RESUMO
Empathy is a cornerstone of social behavior, impairments of which are characteristic of neuropsychiatric disorders such as autism and psychopathy. According to the "shared representations" theory, empathy relies on neural processes similar to those underpinning the first-hand experience of a given emotion. A recent study by Mischkowski, Crocker, and Way (Soc Cogn Affect Neurosci 11: 1345-1353, 2016) provides novel insights into neurobiological underpinnings of empathy by demonstrating that acetaminophen, a widely used painkiller, reduces empathy for other's physical and social pain.
Assuntos
Acetaminofen , Empatia , Emoções , Humanos , Dor , Comportamento SocialRESUMO
Excitation/inhibition imbalance is implicated in symptoms of neuropsychiatric disorders. We discuss a study by Liang et al. (Mol Psychiatry 20: 850-859, 2015) demonstrating that the conditional knockout of neuroligin-2, a postsynaptic adhesion protein, in the prefrontal cortex of adult mice results in alterations in inhibitory synaptic properties. However, behavioral impairments emerged prior to the development of detectable changes in excitation/inhibition ratio. This suggests there may be network-specific excitation/inhibition ratios, some of which are more vulnerable to disruption than others.
Assuntos
Moléculas de Adesão Celular Neuronais , Sinapses , Animais , Camundongos , Proteínas do Tecido Nervoso , Córtex Pré-FrontalRESUMO
Neuronal signal integration as well as synaptic transmission and plasticity highly depend on the morphology of dendrites and their spines. Nogo-A is a membrane protein enriched in the adult central nervous system (CNS) myelin, where it restricts the capacity of axons to grow and regenerate after injury. Nogo-A is also expressed by certain neurons, in particular during development, but its physiological function in this cell type is less well understood. We addressed this question in the cerebellum, where Nogo-A is transitorily highly expressed in the Purkinje cells (PCs) during early postnatal development. We used general genetic ablation (KO) as well as selective overexpression of Nogo-A in PCs to analyze its effect on dendritogenesis and on the formation of their main input synapses from parallel (PFs) and climbing fibers (CFs). PC dendritic trees were larger and more complex in Nogo-A KO mice and smaller than in wild-type in Nogo-A overexpressing PCs. Nogo-A KO resulted in premature soma-to-dendrite translocation of CFs and an enlargement of the CF territory in the molecular layer during development. Although spine density was not influenced by Nogo-A, the size of postsynaptic densities of PF-PC synapses was negatively correlated with the Nogo-A expression level. Electrophysiological studies revealed that Nogo-A negatively regulates the strength of synaptic transmission at the PF-PC synapse. Thus, Nogo-A appears as a negative regulator of PC input synapses, which orchestrates cerebellar connectivity through regulation of synapse morphology and the size of the PC dendritic tree.
Assuntos
Cerebelo/fisiologia , Proteínas da Mielina/fisiologia , Animais , Cerebelo/citologia , Dendritos/fisiologia , Dendritos/ultraestrutura , Fenômenos Eletrofisiológicos , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas da Mielina/deficiência , Proteínas da Mielina/genética , Proteínas da Mielina/metabolismo , Neurônios/fisiologia , Neurônios/ultraestrutura , Proteínas Nogo , Receptor Nogo 1 , Células de Purkinje/fisiologia , Células de Purkinje/ultraestrutura , Receptores de Superfície Celular/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
Adult central nervous system axons show restricted growth and regeneration properties after injury. One of the underlying mechanisms is the activation of the Nogo-A/Nogo receptor (NgR1) signaling pathway. Nogo-A knockout (KO) mice show enhanced regenerative growth in vivo, even though it is less pronounced than after acute antibody-mediated neutralization of Nogo-A. Residual inhibition may involve a compensatory component. By mRNA expression profiling and immunoblots we show increased expression of several members of the Ephrin/Eph and Semaphorin/Plexin families of axon guidance molecules, e.g. EphrinA3 and EphA4, in the intact spinal cord of adult Nogo-A KO vs. wild-type (WT) mice. EphrinA3 inhibits neurite outgrowth of EphA4-positive neurons in vitro. In addition, EphrinA3 KO myelin extracts are less growth-inhibitory than WT but more than Nogo-A KO myelin extracts. EphA4 KO cortical neurons show decreased growth inhibition on Nogo-A KO myelin as compared with WT neurons, supporting increased EphA4-mediated growth inhibition in Nogo-A KO mice. Consistently, in vivo, Nogo-A/EphA4 double KO mice show increased axonal sprouting and regeneration after spinal cord injury as compared with EphA4 KO mice. Our results reveal the upregulation of developmental axon guidance cues following constitutive Nogo-A deletion, e.g. the EphrinA3/EphA4 ligand/receptor pair, and support their role in restricting neurite outgrowth in the absence of Nogo-A.
Assuntos
Axônios/fisiologia , Córtex Cerebral/metabolismo , Gânglios Espinais/metabolismo , Proteínas da Mielina/metabolismo , Regeneração da Medula Espinal , Regulação para Cima , Animais , Axônios/metabolismo , Células Cultivadas , Córtex Cerebral/patologia , Córtex Cerebral/fisiologia , Efrina-A3/genética , Efrina-A3/metabolismo , Efrina-A4/genética , Efrina-A4/metabolismo , Gânglios Espinais/patologia , Gânglios Espinais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas da Mielina/genética , Bainha de Mielina/genética , Bainha de Mielina/metabolismo , Proteínas Nogo , Tratos Piramidais/metabolismo , Tratos Piramidais/patologia , Tratos Piramidais/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Traumatismos da Medula Espinal/metabolismoRESUMO
Wiring of the nervous system is a multi-step process involving complex interactions of the growing fibre with its tissue environment and with neighbouring fibres. Nogo-A is a membrane protein enriched in the adult central nervous system (CNS) myelin, where it restricts the capacity of axons to grow and regenerate after injury. During development, Nogo-A is also expressed by neurons but its function in this cell type is poorly known. Here, we show that neutralization of neuronal Nogo-A or Nogo-A gene ablation (KO) leads to longer neurites, increased fasciculation, and decreased branching of cultured dorsal root ganglion neurons. The same effects are seen with antibodies against the Nogo receptor complex components NgR and Lingo1, or by blocking the downstream effector Rho kinase (ROCK). In the chicken embryo, in ovo injection of anti-Nogo-A antibodies leads to aberrant innervation of the hindlimb. Genetic ablation of Nogo-A causes increased fasciculation and reduced branching of peripheral nerves in Nogo-A KO mouse embryos. Thus, Nogo-A is a developmental neurite growth regulatory factor with a role as a negative regulator of axon-axon adhesion and growth, and as a facilitator of neurite branching.
Assuntos
Proteínas da Mielina/metabolismo , Sistema Nervoso , Neurônios/metabolismo , Animais , Axônios/metabolismo , Embrião de Galinha , Gânglios Espinais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Proteínas Nogo , Ratos , Ratos Wistar , Recombinação Genética , Quinases Associadas a rho/metabolismoRESUMO
Studies report that the microstructural integrity of the uncinate fasciculus (UF; connecting the anterior temporal lobe to the orbitofrontal cortex) is abnormal in adults with psychopathy and children with conduct problems (CP), especially those with high callous-unemotional (CU) traits. However, it is unknown if these abnormalities are 'fixed' or 'reversible'. Therefore, we tested the hypothesis that a reduction in CP symptoms, following a parenting intervention, would be associated with altered microstructural integrity in the UF. Using diffusion tensor imaging tractography we studied microstructural differences (mean diffusivity (MD) and radial diffusivity (RD)) in the UF of 43 typically developing (TD) and 67 boys with CP before and after a 14-week parenting intervention. We also assessed whether clinical response in CP symptoms or CU traits explained changes in microstructure following the intervention. Prior to intervention, measures of MD and RD in the UF were increased in CP compared to TD boys. Following intervention, we found that the CP group had a significant reduction in RD and MD. Further, these microstructural changes were driven by the group of children whose CU traits improved (but not CP symptoms as hypothesized). No significant microstructural changes were observed in the TD group. Our findings suggest, for the first time, that microstructural abnormalities in the brains of children with CP may be reversible following parenting intervention.
Assuntos
Transtorno da Conduta , Substância Branca , Masculino , Adulto , Humanos , Criança , Imagem de Tensor de Difusão/métodos , Substância Branca/diagnóstico por imagem , Poder Familiar , Transtorno da Conduta/diagnóstico por imagem , Transtorno da Conduta/terapia , Transtorno da Personalidade Antissocial/psicologiaRESUMO
The brain is the central and most complex organ in the nervous system, comprising billions of neurons that constantly communicate through trillions of connections called synapses. Despite being formed mainly during prenatal and early postnatal development, synapses are continually refined and eliminated throughout life via complicated and hitherto incompletely understood mechanisms. Failure to correctly regulate the numbers and distribution of synapses has been associated with many neurological and psychiatric disorders, including autism, epilepsy, Alzheimer's disease, and schizophrenia. Therefore, measurements of brain synaptic density, as well as early detection of synaptic dysfunction, are essential for understanding normal and abnormal brain development. To date, multiple synaptic density markers have been proposed and investigated in experimental models of brain disorders. The majority of the gold standard methodologies (e.g., electron microscopy or immunohistochemistry) visualize synapses or measure changes in pre- and postsynaptic proteins ex vivo. However, the invasive nature of these classic methodologies precludes their use in living organisms. The recent development of positron emission tomography (PET) tracers [such as (18F)UCB-H or (11C)UCB-J] that bind to a putative synaptic density marker, the synaptic vesicle 2A (SV2A) protein, is heralding a likely paradigm shift in detecting synaptic alterations in patients. Despite their limited specificity, novel, non-invasive magnetic resonance (MR)-based methods also show promise in inferring synaptic information by linking to glutamate neurotransmission. Although promising, all these methods entail various advantages and limitations that must be addressed before becoming part of routine clinical practice. In this review, we summarize and discuss current ex vivo and in vivo methods of quantifying synaptic density, including an evaluation of their reliability and experimental utility. We conclude with a critical assessment of challenges that need to be overcome before successfully employing synaptic density biomarkers as diagnostic and/or prognostic tools in the study of neurological and neuropsychiatric disorders.
RESUMO
Background: Obstructive sleep apnea (OSA) is a chronic, highly prevalent, multi-system and sleep disorder, which may contribute to cognitive impairment and a variety of structural and neurophysiologic changes. The focus on OSA is warranted given its recognized links with major psychiatric and neurologic disorders, including Alzheimer's disease. Some preliminary studies suggest a dual effect of the inflammatory response in OSA. Neuroinflammation may present with initial, potentially adaptive and homeostatic, and later, a more distinctly maladaptive, precipitating and perpetuating role. Objective: We here propose and argue in favour of the inflammatory process in the brain as a likely binding mechanism behind at least some effects that OSA may have on the brain and its function. Several OSA-triggered molecular and cellular events, that could lead to a neurodegenerative cascade, are similarly discussed. Methods: This perspective reviews the body of literature that investigates potential links between the inflammatory processes in the brain and the OSA. A special emphasis is placed on a potential role for neuroplastin, a novel transmembrane synaptic protein involved in the neuroplasticity and known to be differentially regulated in the OSA. Conclusions: The intricate interplay between neuroinflammation and other mechanistic correlates of OSA add to the evidence that neuroinflammation may be a key target for future therapeutic strategies in a number of comorbid disorders. The future studies will need to answer whether it is sleep fragmentation (SF) or intermittent hypoxia (IH) which may drive any such neuroinflammation.
RESUMO
Autism spectrum disorder (ASD) affects over 1:100 of the population and costs the UK more than £32bn and the USA more than $175bn (£104bn) annually. Its core symptoms are social and communication difficulties, repetitive behaviours and sensory hyper- or hypo-sensitivities. A highly diverse phenotypic presentation likely reflects its etiological heterogeneity and makes finding treatment targets for ASD challenging. In addition, there are no means to identify biologically responsive individuals who may benefit from specific interventions. There is hope however, and in this review we consolidate how findings from magnetic resonance spectroscopy (MRS) add to the evidence that differences in the brain's excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) balance may be both a key biomarker and a tractable treatment target in ASD.
Assuntos
Transtorno do Espectro Autista/diagnóstico por imagem , Transtorno do Espectro Autista/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Animais , HumanosRESUMO
Autism spectrum disorder (ASD) is a pervasive neurodevelopmental syndrome with a high human and economic burden. The pathophysiology of ASD is largely unclear, thus hampering development of pharmacological treatments for the core symptoms of the disorder. Abnormalities in glutamate and GABA signaling have been hypothesized to underlie ASD symptoms, and may form a therapeutic target, but it is not known whether these abnormalities are recapitulated in humans with ASD, as well as in rodent models of the disorder. We used translational proton magnetic resonance spectroscopy ([1H]MRS) to compare glutamate and GABA levels in adult humans with ASD and in a panel of six diverse rodent ASD models, encompassing genetic and environmental etiologies. [1H]MRS was performed in the striatum and the medial prefrontal cortex, of the humans, mice, and rats in order to allow for direct cross-species comparisons in specific cortical and subcortical brain regions implicated in ASD. In humans with ASD, glutamate concentration was reduced in the striatum and this was correlated with the severity of social symptoms. GABA levels were not altered in either brain region. The reduction in striatal glutamate was recapitulated in mice prenatally exposed to valproate, and in mice and rats carrying Nlgn3 mutations, but not in rodent ASD models with other etiologies. Our findings suggest that glutamate/GABA abnormalities in the corticostriatal circuitry may be a key pathological mechanism in ASD; and may be linked to alterations in the neuroligin-neurexin signaling complex.
Assuntos
Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Ácido gama-Aminobutírico/metabolismo , Adulto , Animais , Transtorno do Espectro Autista/diagnóstico por imagem , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Pré-Frontal/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Ratos TransgênicosRESUMO
Individuals of many species rely on odors to communicate, find breeding partners, locate resources and sense dangers. In vertebrates, odorants are detected by chemosensory receptors of the olfactory system. One class of these receptors, the trace amine-associated receptors (TAARs), was recently suggested to mediate male sexual interest and mate choice. Here we tested this hypothesis in mice by generating a cluster deletion mouse (Taar2-9-/-) lacking all TAARs expressed in the olfactory epithelium, and evaluating transduction pathways from odorants to TAARs, neural activity and behaviors reflecting sexual interest. We found that a urinary volatile amine, isobutylamine (IBA), was a potent ligand for TAAR3 (but not TAAR1, 4, 5, and 6). When males were exposed to IBA, brain regions associated with sexual behaviors were less active in Taar2-9-/- than in wild type males. Accordingly, Taar2-9-/- males spent less time sniffing both the urine of females and pure IBA than wild type males. This is the first demonstration of a comprehensive transduction pathway linking odorants to TAARs and male sexual interest. Interestingly, the concentration of IBA in female urine varied across the estrus cycle with a peak during estrus. This variation in IBA concentration may represent a simple olfactory cue for males to recognize receptive females. Our results are consistent with the hypothesis that IBA and TAARs play an important role in the recognition of breeding partners and mate choice.
RESUMO
Functional magnetic resonance imaging (fMRI) has revolutionized neuroscience by opening a unique window that allows neurocircuitry function and pathological alterations to be probed non-invasively across brain disorders. Here we report a novel sustainable anesthesia procedure for small animal neuroimaging that overcomes shortcomings of anesthetics commonly used in rodent fMRI. The significantly improved preservation of cerebrovascular dynamics enhances sensitivity to neural activity changes for which it serves as a proxy in fMRI readouts. Excellent cross-species/strain applicability provides coherence among preclinical findings and is expected to improve translation to clinical fMRI investigations. The novel anesthesia procedure based on the GABAergic anesthetic etomidate was extensively validated in fMRI studies conducted in a range of genetically engineered rodent models of autism and strains commonly used for transgenic manipulations. Etomidate proved effective, yielded long-term stable physiology with basal cerebral blood flow of ~0.5 ml/g/min and full recovery. Cerebrovascular responsiveness of up to 180% was maintained as demonstrated with perfusion- and BOLD-based fMRI upon hypercapnic, pharmacological and sensory stimulation. Hence, etomidate lends itself as an anesthetic-of-choice for translational neuroimaging studies across rodent models of brain disorders.
Assuntos
Anestesia , Imageamento por Ressonância Magnética , Neuroimagem , Anestésicos Inalatórios/farmacologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Circulação Cerebrovascular/efeitos dos fármacos , Circulação Cerebrovascular/fisiologia , Etomidato/farmacologia , Isoflurano/farmacologia , Medetomidina/farmacologia , Camundongos , Ratos , Especificidade da EspécieRESUMO
RATIONALE: Autism spectrum disorder(s) (ASDs) is a neurodevelopmental disorder characterized by stereotyped behaviours and impairments in communication and social interactions. This heterogeneity has been a major obstacle in uncovering the aetiology and biomarkers of ASDs. Rodent models with genetic modifications or environmental insults have been created to study particular endophenotypes and bridge the gap between genetics and behavioural phenotypes. Translational neuroimaging modalities with their ability to screen the brain noninvasively and yield structural, biochemical and functional information provide a unique platform for discovery and evaluation of such endophenotypes in preclinical and clinical research. OBJECTIVES: We reviewed literature on translational neuroimaging in rodent models of ASDs. The most prominent models will be described and the respective neuroimaging endophenotypes will be discussed with reference to human data. A perspective on future directions of translational neuroimaging in animal models of ASDs will be given. RESULTS AND CONCLUSIONS: To date, we experience a proliferation of rodent models which recapitulate specific liabilities identified in ASDs patients. Translational neuroimaging in these models is emerging but is skewed towards magnetic resonance imaging (MRI) modalities. Volumetric and structural assessments of the brain are dominating and a host of endophenotypes have been reported that allude to findings in ASDs patients but with only few to converge among the models. Caveats of current studies are the diverging biological conditions related to genetic background and age of the animals. It is anticipated that longitudinal and functional assessments will gain much importance and will help elucidating mechanistic relationship between behavioural and structural endophenotypes.