Mathematical modelling and numerical simulation of the morphological development of neurons

Background

The morphological development of neurons is a very complex process involving both genetic and environmental components. Mathematical modelling and numerical simulation are valuable tools in helping us unravel particular aspects of how individual neurons grow their characteristic morphologies and eventually form appropriate networks with each other.

Methods

A variety of mathematical models that consider (1) neurite initiation (2) neurite elongation (3) axon pathfinding, and (4) neurite branching and dendritic shape formation are reviewed. The different mathematical techniques employed are also described.

Results

Some comparison of modelling results with experimental data is made. A critique of different modelling techniques is given, leading to a proposal for a unified modelling environment for models of neuronal development.

Conclusion

A unified mathematical and numerical simulation framework should lead to an expansion of work on models of neuronal development, as has occurred with compartmental models of neuronal electrical activity.

     

A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep

Background

Peptidergic neurons containing the melanin-concentrating hormone (MCH) and the hypocretins (or orexins) are intermingled in the zona incerta, perifornical nucleus and lateral hypothalamic area. Both types of neurons have been implicated in the integrated regulation of energy homeostasis and body weight. Hypocretin neurons have also been involved in sleep-wake regulation and narcolepsy. We therefore sought to determine whether hypocretin and MCH neurons express Fos in association with enhanced paradoxical sleep (PS or REM sleep) during the rebound following PS deprivation. Next, we compared the effect of MCH and NaCl intracerebroventricular (ICV) administrations on sleep stage quantities to further determine whether MCH neurons play an active role in PS regulation.

Results

Here we show that the MCH but not the hypocretin neurons are strongly active during PS, evidenced through combined hypocretin, MCH, and Fos immunostainings in three groups of rats (PS Control, PS Deprived and PS Recovery rats). Further, we show that ICV administration of MCH induces a dose-dependant increase in PS (up to 200%) and slow wave sleep (up to 70%) quantities.

Conclusion

These results indicate that MCH is a powerful hypnogenic factor. MCH neurons might play a key role in the state of PS via their widespread projections in the central nervous system.

     

Glycine receptors expression in rat spinal cord and dorsal root ganglion in prostaglandin E2 intrathecal injection models

Background

Glycine receptors (GlyRs) are involved in the development of spinal pain sensitization. The GlyRα3 subunit has recently emerged as a key factor in inflammatory pain pathways in the spinal cord dorsal horn (DH). Our study is to identify the extent of location and cell types expressing different GlyR subunits in spinal cord and dorsal root ganglion (DRGs). To tease out the possible actions of GlyRs on pain transmission, we investigate the effects produced by GlyRs on acute inflammatory pain by behavioral testing using prostaglandin E2 (PGE2) intrathecal injection models. Furthermore, we investigate the changes of GlyR expression in DRGs and spinal cord in rats after the induction of acute inflammatory pain.

Results

Compared to the vehicle administration, the PGE2 intrathecal injection model produced significantly higher hyperalgesia, which started 3 h after PGE2 injection and lasted more than 5 h. PGE2 intrathecal injection significantly decreased GlyRα1 and GlyRα3 protein expressions in the L5 DH at 1 h and lasted to 5 h, and similar results were observed in the L5 DRG at 5 h. Confocal microscopic images showed the co-existence of punctate gephyrin and GlyRα3 immunoreactivity (IR) throughout the gray matter of the spinal cord, mainly in DH laminae I–III neurons and in ventral horn neurons. It also showed the co-existence of punctate gephyrin and GlyRα3 IR in DRG neurons.

Conclusions

In this study, PGE2 intrathecal injection significantly decreased protein expression of gephyrin, GlyRα1 and GlyRα3 in spinal cord DH and DRG. The gephyrin and GlyRα3 were localized on neuron cells both in the DH and DRG.

     

Anatomical location of Macrophage Migration Inhibitory Factor in urogenital tissues,peripheral ganglia and lumbosacral spinal cord of the rat

Background

Previous work suggested that macrophage migration inhibitory factor (MIF) may be involved in bladder inflammation. Therefore, the location of MIF was determined immunohistochemically in the bladder, prostate, major pelvic ganglia, sympathetic chain, the L6-S1 dorsal root ganglia (DRG) and the lumbosacral spinal cord of the rat.

Results

In the pelvic organs, MIF immunostaining was prominent in the epithelia. MIF was widely present in neurons in the MPG and the sympathetic chain. Some of those neurons also co-localized tyrosine hydroxylase (TH). In the DRGs, some of the neurons that stained for MIF also stained for Substance P. In the lumbosacral spinal cord, MIF immunostaining was observed in the white mater, the dorsal horn, the intermediolateral region and in the area around the central canal. Many cells were intensely stained for MIF and glial fibrillary acidic protein (GFAP) suggesting they were glial cells. However, some cells in the lumbosacral dorsal horn were MIF positive, GFAP negative cells suggestive of neurons.

Conclusions

Therefore, MIF, a pro-inflammatory cytokine, is localized to pelvic organs and also in neurons of the peripheral and central nervous tissues that innervate those organs. Changes in MIF's expression at the end organ and at peripheral and central nervous system sites suggest that MIF is involved in pelvic viscera inflammation and may act at several levels to promote inflammatory changes.

     

Relationship between central and peripheral corneal astigmatism in elderly patients

Purpose

We investigated the relationship between central and peripheral corneal astigmatism in elderly patients.

Methods

Seventy-six eyes of 76 elderly subjects (mean age?=?72.6?±?3.0 years) were included in the study. Corneal shape was evaluated using the Pentacam HR (Oculus, Wetzlark, Germany), which is comprised of a rotating Scheimpflug camera and a short-wavelength slit light. The power distribution map was selected and corneal astigmatism was calculated using front K-Readings in zones centered on the pupil. Analyzed zones were 2.0–6.0 mm in diameter.

Results

Corneal astigmatism decreased as diameter increased, similar to what was observed in eyes with with-the-rule astigmatism and against-the-rule astigmatism (ANOVA, p?<?0.01). This effect was more pronounced in eyes with a large central corneal astigmatism (Spearman’s rank-correlation coefficient test, r?=?0.51, p?<?0.01). There was no change as to axis of corneal astigmatism (ANOVA, p?=?0.98).

Conclusion

These results suggest that the relationship between central and peripheral corneal astigmatism should be taken into consideration to optimize vision when astigmatic correction is needed.

     

The significance of anti-neuronal antibodies for acute psychiatric disorders: a retrospective case–controlled study

Background

The clinical significance of anti-neuronal antibodies in patients with psychiatric disorders, but without encephalitis, remains unknown. In patients admitted to acute psychiatric inpatient care we aimed to identify clinical features distinguishing anti-neuronal antibody positive patients from matched controls.

Results

Patients who were serum-positive to N-methyl d-aspartate receptor (NMDAR) (n?=?21), contactin-associated protein 2 (CASPR2) (n?=?14) and/or glutamic acid decarboxylase 65 (GAD65) (n?=?9) antibodies (cases) were age and sex matched (1:2) with serum-negative patients from the same cohort (controls). The prevalence and severity of psychiatric symptoms frequently encountered in NMDAR, CASPR2 and GAD65 antibody associated disorders were compared in cases and controls. NMDAR, CASPR2 and GAD65 antibody positive patients did not differ in their clinical presentation from matched serum negative controls.

Conclusion

In this cohort, patients with and without NMDAR, CASPR2 and GAD65 antibodies admitted to acute psychiatric inpatient care had similar psychiatric phenotypes. This does not exclude their clinical relevance in subgroups of patients, and studies further investigating the clinical significance of anti-neuronal antibodies in patients with psychiatric symptomatology are needed.

     

<Emphasis Type="Italic">parkin</Emphasis> counteracts symptoms in a <Emphasis Type="Italic">Drosophila</Emphasis> model of Parkinson's disease

Background

Parkinson's disease, a prevalent neurodegenerative disease, is characterized by the reduction of dopaminergic neurons resulting in the loss of motor control, resting tremor, the formation of neuronal inclusions and ultimately premature death. Two inherited forms of PD have been linked to mutations in the α-synuclein and parkin genes. The parkin protein functions as an ubiquitin ligase targeting specific proteins for degradation. Expression of human α-synuclein in Drosophila neurons recapitulates the loss of motor control, the development of neuronal inclusions, degeneration of dopaminergic neurons and the ommatidial array to provide an excellent genetic model of PD.

Results

To investigate the role of parkin, we have generated transgenic Drosophila that conditionally express parkin under the control of the yeast UAS enhancer. While expression of parkin has little consequence, co-expression of parkin with α-synuclein in the dopaminergic neurons suppresses the α-synuclein-induced premature loss of climbing ability. In addition directed expression of parkin in the eye counteracts the α-synuclein-induced degeneration of the ommatidial array. These results show that parkin suppresses the PD-like symptoms observed in the α-synuclein-dependent Drosophila model of PD.

Conclusion

The highly conserved parkin E3 ubiquitin ligase can suppress the damaging effects of human α-synuclein. These results are consistent with a role for parkin in targeting α-synuclein to the proteasome. If this relationship is conserved in humans, this suggests that up-regulation of parkin should suppress α-synucleinopathic PD. The development of therapies that regulate parkin activity may be crucial in the treatment of PD.

     

Effect of visual target blurring on accommodation under distance viewing

Purpose

To examine the effect of visual target blurring on accommodation.

Methods

We evaluated the objective refraction values when the visual target (asterisk; 8°) was changed from the state without Gaussian blur (15 s) to the state with Gaussian blur adapted [0(without blur)?→?10, 0?→?50, 0?→?100: 15 s each].

Results

In Gaussian blur 10, when blurring of the target occurred, refraction value did not change significantly. In Gaussian blur 50 and 100, when blurring of the target occurred, the refraction value became significantly myopic.

Conclusion

Blurring of the distant visual target results in intervention of accommodation.

     

Directed neuronal differentiation of human embryonic stem cells

Background

We have developed a culture system for the efficient and directed differentiation of human embryonic stem cells (HESCs) to neural precursors and neurons.HESC were maintained by manual passaging and were differentiated to a morphologically distinct OCT-4⁺/SSEA-4^- monolayer cell type prior to the derivation of embryoid bodies. Embryoid bodies were grown in suspension in serum free conditions, in the presence of 50% conditioned medium from the human hepatocarcinoma cell line HepG2 (MedII).

Results

A neural precursor population was observed within HESC derived serum free embryoid bodies cultured in MedII conditioned medium, around 7–10 days after derivation. The neural precursors were organized into rosettes comprised of a central cavity surrounded by ring of cells, 4 to 8 cells in width. The central cells within rosettes were proliferating, as indicated by the presence of condensed mitotic chromosomes and by phosphoHistone H3 immunostaining. When plated and maintained in adherent culture, the rosettes of neural precursors were surrounded by large interwoven networks of neurites. Immunostaining demonstrated the expression of nestin in rosettes and associated non-neuronal cell types, and a radial expression of Map-2 in rosettes. Differentiated neurons expressed the markers Map-2 and Neurofilament H, and a subpopulation of the neurons expressed tyrosine hydroxylase, a marker for dopaminergic neurons.

Conclusion

This novel directed differentiation approach led to the efficient derivation of neuronal cultures from HESCs, including the differentiation of tyrosine hydroxylase expressing neurons. HESC were morphologically differentiated to a monolayer OCT-4⁺ cell type, which was used to derive embryoid bodies directly into serum free conditions. Exposure to the MedII conditioned medium enhanced the derivation of neural precursors, the first example of the effect of this conditioned medium on HESC.

     

Blockade of NMDA receptor subtype NR2B prevents seizures but not apoptosis of dentate gyrus neurons in bacterial meningitis in infant rats

Background

Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 μl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus.

Results

Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16–25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60–31.8]; (P = NS) and 9.8 [1.7–27.3] (controls: 10.5 [2.4–21.75]) in animals treated with high dose RO 25-6981 (P = NS).

Conclusions

Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.

     

Power-law for axon diameters at branch point

Background

Axon calibers vary widely among different animals, neuron classes, and even within the same neuron. What determines the diameter of axon branches?

Results

We pursue the hypothesis that the axon caliber has evolved to minimize signal propagation delays, while keeping arbor volume to a minimum. For a general cost function, we show that the optimal diameters of mother and daughter branches at a bifurcation satisfy a power law. The derivation relies on the fact that the axon conduction speed scales as a power of axon diameter. Although available data are consistent with the law, there is a large spread in the data. Future experimental tests will determine whether this spread is due to biological variability or measurement error.

Conclusions

Minimization of arbor volume and signal propagation delay may have been an important factor in the evolution of the brain.

     

Relationship between corneal and ocular higher order wavefront aberrations and age in children

Purpose

To evaluate the relationship between corneal and ocular higher order wavefront aberrations (HOAs) and age in young subjects aged 20 years or less.

Methods

Corneal and ocular HOAs of the right eyes of 87 normal subjects were measured using videokeratography and the Hartmann–Shack wavefront aberrometer (KR-9000PW; Topcon Corp., Tokyo, Japan). The HOAs were calculated using Zernike polynomials up to the sixth order. From the Zernike coefficients, the root mean squares (RMS) of coma and spherical aberration were calculated.

Results

Corneal spherical-like aberrations significantly correlated with age (r = 0.420, p < 0.001); however, coma-like aberrations and total HOAs did not significantly correlate with age. None of the ocular HOAs significantly correlated with age. In addition, a gender-wise comparison of the collected data showed that corneal and ocular HOAs did not significantly correlate with age.

Conclusion

In children, the corneal and ocular total HOAs did not vary with age. Compared to the previous reports in adults, we found fewer corneal and ocular HOAs in children.

     

Riboflavin and pyridoxine restore dopamine levels and reduce oxidative stress in brain of rats

Background

Neurological disorders suggest that the excitotoxicity involves a drastic increase in intracellular Ca²⁺ concentrations and the formation of reactive oxygen species. The presence of these free radicals may also affect the dopaminergic system. The aim of this work was to determine if riboflavin (B₂) and pyridoxine (B₆) provide protection to the brain against free radicals generated by 3-nitropropionic acid (3-NPA) by measuring the levels of dopamine (DA) and selected oxidative stress markers.

Methods

Male Fisher rats were grouped (n?=?6) and treated as follows: group 1, control (NaCl 0.9%); group 2, 3-NPA (20 mg/kg); group 3, B₂ (10 mg/kg); group 4, B₂ (10 mg/kg)?+?3-NPA (20 mg/kg); group 5, B₆ (10 mg/kg) and group 6, B₆?+?3-NPA. All treatments were administered every 24 h for 5 days by intraperitoneal route. After sacrifice, the brain was obtained to measure DA, GSH, and lipid peroxidation, Ca²⁺, Mg²⁺, ATPase and H₂O₂.

Main findings

Levels of dopamine increased in cortex, striatum and cerebellum/medulla oblongata of animals that received 3-NPA alone. The lipid peroxidation increased in cortex, striatum, and cerebellum/medulla oblongata, of animals treated with B₂ vitamin alone. ATPase dependent on Ca⁺², Mg⁺² and H₂O₂ increased in all regions of animals that received 3-NPA alone.

Conclusion

The results confirm the capacity of 3-NPA to generate oxidative stress. Besides, the study suggests that B₂ or B₆ vitamins restored the levels of DA and reduced oxidative stress in brain of rats. We believe that these results would help in the study of neurodegenerative diseases.

     

Altered <Emphasis Type="Italic">Slc25</Emphasis> family gene expression as markers of mitochondrial dysfunction in brain regions under experimental mixed anxiety/depression-like disorder

Background

Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the differentially expressed Slc25* family genes encoding mitochondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica (http://genoanalytica.ru/, Moscow, Russia).

Results

Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specific. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifically. Significant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions.

Conclusion

Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders.

     

Enhancement of blood-tumor barrier permeability by Sar-[D-Phe8]des-Arg9BK,a metabolically resistant bradykinin B1 agonist,in a rat C6 glioma model

Background

While it is well known that bradykinin B2 agonists increase plasma protein extravasation (PPE) in brain tumors, the bradykinin B1 agonists tested thus far are unable to produce this effect. Here we examine the effect of the selective B1 agonist bradykinin (BK) Sar-[D-Phe8]des-Arg9BK (SAR), a compound resistant to enzymatic degradation with prolonged activity on PPE in the blood circulation in the C6 rat glioma model.

Results

SAR administration significantly enhanced PPE in C6 rat brain glioma compared to saline or BK (p < 0.01). Pre-administration of the bradykinin B1 antagonist [Leu8]-des-Arg (100 nmol/Kg) blocked the SAR-induced PPE in the tumor area.

Conclusions

Our data suggest that the B1 receptor modulates PPE in the blood tumor barrier of C6 glioma. A possible role for the use of SAR in the chemotherapy of gliomas deserves further study.

     

The effect of anesthetic dose on the motor response induced by low-intensity pulsed ultrasound stimulation

Background

Low-intensity pulsed ultrasound stimulation (LIPUS) has been proven to be a noninvasive method with high spatial resolution and deep penetration. Previous studies have qualitatively demonstrated that the electromyographic response caused by LIPUS in the mouse motor cortex is affected by the anesthetic state of the mice. However, the quantitative relationship between motor response and anesthetic dose remains unclear.

Results

Experimental results show that the success rate decreases stepwise as the isoflurane concentration/mouse weight ratio increases (ratios: [0.004%/g, 0.01%/g], success rate: ~?90%; [0.012%/g, 0.014%/g], ~?40%; [0.016%/g, 0.018%/g], ~?7%; 0.024%/g, 0). The latency and duration of EMG increase significantly when the ratio is more than 0.016%/g. Compared with that at ratios from 0.004 to 0.016%/g, normalized EMG amplitude decreases significantly at ratios of 0.018%/g and 0.020%/g.

Conclusions

Quantitative calculations indicate that the anesthetic dose has a significant regulatory effect on the motor response of mice during LIPUS. Our results have guiding significance for the selection of the anesthetic dose for LIPUS in mouse motor cortex experiments.

     

Mapping the brain's orchestration during speech comprehension: task-specific facilitation of regional synchrony in neural networks

Background

How does the brain convert sounds and phonemes into comprehensible speech? In the present magnetoencephalographic study we examined the hypothesis that the coherence of electromagnetic oscillatory activity within and across brain areas indicates neurophysiological processes linked to speech comprehension.

Results

Amplitude-modulated (sinusoidal 41.5 Hz) auditory verbal and nonverbal stimuli served to drive steady-state oscillations in neural networks involved in speech comprehension. Stimuli were presented to 12 subjects in the following conditions (a) an incomprehensible string of words, (b) the same string of words after being introduced as a comprehensible sentence by proper articulation, and (c) nonverbal stimulations that included a 600-Hz tone, a scale, and a melody. Coherence, defined as correlated activation of magnetic steady state fields across brain areas and measured as simultaneous activation of current dipoles in source space (Minimum-Norm-Estimates), increased within left- temporal-posterior areas when the sound string was perceived as a comprehensible sentence. Intra-hemispheric coherence was larger within the left than the right hemisphere for the sentence (condition (b) relative to all other conditions), and tended to be larger within the right than the left hemisphere for nonverbal stimuli (condition (c), tone and melody relative to the other conditions), leading to a more pronounced hemispheric asymmetry for nonverbal than verbal material.

Conclusions

We conclude that coherent neuronal network activity may index encoding of verbal information on the sentence level and can be used as a tool to investigate auditory speech comprehension.

     

The temporal relationship between reduction of early imitative responses and the development of attention mechanisms

Background

To determine whether early imitative responses fade out following the maturation of attentional mechanisms, the relationship between primitive imitation behaviors and the development of attention was examined in 4-month-old infants. They were divided into high and low imitators, based on an index of imitation. The status of attention was assessed by studying inhibition of return (IOR). Nine-month-old infants were also tested to confirm the hypothesis.

Results

The IOR latency data replicate previous results that infants get faster to produce a covert shift of attention with increasing age. However, those 4-month-olds who showed less imitation had more rapid saccades to the cue before target presentation.

Conclusion

The cortical control of saccade planning appears to be related to an apparent drop in early imitation. We interpret the results as suggesting a relationship between the status of imitation and the neural development of attention-related eye movement.