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1.
Toxicology ; 430: 152341, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-31811891

RESUMO

Xylene and its derivatives are known to be neurotoxic to the central nervous system of animals. Our previous work has shown that para-xylene (PX) can cause an increase in apoptotic cells and abnormal avoidance behavior in Xenopus laevis. However, the mechanism underlying the impact of PX on neuronal structural and functional plasticity is less clear. Here, we examined the effects of PX on neuronal development and plasticity in the developing optic tectum. We found that HuC/D-positive neurons were more vulnerable than SOX2-positive progenitor cells or BLBP-positive radial glial cells after exposure to PX at 1 mM for 48 h. The further measurement of postsynaptic receptors and synaptic vesicle proteins showed that the expression levels of GluA1 and GluA2, but not Rab3a and SNAP25, were significantly decreased in the tectal brain. In vivo time-lapse images and electrophysiological recordings showed that PX exposure resulted in significant deficits in neuronal structure, particularly in the total dendritic branch length (TDBL), and visual stimulation-induced excitatory compound synaptic currents (eCSCs) without altering neurotransmitter release probability. Strikingly, coexposure to d-glucuronolactone (GA) and PX rescued the structural and functional deficits caused by PX exposure alone. Furthermore, we found that visual experience-induced structural, functional and behavioral plasticity was blocked by PX exposure, which was also rescued by the simultaneous administration of GA and PX . Thus, our findings indicate that PX is neurotoxic to brain development and plasticity and that GA may be considered a promising candidate to treat PX-induced defects in neural circuits.


Assuntos
Glucuronatos/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos , Xilenos/toxicidade , Animais , Regulação da Expressão Gênica , Neurogênese/efeitos dos fármacos , Estimulação Luminosa , Transmissão Sináptica/efeitos dos fármacos , Xenopus laevis
2.
Med Hypotheses ; 133: 109407, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31586811

RESUMO

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious non-addictive pharmacotherapies for ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Inibidores de Captação de Serotonina/uso terapêutico , Colículos Superiores/fisiopatologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Ensaios Clínicos como Assunto/métodos , Dioxanos/administração & dosagem , Dioxanos/uso terapêutico , Esquema de Medicação , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Pindolol/farmacologia , Pindolol/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos , Receptor 5-HT1A de Serotonina/fisiologia , Movimentos Sacádicos/fisiologia , Neurônios Serotoninérgicos/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Serotonina/fisiologia , Antagonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/uso terapêutico , Inibidores de Captação de Serotonina/administração & dosagem , Inibidores de Captação de Serotonina/farmacologia , Colículos Superiores/efeitos dos fármacos
3.
Dis Model Mech ; 12(9)2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31481433

RESUMO

Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood and currently no treatment exists to prevent these negative effects. We previously found that the nitric oxide (NO) donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish, and the ability of SNP to prevent these. We incubated 4-days post-fertilisation (dpf) zebrafish embryos in 20 mM glucose or mannitol for 5 days until 9 dpf, with or without 0.1 mM SNP co-treatment for 24 h (8-9 dpf), and quantified vascular NO reactivity, vascular mural cell number, expression of a klf2a reporter, glial fibrillary acidic protein (GFAP) and transient receptor potential cation channel subfamily V member 4 (TRPV4), as well as spontaneous neuronal activation at 9 dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies. We find that glucose exposure significantly reduced NO reactivity, klf2a reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour, we found that glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure. Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype and function of the optic tectum, and on whole-organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.This article has an associated First Person interview with the first author of the paper.


Assuntos
Comportamento Animal , Encéfalo/irrigação sanguínea , Glucose/toxicidade , Nitroprussiato/farmacologia , Peixe-Zebra/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Glutamato-Amônia Ligase/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Larva/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Manitol/farmacologia , Modelos Biológicos , Óxido Nítrico/metabolismo , Colículos Superiores/efeitos dos fármacos , Colículos Superiores/metabolismo , Canais de Cátion TRPV/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
4.
Gen Comp Endocrinol ; 282: 113214, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271760

RESUMO

The optic tectum rapidly inhibits food intake when a visual threat is present. Anatomical and electrophysiological evidence support a role for neuropeptide Y (NPY), originating from cells in the thalamus, in the tectal inhibition of prey capture. Here we test the hypothesis that tectal NPY receptor type 2 (NPY2R) influences prey-capture and predator-avoidance responses in the African clawed frog, Xenopus laevis. We tested two questions: 1) Does tectal NPY administration decrease food intake and alter prey-capture behavior? 2) Does tectal administration of a NPY2R antagonist increase food intake, alter prey-capture behavior, and alter predator avoidance behavior? NPY microinjected bilaterally into the tecta failed to significantly alter food intake at any dose tested, although predator presence significantly reduced food intake. However, NPY differentially altered discrete components of prey capture including increasing the latency to contact food and reducing the amount of time in contact with food. These effects were blocked by the NPY2R antagonist BIIE0246. Additionally, BIIE0246 elevated food intake on its own after bilateral tectal microinjection. Furthermore, BIIE0246 reversed the reduction of food intake caused by exposure to a predator. Overall, these findings indicate that tectal NPY2R activation causes frogs to consume food more quickly, which may be adaptive in predator-rich environments. Blocking tectal NPY2R increases baseline food intake and reduces or eliminates predator-induced changes in prey capture and food intake.


Assuntos
Sistemas Neurossecretores/metabolismo , Comportamento Predatório , Receptores de Neuropeptídeo Y/metabolismo , Colículos Superiores/metabolismo , Xenopus laevis/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Benzazepinas/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Feminino , Neuropeptídeo Y/farmacologia , Sistemas Neurossecretores/efeitos dos fármacos , Comportamento Predatório/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos , Suínos
5.
Eur Neuropsychopharmacol ; 29(7): 858-870, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31227263

RESUMO

Microinjections of N-methyl-d-aspartic acid (NMDA) in the midbrain tectum structures produce panic attack-like defensive behaviours, followed by an antinociceptive response. It has been suggested that fear-related defensive responses organised by brainstem neurons can be modulated by 5-hydroxytryptamine (5-HT). However, there is a shortage of studies showing the role of dorsal raphe nucleus (DRN) 5-HT2A receptors in the modulation of panic-like behaviour and fear-induced antinociception organised by the superior colliculus (SC). The purpose of this study was to investigate the participation of DRN 5-HT2A receptors in the modulation of panic attack-like behaviour and antinociception evoked by intra-SC injections of NMDA. In experiment I, the animals received microinjections of physiological saline or NMDA (6, 9 and 12 nmol) in the deep layers of the SC (dlSC). In experiment II, the most effective dose of NMDA (12 nmol) or vehicle was preceded by microinjections of vehicle or the 5-HT2A receptor selective antagonist R-96544 at different concentrations (0.5, 5 and 10 nM) in the DRN. Both proaversive and antinociceptive effects elicited by intra-dlSC injections of NMDA were attenuated by DRN pretreatment with R-96544. In addition, a morphological analysis showed that 5-HT2A receptors are present in GABAergic interneurons in the DRN. Taken together, these findings suggest that DRN 5-HT2A receptors are critical for the modulation of both panic attack-like defensive behaviour organised by SC neurons and unconditioned fear-induced antinociception. A possible interaction between serotonergic inputs, GABAergic interneurons and serotonergic outputs from the DRN was also considered.


Assuntos
Comportamento Animal/efeitos dos fármacos , Núcleo Dorsal da Rafe/efeitos dos fármacos , Medo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Pânico/efeitos dos fármacos , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Colículos Superiores/efeitos dos fármacos , Animais , Masculino , N-Metilaspartato/farmacologia , Pirrolidinas/farmacologia , Ratos , Ratos Wistar
6.
J Neurosci ; 39(23): 4475-4488, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-30940716

RESUMO

During a critical period in development, spontaneous and evoked retinal activity shape visual pathways in an adaptive fashion. Interestingly, spontaneous activity is sufficient for spatial refinement of visual receptive fields (RFs) in superior colliculus (SC) and visual cortex (V1), but early visual experience is necessary to maintain inhibitory synapses and stabilize RFs in adulthood (Carrasco et al., 2005, 2011; Carrasco and Pallas, 2006; Balmer and Pallas, 2015a). In V1, BDNF and its high-affinity receptor TrkB are important for development of visual acuity, inhibition, and regulation of the critical period for ocular dominance plasticity (Hanover et al., 1999; Huang et al., 1999; Gianfranceschi et al., 2003). To examine the generality of this signaling pathway for visual system plasticity, the present study examined the role of TrkB signaling during the critical period for RF refinement in SC. Activating TrkB receptors during the critical period (P33-P40) in dark reared subjects produced normally refined RFs, and blocking TrkB receptors in light-exposed animals resulted in enlarged adult RFs like those in dark reared animals. We also report here that deprivation- or TrkB blockade-induced RF enlargement in adulthood impaired fear responses to looming overhead stimuli and negatively impacted visual acuity. Thus, early TrkB activation is both necessary and sufficient to maintain visual RF refinement, robust looming responses, and visual acuity in adulthood. These findings suggest a common signaling pathway exists for the maturation of inhibition between V1 and SC.SIGNIFICANCE STATEMENT Receptive field refinement in superior colliculus differs from more commonly studied examples of critical period plasticity in visual pathways in that it does not require visual experience to occur; rather, spontaneous activity is sufficient. Maintenance of refinement beyond puberty requires a brief, early exposure to light to stabilize the lateral inhibition that shapes receptive fields. We find that TrkB activation during a critical period can substitute for visual experience in maintaining receptive field refinement into adulthood, and that this maintenance is beneficial to visual survival behaviors. Thus, as in some other types of plasticity, TrkB signaling plays a crucial role in receptive field refinement.


Assuntos
Envelhecimento/fisiologia , Glicoproteínas de Membrana/fisiologia , Proteínas Tirosina Quinases/fisiologia , Privação Sensorial/fisiologia , Colículos Superiores/fisiologia , Percepção Visual/fisiologia , Animais , Azepinas/farmacologia , Benzamidas/farmacologia , Cricetinae , Período Crítico Psicológico , Escuridão , Medo/fisiologia , Feminino , Flavonas/farmacologia , Masculino , Aprendizagem em Labirinto , Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/antagonistas & inibidores , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Estimulação Luminosa , Processamento de Proteína Pós-Traducional , Proteínas Tirosina Quinases/antagonistas & inibidores , Colículos Superiores/efeitos dos fármacos , Colículos Superiores/crescimento & desenvolvimento , Percepção Visual/efeitos da radiação
7.
Neurosci Lett ; 698: 7-12, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30611891

RESUMO

Interleukin-6 (IL-6) is involved in different processes of the central nervous system. Our aims were to investigate the effect of IL-6 on retinotectal topography and on different signaling pathways. Rats were submitted to an intravitreous injection of either IL-6 (50 ng/ml) or PBS (vehicle) at postnatal day 10 (PND10). At PND11 or PND14, different groups were processed for western blot, histochemistry or immunofluorescence analysis. IL-6 treatment leads to an increase in pSTAT-3 levels in the retina and a disruption in the retinotectal topographic map, suggesting that a transient increase in interleukin-6 levels may impact neural circuitry development.


Assuntos
Interleucina-6/farmacologia , Vias Visuais/crescimento & desenvolvimento , Animais , Interleucina-6/administração & dosagem , Interleucina-6/fisiologia , Injeções Intravítreas , Fosforilação , Ratos , Retina/efeitos dos fármacos , Retina/crescimento & desenvolvimento , Retina/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Colículos Superiores/efeitos dos fármacos , Colículos Superiores/crescimento & desenvolvimento , Colículos Superiores/fisiologia , Vias Visuais/efeitos dos fármacos , Vias Visuais/fisiologia
8.
Nat Commun ; 9(1): 3553, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177726

RESUMO

The causal roles of the frontal eye fields (FEF) and superior colliculus (SC) in spatial selective attention have not been directly compared. Reversible inactivation is an established method for testing causality but comparing results between FEF and SC is complicated by differences in size and morphology of the two brain regions. Here we exploited the fact that inactivation of FEF and SC also changes the metrics of saccadic eye movements, providing an independent benchmark for the strength of the causal manipulation. Using monkeys trained to covertly perform a visual motion-change detection task, we found that inactivation of either FEF or SC could cause deficits in attention task performance. However, SC-induced attention deficits were found with saccade changes half the size needed to get FEF-induced attention deficits. Thus, performance in visual attention tasks is vulnerable to loss of signals from either structure, but suppression of SC activity has a more devastating effect.


Assuntos
Atenção/fisiologia , Lobo Frontal/fisiologia , Movimentos Sacádicos/fisiologia , Percepção Espacial/fisiologia , Colículos Superiores/fisiologia , Animais , Atenção/efeitos dos fármacos , Estimulação Elétrica , Lobo Frontal/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Macaca mulatta , Muscimol/farmacologia , Desempenho Psicomotor , Movimentos Sacádicos/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos
9.
Physiol Behav ; 196: 104-111, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30055218

RESUMO

The dorsal periaqueductal grey matter (dPAG) and the deep layers of the superior colliculus (dlSC) have been implicated in the organisation of innate fear-related defensive behaviours. Furthermore, GABAergic neurons from the substantia nigra pars reticulata (SNpr) connected to the dlSC and dPAG receive convergent disinhibitory inputs from the caudate-putamen (CPu), comprising the neostriatum, and modulate defence responses elicited by midbrain tectum stimulation. The purpose of this work was to study the effect of either excitatory cortico-neostriatal input blockade or neostriato-nigral GABAergic disinhibitory output activation on the responsivity of GABAergic nigro-collicular tonic inhibitory pathways during the elicitation of panic attack-like defensive responses produced by bicuculline administration into the dlSC. Thus, we investigated the effects of microinjection of either the synaptic activity blocker cobalt chloride (CoCl2) or the NMDA receptor agonist N-methyl-D-aspartic acid in the CPu on the elaboration of the defensive behaviour elicited by the selective blockade of GABAA receptors in the dlSC. Our findings showed that pretreatment of the neostriatum with CoCl2 caused clear anxiolytic and panicolytic-like effects, reducing the incidence and duration of alertness and diminishing defensive immobility and explosive escape responses. On the other hand, pretreatment of the neostriatum with NMDA (40 nmol) caused a pro-aversive effect, enhancing running and jumping responses elicited by GABAergic disinhibition in the dlSC. We conclude from the data that the neostriato-nigral disinhibitory and nigro-collicular inhibitory GABAergic pathways modulate innate fear and panic attack-like responses organised by dlSC neurons.


Assuntos
Comportamento Animal/fisiologia , Corpo Estriado/fisiopatologia , Transtorno de Pânico/fisiopatologia , Colículos Superiores/fisiopatologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Cobalto/farmacologia , Corpo Estriado/efeitos dos fármacos , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , N-Metilaspartato/metabolismo , N-Metilaspartato/farmacologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neurotransmissores/farmacologia , Ratos Wistar , Receptores de GABA-A/metabolismo , Colículos Superiores/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
10.
Neuropharmacology ; 138: 118-129, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29879408

RESUMO

Heightened distractibility is a core symptom of Attention Deficit Hyperactivity Disorder (ADHD). Effective treatment is normally with chronic orally administered psychostimulants including amphetamine. Treatment prevents worsening of symptoms but the site of therapeutic processes, and their nature, is unknown. Mounting evidence suggests that the superior colliculus (SC) is a key substrate in distractibility and a therapeutic target, so we assessed whether therapeutically-relevant changes are induced in this structure by chronic oral amphetamine. We hypothesized that amphetamine would alter visual responses and morphological measures. Six-week old healthy male rats were treated with oral amphetamine (2, 5 or 10 mg/kg) or a vehicle for one month after which local field potential and multiunit recordings were made from the superficial layers of the SC in response to whole-field light flashes in withdrawal. Rapid Golgi staining was also used to assess dendritic spines, and synaptophysin staining was used to assess synaptic integrity. Chronic amphetamine increased local field potential responses at higher doses, and increased synaptophysin expression, suggesting enhanced visual input involving presynaptic remodelling. No comparable increases in multiunit activity were found suggesting amphetamine suppresses collicular output activity, counterbalancing the increased input. We also report, for the first time, five different dendritic spine types in the superficial layers and show these to be unaffected by amphetamine, indicating that suppression does not involve gross postsynaptic structural alterations. In conclusion, we suggest that amphetamine produces changes at the collicular level that potentially stabilise the structure and may prevent the worsening of symptoms in disorders like ADHD.


Assuntos
Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Colículos Superiores/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Administração Oral , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/fisiologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Colículos Superiores/citologia , Colículos Superiores/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Sinaptofisina/metabolismo , Percepção Visual/fisiologia
11.
Front Neural Circuits ; 12: 36, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29867370

RESUMO

Defensive behavioral responses are essential for survival in threating situations. The superior colliculus (SC) has been implicated in the generation of defensive behaviors elicited by visual, tactile and auditory stimuli. Furthermore, substantia nigra pars reticulata (SNr) neurons are known to exert a modulatory effect on midbrain tectum neural substrates. However, the functional role of this nigrotectal pathway in threating situations is still poorly understood. Using optogenetics in freely behaving mice, we activated SNr projections at the level of the SC, and assessed consequences on behavioral performance in an open field test (OFT) and the beetle mania task (BMT). The latter confronts a mouse with an erratic moving robo-beetle and allows to measure active and passive defensive responses upon frequent encounter of the threatening object. Channelrhodopsin-2 (ChR2)-mediated activation of the inhibitory nigrotectal pathway did not affect anxiety-like and exploratory behavior in the OFT, but increased the number of contacts between robo-beetle and test mouse in the BMT. Depending on the size of the arena, active avoidance responses were reduced, whereas tolerance and close following of the robo-beetle were significantly increased. We conclude from the data that the nigrotectal pathway plays holds the potential to modulate innate fear by attenuating threat recognition and causing a shift from defensive to approach behavior.


Assuntos
Comportamento Animal/fisiologia , Comportamento de Escolha/fisiologia , Vias Neurais/fisiologia , Colículos Superiores/fisiologia , Animais , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Bicuculina/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Camundongos Endogâmicos C57BL , Vias Neurais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Colículos Superiores/efeitos dos fármacos
12.
J Psychopharmacol ; 31(10): 1347-1361, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28925314

RESUMO

The mechanism of action of psychostimulant drugs in the treatment of Attention Deficit Hyperactivity Disorder is still largely unknown, although recent evidence suggests one possibility is that the drugs affect the superior colliculus (SC). We have previously demonstrated that systemically administered d-amphetamine attenuates/abolishes visual responses to wholefield light flashes in the superficial layers of the SC in anaesthetised rats, and the present study sought to extend this work to methylphenidate (MPH). Anaesthetised rats were administered MPH at a range of doses (or saline) and subjected to monocular wholefield light flashes at two intensities, juxta-threshold and super-threshold. In contrast to d-amphetamine, systemic MPH produced an enhancement of visual activity at both intensities. Methylphenidate was also found to produce activation of the cortical EEG in anaesthetised rats. Furthermore, cortical activation induced by electrical stimulation of the pons was found to enhance visual responses in superficial layers of the SC, and when MPH was paired with pontine-induced cortical activation, the response-enhancing effects of MPH were substantially attenuated. Taken together, the results suggest that the enhancement of visual responses in the superficial layers of the SC by MPH in the anaesthetised rat is an artefact of the drug's interaction with cortical arousal.


Assuntos
Metilfenidato/farmacologia , Colículos Superiores/efeitos dos fármacos , Anfetamina/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina , Masculino , Ratos
13.
Psychopharmacology (Berl) ; 234(20): 3009-3025, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28856406

RESUMO

RATIONALE: Gamma-aminobutyric acid (GABA)ergic neurons of the substantia nigra pars reticulata (SNpr) are connected to the deep layers of the superior colliculus (dlSC). The dlSC, in turn, connect with the SNpr through opioid projections. Nociceptin/orphanin FQ peptide (N/OFQ) is a natural ligand of a Gi protein-coupled nociceptin receptor (ORL1; NOP) that is also found in the SNpr. Our hypothesis is that tectonigral opioid pathways and intranigral orphanin-mediated mechanisms modulate GABAergic nigrotectal connections. OBJECTIVES: Therefore, the aim of this work was to study the role of opioid and NOP receptors in the SNpr during the modulation of defence reactions organised by the dlSC. METHODS: The SNpr was pretreated with either opioid or NOP receptor agonists and antagonists, followed by dlSC treatment with bicuculline. RESULTS: Blockade of GABAA receptors in the dlSC elicited fear-related defensive behaviour. Pretreatment of the SNpr with naloxone benzoylhydrazone (NalBzoH), a µ-, δ-, and κ1-opioid receptor antagonist as well as a NOP receptor antagonist, decreased the aversive effect of bicuculline treatment on the dlSC. Either µ-opioid receptor activation or blockade by SNpr microinjection of endomorphin-1 (EM-1) and CTOP promoted pro-aversive and anti-aversive actions, respectively, that modulated the defensive responses elicited by bicuculline injection into the dlSC. Pretreatment of the SNpr with the selective NOP receptor antagonist JTC801 decreased the aversive effect of bicuculline, and microinjections of the selective NOP receptor agonist NNC 63-0532 promoted the opposite effect. CONCLUSIONS: These results demonstrate that opioid pathways and orphanin-mediated mechanisms have a critical role in modulating the activity of nigrotectal GABAergic pathways during the organisation of defensive behaviours.


Assuntos
Aminoquinolinas/administração & dosagem , Benzamidas/administração & dosagem , Medo/efeitos dos fármacos , Oligopeptídeos/administração & dosagem , Parte Reticular da Substância Negra/efeitos dos fármacos , Receptores Opioides , Somatostatina/análogos & derivados , Analgésicos Opioides/administração & dosagem , Animais , Bicuculina/administração & dosagem , Relação Dose-Resposta a Droga , Medo/fisiologia , Masculino , Naloxona/administração & dosagem , Naloxona/análogos & derivados , Peptídeos Opioides/administração & dosagem , Parte Reticular da Substância Negra/fisiologia , Ratos , Ratos Wistar , Receptores Opioides/fisiologia , Somatostatina/administração & dosagem , Colículos Superiores/efeitos dos fármacos , Colículos Superiores/fisiologia , Ácido gama-Aminobutírico/administração & dosagem
14.
Neurosci Lett ; 657: 38-44, 2017 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-28756191

RESUMO

The serotonin transporter (5-HTT) regulates serotonin homeostasis and has been used as a target for different drugs in depression treatment. Although the serotonergic system has received a lot of attention, little is known about the effects of these drugs over serotonin transporters. In this work, we investigated the expression pattern of 5-HTT during development of the visual system and the influence of fluoxetine on different signaling pathways. Our data showed that the expression of 5-HTT has a gradual increase from postnatal day 0 until 42 and decrease afterwards. Moreover, chronic fluoxetine treatment both in childhood and adolescence induces down regulation of 5-HTT expression and phosphorylation of ERK and AKT signaling pathways. Together these data suggest that the levels of 5-HTT protein could be important for the development of the central nervous system and suggest that the ERK and AKT are involved in the molecular pathways of antidepressants drugs, acting in concert to improve serotonergic signaling.


Assuntos
Fluoxetina/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Fluoxetina/administração & dosagem , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ratos , Inibidores de Captação de Serotonina/administração & dosagem
15.
Dev Neurobiol ; 77(10): 1206-1220, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28589698

RESUMO

Adult neurogenesis occurs more commonly in teleosts, represented by zebrafish, than in mammals. Zebrafish is therefore considered a suitable model to study adult neurogenesis, for which the regulatory molecular mechanisms remain little known. Our previous study revealed that neuroepithelial-like neural stem cells (NSCs) are located at the edge of the dorsomedial region. We also showed that Notch signaling inhibits NSC proliferation in this region. In the present study, we reported the expression of Wnt and Shh signaling components in this region of the optic tectum. Moreover, inhibitors of Wnt and Shh signaling suppressed NSC proliferation, suggesting that these pathways promote NSC proliferation. Shh is particularly required for maintaining Sox2-positive NSCs. Our experimental data also indicate the involvement of these signaling pathways in neural differentiation from NSCs. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1206-1220, 2017.


Assuntos
Proliferação de Células/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Colículos Superiores/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Bromodesoxiuridina , Proliferação de Células/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/farmacologia , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Imidas/farmacologia , Imuno-Histoquímica , Proteínas de Membrana , Microscopia Confocal , Microscopia de Fluorescência , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Receptor Patched-1/metabolismo , Receptor Patched-2/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Quinolinas/farmacologia , Fatores de Transcrição SOX/metabolismo , Colículos Superiores/efeitos dos fármacos , Tiadiazóis/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética , Via de Sinalização Wnt/fisiologia , Peixe-Zebra , Proteínas de Peixe-Zebra/antagonistas & inibidores
16.
Elife ; 52016 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-27879199

RESUMO

In the vertebrate CNS, afferent sensory inputs are targeted to specific depths or layers of their target neuropil. This patterning exists ab initio, from the very beginning, and therefore has been considered an activity-independent process. However, here we report that, during circuit development, the subcellular segregation of the visual and mechanosensory inputs to specific regions of tectal neuron dendrites in the tadpole optic tectum requires NMDA receptor activity. Blocking NMDARs during the formation of these sensory circuits, or removing the visual set of inputs, leads to less defined segregation, and suggests a correlation-based mechanism in which correlated inputs wire to common regions of dendrites. This can account for how two sets of inputs form synapses onto different regions of the same dendrite. Blocking NMDA receptors during later stages of circuit development did not disrupt segregation, indicating a critical period for activity-dependent shaping of patterns of innervation.


Assuntos
Potenciais Somatossensoriais Evocados/fisiologia , Larva/metabolismo , Neurogênese/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Colículos Superiores/metabolismo , Xenopus laevis/metabolismo , Animais , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Dendritos/ultraestrutura , Maleato de Dizocilpina/farmacologia , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Expressão Gênica , Larva/citologia , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento , Neurópilo/citologia , Neurópilo/efeitos dos fármacos , Neurópilo/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Colículos Superiores/citologia , Colículos Superiores/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Potenciais Sinápticos/efeitos dos fármacos , Potenciais Sinápticos/fisiologia , Xenopus laevis/genética , Xenopus laevis/crescimento & desenvolvimento
17.
Dev Biol ; 420(1): 120-135, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27693369

RESUMO

Neurogenesis in the post-embryonic vertebrate brain varies in extent and efficiency between species and brain territories. Distinct neurogenesis modes may account for this diversity, and several neural progenitor subtypes, radial glial cells (RG) and neuroepithelial progenitors (NE), have been identified in the adult zebrafish brain. The neurogenic sequences issued from these progenitors, and their contribution to brain construction, remain incompletely understood. Here we use genetic tracing techniques based on conditional Cre recombination and Tet-On neuronal birthdating to unravel the neurogenic sequence operating from NE progenitors in the zebrafish post-embryonic optic tectum. We reveal that a subpopulation of her5-positive NE cells of the posterior midbrain layer stands at the top of a neurogenic hierarchy involving, in order, the amplification pool of the tectal proliferation zone (TPZ), followed by her4-positive RG cells with transient neurogenic activity. We further demonstrate that the adult her5-positive NE pool is issued in lineage from an identically located NE pool expressing the same gene in the embryonic neural tube. Finally, we show that these features are reminiscent of the neurogenic sequence and embryonic origin of the her9-positive progenitor NE pool involved in the construction of the lateral pallium at post-embryonic stages. Together, our results highlight the shared recruitment of an identical neurogenic strategy by two remote brain territories, where long-lasting NE pools serve both as a growth zone and as the life-long source of young neurogenic RG cells.


Assuntos
Envelhecimento/fisiologia , Linhagem da Célula , Mesencéfalo/embriologia , Células-Tronco Neurais/citologia , Peixe-Zebra/embriologia , Animais , Linhagem da Célula/efeitos dos fármacos , Doxiciclina/farmacologia , Embrião não Mamífero/citologia , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Mesencéfalo/citologia , Mesencéfalo/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Células Neuroepiteliais/citologia , Células Neuroepiteliais/efeitos dos fármacos , Células Neuroepiteliais/metabolismo , Neurogênese/efeitos dos fármacos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Recombinação Genética/genética , Colículos Superiores/citologia , Colículos Superiores/efeitos dos fármacos , Colículos Superiores/embriologia , Colículos Superiores/metabolismo , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia
18.
Soc Cogn Affect Neurosci ; 11(12): 2009-2019, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27510499

RESUMO

Brain circuitry underlying defensive behaviors includes forebrain modulatory sites, e.g. the amygdala and hypothalamus, and midbrain effector regions, such as the deep/intermediate layers of the superior colliculus (DLSC). When disinhibited, this network biases behavior towards reflexive defense reactions. While well characterized in rodent models, little is known about this system in the primate brain. Employing focal pharmacological manipulations, we have previously shown that activation of the DLSC triggers reflexive defensive responses, including cowering, escape behaviors and defensive vocalizations. Here, we show that activation of the DLSC also disrupts normal dyadic social interactions between familiar pairs of monkeys. When the basolateral complex of the amygdala (BLA) was inhibited concurrent with DLSC activation, cowering behavior was attenuated, whereas escape behaviors and defensive vocalizations were not. Moreover, inhibition of the BLA, previously shown to produce a profound increase in dyadic social interactions, was unable to normalize the decrease in social behavior resulting from DLSC activation. Together these data provide an understanding of forebrain-midbrain interactions in a species and circuit with translational relevance for the psychiatry of anxiety and post-traumatic stress disorders.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Ansiedade/fisiopatologia , Colículos Superiores/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Bicuculina/análogos & derivados , Bicuculina/farmacologia , Feminino , Agonistas de Receptores de GABA-A/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Macaca mulatta , Macaca nemestrina , Masculino , Muscimol/farmacologia , Colículos Superiores/efeitos dos fármacos
19.
Eur J Neurosci ; 44(6): 2314-23, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27422659

RESUMO

Melanopsin phototransduction allows intrinsically photosensitive retinal ganglion cells (ipRGCs) to maintain firing under sustained illumination and to encode irradiance. ipRGCs project to different parts of the visual system, including the superficial superior colliculus (sSC), but to date there is no description of melanopsin contributions to the activity of that nucleus. We sought to fill that gap using extracellular recordings to describe light response in the sSC. We failed to observe light responses in the sSC of mice lacking rod and cone function, in which melanopsin provides the only photoreception. Nor did the sSC of intact animals track very gradual ramps in irradiance, a stimulus encoded by melanopsin for other brain regions. However, in visually intact mice we did find maintained responses to extended light steps (30 s) and to an irradiance ramp upon which a high frequency (20 Hz) temporal white noise was superimposed. Both of these responses were deficient when the spectral composition of the stimulus was changed to selectively reduce its effective irradiance for melanopsin. Such maintained activity was also impaired in mice lacking melanopsin, and this effect was specific, as responses of this genotype to higher spatiotemporal frequency stimuli were normal. We conclude that ipRGCs contribute to irradiance-dependent modulations in maintained activity in the sSC, but that this effect is less robust than for other brain regions receiving ipRGC input.


Assuntos
Transdução de Sinal Luminoso/efeitos dos fármacos , Opsinas de Bastonetes/farmacologia , Colículos Superiores/efeitos dos fármacos , Animais , Luz , Camundongos , Estimulação Luminosa/métodos , Células Fotorreceptoras Retinianas Cones/efeitos dos fármacos , Células Fotorreceptoras Retinianas Cones/fisiologia , Células Fotorreceptoras Retinianas Cones/efeitos da radiação , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/efeitos da radiação , Colículos Superiores/efeitos da radiação
20.
Neuroscience ; 331: 177-85, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27343828

RESUMO

Xylene and its derivatives are raw materials widely used in industry and known to be toxic to animals. However, the mechanism underlying the neurotoxicity of para-xylene (PX) to the central nervous system (CNS) in vivo is less clear. Here, we exposed Xenopus laevis tadpoles to sub-lethal concentrations of PX during the critical period of brain development to determine the effects of PX on Xenopus development and visual behavior. We found that the abnormality rate was significantly increased with exposure to increasing concentrations of PX. In particular, the number of apoptotic cells in the optic tectum was dramatically increased with exposure to PX at 2mM. Long-term PX exposure also resulted in significant deficits in visually guided avoidance behavior. Strikingly, co-incubation with PX and d-glucuronolactone (GA) decreased the number of apoptotic cells and rescued the avoidance behavior. Furthermore, we found that the acetylation of H4K12 (H4K12ac) and the dimethylation of H3K9 (H3K9me2) in the optic tectum were significantly increased in PX-treated animals, and these effects were suppressed by GA treatment. In particular, the increase in apoptotic cells in PX-treated brains was also inhibited by GA treatment. These effects indicate that epigenetic regulation plays a key role in PX-induced apoptosis and animal behavior. In an effort to characterize the neurotoxic effects of PX on brain development and behavior, these results suggest that the neurotoxicity of PX requires further evaluation regarding the safety of commercial and industrial uses.


Assuntos
Apoptose/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Colículos Superiores/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Xilenos/toxicidade , Acetilação/efeitos dos fármacos , Animais , Apoptose/genética , Apoptose/fisiologia , Aprendizagem da Esquiva/fisiologia , Deficiências do Desenvolvimento/induzido quimicamente , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/metabolismo , Modelos Animais de Doenças , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Glucuronatos/farmacologia , Histonas/efeitos dos fármacos , Histonas/metabolismo , Metilação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Colículos Superiores/crescimento & desenvolvimento , Colículos Superiores/metabolismo , Colículos Superiores/patologia , Percepção Visual/genética , Percepção Visual/fisiologia , Xenopus laevis
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