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1.
Ann Neurol ; 87(4): 533-546, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32030799

RESUMO

OBJECTIVE: The dual hit hypothesis about the pathogenesis of Parkinson disease (PD) suggests that the brainstem is a convergent area for the propagation of pathological α-synuclein from the periphery to the brain. Although brainstem structures are likely to be affected early in the course of the disease, detailed information regarding specific brainstem regions is lacking. The aim of our study was to investigate the function of the superior colliculus, a sensorimotor brainstem structure, in de novo PD patients compared to controls using brain functional magnetic imaging and visual stimulation paradigms. METHODS: De novo PD patients and controls were recruited. PD subjects were imaged before and after starting PD medications. A recently developed functional magnetic resonance imaging protocol was used to stimulate and visualize the superior colliculus and 2 other visual structures: the lateral geniculate nucleus and the primary visual cortex. RESULTS: In the 22 PD patients, there was no modulation of the superior colliculus responses to the luminance contrasts compared to controls. This implies a hypersensitivity to low luminance contrast and abnormal rapid blood oxygenation level-dependent signal saturation to high luminance contrasts. The lateral geniculate nucleus was only modulated by 3 to 9% luminance contrasts compared to controls. No major differences were found in the primary visual cortex between both groups. INTERPRETATION: Our findings suggest that pathological superior colliculus visual responses in de novo PD patients are present early in the course of the disease. Changes in imaging the superior colliculus could play an important role as a preclinical biomarker of the disease. ANN NEUROL 2020;87:533-546.


Assuntos
Corpos Geniculados/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Colículos Superiores/diagnóstico por imagem , Córtex Visual/diagnóstico por imagem , Adulto , Idoso , Estudos de Casos e Controles , Sensibilidades de Contraste , Feminino , Neuroimagem Funcional , Corpos Geniculados/fisiopatologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Estimulação Luminosa , Colículos Superiores/fisiopatologia , Córtex Visual/fisiopatologia , Vias Visuais/diagnóstico por imagem , Vias Visuais/fisiopatologia
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.
Prog Brain Res ; 249: 285-294, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31325987

RESUMO

Traditional hypotheses for the pathogenesis of dystonia, the third most common movement disorder, have focused primarily on the basal ganglia. Contemporary theories have emphasized the role of the cerebellum. The modulation of peripheral proprioception also affects dystonia. We proposed a unifying network model for dystonia where the cerebellum, basal ganglia, and peripheral proprioception are connected in a circuit that forms the neural integrator network, ensuring steady position. We suggested that impairment anywhere along this circuit leads to common phenomenology-slow drifts followed by corrective movements, resembling dystonic tremor. We tested this concept in a patient with chronic inflammatory demyelinating polyneuropathy with resulting abnormal proprioception. Quantitative assessment of tremor in this patient revealed drifts in limb position followed by corrective movements and superimposed sinusoidal oscillations-consistent with neural integrator dysfunction. This unique case of chronic inflammatory demyelinating polyneuropathy describes the role of proprioception on the unifying network model for dystonia.


Assuntos
Distúrbios Distônicos/fisiopatologia , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Propriocepção/fisiologia , Colículos Superiores/fisiopatologia , Tremor/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica
4.
Prog Brain Res ; 249: 81-94, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31325999

RESUMO

Visuomotor impairments, such as hypometria of visually guided saccades, are common in Parkinson's disease (PD). Explaining the mechanistic underpinning of such abnormal voluntary (eye) movements can provide insights into the pathophysiology of limb movement disorders in PD. We measured visually guided saccades in 20 PD patients using quantitative high-resolution oculography. The experiments source to determine whether common motor deficits in PD, such as those affecting visually-guided saccades reflect excessive inhibition of the superior colliculus or rather involvement of brainstem saccade generators. We found slowing, interruptions, and curvatures in the saccade trajectory. The curvature not only reflected the mismatch in the velocity of relatively slower vertical (compared to horizontal) saccades, but could be due to aberrant activation of the superior colliculus. The irregularities in the saccade trajectory and slowing were prominent in the vertical direction. We suggest that abnormal saccades in PD not only reflect abnormal tectal function, but also suggest abnormal oscillatory behavior in the reciprocally innervating circuit of excitatory and inhibitory burst neurons. Impaired function of excitatory and inhibitory burst neurons causing maladaptive feedback and premature activation of the superior colliculus can cause irregularity in saccade trajectory.


Assuntos
Gânglios da Base/fisiopatologia , Transtornos da Motilidade Ocular/fisiopatologia , Doença de Parkinson/fisiopatologia , Movimentos Sacádicos/fisiologia , Colículos Superiores/fisiopatologia , Idoso , Medições dos Movimentos Oculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/etiologia , Doença de Parkinson/complicações
5.
J Neurophysiol ; 122(3): 1254-1263, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31339793

RESUMO

Deficits of convergence and accommodation are common following traumatic brain injury, including mild traumatic brain injury, although the mechanism and localization of these deficits have been unclear and supranuclear control of the near-vision response has been incompletely understood. We describe a patient who developed profound instability of the near-vision response with inability to maintain convergence and accommodation following mild traumatic brain injury, who was identified to have a structural lesion on brain MRI in the pulvinar of the caudal thalamus, the pretectum, and the rostral superior colliculus. We discuss the potential relationship between posttraumatic clinical near-vision response deficits and the MRI lesion in this patient. We further propose that the MRI lesion location, specifically the rostral superior colliculus, participates in neural integration for convergence holding, given its proven anatomic connections with the central mesencephalic reticular formation and C-group medial rectus motoneurons in the oculomotor nucleus, which project to extraocular muscle nontwitch fibers specialized for fatigue-resistant, slow, tonic activity such as vergence holding.NEW & NOTEWORTHY Supranuclear control of the near-vision response has been incompletely understood to date. We propose, based on clinical and anatomic evidence, functional pathways for vergence that participate in the generation of the near triad, "slow vergence," and vergence holding.


Assuntos
Acomodação Ocular/fisiologia , Concussão Encefálica/fisiopatologia , Convergência Ocular/fisiologia , Transtornos da Motilidade Ocular/fisiopatologia , Colículos Superiores/fisiopatologia , Transtornos da Visão/fisiopatologia , Concussão Encefálica/complicações , Concussão Encefálica/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neurociências , Transtornos da Motilidade Ocular/etiologia , Área Pré-Tectal/lesões , Pulvinar/lesões , Colículos Superiores/lesões , Transtornos da Visão/etiologia
6.
PLoS One ; 14(6): e0218667, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220164

RESUMO

In contrast to mammals, retinal ganglion cells (RGC) axons of the optic nerve even in mature zebrafish exhibit a remarkable capacity for spontaneous regeneration. One constraint of using adult zebrafish is the limited ability to visualize the regeneration process in live animals. To dynamically visualize and trace the degree of target specific optic nerve regeneration, we took advantage of the optical transparency still preserved in post developmental larval zebrafish. We developed a rapid and robust assay to physically transect the larval optic nerve and find that by 96 hours post injury RGC axons have robustly regrown onto the optic tectum. We observe functional regeneration by 8 days post injury, and demonstrate that similar to adult zebrafish, optic nerve transection in larval zebrafish does not prominently induce cell death or proliferation of RGC neurons. Furthermore, we find that partial optic nerve transection results in axonal growth predominantly to the original, contralateral tectum, while complete transection results in innervation of both the correct contralateral and 'incorrect' ipsilateral tectum. Axonal tracing reveals that although regenerating axons innervate the 'incorrect' ipsilateral tectum, they successfully target their topographically appropriate synaptic areas. Combined, our results validate post developmental larval zebrafish as a powerful model for optic nerve regeneration, and reveal intricate mechanistic differences between axonal growth, midline guidance and synaptic targeting during zebrafish optic nerve regeneration.


Assuntos
Axônios/fisiologia , Regeneração Nervosa/fisiologia , Nervo Óptico/fisiopatologia , Células Ganglionares da Retina/fisiologia , Colículos Superiores/fisiopatologia , Peixe-Zebra/fisiologia , Animais , Animais Geneticamente Modificados , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Larva , Traumatismos do Nervo Óptico/reabilitação , Traumatismos do Nervo Óptico/veterinária , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Peixe-Zebra/crescimento & desenvolvimento
7.
Invest Ophthalmol Vis Sci ; 60(4): 944-953, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30849170

RESUMO

Purpose: Evidence from animals and blind humans suggests that early visual experience influences the developmental calibration of auditory localization. Hypothesizing that unilateral amblyopia may involve cross-modal deficits in spatial hearing, we measured the precision and accuracy of sound localization in humans with amblyopia. Methods: All participants passed a standard hearing test. Experiment 1 measured sound localization precision for click stimuli in 10 adults with amblyopia and 10 controls using a minimum audible angle (MAA) task. Experiment 2 measured sound localization error (i.e., accuracy) for click train stimuli in 14 adults with amblyopia and 16 controls using an absolute sound localization task. Results: In Experiment 1, the MAA (mean ± SEM) was significantly greater in the amblyopia group compared with controls (2.75 ± 0.30° vs. 1.69 ± 0.09°, P = 0.006). In Experiment 2, the overall sound localization error was significantly greater in the amblyopia group compared with controls (P = 0.047). The amblyopia group also showed significantly greater sound localization error in the auditory hemispace ipsilateral to the amblyopic eye (P = 0.036). At a location within this auditory hemispace, the magnitude of sound localization error correlated significantly with deficits in stereo acuity (P = 0.036). Conclusions: The precision and accuracy of sound localization are impaired in unilateral amblyopia. The asymmetric pattern of sound localization error suggests that amblyopic vision may interfere with the development of spatial hearing via the retinocollicular pathway.


Assuntos
Ambliopia/fisiopatologia , Perda Auditiva/fisiopatologia , Retina/fisiopatologia , Localização de Som/fisiologia , Colículos Superiores/fisiopatologia , Estimulação Acústica , Adulto , Mapeamento Encefálico , Calibragem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pessoas com Deficiência Auditiva , Psicometria , Adulto Jovem
8.
J Neurosci ; 39(12): 2313-2325, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30655352

RESUMO

Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) in the eye, which ultimately results in visual impairment or even blindness. Because current therapies often fail to halt disease progression, there is an unmet need for novel neuroprotective therapies to support RGC survival. Various research lines suggest that visual target centers in the brain support RGC functioning and survival. Here, we explored whether increasing neuronal activity in one of these projection areas could improve survival of RGCs in a mouse glaucoma model. Prolonged activation of an important murine RGC target area, the superior colliculus (SC), was established via a novel optogenetic stimulation paradigm. By leveraging the unique channel kinetics of the stabilized step function opsin (SSFO), protracted stimulation of the SC was achieved with only a brief light pulse. SSFO-mediated collicular stimulation was confirmed by immunohistochemistry for the immediate-early gene c-Fos and behavioral tracking, which both demonstrated consistent neuronal activity upon repeated stimulation. Finally, the neuroprotective potential of optogenetic collicular stimulation was investigated in mice of either sex subjected to a glaucoma model and a 63% reduction in RGC loss was found. This work describes a new paradigm for optogenetic collicular stimulation and a first demonstration that increasing target neuron activity can increase survival of the projecting neurons.SIGNIFICANCE STATEMENT Despite glaucoma being a leading cause of blindness and visual impairment worldwide, no curative therapies exist. This study describes a novel paradigm to reduce retinal ganglion cell (RGC) degeneration underlying glaucoma. Building on previous observations that RGC survival is supported by the target neurons to which they project and using an innovative optogenetic approach, we increased neuronal activity in the mouse superior colliculus, a main projection target of rodent RGCs. This proved to be efficient in reducing RGC loss in a glaucoma model. Our findings establish a new optogenetic paradigm for target stimulation and encourage further exploration of the molecular signaling pathways mediating retrograde neuroprotective communication.


Assuntos
Glaucoma/fisiopatologia , Neurônios/fisiologia , Optogenética , Células Ganglionares da Retina/fisiologia , Colículos Superiores/fisiopatologia , Animais , Modelos Animais de Doenças , Feminino , Glaucoma/prevenção & controle , Masculino , Camundongos Endogâmicos C57BL
9.
Artigo em Inglês | MEDLINE | ID: mdl-30510845

RESUMO

Background: Cervical dystonia is a hyperkinetic movement disorder of unknown cause. Symptoms of cervical dystonia have been induced in animals in which the integrity of the nigro-tectal pathway is disrupted, resulting in reduced inhibition of the deep layers of the superior colliculus. This same pathway is believed to play a critical role in saccade generation, particularly visually guided, express saccades. It was hypothesized that individuals with cervical dystonia would present with a higher frequency of express saccades and more directional errors. Methods: Eight individuals with cervical dystonia and 11 age- and sex-matched control participants performed three saccadic paradigms: pro-saccade, gap, and anti-saccade (120 trials per task). Eye movements were recorded using electro-oculography. Results: Mean saccadic reaction times were slower in the cervical dystonia group (only statistically significant in the anti-saccade task, F(1, 35)  =  4.76, p  =  0.036); participants with cervical dystonia produced fewer directional errors (mean 14% vs. 22%) in the anti-saccade task; and had similar frequencies of express saccades in the gap task relative to our control population (chi-square  =  1.13, p  =  0.287). All cervical dystonia participants had lower frequencies of express saccades ipsilateral to their dystonic side (the side to which their head turns), (chi-square  =  3.57, p  =  0.059). Discussion: The finding of slower saccadic reaction times in cervical dystonia does not support the concept of reduced inhibition in the nigro-tectal pathway. Further research is required to confirm the observed relationship between the lateralization of lower frequencies of express saccades and direction of head rotation in cervical dystonia.


Assuntos
Movimentos Sacádicos/fisiologia , Substância Negra/fisiopatologia , Colículos Superiores/fisiopatologia , Torcicolo/fisiopatologia , Medições dos Movimentos Oculares , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia
10.
J Vis Exp ; (140)2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30417886

RESUMO

Time-lapse imaging is a powerful method to analyze migrating cell behavior. After fluorescent cell labeling, the movement of the labeled cells in culture can be recorded under video microscopy. For analyzing cell migration in the developing brain, slice culture is commonly used to observe cell migration parallel to the slice section, such as radial cell migration. However, limited information can be obtained from the slice culture method to analyze cell migration perpendicular to the slice section, such as tangential cell migration. Here, we present the protocols for time-lapse imaging to visualize tangential cell migration in the developing chick optic tectum. A combination of cell labeling by electroporation in ovo and a subsequent flat-mount culture on the cell culture insert enables detection of migrating cell movement in the horizontal plane. Moreover, our method facilitates detection of both individual cell behavior and the collective action of a group of cells in the long term. This method can potentially be applied to detect the sequential change of the fluorescent-labeled micro-structure, including the axonal elongation in the neural tissue or cell displacement in the non-neural tissue.


Assuntos
Neurogênese/fisiologia , Colículos Superiores/fisiopatologia , Animais , Técnicas de Cultura de Células , Movimento Celular , Galinhas
11.
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
12.
J Pediatr Ophthalmol Strabismus ; 55(5): 335-338, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-29809266

RESUMO

PURPOSE: To assess the outcome of free tenotomy of the medial rectus muscle in post-natal monkeys. METHODS: The medial rectus muscle was disinserted in both eyes of 6 macaques at age 4 weeks to induce an alternating exotropia. After the impact on the visual cortex and superior colliculus was investigated, the animals were examined post-mortem to assess the anatomy of the medial rectus muscles. RESULTS: After tenotomy, the monkeys eventually recovered partial adduction. Necropsy revealed that all 12 medial rectus muscles had reattached to the globe. They were firmly connected via an abnormally long tendon, but at the native insertion site. CONCLUSIONS: Medial rectus muscles are able to reattach spontaneously to the eye following free tenotomy in post-natal macaques. The early timing of surgery and the large size of the globe relative to the orbit may explain why reinsertion occurs more readily in monkeys than in children with a lost muscle after strabismus surgery. [J Pediatr Ophthalmol Strabismus. 2018;55(5):335-338.].


Assuntos
Exotropia/fisiopatologia , Músculos Oculomotores/fisiopatologia , Músculos Oculomotores/cirurgia , Colículos Superiores/fisiopatologia , Tenotomia , Córtex Visual/fisiopatologia , Animais , Exotropia/etiologia , Macaca mulatta , Masculino , Procedimentos Cirúrgicos Oftalmológicos
13.
J Neurosci ; 38(16): 4048-4058, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29610441

RESUMO

Following the loss of a sensory modality, such as deafness or blindness, crossmodal plasticity is commonly identified in regions of the cerebrum that normally process the deprived modality. It has been hypothesized that significant changes in the patterns of cortical afferent and efferent projections may underlie these functional crossmodal changes. However, studies of thalamocortical and corticocortical connections have refuted this hypothesis, instead revealing a profound resilience of cortical afferent projections following deafness and blindness. This report is the first study of cortical outputs following sensory deprivation, characterizing cortical projections to the superior colliculus in mature cats (N = 5, 3 female) with perinatal-onset deafness. The superior colliculus was exposed to a retrograde pathway tracer, and subsequently labeled cells throughout the cerebrum were identified and quantified. Overall, the percentage of cortical projections arising from auditory cortex was substantially increased, not decreased, in early-deaf cats compared with intact animals. Furthermore, the distribution of labeled cortical neurons was no longer localized to a particular cortical subregion of auditory cortex but dispersed across auditory cortical regions. Collectively, these results demonstrate that, although patterns of cortical afferents are stable following perinatal deafness, the patterns of cortical efferents to the superior colliculus are highly mutable.SIGNIFICANCE STATEMENT When a sense is lost, the remaining senses are functionally enhanced through compensatory crossmodal plasticity. In deafness, brain regions that normally process sound contribute to enhanced visual and somatosensory perception. We demonstrate that hearing loss alters connectivity between sensory cortex and the superior colliculus, a midbrain region that integrates sensory representations to guide orientation behavior. Contrasting expectation, the proportion of projections from auditory cortex increased in deaf animals compared with normal hearing, with a broad distribution across auditory fields. This is the first description of changes in cortical efferents following sensory loss and provides support for models predicting an inability to form a coherent, multisensory percept of the environment following periods of abnormal development.


Assuntos
Córtex Auditivo/fisiopatologia , Surdez/fisiopatologia , Colículos Superiores/fisiopatologia , Animais , Córtex Auditivo/patologia , Vias Auditivas/patologia , Vias Auditivas/fisiopatologia , Gatos , Surdez/patologia , Feminino , Masculino , Neurônios Eferentes/patologia , Colículos Superiores/patologia
14.
Glia ; 66(7): 1382-1394, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29411422

RESUMO

Zebrafish have superior abilities to generate new neurons in the adult brain and to regenerate brain tissue after brain injury compared with mammals. There exist two types of neural stem cells (NSCs): neuroepithelial-like stem cells (NE) and radial glia (RG) in the optic tectum. We established an optic tectum stab injury model to analyze the function of NSCs in the regenerative condition and confirmed that the injury induced the proliferation of RG, but not NE and that the proliferated RG differentiated into new neurons after the injury. We then analyzed the involvement of Wnt signaling after the injury, using a Wnt reporter line in which canonical Wnt signaling activation induced GFP expression and confirmed that GFP expression was induced specifically in RG after the injury. We also analyzed the expression level of genes related to Wnt signaling, and confirmed that endogenous Wnt antagonist dkk1b expression was significantly decreased after the injury. We observed that Wnt signal inhibitor IWR1 treatment suppressed the proliferation and differentiation of RG after the injury, suggesting that up-regulation of Wnt signaling in RG after the stab injury was required for optic tectum regeneration. We also confirmed that Wnt activation by treatment with GSK3ß inhibitor BIO in uninjured zebrafish induced proliferation of RG in the optic tectum. This optic tectum stab injury model is useful for the study of the molecular mechanisms of brain regeneration and analysis of the RG functions in physiological and regenerative conditions.


Assuntos
Células Ependimogliais/fisiologia , Regeneração Nervosa/fisiologia , Colículos Superiores/lesões , Colículos Superiores/fisiopatologia , Via de Sinalização Wnt/fisiologia , Ferimentos Perfurantes/fisiopatologia , Animais , Animais Geneticamente Modificados , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Células Ependimogliais/patologia , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neurônios/patologia , Neurônios/fisiologia , Colículos Superiores/patologia , Ferimentos Perfurantes/patologia , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
15.
Exp Anim ; 67(1): 23-29, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-28747592

RESUMO

To provide clear information on the cerebral regions according to peripheral neuropathy, the functional activation was investigated using manganese-enhanced magnetic resonance imaging (MEMRI). L5-spinal nerve ligation (SNL) was applied to the rats to induce neuropathic pain. Mechanical allodynia and thermal hyperalgesia were measured to confirm neuropathic pain induction following before and after gabapentin (GBP) treatment. The cerebral regions were investigated using a 4.7T MRI system in the sham, SNL, and GBP-treated SNL rats. Neuropathic pain was severely induced by SNL on the postoperative day 14, excepting the sham group. While MEMRI indicated many activation regions in the brain of SNL rats before GBP treatment, the activities were chronologically attenuated after GBP treatment. The brain regions relating SNL-induced neuropathic pain were as follows: the posterior association area of the parietal region, superior colliculus, inferior colliculus, primary somatosensory area, cingulate cortex, and cingulum bundle. SNL induced- neuropathic pain is transmitted to the primary somatosensory area and parietal region through the cingulum bundle and limbic system. These findings would be helpful for the understanding of neuropathic pain-associated process and be an accurate target for a relief of neuropathic pain.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Aumento da Imagem , Imagem por Ressonância Magnética/métodos , Manganês , Neuralgia/fisiopatologia , Nervos Espinhais , Aminas/uso terapêutico , Animais , Ácidos Cicloexanocarboxílicos/uso terapêutico , Modelos Animais de Doenças , Gabapentina , Giro do Cíngulo/fisiopatologia , Hiperalgesia , Ligadura , Sistema Límbico/fisiopatologia , Masculino , Neuralgia/tratamento farmacológico , Lobo Parietal/fisiopatologia , Ratos Sprague-Dawley , Córtex Somatossensorial/fisiopatologia , Colículos Superiores/fisiopatologia , Ácido gama-Aminobutírico/uso terapêutico
16.
Hum Brain Mapp ; 39(1): 563-574, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29134717

RESUMO

OBJECTIVES: The innate alarm system (IAS) models the neurocircuitry involved in threat processing in posttraumatic stress disorder (PTSD). Here, we investigate a primary subcortical structure of the IAS model, the superior colliculus (SC), where the SC is thought to contribute to the mechanisms underlying threat-detection in PTSD. Critically, the functional connectivity between the SC and other nodes of the IAS remains unexplored. EXPERIMENTAL DESIGN: We conducted a resting-state fMRI study to investigate the functional architecture of the IAS, focusing on connectivity of the SC in PTSD (n = 67), its dissociative subtype (n = 41), and healthy controls (n = 50) using region-of-interest seed-based analysis. PRINCIPAL OBSERVATIONS: We observed group-specific resting state functional connectivity between the SC for both PTSD and its dissociative subtype, indicative of dedicated IAS collicular pathways in each group of patients. When comparing PTSD to its dissociative subtype, we observed increased resting state functional connectivity between the left SC and the right dorsolateral prefrontal cortex (DLPFC) in PTSD. The DLPFC is involved in modulation of emotional processes associated with active defensive responses characterising PTSD. Moreover, when comparing PTSD to its dissociative subtype, increased resting state functional connectivity was observed between the right SC and the right temporoparietal junction in the dissociative subtype. The temporoparietal junction is involved in depersonalization responses associated with passive defensive responses typical of the dissociative subtype. CONCLUSIONS: Our findings suggest that unique resting state functional connectivity of the SC parallels the unique symptom profile and defensive responses observed in PTSD and its dissociative subtype. Hum Brain Mapp 39:563-574, 2018. © 2017 Wiley Periodicals, Inc.


Assuntos
Transtornos Dissociativos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Colículos Superiores/fisiopatologia , Adulto , Análise de Variância , Mapeamento Encefálico , Transtornos Dissociativos/diagnóstico por imagem , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Escalas de Graduação Psiquiátrica , Descanso , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Colículos Superiores/diagnóstico por imagem
17.
Sci Rep ; 7(1): 16753, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196716

RESUMO

Cervical dystonia is a common neurological movement disorder characterised by muscle contractions causing abnormal movements and postures affecting the head and neck. The neural networks underpinning this condition are incompletely understood. While animal models suggest a role for the superior colliculus in its pathophysiology, this link has yet to be established in humans. The present experiment was designed to test the hypothesis that disrupted superior collicular processing is evident in affected patients and in relatives harbouring a disease-specific endophenotype (abnormal temporal discrimination). The study participants were 16 cervical dystonia patients, 16 unaffected first-degree relatives with abnormal temporal discrimination, 16 unaffected first-degree relatives with normal temporal discrimination and 16 healthy controls. The response of participant's superior colliculi to looming stimuli was assessed by functional magnetic resonance imaging. Cervical dystonia patients and relatives with abnormal temporal discrimination demonstrated (i) significantly reduced superior collicular activation for whole brain and region of interest analysis; (ii) a statistically significant negative correlation between temporal discrimination threshold and superior collicular peak values. Our results support the hypothesis that disrupted superior collicular processing is involved in the pathogenesis of cervical dystonia. These findings, which align with animal models of cervical dystonia, shed new light on pathomechanisms in humans.


Assuntos
Distonia/etiologia , Distonia/fisiopatologia , Colículos Superiores/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Discriminação Psicológica , Distonia/diagnóstico , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Limiar Sensorial , Colículos Superiores/diagnóstico por imagem , Avaliação de Sintomas
18.
Sci Rep ; 7(1): 14755, 2017 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-29116187

RESUMO

Rapidly approaching objects indicating threats can induce defensive response through activating a subcortical pathway comprising superior colliculus (SC), lateral posterior nucleus (LP), and basolateral amygdala (BLA). Abnormal defensive response has been reported in autism, and impaired synaptic connections could be the underlying mechanism. Whether the SC-LP-BLA pathway processes looming stimuli abnormally in autism is not clear. Here, we found that looming-evoked defensive response is impaired in a subgroup of the valproic acid (VPA) mouse model of autism. By combining the conventional neurotracer and transneuronal rabies virus tracing techniques, we demonstrated that synaptic connections in the SC-LP-BLA pathway were abnormal in VPA mice whose looming-evoked defensive responses were absent. Importantly, we further translated the finding to children with autism and observed that they did not present looming-evoked defensive response. Furthermore, the findings of the DTI with the probabilistic tractography showed that the structural connections of SC-pulvinar-amygdala in autism children were weak. The pulvinar is parallel to the LP in a mouse. Because looming-evoked defensive response is innate in humans and emerges much earlier than do social and language functions, the absence of defensive response could be an earlier sign of autism in children.


Assuntos
Transtorno Autístico/fisiopatologia , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Núcleos Laterais do Tálamo/fisiopatologia , Colículos Superiores/fisiopatologia , Pesquisa Médica Translacional , Animais , Comportamento Animal , Modelos Animais de Doenças , Medo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probabilidade
19.
Sci Rep ; 7(1): 3163, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28600558

RESUMO

Individuals with Autism Spectrum Disorder (ASD) seem to have difficulties looking others in the eyes, but the substrate for this behavior is not well understood. The subcortical pathway, which consists of superior colliculus, pulvinar nucleus of the thalamus, and amygdala, enables rapid and automatic face processing. A specific component of this pathway - i.e., the amygdala - has been shown to be abnormally activated in paradigms where individuals had to specifically attend to the eye-region; however, a direct examination of the effect of manipulating the gaze to the eye-regions on all the components of the subcortical system altogether has never been performed. The subcortical system is particularly important as it shapes the functional specialization of the face-processing cortex during development. Using functional MRI, we investigated the effect of constraining gaze in the eye-region during dynamic emotional face perception in groups of participants with ASD and typical controls. We computed differences in activation in the subcortical face processing system (superior colliculus, pulvinar nucleus of the thalamus and amygdala) for the same stimuli seen freely or with the gaze constrained in the eye-region. Our results show that when constrained to look in the eyes, individuals with ASD show abnormally high activation in the subcortical system, which may be at the basis of their eye avoidance in daily life.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Transtorno do Espectro Autista/fisiopatologia , Potenciais Evocados Visuais , Pulvinar/fisiopatologia , Colículos Superiores/fisiopatologia , Adolescente , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Transtorno do Espectro Autista/diagnóstico por imagem , Estudos de Casos e Controles , Criança , Reconhecimento Facial/fisiologia , Feminino , Fixação Ocular/fisiologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pulvinar/diagnóstico por imagem , Colículos Superiores/diagnóstico por imagem
20.
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
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