Organization Of Nervous System Research Articles

Reticulons 1 and 3 are essential for axonal growth and synaptic maintenance associated with intellectual development.

Reticulon (RTN) proteins are a family of proteins biochemically identified for shaping tubular endoplasmic reticulum, a subcellular structure important for vesicular transport and cell-to-cell communication. In our recent study of mice with knockout of both reticulon 1 (Rtn1) and Rtn3, we discovered that Rtn1-/-;Rtn3-/- (brief as R1R3dKO) mice exhibited neonatal lethality, despite the fact that mice deficient in either RTN1 or RTN3 alone exhibit no discernible phenotypes. This has been the first case to find early lethality in animals with deletion of partial members of RTN proteins. The complete penetrance for neonatal lethality can be attributed to multiple defects including the impaired neuromuscular junction found in the diaphragm. We also observed significantly impaired axonal growth in a regional-specific manner, detected by immunohistochemical staining with antibodies to neurofilament light chain and neurofilament medium chain. Ultrastructural examination by electron microscopy revealed a significant reduction in synaptic active zone length in the hippocampus. Mechanistic exploration by unbiased proteomic assays revealed reduction of proteins such as FMR1, Staufen2, Cyfip1, Cullin-4B and PDE2a, which are known components in the fragile X mental retardation pathway. Together, our results reveal that RTN1 and RTN3 are required to orchestrate neurofilament organization and intact synaptic structure of the central nervous system.

Human acute microelectrode array recordings with broad cortical access, single-unit resolution, and parallel behavioral monitoring

There are vast gaps in our understanding of the organization and operation of the human nervous system at the level of individual neurons and their networks. Here, we report reliable and robust acute multichannel recordings using planar microelectrode arrays (MEAs) implanted intracortically in awake brain surgery with open craniotomies that grant access to large parts of the cortical hemisphere. We obtained high-quality extracellular neuronal activity at the microcircuit, local field potential level and at the cellular, single-unit level. Recording from the parietal association cortex, a region rarely explored in human single-unit studies, we demonstrate applications on these complementary spatial scales and describe traveling waves of oscillatory activity as well as single-neuron and neuronal population responses during numerical cognition, including operations with uniquely human number symbols. Intraoperative MEA recordings are practicable and can be scaled up to explore cellular and microcircuit mechanisms of a wide range of human brain functions.

Parallel trajectories in the discovery of the SCN-OVLT and pituitary portal pathways: Legacies of Geoffrey Harris.

A map of central nervous system organization based on vascular networks provides a layer of organization distinct from familiar neural networks or connectomes. As a well-established example, the capillary networks of the pituitary portal system enable a route for small amounts of neurochemical signals to reach local targets by traveling along specialized pathways, thereby avoiding dilution in the systemic circulation. The first evidence of such a pathway in the brain came from anatomical studies identifying a portal pathway linking the hypothalamus and the pituitary gland. Almost a century later, we demonstrated a vascular portal pathway that joined the capillary beds of the suprachiasmatic nucleus and a circumventricular organ, the organum vasculosum of the lamina terminalis, in a mouse brain. For each of these portal pathways, the anatomical findings opened many new lines of inquiry, including the determination of the direction of flow of information, the identity of the signal that flowed along this pathway, and the function of the signals that linked the two regions. Here, we review landmark steps to these discoveries and highlight the experiments that reveal the significance of portal pathways andmore generally, the implications of morphologically distinct nuclei sharing capillary beds.

A blinking focal pattern of re-entrant activity in the avian tectum

Re-entrant connections are inherent to nervous system organization; however, a comprehensive understanding of their operation is still lacking. In birds, topographically organized re-entrant signals, carried by axons from the nucleus-isthmi-parvocellularis (Ipc), are distinctly recorded as bursting discharges across the optic tectum (TeO). Here, we used up to 48 microelectrodes regularly spaced on the superficial tectal layers of anesthetized pigeons to characterize the spatial-temporal pattern of this axonal re-entrant activity in response to different visual stimulation. We found that a brief luminous spot triggered repetitive waves of bursting discharges that, appearing from initial sources, propagated horizontally to areas representing up to 28° of visual space, widely exceeding the area activated by the retinal fibers. In response to visual motion, successive burst waves started along and around the stimulated tectal path, tracking the stimulus in discontinuous steps. When two stimuli were presented, the burst-wave sources alternated between the activated tectal loci, as if only one source could be active at any given time. Because these re-entrant signals boost the retinal input to higher visual areas, their peculiar dynamics mimic a blinking "spotlight," similar to the internal searching mechanism classically used to explain spatial attention. Tectal re-entry from Ipc is thus highly structured and intrinsically discontinuous, and higher tectofugal areas, which lack retinotopic organization, will thus receive incoming visual activity in a sequential and piecemeal fashion. We anticipate that analogous re-entrant patterns, perhaps hidden in less bi-dimensionally organized topographies, may organize the flow of neural activity in other parts of the brain as well.

Serotonin disruption at gestation alters expression of genes associated with serotonin synthesis and reuptake at weaning.

Serotonin (5-HT) is a monoamine neuromodulator that plays a key role in the organization of the central nervous system. 5-HT alterations may be associated to the emergence of social deficits and psychiatric disorders, including anxiety, depression, and substance abuse disorders. Notably, disruption of the 5-HT system during sensitive periods of development seems to exert long-term consequences, including altered anxiety responses and problematic use of alcohol. We analyzed, in mice, the effects of transient 5-HT depletion at gestation (a developmental stage when medial prefrontal cortex (mPFC) 5-HT levels depend exclusively on placental 5-HT availability) on 5-HT central synthesis and reuptake at weaning. We also explored if 5-HT disruption at the embryonic stage influences behavioral outcomes that may serve as a proxy for autistic- or anxiety-like phenotypes. C57/BL6 male and female mice, born from dams treated with a 5-HT synthesis inhibitor (PCPA; 4-Chloro-DL-phenylalanine methyl ester hydrochloride) at gestational days (G)13.5-16.5, were subjected to a behavioral battery that assesses social preference and novelty, compulsive behavior, stereotypies, and ethanol's anti-anxiety effects, at postnatal days (P) 21-28. Afterwards, expression of the genes that encode for 5-HT synthesis (Tph2) and SERT (5-HT transporter) were analyzed in mPFC via real-time RT-PCR. Dopamine 2 receptor (D2R) expression was also analyzed via RT-PCR to further explore possible effects of PCPA on dopaminergic transmission. Transient 5-HT disruption at G13.5-16.5 reduced Tph2 expression of both male and female mice in mPFC at P23. Notably, female mice also exhibited higher SERT expression and reduced D2R expression in mPFC. Mice derived from 5-HT depleted dams displayed heightened compulsive behavior at P21, when compared to control mice. Alcohol anti-anxiety effects at early adolescence (P28) were exhibited by mice derived from 5-HT depleted dams, but not by control counterparts. No social deficits or stereotyped behaviors were observed. Transient 5-HT inhibition at gestation resulted in altered expression of genes involved in 5-HT synthesis and reuptake in mPFC at weaning, a period in which the 5-HT system is still developing. These alterations may exert lingering effects, which translate to significant compulsivity and heightened sensitivity to the anxiolytic effects of alcohol at early adolescence.

Single-cell analyses of axolotl telencephalon organization, neurogenesis, and regeneration.

Salamanders are tetrapod models to study brain organization and regeneration; however, the identity and evolutionary conservation of brain cell types are largely unknown. We delineated the cell populations in the axolotl telencephalon during homeostasis and regeneration using single-cell genomic profiling. We identified glutamatergic neurons with similarities to amniote neurons of hippocampus, dorsal and lateral cortex, and conserved γ-aminobutyric acid-releasing (GABAergic) neuron classes. We inferred transcriptional dynamics and gene regulatory relationships of postembryonic, region-specific neurogenesis and unraveled conserved differentiation signatures. After brain injury, ependymoglia activate an injury-specific state before reestablishing lost neuron populations and axonal connections. Together, our analyses yield insights into the organization, evolution, and regeneration of a tetrapod nervous system.

Aluminium exposure leads to neurodegeneration and alters the expression of marker genes involved to parkinsonism in zebrafish brain

Aluminium, despite being extremely widespread in the world, is a non-essential metal to human metabolism. This metal is known to have toxic effects on a variety of organs including the brain and is considered an etiological factor in neurodegenerative diseases. However, the molecular mechanisms by which aluminium exerts neurotoxic effects are not yet completely understood. Zebrafish is an animal model also used to study neurodegenerative diseases since the overall anatomical organization of the central nervous system is relatively conserved and similar to mammals. Adult zebrafish were exposed to 11 mg/L of Al for 10, 15, and 20 days and the neurotoxic effects of aluminium were analysed by histological, biochemical, and molecular evaluations. Histological stainings allowed to evaluation of the morphology of the brain parenchyma, the alteration of myelin and the activation of neurodegenerative processes. The expression of the Glial Fibrillary Acidic Protein, a marker of glial cells, was evaluated to observe the quantitative alteration of this important protein for the nervous system. In addition, the poly(ADP-ribose) polymerase activity was measured to verify a possible oxidative DNA damage caused by exposure to this metal. Finally, the evaluation of the markers involved in Parkinsonism was assessed by Real-Time PCR to better understand the role of aluminium in the regulation of genes related to Parkinson's neurodegenerative disease. Data showed that aluminium significantly affected the histology of cerebral tissue especially in the first periods of exposure, 10 and 15 days. This trend was also followed by the expression of GFAP. At longer exposure times, there was an improvement/stabilization of the overall neurological conditions and decrease in PARP activity.In addition, aluminium is involved in the deregulation of the expression of genes closely related to Parkinsonism. Overall, the data confirm the neurotoxicity induced by aluminium and shed a light on its involvement in neurodegenerative processes.

Lessons for Robotics From the Control Architecture of the Octopus.

Biological and artificial agents are faced with many of the same computational and mechanical problems, thus strategies evolved in the biological realm can serve as inspiration for robotic development. The octopus in particular represents an attractive model for biologically-inspired robotic design, as has been recognized for the emerging field of soft robotics. Conventional global planning-based approaches to controlling the large number of degrees of freedom in an octopus arm would be computationally intractable. Instead, the octopus appears to exploit a distributed control architecture that enables effective and computationally efficient arm control. Here we will describe the neuroanatomical organization of the octopus peripheral nervous system and discuss how this distributed neural network is specialized for effectively mediating decisions made by the central brain and the continuous actuation of limbs possessing an extremely large number of degrees of freedom. We propose top-down and bottom-up control strategies that we hypothesize the octopus employs in the control of its soft body. We suggest that these strategies can serve as useful elements in the design and development of soft-bodied robotics.

Structural and function organization of intrathoracic extracardiac autonomic projections to the porcine heart: Implications for targeted neuromodulation therapy.

Mapping the structure/function organization of the cardiac nervous system is foundational for implementation of targeted neuromodulation-based therapeutics for the treatment of cardiac disease. The purpose of this study was to define the spatial organization of intrathoracic parasympathetic and sympathetic efferent projections to the heart. Yucatan mini-pigs (N = 11) were anesthetized and the thoracic cavity exposed. Electrical stimulation of the cervical vagi and stellate ganglia was performed individually, and hemodynamic responses were assessed in the intact state and after progressive debranching of each thoracic vagosympathetic trunk (VST). Subsequently, residual cardiac efferent projections arising from paravertebral chain ganglia (T1-T4) were evaluated by stimulation before and after individual ganglionic debranching. Stimulation of the cervical vagi decreased heart rate and contractility while prolonging the activation-recovery interval (ARI). Stimulation of the stellate ganglia increased heart rate and contractility and decreased ARI. The majority of parasympathetic and sympathetic cardiac-evoked responses were mitigated after debranching of the right VST rostral to heart, whereas the left VST demonstrated a distribution with greater dispersion and caudal intrathoracic shift compared to the right. After complete thoracic VST debranching, stimulation of the T4 paravertebral chain ganglia demonstrated residual cardiac sympathetic efferent innervation to the heart in ∼50% of animals. That response was mitigated by transecting medial ganglionic branches. The nexus point for optimum neuromodulation engagement of parasympathetic efferent projections to the heart is the cervical vagus and the T1-T2 paravertebral chain ganglia for sympathetic control. Removal of principal sympathetic efferent projections to heart requires targeting the T1-T4 regions of the paravertebral chain.

Developing a diceCT brain atlas: Comparison of diceCT neuroanatomy and brain histology in a rat model

Significant advancements and refinement of neurological imaging modalities can enable new understanding in nervous system organization. One recent example, diffusible iodine‐based contrast‐enhanced computed tomography (diceCT), is an iodine staining and X‐ray μCT‐imaging technique that allows for the differentiation of myelinated from unmyelinated nervous tissues at finer scales of spatial resolution than standard three‐dimensional (3D) brain‐imaging tools allow. DiceCT is versatile, capable of imaging specimens across several orders of magnitude in size. It enables large and complex structures such as human brains to be studied alongside those of less complex nervous systems (e.g., fish, frogs, rodents, birds). One key feature is that the staining agent can be removed, allowing the subsequent application of acetate, fluorescent, and immunofluorescent histology following diceCT imaging. Nevertheless, the relative novelty of diceCT as a neuroanatomical visualization tool also demands ground‐truthing by determining its practical reliably for distinguishing precise boundaries between brain structures. For example, some adjacent, tissue‐level neuroanatomical features are poorly differentiated due to staining similarity or inherently obscure boundaries (such as the thalamus, which houses many small white‐matter tracts). To address this, we compare 3D orientation‐matched image stacks of diceCT juvenile Sprague Dawley rat brains to the Paxinos and Watson atlas, a gold‐standard rat‐brain reference. Visual identification of brain structures was attempted for all brain regions. Cardinal boundaries for each structure's dorsal, ventral, medial, and lateral edges were scored as distinguishable or non‐distinguishable. Right/left staining asymmetries were also scored. We used this outline to compare and contrast the neuroanatomical structures identified by diceCT with those described by Paxinos and Watson. Preliminary results indicate that 42% of all scored structures were visible via most (e.g., 3–4) of their cardinal boundaries, whereas 25% of atlas structures showed no distinguishable boundaries using diceCT. Overall, diceCT rat‐brain sections align well with standard histological sections, and visibility of neuroanatomical features is similar to tissue‐based, 3D magnetic resonance imaging atlases of comparable resolution.

Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review.

Hedgehog (Hh) signaling is evolutionarily conserved and plays an instructional role in embryonic morphogenesis, organogenesis in various animals, and the central nervous system organization. Multiple feedback mechanisms dynamically regulate this pathway in a spatiotemporal and context-dependent manner to confer differential patterns in cell fate determination. Hh signaling is complex due to canonical and non-canonical mechanisms coordinating cell-cell communication. In addition, studies have demonstrated a regulatory framework of Hh signaling and shown that cholesterol is vital for Hh ligand biogenesis, signal generation, and transduction from the cell surface to intracellular space. Studies have shown the importance of a specific cholesterol pool, termed accessible cholesterol, which serves as a second messenger, conveying signals between smoothened (Smo) and patched 1 (Ptch1) across the plasma and ciliary membranes. Remarkably, recent high-resolution structural and molecular studies shed new light on the interplay between Hh signaling and cholesterol in membrane biology. These studies elucidated novel mechanistic insight into the release and dispersal of cholesterol-anchored Hh and the basis of Hh recognition by Ptch1. Additionally, the putative model of Smo activation by cholesterol binding and/or modification and Ptch1 antagonization of Smo has been explicated. However, the coupling mechanism of Hh signaling and cholesterol offered a new regulatory principle in cell biology: how effector molecules of the Hh signal network react to and remodel cholesterol accessibility in the membrane and selectively activate Hh signaling proteins thereof. Recognizing the biological importance of cholesterol in Hh signaling activation and transduction opens the door for translational research to develop novel therapeutic strategies. This review looks in-depth at canonical and non-canonical Hh signaling and the distinct proposed model of cholesterol-mediated regulation of Hh signaling components, facilitating a more sophisticated understanding of the Hh signal network and cholesterol biology.

Parcellation in the dorsal column nuclei of Florida manatees (Trichechus manatus latirostris) and rock hyraxes (Procavia capensis) indicates the presence of body barrelettes.

Florida manatees (Trichechus manatus latirostris) and rock hyraxes (Procavia capensis) exhibit expanded tactile arrays of vibrissae that are distributed not only on the face but also on the entire postfacial body. In contrast, the vibrissae of most mammals are principally restricted to the face. These facial vibrissae may be associated with central nervous system representations known as barrels in the cerebral cortex, barreloids in the thalamus, and barrelettes in the trigeminal nuclei of the brainstem. To date, vibrissae representations found within the brainstem have been principally limited to facial vibrissae representations in the trigeminal nuclei. We hypothesized that the tactile specializations of the manatee and rock hyrax would produce a unique modification of typical mammalian central nervous system organization, with postfacial vibrissae representations appearing in the cuneate and gracile nuclei as "body barrelettes." Using histological and histochemical methods, including cresyl violet, myelin, and cytochrome oxidase processing, we first delineated the rostral, middle, and caudal zones of the cuneate and gracile nuclei. Within the middle zone, divisions were present, including extensive parcellation in the cluster region, particularly in manatees. These clusters were particularly densely distributed and distinguishable in the presumptive postfacial body representations in the cuneate and gracile nuclei but otherwise shared many attributes with the barrelettes found in the trigeminal nuclei of other species. This study represents the first characterization of postfacial body vibrissae representations, or "body barrelettes," in the brainstem of any species. Previous studies have predominantly focused on facial vibrissae representations, which have served for decades as a model for sensory organization and plasticity. Our results extend what is known about vibrissae representations in the central nervous system to include expansions related to peripheral specializations of the postfacial body. Unusual somatosensory adaptations in the manatee and rock hyrax are highly informative regarding how mammalian brain organization responds to evolutionary pressures on sensory systems.

Development of a mobile low-field MRI scanner

Magnetic resonance imaging (MRI) allows important visualization of the brain and central nervous system anatomy and organization. However, unlike electroencephalography (EEG) or functional near infrared spectroscopy, which can be brought to a patient or study participant, MRI remains a hospital or center-based modality. Low magnetic field strength MRI systems, however, offer the potential to extend beyond these traditional hospital and imaging center boundaries. Here we describe the development of a modified cargo van that incorporates a removable low-field permanent magnet MRI system and demonstrate its proof-of-concept. Using phantom scans and in vivo T2-weighted neuroimaging data, we show no significant differences with respect to geometric distortion, signal-to-noise ratio, or tissue segmentation outcomes in data acquired in the mobile system compared to a similar static system in a laboratory setting. These encouraging results show, for the first time, MRI that can be performed at a participant’s home, community center, school, etc. Breaking traditional barriers of access, this mobile approach may enable imaging of patients and participants who have mobility challenges, live long distances from imaging centers, or are otherwise unable to travel to an imaging center or hospital.

Sensory cells and the organization of the peripheral nervous system of the siboglinid Oligobrachia haakonmosbiensis Smirnov, 2000

BackgroundThe nervous system of siboglinids has been studied mainly in Osedax and some Vestimentifera, while data in Frenulata – one of the four pogonophoran main branches – is still fragmentary. In most of the studies, the focus is almost always on the central nervous system, while the peripheral nervous system has traditionally received little attention. In contrast to other annelids, the structure and diversity of sensory structures in siboglinids are still quite undescribed. Meanwhile, the peripheral nervous system, as well as sensory elements, are extremely evolutionarily labile, and information about their organization is of high importance to understand lifestyles and behavior as well as main trends that lead siboglinids to their peculiar organization.ResultsThe structure of the peripheric nervous system, sensory elements, and neuromuscular relationships of Oligobrachia haakonmosbiensis were studied using both scanning electron and confocal laser microscopy. A significant number of monociliary sensory cells, as well as sensory complexes located diffusely in the epithelium of the whole body were revealed. The latter include the cephalic tentacles, sensory cells accumulations along the dorsal furrow and ciliary band, areas of the openings of the tubiparous glands, and papillae. The oval ciliary spot located on the cephalic lobe at the base of the tentacles can also be regarded as a sensory organ. Most of the detected sensory cells show immunoreactivity to substance P and/or acetylated α-tubulin. FMRFamide- and serotonin-like immunoreactivity are manifested by neurons that mainly innervate tentacles, muscles, body wall epithelium, skin glands, tubiparous glands, and papillae. In the larva of O. haakonmosbiensis, monociliary sensory elements were revealed in the region of the apical organ, along the body, and on the pygidium.ConclusionsThe diversity of sensory structures in O. haakonmosbiensis comprises epidermal solitary sensory cells, sensory spots around tubiparous glands openings, and putative sensory organs such as cephalic tentacles, an oval ciliary spot on the cephalic lobe, the dorsal furrow, and papillae. Sensory structures associated with papillae and tubiparous glands play presumable mechanosensory functions and are associated with regulation of tube building as well as anchorage of the worm inside the tube. Sensory structures of the dorsal furrow are presumably engaged in the regulation of reproductive behavior. An overall low level of morphological differentiation of O. haakonmosbiensis peripheral nervous system is not typical even for annelids with the intraepithelial nervous system. This can be considered as a plesiomorphic feature of its peripheral plexus’s organization, or as evidence for the neotenic origin of Siboglinidae.

Neuroanatomy in a middle Cambrian mollisoniid and the ancestral nervous system organization of chelicerates

Recent years have witnessed a steady increase in reports of fossilized nervous tissues among Cambrian total-group euarthropods, which allow reconstructing the early evolutionary history of these animals. Here, we describe the central nervous system of the stem-group chelicerate Mollisonia symmetrica from the mid-Cambrian Burgess Shale. The fossilized neurological anatomy of M. symmetrica includes optic nerves connected to a pair of lateral eyes, a putative condensed cephalic synganglion, and a metameric ventral nerve cord. Each trunk tergite is associated with a condensed ganglion bearing lateral segmental nerves, and linked by longitudinal connectives. The nervous system is preserved as reflective carbonaceous films underneath the phosphatized digestive tract. Our results suggest that M. symmetrica illustrates the ancestral organization of stem-group Chelicerata before the evolution of the derived neuroanatomical characters observed in Cambrian megacheirans and extant representatives. Our findings reveal a conflict between the phylogenetic signals provided by neuroanatomical and appendicular data, which we interpret as evidence of mosaic evolution in the chelicerate stem-lineage.

Application of Optimization Method for Identifying Human Operator Model Parameters

The development of automation technologies in various fields of human life poses the problem of studying human-machine systems interaction and the influence of human on machine actions. The varied human behavior and the complexity of his central nervous system organization are a disability to his mathematical description. However, despite this, the human operator has efficient properties of trainability, adaptation to task variables, and optimization of system parameters. These properties allow researchers to introduce various assumptions in modeling and use them to identify the human model parameters. The purpose of this paper is to propose an approach to human operator model parameters identification by systems optimization methods. The paper is aimed to obtain a model of the human operator, which acts as a closed-loop feedback controller. The human operator model is taken in the form of the delayed lead-lag filter. Based on the assumption that the human operator optimizes system quality index, employing the optimization procedure to obtain/identify the human operator dynamics. The controlled plant model is assumed to be known and its parameters are fixed. The paper presents the results of the optimization-based identification procedure where the McRuer model in the compensatory control system was used. The proposed algorithm for calculation of the cost function is described mathematically and presented in pseudocode. Its reliability is demonstrated by comparing the numerical values of the human operator model parameters with the experimental results given in the literature.

The Future of Neurotoxicology: A Neuroelectrophysiological Viewpoint.

Neuroelectrophysiology is an old science, dating to the 18th century when electrical activity in nerves was discovered. Such discoveries have led to a variety of neurophysiological techniques, ranging from basic neuroscience to clinical applications. These clinical applications allow assessment of complex neurological functions such as (but not limited to) sensory perception (vision, hearing, somatosensory function), and muscle function. The ability to use similar techniques in both humans and animal models increases the ability to perform mechanistic research to investigate neurological problems. Good animal to human homology of many neurophysiological systems facilitates interpretation of data to provide cause-effect linkages to epidemiological findings. Mechanistic cellular research to screen for toxicity often includes gaps between cellular and whole animal/person neurophysiological changes, preventing understanding of the complete function of the nervous system. Building Adverse Outcome Pathways (AOPs) will allow us to begin to identify brain regions, timelines, neurotransmitters, etc. that may be Key Events (KE) in the Adverse Outcomes (AO). This requires an integrated strategy, from in vitro to in vivo (and hypothesis generation, testing, revision). Scientists need to determine intermediate levels of nervous system organization that are related to an AO and work both upstream and downstream using mechanistic approaches. Possibly more than any other organ, the brain will require networks of pathways/AOPs to allow sufficient predictive accuracy. Advancements in neurobiological techniques should be incorporated into these AOP-base neurotoxicological assessments, including interactions between many regions of the brain simultaneously. Coupled with advancements in optogenetic manipulation, complex functions of the nervous system (such as acquisition, attention, sensory perception, etc.) can be examined in real time. The integration of neurophysiological changes with changes in gene/protein expression can begin to provide the mechanistic underpinnings for biological changes. Establishment of linkages between changes in cellular physiology and those at the level of the AO will allow construction of biological pathways (AOPs) and allow development of higher throughput assays to test for changes to critical physiological circuits. To allow mechanistic/predictive toxicology of the nervous system to be protective of human populations, neuroelectrophysiology has a critical role in our future.

Integrated mRNA-miRNA transcriptome analysis of bladder biopsies from patients with bladder pain syndrome identifies signaling alterations contributing to the disease pathogenesis

BackgroundInterstitial cystitis, or bladder pain syndrome (IC/BPS), is a chronic bladder disorder characterized by lower abdominal pain associated with the urinary bladder and accompanied by urinary frequency and urgency in the absence of identifiable causes. IC/PBS can be separated into the classic Hunner’s ulcerative type and the more prevalent non-ulcerative disease. Our aim was to unravel the biological processes and dysregulated cell signaling pathways leading to the bladder remodeling in non-ulcerative bladder pain syndrome (BPS) by studying the gene expression changes in the patients’ biopsies.MethodsWe performed paired microRNA (miRNA) and mRNA expression profiling in the bladder biopsies of BPS patients with non-Hunner interstitial cystitis phenotype, using comprehensive Next-generation sequencing (NGS) and studied the activated pathways and altered biological processes based on the global gene expression changes. Paired mRNA-miRNA transcriptome analysis delineated the regulatory role of the dysregulated miRNAs by identifying their targets in the disease-induced pathways.ResultsEIF2 Signaling and Regulation of eIF4 and p70S6K Signaling, activated in response to cellular stress, were among the most significantly regulated processes during BPS. Leukotriene Biosynthesis nociceptive pathway, important in inflammatory diseases and neuropathic pain, was also significantly activated. The biological processes identified using Gene Ontology over-representation analysis were clustered into six main functional groups: cell cycle regulation, chemotaxis of immune cells, muscle development, muscle contraction, remodeling of extracellular matrix and peripheral nervous system organization and development. Compared to the Hunner’s ulcerative type IC, activation of the immune pathways was modest in non-ulcerative BPS, limited to neutrophil chemotaxis and IFN-γ-mediated signaling. We identified 62 miRNAs, regulated and abundant in BPS and show that they target the mRNAs implicated in eIF2 signalling pathway.ConclusionsThe bladders of non-ulcerative BPS patients recruited in this study had alterations consistent with a strong cell proliferative response and an up-regulation of smooth muscle contractility, while the contribution of inflammatory processes was modest. Pathway analysis of the integrated mRNA-miRNA NGS dataset pinpointed important regulatory miRNAs whose dysregulation might contribute to the pathogenesis. Observed molecular changes in the peripheral nervous system organization and development indicate the potential role of local bladder innervation in the pain perceived in this type of BPS.

Contemporary concept about organization of central nervous system: human connectome and neural networks

The aim. To systematize contemporary concept about the structural and functional organization of the central nervous system (CNS) and the importance of developing the concept of the human connectome.Main concepts. Signifcant progress in understanding the organization of the CNS in normal and in various pathological conditions was achieved after the introduction of structural and functional neuroimaging methods frst into scientifc and then into clinical practice. Recently, when studying the neuropsychiatric sphere, special attention has been paid to neural networks. One of the achievements in this feld is the construction of the human connectome – a system of structural and functional connections between various cerebral areas, the state of which is assessed using multimodal methods of functional neuroimaging. Thus, the development of brain sciences has reached a completely different level – the level of systemic psychoneurology, when the existing processes are analyzed comprehensively, with the involvement of specialists in various felds – neurology, psychiatry, neuroimaging, mathematics, etc. The human connectome is basically a biological system, therefore, although the analogy with artifcial intelligence can be traced, it does not take the frst place. The functioning of the human connectome is based on the principle of parallel, rather than sequential, information processing. Taking into account the inherent ability of the brain (at least, some of its areas) to generate spontaneous non-rhythmic oscillations, this leads to the implementation of the basic principle of the functioning of the CNS – minimizing energy consumption. In addition, the presence of spontaneous non-rhythmic oscillations (the principle of uncertainty) probably underlies the inherent human ability to intuitively think, develop new ideas. The state of the connectome in a rest is determined by past experience, the duration of external influences, and age. It affects the nature and severity of neuroplastic processes, as well as, in particular, the effectiveness of certain pharmacological drugs in a given individual. At the same time, the fnal result of neuroplastic changes may be of a different nature. It can be favorable for the body (the so-called adaptive plasticity), do not affect the body in any way, or even have a negative result (the so-called maladaptive neuroplasticity). In children, such maladaptive manifestations are less pronounced. Currently, hardware methods of influencing the connectome are being actively studied. For example, it was shown that the structure of the connectome in a rest state can change after transcranial magnetic stimulation. Further studies of this problem will open up new opportunities for studying the activity of such a complexly organized system as the brain – in normal and in various pathological conditions – and to develop more effective methods of neurorehabilitation.

Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development.

Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.