Connections In Central Nervous System Research Articles

On the connectivity in the central nervous system and the age-induced changes of its network organization

Intercellular communication plays a crucial role as the structural substrate for the brain functions. It occurs according to two main processes, namely wiring transmission, i.e. the transmission of signals through physical contacts between cells, and volume transmission, i.e. the chemical signal diffusion along the interstitial fluid pathways. Intercellular communication represents the main rationale for the emerging field of connectomics, defined as the comprehensive study of all aspects of central nervous system connectivity, aimed at creating a comprehensive map (connectome) of the cellular networks in the brain to better understand brain functions. A consensus exists that the brain connectome structure follows a hierarchical or nested architecture, and macro-, meso- and microscales have been defined. Available data on network organization at these different miniaturization levels will be here briefly reviewed. The connectome, however, is also a dynamical entity, undergoing changes during lifetime. Thus, a specific focus will be maintained on the changes the network organization undergoes during normal aging.

Xenpozyme: the first spellbound therapy

Xenpozyme: the first spellbound therapy

Deficits in Auditory Rhythm Perception in Children With Auditory Processing Disorder Are Unrelated to Attention.

Auditory processing disorder (APD) is defined as a specific deficit in the processing of auditory information along the central auditory nervous system, including bottom-up and top-down neural connectivity. Even though music comprises a big part of audition, testing music perception in APD population has not yet gained wide attention in research. This work tests the hypothesis that deficits in rhythm perception occur in a group of subjects with APD. The primary focus of this study is to measure perception of a simple auditory rhythm, i.e., short isochronous sequences of beats, in APD children and to compare their performance to age-matched normal controls. The secondary question is to study the relationship between cognition and auditory processing of rhythm perception. We tested 39 APD children and 25 control children aged between 6 and 12 years via (a) clinical APD tests, including a monaural speech in noise test, (b) isochrony task, a test measuring the detection of small deviations from perfect isochrony in a isochronous beats sequence, and (c) two cognitive tests (auditory memory and auditory attention). APD children scored worse in isochrony task compared to the age-matched control group. In the APD group, neither measure of cognition (attention nor memory) correlated with performance in isochrony task. Left (but not right) speech in noise performance correlated with performance in isochrony task. In the control group a large correlation (r = −0.701, p = 0.001) was observed between isochrony task and attention, but not with memory. The results demonstrate a deficit in the perception of regularly timed sequences in APD that is relevant to the perception of speech in noise, a ubiquitous complaint in this condition. Our results suggest (a) the existence of a non-attention related rhythm perception deficit in APD children and (b) differential effects of attention on task performance in normal vs. APD children. The potential beneficial use of music/rhythm training for rehabilitation purposes in APD children would need to be explored.

Age attenuates noise and increases symmetry of head movements during sleep resting-state fMRI in healthy neonates, infants, and toddlers

Newborns produce spontaneous movements during sleep that are functionally important for their future development. This nuance has been previously studied using animal models and more recently using movement data from sleep resting-state fMRI (rs-fMRI) scans. Age-related trajectory of statistical features of spontaneous movements of the head is under-examined. This study quantitatively mapped a developmental trajectory of spontaneous head movements during an rs-fMRI scan acquired during natural sleep in 91 datasets from healthy children from ∼birth to 3 years old, using the Open Science Infancy Research upcycling protocol. The youngest participants studied, 2–3 week-old neonates, showed increased noise-to-signal levels as well as lower symmetry features of their movements; noise-to-signal levels were attenuated and symmetry was increased in the older infants and toddlers (all Spearman's rank-order correlations, P < 0.05). Thus, statistical features of spontaneous head movements become more symmetrical and less noisy from birth to ∼3 years in children. Because spontaneous movements during sleep in early life may trigger new neuronal activity in the cortex, the key outstanding question for in vivo, non-invasive neuroimaging studies in young children is not “How can we correct head movement better?” but rather: How can we represent all important sources of neuronal activity that shape functional connections in the still-developing human central nervous system?

Hypoxia and connectivity in the developing vertebrate nervous system.

ABSTRACTThe developing nervous system depends upon precise regulation of oxygen levels. Hypoxia, the condition of low oxygen concentration, can interrupt developmental sequences and cause a range of molecular, cellular and neuronal changes and injuries. The roles and effects of hypoxia on the central nervous system (CNS) are poorly characterized, even though hypoxia is simultaneously a normal component of development, a potentially abnormal environmental stressor in some settings, and a clinically important complication, for example of prematurity. Work over the past decade has revealed that hypoxia causes specific disruptions in the development of CNS connectivity, altering axon pathfinding and synapse development. The goals of this article are to review hypoxia's effects on the development of CNS connectivity, including its genetic and molecular mediators, and the changes it causes in CNS circuitry and function due to regulated as well as unintended mechanisms. The transcription factor HIF1α is the central mediator of the CNS response to hypoxia (as it is elsewhere in the body), but hypoxia also causes a dysregulation of gene expression. Animals appear to have evolved genetic and molecular responses to hypoxia that result in functional behavioral alterations to adapt to the changes in oxygen concentration during CNS development. Understanding the molecular pathways underlying both the normal and abnormal effects of hypoxia on CNS connectivity may reveal novel insights into common neurodevelopmental disorders. In addition, this Review explores the current gaps in knowledge, and suggests important areas for future studies.

New dimensions of connectomics and network plasticity in the central nervous system.

Cellular network architecture plays a crucial role as the structural substrate for the brain functions. Therefore, it represents the main rationale for the emerging field of connectomics, defined as the comprehensive study of all aspects of central nervous system connectivity. Accordingly, in the present paper the main emphasis will be on the communication processes in the brain, namely wiring transmission (WT), i.e. the mapping of the communication channels made by cell components such as axons and synapses, and volume transmission (VT), i.e. the chemical signal diffusion along the interstitial brain fluid pathways. Considering both processes can further expand the connectomics concept, since both WT-connectomics and VT-connectomics contribute to the structure of the brain connectome. A consensus exists that such a structure follows a hierarchical or nested architecture, and macro-, meso- and microscales have been defined. In this respect, however, several lines of evidence indicate that a nanoscale (nano-connectomics) should also be considered to capture direct protein-protein allosteric interactions such as those occurring, for example, in receptor-receptor interactions at the plasma membrane level. In addition, emerging evidence points to novel mechanisms likely playing a significant role in the modulation of intercellular connectivity, increasing the plasticity of the system and adding complexity to its structure. In particular, the roamer type of VT (i.e. the intercellular transfer of RNA, proteins and receptors by extracellular vesicles) will be discussed since it allowed us to introduce a new concept of 'transient changes of cell phenotype', that is the transient acquisition of new signal release capabilities and/or new recognition/decoding apparatuses.

Mesoscopic model of neuronal system deficits in Multiple Sclerosis

Multiple Sclerosis (MS) is a devastating autoimmune disease which deteriorates the connections in central nervous system (CNS) through the attacks to oligodendrocytes. Studying its origin and progression, in addition to clinical developments such as MRI brain images, cerebrospinal fluid (CSF) variation and quantitative measures of disability (EDSS), which sought to early diagnosis and efficient therapy, there is an increasing interest in developing computational models using the experimental data obtained from MS patients. From the perspective of mathematical modelling, although the origin of systemic symptoms might be attributed to cellular phenomena in microscopic level such as axonal demyelination, symptoms mainly are observed in macroscopic levels. How to fill the gap between these two levels of system modelling, however, remains as a challenge in systems biology studies. Trying to provide a conceptual framework to bridge between these two levels of modelling in systems biology, we have suggested a mesoscopic model composed of interacting neuronal population, which successfully replicates the changes in neuronal population synchrony due to MS progression.

Temporal Dysynchrony in brain connectivity gene expression following hypoxia

BackgroundDespite the fundamental biological importance and clinical relevance of characterizing the effects of chronic hypoxia exposure on central nervous system (CNS) development, the changes in gene expression from hypoxia are unknown. It is not known if there are unifying principles, properties, or logic in the response of the developing CNS to hypoxic exposure. Here, we use the small vertebrate zebrafish (Danio rerio) to study the effects of hypoxia on connectivity gene expression across development. We perform transcriptional profiling at high temporal resolution to systematically determine and then experimentally validate the response of CNS connectivity genes to hypoxia exposure.ResultsWe characterized mRNA changes during development, comparing the effects of chronic hypoxia exposure at different time-points. We focused on changes in expression levels of a subset of 1270 genes selected for their roles in development of CNS connectivity, including axon pathfinding and synapse formation. We found that the majority of CNS connectivity genes were unaffected by hypoxia. However, for a small subset of genes hypoxia significantly affected their gene expression profiles. In particular, hypoxia appeared to affect both the timing and levels of expression, including altering expression of interacting gene pairs in a fashion that would potentially disrupt normal function.ConclusionsOverall, our study identifies the response of CNS connectivity genes to hypoxia exposure during development. While for most genes hypoxia did not significantly affect expression, for a subset of genes hypoxia changed both levels and timing of expression. Importantly, we identified that some genes with interacting proteins, for example receptor/ligand pairs, had dissimilar responses to hypoxia that would be expected to interfere with their function. The observed dysynchrony of gene expression could impair the development of normal CNS connectivity maps.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2638-x) contains supplementary material, which is available to authorized users.

The role of central nervous system connections in POTS and pediatric FGID

The role of central nervous system connections in POTS and pediatric FGID

Feeling Threatened? Get Some Rest

Sleep deprivation may affect the assessment of threat and alter the central and peripheral nervous system connections that underlie threat assessment.

RAFting the rapids of axon regeneration signaling.

The functional regeneration of damaged axons and severed connections in the mature central nervous system (CNS) remains a challenging goal of neurological research. Mature CNS neurons are refractory to axon regeneration for two major reasons, one, because the activity of cell-intrinsic mechanisms that drive axon growth during development is low – and often further suppressed after an injury – and two, because certain molecules that are part of mature extracellular matrix and myelin act as strong inhibitors of axon growth. Genetic removal of growth inhibitory molecules can increase axon sprouting, but is not sufficient to enable long-range axon growth. Since axon growth is robust during early developmental stages, it has long been hypothesized that mature injured neurons may be “reprogrammed” to the earlier growth state by re-activation of the intracellular growth signaling cascades that drive axon elongation in the developing fetus.

Homeostatic control of presynaptic neurotransmitter release.

It is well established that the active properties of nerve and muscle cells are stabilized by homeostatic signaling systems. In organisms ranging from Drosophila to humans, neurons restore baseline function in the continued presence of destabilizing perturbations by rebalancing ion channel expression, modifying neurotransmitter receptor surface expression and trafficking, and modulating neurotransmitter release. This review focuses on the homeostatic modulation of presynaptic neurotransmitter release, termed presynaptic homeostasis. First, we highlight criteria that can be used to define a process as being under homeostatic control. Next, we review the remarkable conservation of presynaptic homeostasis at the Drosophila, mouse, and human neuromuscular junctions and emerging parallels at synaptic connections in the mammalian central nervous system. We then highlight recent progress identifying cellular and molecular mechanisms. We conclude by reviewing emerging parallels between the mechanisms of homeostatic signaling and genetic links to neurological disease.

Use of Diffusion Tensor Imaging in the Resection of Gliomas

Standard magnetic resonance imaging techniques provide only anatomic information without information regarding central nervous system connectivity. Overcoming this limitation, diffusion tensor imaging (DTI) can demonstrate the structural integrity and white matter tracts of the brain. In this paper, we will overview the basic principles and techniques of DTI. We will also review the application of DTI in neurosurgery, particularly its application in the resection of gliomas. Tractography provides visualization of the motor tracts and language tracts, which has been corroborated using subcortical mapping/direct stimulation. Furthermore, DTI can also provide information about the arrangement of visual fibers in relation to tumors. Given these advantages, DTI is becoming increasingly used as a surgical planning tool. DTI may provide a safer means for tumor resection by minimizing iatrogenic injury of important functional tracts. Some studies suggest that the use of DTI in tumor surgery may lead to greater Karnofsky performance status scores, greater extent of tumor resection, and increased overall survival.

Central and peripheral monosynaptic, polysynaptic and collaterals connectivity in the rat

Central and peripheral monosynaptic, polysynaptic and collaterals connectivity in the rat

Modeling of interstitial branching of axonal networks

A mathematical model is developed to describe and investigate interstitial branching of axonal networks during nervous system development. The model under consideration describes axonal network growth in which the concentration of axon guidance molecules controls axon's growth and interstitial branching from axon shaft. Numerical simulations show that in the model framework axonal networks branch similarly to real neural networks in vitro.

Evidence for a physical component to the radiation-induced bystander effect?

Purpose: The nature of the transferrable factor which goes from irradiated objects to bystander objects remains undefined. Most agree that a chemical entity is the likely ‘factor’ although some authors have produced in vitro evidence for the involvement of a physical component or a very potent volatile capable of traveling through air distances. In this paper we test the hypothesis that the communicated signal may be physical at least in part.Methods: The in vivo fish model was used to allow signal production and response to occur in organisms in vivo without any shared blood or central nervous system (CNS) connections. A reporter assay and calcium flux measurements were used to detect signal production when irradiated fish were separated from unirradiated fish by (a) a plastic container, and (b) a foil-wrapped plastic container.Results: The unirradiated fish showed bystander effects in both cases. The use of foil excludes the possibility of a light signal and although a highly active volatile could travel from one tank to another, the arrangement of sham and irradiated tanks makes it highly unlikely that this could explain our result.Conclusion: We conclude that there must be a physical component in the mechanism such as a weak acoustic or electromagnetic signal.

Distinct roles of neuroligin-1 and SynCAM1 in synapse formation and function in primary hippocampal neuronal cultures

Neuroligins are a family of cell adhesion molecules critical in establishing proper central nervous system connectivity; disruption of neuroligin signaling in vivo precipitates a broad range of cognitive deficits. Despite considerable recent progress, the specific synaptic function of neuroligin-1 (NL1) remains unclear. A current model proposes that NL1 acts exclusively to mature pre-existent synaptic connections in an activity-dependent manner. A second element of this activity-dependent maturation model is that an alternate molecule acts upstream of NL1 to initiate synaptic connections. SynCAM1 (SC1) is hypothesized to function in this capacity, though several uncertainties remain regarding SC1 function. Using overexpression and chronic pharmacological blockade of synaptic activity, we now demonstrate that NL1 is capable of robustly recruiting synapsin-positive terminals independent of synaptic maturation and activity in 2-week old primary hippocampal neuronal cultures. We further report that neither SC1 overexpression nor knockdown of endogenous SC1 impacts synapsin punctum densities, suggesting that SC1 is not a limiting factor of synapse initiation in maturing hippocampal neurons in vitro. Consistent with these findings, we observed profoundly greater recruitment of synapsin-positive presynaptic terminals by NL1 than SC1 in a mixed-culture assay of artificial synaptogenesis between primary neurons and heterologous cells. Collectively, our results contend multiple aspects of the proposed model of NL1 and SC1 function and motivate an alternative model whereby SC1 may mature synaptic connections forged by NL1. Supporting this model, we present evidence that combined NL1 and SC1 overexpression triggers excitotoxic neurodegeneration through SC1 signaling at synaptic connections initiated by NL1.

New Challenges in CNS Repair: The Immune and Nervous Connection

The Central Nervous System (CNS) is the organ with the least capacity for repair in mammals. Diseases of the CNS may follow developmental deficits, inappropriate environmental factors and acquired damages after maturation. The latter damages may consist of neuronal cell death, like Alzheimers disease and/or to a lesion of the axon, like in the paraplegic patients. Hopes of obtaining a functional recovery after trauma or neurodegeneration, are very low and clinicians have very low possibilities for therapeutic interventions. The causes of the regenerative block in the adult CNS are only partially attributable to the neural component. Direct or indirect interactions with glial cells, the resident CNS immune cells, and with the extracellular matrix play a crucial role in determining the relative inability of adult CNS connections to be modified: adult neurites find themselves within an environment rich in molecules strongly inhibitory for regrowth and sprouting. A further complication arises from the fact that regenerative processes are always accompanied by an inflammatory reaction with the consequent activation of astrocytes and microglia; this activation alters the properties of the extracellular milieu. Thus, research on post lesional plasticity must not only study the molecular mechanisms active in neurons but also consider the role of glial cells and the extracellular environment. Keywords: Axon regeneration, myelination, neuron survival, neuronal growth factors, Central Nervous System, neurological medicine, Neurodegenerative disease, oligodendrocytes, cerebellar pathology

Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders

Although the brain has classically been considered “immune-privileged”, current research suggests an extensive communication between the immune and nervous systems in both health and disease. Recent studies demonstrate that immune molecules are present at the right place and time to modulate the development and function of the healthy and diseased central nervous system (CNS). Indeed, immune molecules play integral roles in the CNS throughout neural development, including affecting neurogenesis, neuronal migration, axon guidance, synapse formation, activity-dependent refinement of circuits, and synaptic plasticity. Moreover, the roles of individual immune molecules in the nervous system may change over development. This review focuses on the effects of immune molecules on neuronal connections in the mammalian central nervous system – specifically the roles for MHCI and its receptors, complement, and cytokines on the function, refinement, and plasticity of geniculate, cortical and hippocampal synapses, and their relationship to neurodevelopmental disorders. These functions for immune molecules during neural development suggest that they could also mediate pathological responses to chronic elevations of cytokines in neurodevelopmental disorders, including autism spectrum disorders (ASD) and schizophrenia.

A novel decalcification method for adult rodent bone for histological analysis of peripheral–central nervous system connections

Histological analysis of bone encased tissue is severely hampered by technical difficulties associated with sectioning calcified tissue. Cryosectioning of bone is possible but requires significant technical adaptation and expensive materials and is often time-consuming. Some decalcifying reagents in common use result in successful cryosectioning in less time but the integrity of the soft tissue of the spinal column is often compromised during processing. This can result in significant loss of cellular detail. In order to find a method that would allow cryosectioning of the bone without loss of structural integrity of the underlying soft tissue we assessed the efficacy of four different decalcifying reagents with respect to their effects on the cellular structure of the myelin of the grey and white matter of the spinal cord. The antigenic integrity of the spinal cord white matter was evaluated using tissue structural integrity and quality of myelin basic protein immunostaining. The result of this research shows that 6% TCA not only decalcifies intact spinal column suitably for cryosectioning but does so without compromising the antigenic integrity of the tissue. The ease of application, speed of processing and a favorable cost-effective profile were secondary benefits noted with the use of the 6% TCA decalcifying solution. The ability to utilize a decalcifying solution that allows for both histomorphometry and immunohistochemistry in the same spinal column segment represents a novel technique that will provide new insights into pathophysiological aspects and therapeutic approaches ispinal cord damage or disease.