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.

     

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.

     

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.

     

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.

     

Learning course adjustments during arm movements with reversed sensitivity derivatives

Background

To learn, a motor system needs to know its sensitivity derivatives, which quantify how its neural commands affect motor error. But are these derivatives themselves learned, or are they known solely innately? Here we test a recent theory that the brain's estimates of sensitivity derivatives are revisable based on sensory feedback. In its simplest form, the theory says that each control system has a single, adjustable estimate of its sensitivity derivatives which affects all aspects of its task, e.g. if you learn to reach to mirror-reversed targets then your revised estimate should reverse not only your initial aiming but also your online course adjustments when the target jumps in mid-movement.

Methods

Human subjects bent a joystick to move a cursor to a target on a computer screen, but the cursor's motion was reversed relative to the joystick's. The target jumped once during each movement. Subjects had up to 4000 trials to practice aiming and responding to target jumps.

Results

All subjects learned to reverse both initial aiming and course adjustments.

Conclusions

Our study confirms that sensitivity derivatives can be relearned. It is consistent with the idea of a single, all-purpose estimate of those derivatives; and it suggests that the estimate is a function of context, as one would expect given that the true sensitivity derivatives may vary with the state of the controlled system, the target, and the motor commands.

     

Beneficial effects of word final stress in segmenting a new language: evidence from ERPs

Background

How do listeners manage to recognize words in an unfamiliar language? The physical continuity of the signal, in which real silent pauses between words are lacking, makes it a difficult task. However, there are multiple cues that can be exploited to localize word boundaries and to segment the acoustic signal. In the present study, word-stress was manipulated with statistical information and placed in different syllables within trisyllabic nonsense words to explore the result of the combination of the cues in an online word segmentation task.

Results

The behavioral results showed that words were segmented better when stress was placed on the final syllables than when it was placed on the middle or first syllable. The electrophysiological results showed an increase in the amplitude of the P2 component, which seemed to be sensitive to word-stress and its location within words.

Conclusion

The results demonstrated that listeners can integrate specific prosodic and distributional cues when segmenting speech. An ERP component related to word-stress cues was identified: stressed syllables elicited larger amplitudes in the P2 component than unstressed ones.

     

Topography-specific spindle frequency changes in Obstructive Sleep Apnea

Background

Sleep spindles, as detected on scalp electroencephalography (EEG), are considered to be markers of thalamo-cortical network integrity. Since obstructive sleep apnea (OSA) is a known cause of brain dysfunction, the aim of this study was to investigate sleep spindle frequency distribution in OSA. Seven non-OSA subjects and 21 patients with OSA (11 mild and 10 moderate) were studied. A matching pursuit procedure was used for automatic detection of fast (≥13Hz) and slow (<13Hz) spindles obtained from 30min samples of NREM sleep stage 2 taken from initial, middle and final night thirds (sections I, II and III) of frontal, central and parietal scalp regions.

Results

Compared to non-OSA subjects, Moderate OSA patients had higher central and parietal slow spindle percentage (SSP) in all night sections studied, and higher frontal SSP in sections II and III. As the night progressed, there was a reduction in central and parietal SSP, while frontal SSP remained high. Frontal slow spindle percentage in night section III predicted OSA with good accuracy, with OSA likelihood increased by 12.1%for every SSP unit increase (OR 1.121, 95% CI 1.013 - 1.239, p=0.027).

Conclusions

These results are consistent with diffuse, predominantly frontal thalamo-cortical dysfunction during sleep in OSA, as more posterior brain regions appear to maintain some physiological spindle frequency modulation across the night. Displaying changes in an opposite direction to what is expected from the aging process itself, spindle frequency appears to be informative in OSA even with small sample sizes, and to represent a sensitive electrophysiological marker of brain dysfunction in OSA.

     

PKCε phosphorylation regulates the mitochondrial translocation of ATF2 in ischemia-induced neurodegeneration

Background

Global cerebral ischemia triggers neurodegeneration in the hippocampal CA1 region, but the mechanism of neuronal death remains elusive. The epsilon isoform of protein kinase C (PKCε) has recently been identified as a master switch that controls the nucleocytoplasmic trafficking of ATF2 and the survival of melanoma cells. It is of interest to assess the role of PKCε–ATF2 signaling in neurodegeneration.

Results

Phosphorylation of ATF2 at Thr-52 was reduced in the hippocampus of PKCε null mice, suggesting that ATF2 is a phosphorylation substrate of PKCε. PKCε protein concentrations were significantly reduced 4, 24, 48 and 72 h after transient global cerebral ischemia, resulting in translocation of nuclear ATF2 to the mitochondria. Degenerating neurons staining positively with Fluoro-Jade C exhibited cytoplasmic ATF2.

Conclusions

Our results support the hypothesis that PKCε regulates phosphorylation and nuclear sequestration of ATF2 in hippocampal neurons during ischemia-induced neurodegeneration.

     

Offline encoding impaired by epigenetic regulations of monoamines in the guided propagation model of autism

Background

Environmental factors can modify the expression of genes, including those involved in the metabolism of neurotransmitters. Accounting for a control role of monoamine neurotransmitters, the guided propagation (GP) memory model may contribute to investigate the consequences of neuromodulation impairments on development disorders such as autism. A prenatal transient excess of ‘monoamine oxidase A’ enzyme is assumed here to trigger persistent epigenetic regulations that would induce imbalanced metabolisms of synaptic monoamines. When imported into the ‘offline’ encoding cycles of a GP model, the consequent ‘serotoninergic noise’ leads to aberrant memory structures that can be linked with autism symptoms.

Results

In computer experiments, different levels of uncoupling between representations of monoamines correlate with the amount of impaired GP modules, the severity of irrelevant connections, as well as network overgrowth. Two types of faulty connections are respectively assumed to underlie autism traits, namely repetitive behavior and perceptual oversensitivity. Besides computational modelling, a genetic family-tree shows how the autism sex-ratio can result from combinations of pharmacological and epigenetic features.

Conclusions

These results suggest that the current rise of autism is favored by three possible sources of biological masking: (1) during sleep, when cyclic variations of monoamines may undergo disrupted enzymatic activities; (2) across generations of ‘healthy carriers’ protected by the X-chromosome silencing and a specific genetic variant; (3) early in life, as long as the brain development draws on pools of neurons born when the transient enzymatic excess and its persistent epigenetic regulation overlapped, and as long as the B type of monoamine oxidase does not significantly impact dopamine. A disease-modifying therapy can be derived from this study, which involves relevant biomarkers to be first monitored over several months of clinical trial.

     

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.

     

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.

     

Anti-Nogo-A antibody treatment does not prevent cell body shrinkage in the motor cortex in adult monkeys subjected to unilateral cervical cord lesion

Background

After unilateral cervical cord lesion at the C7/C8 border interrupting the dorsolateral funiculus in adult monkeys, neutralization of Nogo-A using a specific monoclonal antibody promoted sprouting of corticospinal (CS) axons rostral and caudal to the lesion and, in parallel, improved functional recovery. In monkeys lesioned but not treated with the anti-Nogo-A antibody, the CS neurons in the contralesional primary motor cortex (M1) survived to the axotomy, but their soma shrank. Because the anti-Nogo-A treatment induces regeneration and/or sprouting of CS axons, it may improve access to neurotrophic factors. The question therefore arises as to whether anti-Nogo-A treatment prevents the soma shrinkage observed in the contralesional M1?

Results

Using the marker SMI-32, a quantitative and qualitative anatomical assessment of the pyramidal neurons in the layer V (thus including the CS cells) in M1 was performed and compared across three groups of animals: intact monkeys (n = 5); monkeys subjected to the cervical cord lesion and treated with a control antibody (n = 4); monkeys with the cervical lesion and treated with anti-Nogo-A antibody (n = 5). SMI-32 positive neurons on the side contralateral to the lesion were generally less well stained than those on the ipsilesional hemisphere, suggesting that they expressed less neurofilaments. Nevertheless, in all three groups of monkeys, the amount of SMI-32 positive neurons in both hemispheres was generally comparable, confirming the notion that most axotomized CS neurons survived. However, shrinkage of CS cell body area was observed in the contralesional hemisphere in the two groups of lesioned monkeys. The cell surface shrinkage was found to be of the same magnitude in the monkeys treated with the anti-Nogo-A antibody as in the control antibody treated monkeys.

Conclusion

The anti-Nogo-A antibody treatment did not preserve the axotomized CS cells from soma shrinkage, indicating that the anti-Nogo-A antibody treatment affects morphologically the axotomized CS neurons mainly at distal levels, especially the axon collateralization in the cervical cord, and little or not at all at the level of their soma.

     

On the matching of top-down knowledge with sensory input in the perception of ambiguous speech

Background

How does the brain repair obliterated speech and cope with acoustically ambivalent situations? A widely discussed possibility is to use top-down information for solving the ambiguity problem. In the case of speech, this may lead to a match of bottom-up sensory input with lexical expectations resulting in resonant states which are reflected in the induced gamma-band activity (GBA).

Methods

In the present EEG study, we compared the subject's pre-attentive GBA responses to obliterated speech segments presented after a series of correct words. The words were a minimal pair in German and differed with respect to the degree of specificity of segmental phonological information.

Results

The induced GBA was larger when the expected lexical information was phonologically fully specified compared to the underspecified condition. Thus, the degree of specificity of phonological information in the mental lexicon correlates with the intensity of the matching process of bottom-up sensory input with lexical information.

Conclusions

These results together with those of a behavioural control experiment support the notion of multi-level mechanisms involved in the repair of deficient speech. The delineated alignment of pre-existing knowledge with sensory input is in accordance with recent ideas about the role of internal forward models in speech perception.

     

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.

     

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.

     

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.

     

Biaryl scaffold-focused virtual screening for anti-aggregatory and neuroprotective effects in Alzheimer’s disease

Background

Alzheimer’s disease (AD) is a primary cause of dementia in ageing population affecting more than 35 million people around the globe. It is a chronic neurodegenerative disease caused by defected folding and aggregation of amyloid beta (Aβ) protein. Aβ is formed by the cleavage of membrane embedded amyloid precursor protein (APP) by using enzyme ‘transmembrane aspartyl protease, β-secretase’. Inhibition of β-secretase is a viable strategy to prevent neurotoxicity in AD. Another strategy in the treatment of AD is inhibition of acetylcholinesterase. This inhibition reduces the degradation of acetylcholine and temporarily restores the cholinergic function of neurons and improves cognitive function. Monoamine oxidase and higher glutamate levels are also found to be linked with Aβ peptide related oxidative stress. Oxidative stress leads to reduced activity of glutamate synthase resulting in significantly higher level of glutamate in brain. The aim of this study is to perform in silico screening of a virtual library of biaryl scaffold containing compounds potentially used for the treatment of AD. Screening was done against the primary targets of AD therapeutics, acetylcholinesterase, β-secretase (BACE1), Monoamine oxidases (MAO) and N-Methyl-D-aspartate (NMDA) receptor. Compounds were screened for their inhibitory potential by employing molecular docking approach using AutoDock vina. Binding energy scores were embodied in the heatmap to display varies strengths of interactions of the ligands targeting AD.

Results

Several ligands showed notable interaction with at least two targets, but the strong interaction with all the targets is shown by very few ligands. The pharmacokinetics of the interacting ligands was also predicted. The interacting ligands have good drug-likeness and brain availability essential for drugs with intracranial targets.

Conclusion

These results suggest that biaryl scaffold may be pliable to drug development for neuroprotection in AD and that the synthesis of further analogues to optimize these properties should be considered.

     

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.

     

Comparison of the responses of the chorda tympani and glossopharyngeal nerves to taste stimuli in C57BL/6J mice

Background

Recent progress in discernment of molecular pathways of taste transduction underscores the need for comprehensive phenotypic information for the understanding of the influence of genetic factors in taste. To obtain information that can be used as a base line for assessment of effects of genetic manipulations in mice taste, we have recorded the whole-nerve integrated responses to a wide array of taste stimuli in the chorda tympani (CT) and glossopharyngeal (NG) nerves, the two major taste nerves from the tongue.

Results

In C57BL/6J mice the responses in the two nerves were not the same. In general sweeteners gave larger responses in the CT than in the NG, while responses to bitter taste in the NG were larger. Thus the CT responses to cyanosuosan, fructose, NC00174, D-phenylalanline and sucrose at all concentrations were significantly larger than in the NG, whereas for acesulfame-K, L-proline, saccharin and SC45647 the differences were not significant. Among bitter compounds amiloride, atropine, cycloheximide, denatonium benzoate, L-phenylalanine, 6-n-propyl-2-thiouracil (PROP) and tetraethyl ammonium chloride (TEA) gave larger responses in the NG, while the responses to brucine, chloroquine, quinacrine, quinine hydrochloride (QHCl), sparteine and strychnine, known to be very bitter to humans, were not significantly larger in the NG than in the CT.

Conclusion

These data provide a comprehensive survey and comparison of the taste sensitivity of the normal C57BL/6J mouse against which the effects of manipulations of its gustatory system can be better assessed.