55 research outputs found
From genetics to epigenetics: new perpectives in Tourette Syndrome research
Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder marked by the appearance of multiple involuntary motor and vocal tics. TS presents high comorbidity rates with other disorders such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). TS is highly heritable and has a complex polygenic background. However, environmental factors also play a role in the manifestation of symptoms. Different epigenetic mechanisms may represent the link between these two causalities. Epigenetic regulation has been shown to have an impact in the development of many neuropsychiatric disorders, however very little is known about its effects on Tourette Syndrome.This review provides a summary of the recent findings in the genetic background of TS, followed by an overview on different epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs in the regulation of gene expression. Epigenetic studies in other neurological and psychiatric disorders are discussed along with the TS-related epigenetic findings available in the literature to date. Moreover, we are proposing that some general epigenetic mechanisms seen in other neuropsychiatric disorders may also play a role in the pathogenesis of TS
Neuroanatomical and psychopharmacological study of the striated-nigro-tectal GABAergic link, intramesencephalic connections and the influence of these pathways on the defense behavior elicited by stimulation of the inferior colliculus
A estimulação elétrica e química de algumas estruturas mesencefálicas, tais como a substância cinzenta periaquedutal dorsal (SCPd), as camadas profundas do colículo superior (CPCS) e o núcleo central do colículo inferior (NCCI) eliciam respostas defensivas, associadas ao medo, que muito se assemelham àquelas que caracterizam a síndrome do pânico em humanos. A substância negra, rica em neurônios GABAérgicos, recebe aferências também GABAérgicas provenientes do corpo estriado e se projeta para o mesencéfalo dorsal, mais cranialmente, modulando o substrato neural do medo no colículo superior e SCPd. O objetivo deste trabalho foi investigar se essas conexões GABAérgicas nigro-tectais também se estendem ao substrato aversivo do colículo inferior de ratos, determinando sua influência sobre a modulação de respostas aversivas eliciadas por estimulação elétrica do teto mesencefálico dorsal, situado caudalmente. Também foi estudada a neuroanatomia de conexões entre o núcleo central do colículo inferior e as colunas dorsais e ventrais posteriores da substância cinzenta periaquedutal. A via foi traçada com o neurotraçador fluorescente \"fast blue\", de captação e transporte retrógrado, microinjetado no núcleo central do colículo interior (NCCI) e com o biodextran, um neurotraçador, anterógrado, microinjetado na substância negra, parte reticulada (SNpr) ou no NCCI. Os efeitos da diminuição de atividade dessa via foram estudados, através de lesões eletrolíticas e neuroquímicas (com ácido ibotênico) da substância negra, parte reticulada. O neurotraçamento retrógrado mostrou células neuroniais localizadas na substância negra, parte reticulada que se projetam ipsi e contralateralmente ao núcleo central do colículo inferior. Essa conexão nigro-tectal foi confirmada pelo neurotraçamento anterógrado, que mostrou fibras axônicas no núcleo central do colículo inferior, após a microinjeção de biodextran na substância negra, parte reticulada. Tanto a lesão eletrolítica como a lesão neuroquímica da substância negra, parte reticulada, sensibilizaram o teto mesencefálico à estimulação aversiva. O estudo das conexões intramesencefálicas, estudadas através da microinjeção iontoforética de biodextran no núcleo central do colículo inferior, permitiu a identificação de uma via rica em fibras varicosas conectando o NCCI, às colunas dorsomediais e laterais mais posteriores da substância cinzenta periaquedutal (SCP). O bloqueio de receptores GABA-A no núcleo central do colículo inferior induziu vigorosas respostas defensivas, caracterizadas por congelamento, seguido de corridas, saltos e rotações, sugerindo o bloqueio GABAérgico tônico sobre neurônios localizados no substrato neural responsável pela elaboração do comportamento defensivo no núcleo central do colículo inferior.The electrical and chemical stimulation of some midbrain structures, such as the dorsal periaqueductal gray matter (DPAG), deep layers of the superior colliculus and central e pericentral nucleus of the interior colliculus, elicit defensive behavior, similar to these feel-like reactions described in panic disorder. The substantia nigra, a midbrain structure rich in GABAergic neurons, also receives GABAergics inputs from the striatum and sends inputs to the dorsal mesencephalon, more rostrally, modulating the neural substrate of fear in the superior colliculus and DPAG. The aim of this work consist in studying if these GABAergic connections reach also modulatory targets in the aversive substrate of the inferior colliculus, effecting aversive responses elicited by electrical stimulation of the caudal midbrain tectum. The neuroanatomy of the connections between the central nucleus of the inferior colliculus and the dorsal columns of the periaqueductal gray matter was also investigated. The nigrotectal pathway was labeled with retrograde fluorescent neurotracer fast blue, microinjected in the central nucleus of the inferior colliculus and with the non-fluorescent neurotracer biodextran, iontophoretically microinjected in the substantia nigra, pars reticulata (SNpr). The effects of the decrease of the activity of this pathway were studied, through electrolytic and neurochemical lesions (with ibotenic acid) of the substantia nigra, pars reticulata. The retrograde neurotracer showed neuronal cells located in the substantia nigra, pars reticulata, both ipsi- and contralaterally. This nigro-tectal pathway was corroborated by the anterograde neurotracer (BDA), that showed axonal fibers in the central nucleus of the inferior colliculus. Both the electrolytic and the neurochemical lesions of the SNpr decreased the aversive thresholds elicited by electrical stimulation of the interior colliculus. Intramesencephalic connections were studied by means of iontophoretical microinjections of biodextran in the central nucleus of the inferior colliculus, allowing the identification of pathway with axons rich in varicosities connecting the central nucleus of the inferior colliculus to caudal dorsomedial and lateral columns of the periaqueductal gray matter, where fear-induced behavior may be organized. The GABA-A receptors blockade in the central nucleus of the inferior colliculus was followed by vigorous defensive responses, characterized by freezing, following by running, jumping and rotations, suggesting a tonic inhibitory role of GABAergic pathways on the neural substrate responsible by elaboration of fear-like responses in the inferior colliculus, central nucleus
- …