SMAD4 protein is decreased in the dorsolateral prefrontal and anterior cingulate cortices in schizophrenia.
- 作者列表："Gibbons AS","Hoyer D","Dean B
OBJECTIVES:SMADs are a family of signal transduction factors that mediate signalling of the TGFB-superfamily of cell regulatory proteins. A recent transcriptomic analysis of post-mortem, cortical tissue from subjects with schizophrenia found decreased mRNA expression of SMAD2 and SMAD4 in the dorsolateral prefrontal cortex (DLPFC) associated with the disorder. To expand this initial finding, we sought to determine whether SMAD2 and SMAD4 protein were also altered in the cortex from subjects with schizophrenia. METHODS:Western blotting was used to measure SMAD2 and SMAD4 protein levels in DLPFC and anterior cingulate cortex (ACC) taken post-mortem from subjects with schizophrenia (n = 20) and matched control (n = 20) subjects. RESULTS:Compared to controls, levels of SMAD4 were 25% lower in the DLPFC and 38% lower in the ACC from subjects with schizophrenia. By contrast, SMAD2 levels were not altered in either DLPFC or ACC. CONCLUSIONS:Our finding of lower SMAD4 protein in the cortex suggests there are likely to be abnormalities in cortical TGFB-superfamily signalling in schizophrenia.
目的: SMADs 是介导 TGFB-细胞调节蛋白超家族信号传导的信号转导因子家族。最近对精神分裂症受试者死后皮质组织的转录组学分析发现，与该疾病相关的背外侧前额叶皮质 (DLPFC) 中 SMAD2 和 SMAD4 的 mRNA 表达降低。为了扩大这一初步发现，我们试图确定 SMAD2 和 SMAD4 蛋白是否也在精神分裂症受试者的皮层中发生了改变。 方法: 采用 Western blotting 检测精神分裂症患者 (n = 20) 死后 DLPFC 和前扣带皮层 (ACC) 中 SMAD2 和 SMAD4 蛋白水平和匹配的对照 (n = 20) 受试者。 结果: 与对照组相比，精神分裂症受试者的 DLPFC 中 SMAD4 水平低 25%，ACC 中 SMAD4 水平低 38%。相比之下，在 DLPFC 或 ACC 中 SMAD2 水平没有改变。 结论: 我们在皮质中发现了较低的 SMAD4 蛋白，提示精神分裂症的皮质 TGFB-超家族信号很可能存在异常。
METHODS::In recent years, transcranial electrical stimulation (tES) has been used to improve cognitive and perceptual abilities and to boost learning. In the visual domain, transcranial random noise stimulation (tRNS), a type of tES in which electric current is randomly alternating in between two electrodes at high frequency, has shown potential in inducing long lasting perceptual improvements when coupled with tasks such as contrast detection. However, its cortical mechanisms and online effects have not been fully understood yet, and it is still unclear whether these long-term improvements are due to early-stage perceptual enhancements of contrast sensitivity or later stage mechanisms such as learning consolidation. Here we tested tRNS effects on multiple spatial frequencies and orientation, showing that tRNS enhances detection of a low contrast Gabor, but only for oblique orientation and high spatial frequency (12 cycles per degree of visual angle). No improvement was observed for low contrast and vertical stimuli. These results indicate that tRNS can enhance contrast sensitivity already after one training session, however this early onset is dependent on characteristics of the stimulus such as spatial frequency and orientation. In particular, the shallow depth of tRNS is likely to affect superficial layers of the visual cortex where neurons have higher preferred spatial frequencies than cells in further layers, while the lack of effect on vertical stimuli might reflect the optimization of the visual system to see cardinally oriented low contrast stimuli, leaving little room for short-term improvement. Taken together, these results suggest that online tRNS effects on visual perception are the result of a complex interaction between stimulus intensity and cortical anatomy, consistent with previous literature on brain stimulation.
METHODS:OBJECTIVE:There is growing interest in treating diseases by electrical stimulation and block of peripheral autonomic nerves, but a paucity of studies on excitation and block of small diameter autonomic axons. We conducted in vivo quantification of the strength-duration properties, activity-dependent slowing (ADS), and responses to kilohertz frequency (KHF) signals for the rat vagus nerve (VN). APPROACH:We conducted acute in vivo experiments in urethane-anesthetised rats. We placed two cuff electrodes on the left cervical VN and one cuff electrode on the anterior subdiaphragmatic VN. The rostral cervical cuff was used to deliver pulses to quantify recruitment and ADS. The caudal cervical cuff was used to deliver KHF signals. The subdiaphragmatic cuff was used to record compound action potentials (CAPs). MAIN RESULTS:We quantified the input-output recruitment and strength-duration curves. Fits to the data using standard strength-duration equations were qualitatively similar, but the resulting chronaxie and rheobase estimates varied substantially. We measured larger thresholds for the slowest fibres (0.5 to 1 m/s), especially at shorter pulse widths. Using a novel cross-correlation CAP-based analysis, we measured ADS of ~2.3% after 3 min of 2 Hz stimulation, which is comparable to ADS reported for sympathetic efferents in somatic nerves, but much smaller than ADS in cutaneous nociceptors. We found greater ADS with higher stimulation frequency and non-monotonic changes in CV in select cases. We found monotonically increasing block thresholds across frequencies from 10 to 80 kHz for both fast and slow fibres. Further, following 25 s of KHF signal, neural conduction could require tens of seconds to recover. SIGNIFICANCE:The quantification of mammalian autonomic nerve responses to conventional and KHF signals provides essential information for development of peripheral nerve stimulation therapies and for understanding their mechanisms of action.
METHODS:BACKGROUND:Early accounts of forced thought were reported at the onset of a focal seizure, and characterized as vague, repetitive, and involuntary intellectual auras distinct from perceptual or psychic hallucinations or illusions. Here, we examine the neural underpinnings involved in conceptual thought by presenting a series of 3 patients with epilepsy reporting intrusive thoughts during electrical stimulation of the left lateral prefrontal cortex (PFC) during invasive surgical evaluation. We illustrate the widespread networks involved through two independent brain imaging modalities: resting state functional magnetic resonance imaging (fMRI) (rs-fMRI) and task-based meta-analytic connectivity modeling (MACM). METHODS:We report the clinical and stimulation characteristics of three patients with left hemispheric language dominance who demonstrate forced thought with functional mapping. To examine the brain networks underlying this phenomenon, we used the regions of interest (ROI) centered at the active electrode pairs. We modeled functional networks using two approaches: (1) rs-fMRI functional connectivity analysis, representing 81 healthy controls and (2) meta-analytic connectivity modeling (MACM), representing 8260 healthy subjects. We also determined the overlapping regions between these three subjects' rs-fMRI and MACM networks through a conjunction analysis. RESULTS:We identified that left PFC was associated with a large-scale functional network including frontal, temporal, and parietal regions, a network that has been associated with multiple cognitive functions including semantics, speech, attention, working memory, and explicit memory. CONCLUSIONS:We illustrate the neural networks involved in conceptual thought through a unique patient population and argue that PFC supports this function through activation of a widespread network.