type specific activation. However, corresponding lines to silence these monoaminergic neurons have been lacking. We have generated two BAC transgenic mouse lines expressing the outward proton pump, enhanced ArchT3.0 (eArchT3.0), and GFP under control of the regulatory elements of either the dopamine transporter (DAT; Jax# 031663) or the tryptophan hydroxylase 2 (TPH2; Jax# 031662) gene locus. We demonstrate highly faithful and specific expression of these lines in dopaminergic and serotonergic neurons respectively. Additionally we validate effective and sensitive eArchT3.0-mediated silencing of these neurons using slice electrophysiology as well as with a well-established behavioral assay. These new transgenic tools will help expedite the study of dopaminergic and serotonergic system function in normal behavior and disease.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Optogenética , Neurônios Serotoninérgicos/fisiologia , Potenciais de Ação/genética , Animais , Encéfalo/citologia , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Estimulação Elétrica , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Patch-Clamp , RNA Mensageiro/metabolismo , Transfecção , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo
14.
Behav Brain Res ; 363: 77-82, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30711444

RESUMO

Midbrain dopamine (DA) neurons play a crucial role in the formation of conditioned associations between environmental cues and appetitive events. Activation of N-methyl-d-aspartate (NMDA) receptors is a key mechanism responsible for the generation of conditioned responses of DA neurons to reward cues. Here, we tested the effects of the cell type-specific inactivation of NMDA receptors in DA neurons in adult mice on stimulus-reward learning. Animals were trained in a Pavlovian learning paradigm in which they had to learn the predictive value of two conditioned stimuli, one of which (CS+) was paired with the delivery of a water reward. Over the course of conditioning, mutant mice learned that the CS+ predicted reward availability, and they approached the reward receptacle more frequently during CS+ trials than CS- trials. However, conditioned responses to the CS+ were weaker in the mutant mice, possibly indicating that they did not attribute incentive salience to the CS+. To further assess whether the attribution of incentive salience was impaired by the mutation, animals were tested in a conditioned reinforcement test. The test revealed that mutant mice made fewer instrumental responses paired with CS+ presentation, confirming that the CS+ had a weaker incentive value. Taken together, these results indicate that reward prediction learning does occur in the absence of NMDA receptors in DA neurons, but the ability of reward-paired cues to invigorate and reinforce behavior is attenuated.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Motivação/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Condicionamento Clássico/fisiologia , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Aprendizagem/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos , Reforço (Psicologia) , Recompensa
15.
Proc Natl Acad Sci U S A ; 116(9): 3817-3826, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808767

RESUMO

Midbrain dopamine neurons, which can be regulated by neuropeptides and hormones, play a fundamental role in controlling cognitive processes, reward mechanisms, and motor functions. The hormonal actions of insulin-like growth factor 1 (IGF-1) produced by the liver have been well described, but the role of neuronally derived IGF-1 remains largely unexplored. We discovered that dopamine neurons secrete IGF-1 from the cell bodies following depolarization, and that IGF-1 controls release of dopamine in the ventral midbrain. In addition, conditional deletion of dopamine neuron-derived IGF-1 in adult mice leads to decrease of dopamine content in the striatum and deficits in dopamine neuron firing and causes reduced spontaneous locomotion and impairments in explorative and learning behaviors. These data identify that dopamine neuron-derived IGF-1 acts as a regulator of dopamine neurons and regulates dopamine-mediated behaviors.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Fator de Crescimento Insulin-Like I/genética , Locomoção/genética , Mesencéfalo/fisiologia , Animais , Cognição/fisiologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/fisiologia , Comportamento Exploratório/fisiologia , Hormônios/metabolismo , Fator de Crescimento Insulin-Like I/biossíntese , Aprendizagem/fisiologia , Locomoção/fisiologia , Mesencéfalo/metabolismo , Camundongos , Neuropeptídeos/genética
16.
Neurosci Biobehav Rev ; 100: 129-165, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30629980

RESUMO

Parkinson's disease (PD) is a devastating diagnosis with, however, potential for an extremely intriguing aesthetic component. Despite motor and cognitive deficits, an emerging collection of studies report a burst of visual artistic output and alterations in produced art in a subgroup of patients. This provides a unique window into the neurophysiological bases for why and how we might create and enjoy visual art, as well as into general brain function and the nature of PD or other neurodegenerative diseases. However, there has not been a comprehensive organization of literature on this topic. Nor has there been an attempt to connect case evidence and knowledge on PD with present understanding of visual art making in psychology and neuroaesthetics in order to propose hypotheses for documented artistic changes. Here, we collect the current research on this topic, tie this to PD symptoms and neurobiology, and provide new theories focusing on dopaminergic neuron damage, over-stimulation from dopamine agonist therapy, and context or genetic factors revealing the neurobiological basis of the visual artistic brain.


Assuntos
Arte , Encéfalo/fisiopatologia , Criatividade , Motivação/fisiologia , Doença de Parkinson/fisiopatologia , Doença de Parkinson/psicologia , Dopamina/fisiologia , Neurônios Dopaminérgicos/fisiologia , Estética , Humanos , Doença de Parkinson/genética , Percepção Visual/fisiologia
17.
Geroscience ; 41(1): 39-49, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30623286

RESUMO

Repetitive DNA sequences represent about half of the human genome. They have a central role in human biology, especially neurobiology, but are notoriously difficult to study. The purpose of this study was to quantify the transcription from repetitive sequences in a progerin-expressing cellular model of neuronal aging. Progerin is a nuclear protein causative of the Hutchinson-Gilford progeria syndrome that is also incrementally expressed during the normal aging process. A dedicated pipeline of analysis allowed to quantify transcripts containing repetitive sequences from RNAseq datasets oblivious of their genomic localization, tolerating a sufficient degree of mutational noise, all with low computational requirements. The pipeline has been applied to a published panel of RNAseq datasets derived from a well-established and well-described cellular model of aging of dopaminergic neurons. Progerin expression strongly downregulated the transcription from all the classes of repetitive sequences: satellites, long and short interspersed nuclear elements, human endogenous retroviruses, and DNA transposon. The Alu element represented by far the principal source of transcript originating either from repetitive sequences or from canonical coding genes; it was expressed on average at 192,493.5 reads per kilobase million (RPKM) (SE = 21,081.3) in the control neurons and dropped to 43,760.1 RPKM (SE = 5315.0) in the progerin-expressing neurons, being significant downregulated (p = 0.0005). The results highlighted a global perturbation of transcripts derived from repetitive sequences in a cellular model of aging and provided a direct link between progerin expression and alteration of transcription from human repetitive elements.


Assuntos
Elementos Alu/genética , Senescência Celular/genética , Neurônios Dopaminérgicos/fisiologia , Regulação para Baixo/genética , Lamina Tipo A/genética , Transcrição Genética/genética , Envelhecimento/genética , Fibroblastos/fisiologia , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Progéria/genética , Retroelementos/genética
18.
Behav Brain Res ; 363: 199-215, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30599154

RESUMO

Gait and postural control dysfunction are prototypical symptoms compromising quality of life for patients with Parkinson's disease (PD). Hallmarks of cellular pathology are dopaminergic degeneration and accumulation of the cytosolic protein alpha-synuclein, linked to impaired autophagy-lysosome pathway (ALP) clearance. Physical exercise improves gait in PD patients and motor function in rodent lesion models. Moreover, exercise is considered neuroprotective and ALP induction has been reported, e.g. in human skeletal muscle, rodent peripheral and cerebral tissues. A combined analysis of how distinct exercise paradigms affect motor and central biochemical aspects of PD could maximize benefits for patients. Here we examine the effect of 4 weeks treadmill exercise intervention in 7-8 month non-lesioned mice on a) distinct gait categories, b) ALP activity, c) dopaminergic and alpha-synuclein homeostasis. The study includes wild type, alpha-synuclein knockout, and mice exclusively expressing human alpha-synuclein. Parameters of gait regularity and stability, activity, and dynamic postural control during unforced walk, were assessed by an automated system (CatWalk XT). At baseline, alpha-synuclein mouse models exhibited irregular and less active gait, with impaired dynamic postural control, compared to wild type mice. Treadmill exercise particularly improved speed and stride length, while increasing dual diagonal versus three-paw body support in both the alpha-synuclein knockout and transgenic mice. Biochemical analyses showed higher striatal tyrosine hydroxylase immuno-reactivity and reduced higher-order alpha-synuclein species in the cerebral cortex. However, no significant cerebral ALP induction was measured. In summary, treadmill exercise improved gait activity and postural stability, and promoted dopaminergic and alpha-synuclein homeostasis, without robustly inducing cerebral ALP.


Assuntos
Marcha/fisiologia , Condicionamento Físico Animal/fisiologia , Esforço Físico/fisiologia , Animais , Autofagia/fisiologia , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Terapia por Exercício/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Neuroproteção , Doença de Parkinson/fisiopatologia , Postura/fisiologia , Substância Negra/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , alfa-Sinucleína/fisiologia
19.
Science ; 363(6424)2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30655412

RESUMO

The cerebellum has been implicated in a number of nonmotor mental disorders such as autism spectrum disorder, schizophrenia, and addiction. However, its contribution to these disorders is not well understood. In mice, we found that the cerebellum sends direct excitatory projections to the ventral tegmental area (VTA), one of the brain regions that processes and encodes reward. Optogenetic activation of the cerebello-VTA projections was rewarding and, in a three-chamber social task, these projections were more active when the animal explored the social chamber. Intriguingly, activity in the cerebello-VTA pathway was required for the mice to show social preference in this task. Our data delineate a major, previously unappreciated role for the cerebellum in controlling the reward circuitry and social behavior.


Assuntos
Comportamento Animal , Núcleos Cerebelares/fisiologia , Recompensa , Comportamento Social , Área Tegmentar Ventral/fisiologia , Animais , Axônios/fisiologia , Neurônios Dopaminérgicos/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Optogenética , Sinapses/fisiologia
20.
J Matern Fetal Neonatal Med ; 32(3): 461-471, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28931341

RESUMO

AIM: Teratogenicity is a problematic issue for pregnant women because of X-ray radiation, drugs, and genetic and unknown variables. First-generation antiepileptic drugs (AED) like valproic acid are well-known teratogens for developing fetuses. However, their usage is necessary in order to prevent maternal seizures. The underlying mechanism of birth defects associated with AED exposure remains unclear and information about the neurotoxic effects of prenatal exposure to AED is still limited. Oxcarbazepine (OXC) and gabapentin (GBP) are second-generation AED. It still remains unclear how much these drugs are safe during pregnancy. This study aimed to investigate whether any neurotoxic effect of OXC and GBP in utero exposure on the developing brain. METHODS: Eighteen pregnant Wistar albino rats were divided into six groups. The first group was exposed to OXC at 100 mg/kg/day, the second to GBP at 50 mg/kg/day, and third to saline (0.9% NaCl) at 1.5 ml/day between the first and the fifth days of gestation. The same procedure was applied at the same dosages between the 6th and the 15th days of gestation for the 2nd three groups. Five female offspring (total n = 30, 45 days old) were taken from each group and stereological methods were applied in order to analyze the total and dopaminergic neuron number of the substantia nigra pars compacta (SNc). CONCLUSION: The result is that the OXC and GBP exposure at different gestational periods may not give rise to congenital malformation and it appears that the GBP exposure during the organogenesis period proliferatively affects the total number of neurons.


Assuntos
Gabapentina/toxicidade , Síndromes Neurotóxicas/congênito , Oxcarbazepina/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Anormalidades Induzidas por Medicamentos/patologia , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Feminino , Síndromes Neurotóxicas/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos , Ratos Wistar
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