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Discover the most talked about and latest scientific content & concepts.

Journal: Developmental neurobiology

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Atypical functional connectivity has been implicated in autism spectrum disorders (ASDs). However, the literature to date has been largely inconsistent, with mixed and conflicting reports of hypo- and hyper-connectivity. These discrepancies are partly due to differences between various neuroimaging modalities. Functional magnetic resonance imaging (fMRI), electroencephalography (EEG), and magnetoencephalography (MEG) measure distinct indices of functional connectivity (e.g., blood-oxygenation level-dependent [BOLD] signal vs. electrical activity). Furthermore, each method has unique benefits and disadvantages with respect to spatial and temporal resolution, vulnerability to specific artifacts, and practical implementation. Thus far, functional connectivity research on ASDs has remained almost exclusively unimodal; therefore, interpreting findings across modalities remains a challenge. Multimodal integration of fMRI, EEG, and MEG data is critical in resolving discrepancies in the literature, and working toward a unifying framework for interpreting past and future findings. The current review aims to provide a theoretical foundation for future multimodal research on ASDs. First, we will discuss the merits and shortcomings of several popular theories in ASD functional connectivity research, using examples from the literature to date. Next, the neurophysiological relationships between imaging modalities, including their relationship with invasive neural recordings, will be reviewed. Finally, methodological approaches to multimodal data integration will be presented, and their future application to ASDs will be discussed. Analyses relating transient patterns of neural activity (“states”) are particularly promising. This strategy provides a comparable measure across modalities, captures complex spatiotemporal patterns, and is a natural extension of recent dynamic fMRI research in ASDs. This article is protected by copyright. All rights reserved.

Concepts: Scientific method, Brain, Neuroscience, Magnetic resonance imaging, Electroencephalography, Autism, Functional magnetic resonance imaging, Functional neuroimaging

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Recent research is beginning to shift the focus of our understanding of microglia from passive members of the brain’s immune system to active participants in brain development. Despite these advances, little attention has been paid to one of the most critical components of early brain development- sexual differentiation. Mounting evidence suggests that the normal developmental functions microglia perform- cell number regulation and synaptic connectivity, may be involved in the sex-specific patterning of the brain during these early critical periods, with lasting sex-dependent and sex-independent effects on behavior. In this review, we outline the known functions of microglia during development, and highlight the role they play in the establishment of sex differences in the brain and behavior. Additionally, we propose a framework for how researchers may incorporate microglia in their study of sex differences and vice versa. This article is protected by copyright. All rights reserved.

Concepts: Nervous system, Psychology, Developmental biology, Developmental psychology, Child development, All rights reserved, Copyright, Critical period

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Microglia participate in synapse remodeling in the cortex and hippocampus during mouse postnatal development. Although sex differences in microglia activity during embryonic development have been reported in these regions, it remains unexplored whether microglia show sexually dimorphic features during the early postnatal period, a critical window for synapse formation and maturation. Here, we investigated morphological and functional features of microglia across early postnatal development as well as morphological features of both pre- and postsynaptic neuronal compartments in the mouse hippocampus. We found a sex-dependent shift in microglia volume and phagocytic capacity across the first four postnatal weeks. Measurements of synaptic features revealed sex differences in the density of synaptic spines and boutons during the second postnatal week. These data are consistent with a precocious development of both microglia and synapses in the female brain. We further hypothesize that this bias may contribute to sex-specific brain wiring. This article is protected by copyright. All rights reserved.

Concepts: Neuron, Brain, Male, Sexual dimorphism, Gender, Sex, Synapse, Postnatal

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Long interspersed element-1 (LINE-1 or L1) is a transposable element with the ability to self-mobilize throughout the human genome. The L1 elements found in the human brain is hypothesized to date back 56 million years ago and has survived evolution, currently accounting for 17% of the human genome. L1 retrotransposition has been theorized to contribute to somatic mosaicism. This review focuses on the presence of L1 in the healthy and diseased human brain, such as in autism spectrum disorders (ASD). Throughout this exploration, we will discuss the impact L1 has on neurological disorders that can occur throughout the human lifetime. With this, we hope to better understand the complex role of L1 in the human brain development and its implications to human cognition. This article is protected by copyright. All rights reserved.

Concepts: Nervous system, Genetics, Brain, Evolution, Human Genome Project, Human brain, Autism, Transposon

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Neurons are extremely large and complex cells, and they regulate membrane potentials in multiple subcellular compartments using a variety of ion channels. Voltage-gated sodium (Nav) and potassium (Kv) channels are crucial in regulating neuronal membrane excitability owing to their diversity in subtypes, biophysical properties, and localizations. In particular, specific localizations of Nav and Kv channels in specific membrane compartments are essential to achieve a precise control of local membrane excitability. Recent advancement in super-resolution microscopy further substantiated nano-scale localizations of different ion channels in neuronal membranes. New questions arise from these new lines of evidence regarding how Nav and Kv channels are trafficked to a specific location and maintained against lateral diffusion. In this review, I aim to summarize current information about ion channel localizations at nanoscopic levels and discuss what we can infer regarding the mechanisms. This article is protected by copyright. All rights reserved.

Concepts: Neuron, Action potential, Ion channel, Electrophysiology, Voltage-gated ion channel, Sodium, Potassium, Membrane potential

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In addition to the social, communicative and behavioral symptoms that define the disorder, individuals with ASD have difficulty re-orienting attention quickly and accurately. Similarly, fast re-orienting saccadic eye movements are also inaccurate and more variable in both endpoint and timing. Atypical gaze and attention are among the earliest symptoms observed in ASD. Disruption of these foundation skills critically affects development of higher level cognitive and social behavior. We propose that interventions aimed at these early deficits that support social and cognitive skills will be broadly effective. We conducted a pilot clinical trial designed to demonstrate the feasibility and preliminary efficacy of using gaze-contingent video games for low-cost in-home training of attention and eye movement. Eight adolescents with ASD participated in an 8-week training, with pre-, mid- and post-testing of eye movement and attention control. Six of the eight adolescents completed the 8 weeks of training and all six showed improvement in attention (orienting, disengagement) and eye movement control or both. All game systems remained intact for the duration of training and all participants could use the system independently.

Concepts: Psychology, Clinical trial, Effectiveness, Cognition, Eye, Saccade, Eye movement, Human behavior

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Recent studies have strongly suggested a role for the synaptic scaffolding protein SHANK1 in normal synaptic structure and signaling. Global SHANK1 knockout (SHANK1-/-) mice demonstrate reduced dendritic spine density, an immature dendritic spine phenotype and impairments in various cognitive tasks. SHANK1 overexpression is associated with increased dendritic spine size and impairments in fear conditioning. These studies suggest proper regulation of SHANK1 is crucial for appropriate synaptic structure and cognition. However, little is known regarding SHANK1’s developmental expression in brain regions critical for learning. The current study quantified cell specific developmental expression of SHANK1 in the hippocampus, a brain region critically involved in various learning paradigms shown to be disrupted by SHANK1 dysregulation. Consistent with prior studies, SHANK1 was found to be strongly co-expressed with dendritic markers, with significant increased co-expression at postnatal day (PND) 15, an age associated with increased synaptogenesis in the hippocampus. Interestingly, SHANK1 was also found to be expressed in astrocytes and microglia. To our knowledge, this is the first demonstration of glial SHANK1 localization; therefore, these findings were further examined via a glial purified primary cell culture fraction using magnetic cell sorting. This additional analysis further demonstrated that SHANK1 was expressed in glial cells, supporting our immunofluorescence co-expression findings. Developmentally, astroglial SHANK1 co-expression was found to be significantly elevated at PND 5 with a reduction into adulthood, while SHANK1 microglial co-expression did not significantly change across development. These data collectively implicate a more global role for SHANK1 in mediating normal cellular signaling in the brain. This article is protected by copyright. All rights reserved.

Concepts: Neuron, Gene expression, Brain, Cell biology, Cerebral cortex, Cerebrum, Hippocampus, Dendritic spine

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Autophagy is a lysosomal degradation pathway that is critical to maintaining neuronal homeostasis and viability. Autophagy sequesters damaged and aged cellular components from the intracellular environment, and shuttles these diverse macromolecules to lysosomes for destruction. This active surveillance of the quality of the cytoplasm and organelles is essential in neurons to sustain their long-term functionality and viability. Indeed, defective autophagy is linked to neurodevelopmental abnormalities and neurodegeneration in mammals. Here, we review the mechanisms of autophagy in neurons and functional roles for autophagy in neuronal homeostasis. We focus on the compartment-specific dynamics of autophagy in neurons, and how autophagy might perform non-canonical functions critical for neurons. We suggest the existence of multiple populations of autophagosomes with compartment-specific functions important for neural activity and function. This article is protected by copyright. All rights reserved.

Concepts: Nervous system, Neuron, Cell, Function, Organelle, Lysosome, All rights reserved, Copyright

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Early adverse experiences disrupt brain development and behavior, but little is known about how such experiences impact on the development of the peripheral nervous system. Recently, we found alterations in the electrophysiological and histological characteristics of the sensory sural (SU) nerve in maternally-deprived, artificially-reared (AR) adult male rats, as compared to maternally-reared (MR) control rats. In the present study, our aim was to characterize the ontogeny of these alterations. Thus, male pups of 4 postnatal days (PND) were 1) artificially reared (AR group), 2) artificially reared and received daily tactile stimulation to the body and anogenital region (AR-Tactile group); or 3) reared by their mother (MR group). At PND 7, 14, or 21, electrophysiological properties and histological characteristics of the SU nerves were assessed. At PND 7, the electrophysiological properties and most histological parameters of the SU nerve did not differ among MR, AR and AR-Tactile groups. By contrast, at PND 14 and/or 21, the SU nerve of AR rats showed a lower CAP amplitude and area, and a significant reduction in myelin area and myelin thickness, which were accompanied by a reduction in axon area (day 21 only) compared to the nerves of MR rats. Tactile stimulation (AR-Tactile group) partially prevented most of these alterations. These results suggest that sensory cues from the mother and/or littermates during the first 7-14 PND are relevant for the proper development and function of the adult SU nerve. This article is protected by copyright. All rights reserved.

Concepts: Nervous system, Neuron, Action potential, Neuroscience, Axon, Postnatal, Nerve, Copyright

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During mammalian visual system development, retinal ganglion cells (RGCs) undergo extensive apoptotic death. In mouse retina, approximately 50% of RGCs present at birth (postnatal day 0; P0) die by P5, at a time when axons innervate central targets such as the superior colliculus (SC). We examined whether RGCs that make short-range axonal targeting errors within the contralateral SC are more likely to be eliminated during the peak period of RGC death (P1-P5), compared with RGCs initially making more accurate retinotopic connections. A small volume (2.3nl) of the retrograde nucleophilic dye Hoechst 33342 was injected into the superficial left SC of anaesthetised neonatal C57Bl/6J mice at P1 (n=5) or P4 (n=8), and the contralateral retina wholemounted 12 hours later. Retrogradely labelled healthy and dying (pyknotic) RGCs were identified by morphological criteria and counted. The percentage of pyknotic RGCs was analysed in relation to distance from the area of highest density RGC labelling, presumed to represent the most topographically accurate population. As expected, pyknotic RGC density at P1 was significantly greater than P4 (p<0.05). At P4, the density of healthy RGCs 500-750┬Ám away from the central region was significantly less, although this was not reflected in altered pyknotic rates. However, at P1 there was a trend (p=0.08) for an increased proportion of pyknotic RGCs, specifically in temporal parts of the retina outside the densely labelled centre. Overall, the lack of consistent association between short-range targeting errors and cell death suggests that most postnatal RGC loss is not directly related to topographic accuracy. This article is protected by copyright. All rights reserved.

Concepts: Nervous system, Ganglion, Retina, Photoreceptor cell, Visual system, Retinal ganglion cell, Amacrine cell, Ganglion cell