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S100B has been linked to glial pathology in several psychiatric disorders. Previous studies found higher S100B serum levels in patients with schizophrenia compared to healthy controls, and a number of covariates influencing the size of this effect have been proposed in the literature. Here, we conducted a meta-analysis and meta-regression analysis on alterations of serum S100B in schizophrenia in comparison with healthy control subjects. The meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to guarantee a high quality and reproducibility. With strict inclusion criteria 19 original studies could be included in the quantitative meta-analysis, comprising a total of 766 patients and 607 healthy control subjects. The meta-analysis confirmed higher values of the glial serum marker S100B in schizophrenia if compared with control subjects. Meta-regression analyses revealed significant effects of illness duration and clinical symptomatology, in particular the total score of the Positive and Negative Syndrome Scale (PANSS), on serum S100B levels in schizophrenia. In sum, results confirm glial pathology in schizophrenia that is modulated by illness duration and related to clinical symptomatology. Further studies are needed to investigate mechanisms and mediating factors related to these findings.
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Ciliary neurotrophic factor (CNTF), originally described as a neurocytokine that could support the survival of neurons, has been recently found to alleviate demyelination, prevent axon loss, and improve functional recovery in a rat model of acute experimental autoimmune encephalomyelitis (EAE). However, poor penetration into the brain parenchyma and unfavorable side effects limit the utility of CNTF. Here, we evaluated the therapeutic potential of a protein downstream of CNTF, regeneration gene protein 2 (Reg-2). Using multiple morphological, molecular biology, and electrophysiological methods to assess neuroinflammation, axonal loss, demyelination, and functional impairment, we observed that Reg-2 and CNTF exert similar effects in the acute phase of EAE. Both treatments attenuated axonal loss and demyelination, improved neuronal survival, and produced functional improvement. With a smaller molecular weight and improved penetration into the brain parenchyma, Reg-2 may be a useful substitute for CNTF therapy in EAE and multiple sclerosis (MS).
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Attentional blink (AB) refers to the phenomenon whereby the correct identification of a visual or auditory target impairs processing of a subsequent probe. Although it has been shown that knowing in advance, when the probe would be presented, reduces the attentional blink and increases the amplitude of event-related potential (ERP) elicited by the probe, the neural mechanism by which attention mitigates the AB remains unclear. Here, we used time-frequency analysis to further explore the mechanism of the auditory attentional blink. Participants were presented a series of rapid auditory stimuli and asked to indicate whether a target and a probe were present in the sequence. In half of the trials, participants were cued to the probe position relative to the target ('early' or 'late'). Probe detection and ERP amplitude elicited by the probe decreased when the probe was presented shortly after the target compared to when it was presented later after the target. Importantly, the behavioural and ERP correlates of probe discrimination significantly improved when the 'early' cue was presented. The improvement in processing the probe in the cued condition was accompanied by the decrease of alpha activity (8-13 Hz) after the time when the probe was expected; suggesting that successfully directing attention to time-window where the probe would likely occur reduces the processing resources needed to suppress distractors. This in turn freed up available processing resources for the target and probe at the short-term consolidation stage, which ultimately reduced the auditory attentional blink. This article is protected by copyright. All rights reserved.
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Frontal cortical dysfunction is thought to contribute to cognitive and behavioral features of autism spectrum disorders; however, underlying mechanisms are poorly understood. The present study sought to define how loss of Mecp2, the gene mutated in Rett syndrome (RTT), disrupts function in the murine medial prefrontal cortex (mPFC) using acute brain slices and behavioral testing. Compared with wildtype, pyramidal neurons in the Mecp2 null mPFC exhibit significant reductions in excitatory postsynaptic currents, the duration of excitatory UP-states, evoked population activity, and the ratio of NMDA:AMPA currents, as well as an increase in the relative fraction of NR2B currents. These functional changes are associated with reductions in the density of excitatory dendritic spines, the ratio of vesicular glutamate to GABA transporters and GluN1 expression. In contrast to recent reports on circuit defects in other brain regions, we observed no effect of Mecp2 loss on inhibitory synaptic currents or expression of the inhibitory marker parvalbumin. Consistent with mPFC hypofunction, Mecp2 nulls exhibit respiratory dysregulation in response to behavioral arousal. Our data highlight functional hypoconnectivity in the mPFC as a potential substrate for behavioral disruption in RTT and other disorders associated with reduced expression of Mecp2 in frontal cortical regions.
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Tissue and organ function has been conventionally understood in terms of the interactions among discrete and homogeneous cell types. This approach has proven difficult in neuroscience due to the marked diversity across different neuron classes, but it may be further hampered by prominent within-class variability. Here, we considered a well-defined canonical neuronal population—hippocampal CA1 pyramidal cells (CA1 PCs)—and systematically examined the extent and spatial rules of transcriptional heterogeneity. Using next-generation RNA sequencing, we identified striking variability in CA1 PCs, such that the differences within CA1 along the dorsal-ventral axis rivaled differences across distinct pyramidal neuron classes. This variability emerged from a spectrum of continuous gene-expression gradients, producing a transcriptional profile consistent with a multifarious continuum of cells. This work reveals an unexpected amount of variability within a canonical and narrowly defined neuronal population and suggests that continuous, within-class heterogeneity may be an important feature of neural circuits.
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Ultrafast and temporally precise action potentials (APs) are biophysical specializations of auditory brainstem neurons; properties necessary for encoding sound localization and communication cues. Fundamental to these specializations are voltage dependent potassium (KV) and sodium (NaV) ion channels. Here, we characterized the functional development of these ion channels and quantified how they shape AP properties in the avian cochlear nucleus magnocellularis (NM). We report that late developing NM neurons (embryonic [E] days 19-21) generate fast APs that reliably phase lock to sinusoidal inputs at 75 Hz. In contrast, early developing neurons (E19) contained NaV channels that inactivate at more negative voltages, suggesting alterations in NaV channel subtypes. Taken together, our results indicate that the refinement of passive and active ion channel properties operate differentially in order to develop fast and reliable APs in the avian NM.
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Clinical assessment of brain function relies heavily on indirect behavior-based tests. Unfortunately, behavior-based assessments are subjective and therefore susceptible to several confounding factors. Event-related brain potentials (ERPs), derived from electroencephalography (EEG), are often used to provide objective, physiological measures of brain function. Historically, ERPs have been characterized extensively within research settings, with limited but growing clinical applications. Over the past 20 years, we have developed clinical ERP applications for the evaluation of functional status following serious injury and/or disease. This work has identified an important gap: the need for a clinically accessible framework to evaluate ERP measures. Crucially, this enables baseline measures before brain dysfunction occurs, and might enable the routine collection of brain function metrics in the future much like blood pressure measures today. Here, we propose such a framework for extracting specific ERPs as potential "brain vital signs." This framework enabled the translation/transformation of complex ERP data into accessible metrics of brain function for wider clinical utilization. To formalize the framework, three essential ERPs were selected as initial indicators: (1) the auditory N100 (Auditory sensation); (2) the auditory oddball P300 (Basic attention); and (3) the auditory speech processing N400 (Cognitive processing). First step validation was conducted on healthy younger and older adults (age range: 22-82 years). Results confirmed specific ERPs at the individual level (86.81-98.96%), verified predictable age-related differences (P300 latency delays in older adults, p < 0.05), and demonstrated successful linear transformation into the proposed brain vital sign (BVS) framework (basic attention latency sub-component of BVS framework reflects delays in older adults, p < 0.05). The findings represent an initial critical step in developing, extracting, and characterizing ERPs as vital signs, critical for subsequent evaluation of dysfunction in conditions like concussion and/or dementia.
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The central amygdala (CeA) nucleus, a subcortical structure composed of mostly GABA-releasing (GABAergic) neurons, controls fear expression via projections to downstream targets in the hypothalamus and brainstem. The CeA consists of the lateral (CeL) and medial (CeM) subdivisions. The CeL strongly gates information transfer to the CeM, the main output station of the amygdala, but little is known about the functional organization of local circuits in this region. Using cluster analysis, we identified two major electrophysiologically distinct CeL neuron classes in mouse amygdala slices, the early-spiking (ES) and late-spiking (LS) neurons. These two classes displayed distinct autaptic transmission. Compared with LS neurons, ES neurons had strong and depressing autapses, which enhanced spike-timing precision. With multiple patch-clamp recordings, we found that CeL neurons made chemical, but not electrical, synapses. Analysis of individual connections revealed cannabinoid type 1 receptor-mediated suppression of the ES, but not of the LS cell output synapse. More interestingly, the efficacy of the ES→LS or LS→ES synapse was ∼2-fold greater than that of the LS→LS or ES→ES synapse. When tested at 20 Hz, synapses between different neurons, but not within the same class, were markedly depressing and were more powerful to sculpt activity of postsynaptic neurons. Moreover, neurons of different classes also form synapses with higher degree of connectivity. We demonstrate that ES and LS neurons represent two functionally distinct cell classes in the CeL and interactions between presynaptic and postsynaptic neurons dictate synaptic properties between neurons. The central lateral amygdala (CeL) is a key node in fear circuits, but the functional organization of local circuits in this region is largely unknown. The CeL consists of mostly GABAergic inhibitory neurons with different functional and molecular features. Here, we report that the presynaptic cell class determines functional properties of autapses and cannabinoid-mediated modulation of synaptic transmission between neurons, whereas presynaptic versus postsynaptic cell classes dictate the connectivity, efficacy, and dynamics of GABAergic synapses between any two neurons. The wiring specificity and synaptic diversity have a great impact on neuronal output in amygdala inhibitory networks. Such synaptic organizing principles advance our understanding of the significance of physiologically defined neuronal phenotypes in amygdala inhibitory networks.
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Retinal waves are correlated bursts of spontaneous activity whose spatiotemporal patterns are critical for early activity-dependent circuit elaboration and refinement in the mammalian visual system. Three separate developmental wave epochs or stages have been described, but the mechanism(s) of pattern generation of each and their distinct roles in visual circuit development remain incompletely understood. We used neuroanatomical,in vitroandin vivoelectrophysiological, and optical imaging techniques in genetically manipulated mice to examine the mechanisms of wave initiation and propagation and the role of wave patterns in visual circuit development. Through deletion of β2 subunits of nicotinic acetylcholine receptors (β2-nAChRs) selectively from starburst amacrine cells (SACs), we show that mutual excitation among SACs is critical for Stage II (cholinergic) retinal wave propagation, supporting models of wave initiation and pattern generation from within a single retinal cell type. We also demonstrate that β2-nAChRs in SACs, and normal wave patterns, are necessary for eye-specific segregation. Finally, we show that Stage III (glutamatergic) retinal waves are not themselves necessary for normal eye-specific segregation, but elimination of both Stage II and Stage III retinal waves dramatically disrupts eye-specific segregation. This suggests that persistent Stage II retinal waves can adequately compensate for Stage III retinal wave loss during the development and refinement of eye-specific segregation. These experiments confirm key features of the "recurrent network" model for retinal wave propagation and clarify the roles of Stage II and Stage III retinal wave patterns in visual circuit development. Spontaneous activity drives early mammalian circuit development, but the initiation and patterning of activity vary across development and among modalities. Cholinergic "retinal waves" are initiated in starburst amacrine cells and propagate to retinal ganglion cells and higher-order visual areas, but the mechanism responsible for creating their unique and critical activity pattern is incompletely understood. We demonstrate that cholinergic wave patterns are dictated by recurrent connectivity within starburst amacrine cells, and retinal ganglion cells act as "readouts" of patterned activity. We also show that eye-specific segregation occurs normally without glutamatergic waves, but elimination of both cholinergic and glutamatergic waves completely disrupts visual circuit development. These results suggest that each retinal wave pattern during development is optimized for concurrently refining multiple visual circuits.
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Microsaccades exhibit systematic oscillations in direction after spatial cueing, and these oscillations correlate with facilitatory and inhibitory changes in behavioral performance in the same tasks. However, independent of cueing, facilitatory and inhibitory changes in visual sensitivity also arise pre-microsaccadically. Given such pre-microsaccadic modulation, an imperative question to ask becomes: how much of task performance in spatial cueing may be attributable to these peri-movement changes in visual sensitivity? To investigate this question, we adopted a theoretical approach. We developed a minimalist model in which: (1) microsaccades are repetitively generated using a rise-to-threshold mechanism, and (2) pre-microsaccadic target onset is associated with direction-dependent modulation of visual sensitivity, as found experimentally. We asked whether such a model alone is sufficient to account for performance dynamics in spatial cueing. Our model not only explained fine-scale microsaccade frequency and direction modulations after spatial cueing, but it also generated classic facilitatory (i.e., attentional capture) and inhibitory [i.e., inhibition of return (IOR)] effects of the cue on behavioral performance. According to the model, cues reflexively reset the oculomotor system, which unmasks oscillatory processes underlying microsaccade generation; once these oscillatory processes are unmasked, "attentional capture" and "IOR" become direct outcomes of pre-microsaccadic enhancement or suppression, respectively. Interestingly, our model predicted that facilitatory and inhibitory effects on behavior should appear as a function of target onset relative to microsaccades even without prior cues. We experimentally validated this prediction for both saccadic and manual responses. We also established a potential causal mechanism for the microsaccadic oscillatory processes hypothesized by our model. We used retinal-image stabilization to experimentally control instantaneous foveal motor error during the presentation of peripheral cues, and we found that post-cue microsaccadic oscillations were severely disrupted. This suggests that microsaccades in spatial cueing tasks reflect active oculomotor correction of foveal motor error, rather than presumed oscillatory covert attentional processes. Taken together, our results demonstrate that peri-microsaccadic changes in vision can go a long way in accounting for some classic behavioral phenomena.
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