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The neuromuscular system responds to perturbation and increasing locomotor task difficulty by altering the stability of neuromuscular output signals. The purpose of this study was to determine the effects of two different military load carriage systems on the dynamic stability of gait and muscle activation signals. 14 army office cadets (20 ± 1 years) performed 4-minute treadmill walking trials on level (0%) and uphill (10%) gradients while unloaded, and with 11 kg backpack and 11 kg webbing loads while the activity of 6 leg and trunk muscles and the motion of the centre of mass (COM) were recorded. Loaded and uphill walking decreased stability and increased magnitude of muscle activations compared to loaded and level gradient walking. Backpack loads increased the medio-lateral stability of COM and uphill walking decreased stability of vertical COM motion and increased stride time variability. However, there was no difference between the two load carriage systems for any variable. The reduced stability of muscle activations in loaded and uphill conditions indicates an impaired ability of the neuromuscular control systems to accommodate perturbations in these conditions which may have implications on the operational performance of military personnel. However, improved medio-lateral stability in backpack conditions may indicate that participants were able to compensate for the loads used in this study, despite the decreased vertical stability and increased stride time variability evident in uphill walking. This study did not find differences between load carriage systems however, specific load carriage system effects may be elicited by greater load carriage masses.Highlights Loaded and uphill walking decreased dynamic stability of muscle activationsLower activation stability indicates impaired neuromotor resistance to perturbationBackpack and webbing loads produced similar effects on muscle activations.

Anxiety and balance and postural control are linked via common neural pathways, such as the parabrachial nucleus network. A laboratory-based model of general anxiety disorder (GAD) using the CO

Visual input facilitates stable postural control; however, ageing alters visual gaze strategies and visual input processing times. Understanding the complex interaction between visual gaze behaviour and the effects of age may inform future interventions to improve postural control in older adults. The purpose of this study was to determine effects of age and dual task on gaze and postural sway dynamics, and the sway-gaze complexity coupling to explore the coupling between sensory input and motor output. Ten older and 10 younger adults performed single and dual task quiet standing while gaze behaviour and centre of mass motion were recorded. The complexity and stability of postural sway, saccade characteristics, visual input duration and complexity of gaze were calculated in addition to sway-gaze coupling quantified by cross-sample entropy. Dual tasking increased complexity and decreased stability of sway with increased gaze complexity and visual input duration, suggesting greater automaticity of sway with greater exploration of the visual field but with longer visual inputs to maintain postural stability in dual task conditions. In addition, older adults had lower complexity and stability of sway than younger adults indicating less automated and stable postural control. Older adults also demonstrated lower gaze complexity, longer visual input durations and greater sway-gaze coupling. These findings suggest older adults adopted a strategy to increase the capacity for visual information input, whilst exploring less of the visual field than younger adults.

We report the development of a portable NICE-OHMS device with the aim of ultra-sensitive (<1 nmol/mol), real-time (<1 min) detection of HCl and monitoring of water vapor for applications in microelectronic fabrication cleanrooms.

The aim of the study was to determine the stability and complexity of muscle synergies to provide insight to the neural control of gait stability in walking and running and when performing a concurrent cognitive dual task. Eighteen healthy young adults performed walking and running at preferred speeds and 120% of preferred speeds in single and dual task conditions. Muscle synergies were determined from the activity of 9 trunk and leg muscles and centre of mass (COM) motion was recorded with an inertial measurement unit. Local dynamic stability, complexity and width of synergies, and stability and complexity of COM motion were determined, in addition to the cross sample entropy to determine the coupling between COM motion and muscle synergies. Increasing locomotion speed increased complexity and decreased stability of COM motion with a concurrent decrease in synergy complexity and stability but with no change in synergy width. The coupling of COM motion and muscle synergies also increased with increasing speed. Vertical COM motion was more complex and less stable but with no change in anterior-posterior or medio-lateral directions in dual task locomotion. Muscle synergies were also more stable in dual task conditions. These findings indicate that changes in neuromotor dynamics may underpin reported changes in COM local stability during gait as the neural commands responsible for generating the movement are altered in response to increasing task demands. Increased cognitive demands lead to more stable neuromotor commands possibly to maintain local stability of COM motion in the anterior-posterior and medio-lateral directions.

In the vertebrate central nervous system, groups of functionally-related neurons, including cranial motor neurons of the brainstem, are frequently organised as nuclei. The molecular mechanisms governing the emergence of nuclear topography and circuit function are poorly understood. Here we investigate the role of cadherin-mediated adhesion in the development of zebrafish ocular motor (sub)nuclei. We find that developing ocular motor (sub)nuclei differentially express classical cadherins. Perturbing cadherin function in these neurons results in distinct defects in neuronal positioning, including scattering of dorsal cells and defective contralateral migration of ventral subnuclei. In addition, we show that cadherin-mediated interactions between adjacent subnuclei are critical for subnucleus position. We also find that disrupting cadherin adhesivity in dorsal oculomotor neurons impairs the larval optokinetic reflex, suggesting that neuronal clustering is important for co-ordinating circuit function. Our findings reveal that cadherins regulate distinct aspects of cranial motor neuron positioning and establish subnuclear topography and motor function.

The aim of this study was to investigate the effects of backpack load carriage on quiet standing postural control and limits of stability (LOS) of older adults. Fourteen older adults (65 [6] y) performed quiet standing and a forward, right, and left LOS test in 3 conditions, unloaded, stable, and unstable backpack loads while activity of 4 leg muscles was recorded. Stable and unstable loads decreased postural sway (main effect , stable P P , stable P = .002, unstable P = .018) and anterior–posterior (main effect , stable P P = .001) fractal dimension, and LOS distance (main effect , stable P = .011, unstable P = .046) compared with unloaded. Rectus femoris (main effect , stable P = .001, unstable P = .010) and gastrocnemius (main effect , unstable P = .027) activity increased in loaded conditions during LOS and quiet standing. Gastrocnemius–tibialis anterior coactivation was greater in unstable load than stable loaded quiet standing (main effect , P = .040). These findings suggest older adults adopt conservative postural control strategies minimizing the need for postural corrections in loaded conditions. Reduced LOS may also increase fall risk when carrying a load. However, there was no difference between unstable and stable loads for postural control variables.

Load carriage perturbs the neuromuscular system, which can be impaired due to ageing. The ability to counteract perturbations is an indicator of neuromuscular function but if the response is insufficient the risk of falls will increase. However, it is unknown how load carriage affects older adults. Fourteen older adults (65 ± 6 years) attended a single visit during which they performed 4 min of walking in 3 conditions, unloaded, stable backpack load and unstable backpack load. During each walking trial, 3-dimensional kinematics of the lower limb and trunk movements and electromyographic activity of 6 lower limb muscles were recorded. The local dynamic stability (local divergence exponents), joint angle variability and spatio-temporal variability were determined along with muscle activation magnitudes. Medio-lateral dynamic stability was lower (p = 0.018) and step width (p = 0.019) and step width variability (p = 0.015) were greater in unstable load walking and step width variability was greater in stable load walking (p = 0.009) compared to unloaded walking. However, there was no effect on joint angle variability. Unstable load carriage increased activity of the Rectus Femoris (p = 0.001) and Soleus (p = 0.043) and stable load carriage increased Rectus Femoris activity (p = 0.006). These results suggest that loaded walking alters the gait of older adults and that unstable load carriage reduces dynamic stability compared to unloaded walking. This can potentially increase the risk of falls, but also offers the potential to use unstable loads as part of fall prevention programmes.

Prolonged walking could alter postural control leading to an increased risk of falls in older adults. The aim of this study was to determine the effect of level and uphill prolonged walking on the postural control of older adults. Sixteen participants (64 ± 5 years) attended 3 visits. Postural control was assessed during quiet standing and the limits of stability immediately pre, post and post 15 min rest a period of 30 min walking on level and uphill (5.25%) gradients on separate visits. Each 30 min walk was divided into 3 10 min blocks, the limits of stability were measured between each block. Postural sway elliptical area (PRE: 1.38 ± 0.22 cm2, POST: 2.35 ± 0.50 cm2, p = .01), medio-lateral (PRE: 1.33 ± 0.03, POST: 1.40 ± 0.03, p = .01) and anterio-posterior detrended fluctuation analysis alpha exponent (PRE: 1.43 ± 0.02, POST: 1.46 ± 0.02, p = .04) increased following walking. Medio-lateral alpha exponent decreased between post and post 15 min’ rest (POST: 1.40 ± 0.03, POST15: 1.36 ± 0.03, p = .03). Forward limits of stability decreased between the second walking interval and post 15 min’ rest (Interval 2: 28.1 ± 1.6%, POST15: 25.6 ± 1.6%, p = .01) and left limits of stability increased from pre-post 15 min’ rest (PRE: 27.7 ± 1.2%, POST15: 29.4 ± 1.1%, p = .01). The neuromuscular alterations caused by prolonged walking decreased the anti-persistence of postural sway and altered the limits of stability in older adults. However, 15 min’ rest was insufficient to return postural control to pre-exercise levels.

The importance of warm up procedures prior to athletic performance is well established. A common component of such procedures is muscle stretching. There is conflicting evidence regarding the effect of static stretching (SS) as part of warm up procedures on knee joint position sense (KJPS) and the effect of dynamic stretching (DS) on KJPS is currently unknown. The aim of this study was to determine the effect of dynamic and static stretching as part warm up procedures on KJPS and knee extension and flexion strength.This study had a randomised cross-over design and ten healthy adults (20±1years) attended 3 visits during which baseline KJPS, at target angles of 20° and 45°, and knee extension and flexion strength tests were followed by 15min of cycling and either a rest period (CON), SS, or DS and repeat KJPS and strength tests. All participants performed all conditions, one condition per visit.There were warm up×stretching type interactions for KJPS at 20° (p=0.024) and 45° (p=0.018), and knee flexion (p=0.002) and extension (p0.001) strength. The SS and DS improved KJPS but CON condition did not and SS decreased strength. No change in strength was present for DS or CON.Both SS and DS improve KJPS as part of pre-exercise warm up procedures. However, the negative impact of SS on muscle strength limits the utility of SS before athletic performance. If stretching is to be performed as part of a warm up, DS should be favoured over SS.

The regulation of cell cycle progression and differentiation in retinal progenitor cells is a fundamental feature controlling organ size of the eye in vertebrates. Nance-Horan Syndrome (NHS) is a rare X-linked disorder caused by mutations in the NHS gene. Dysmorphic features of NHS include severe congenital cataracts, micropthalmia, facial dysmorphisms, and visual impairment. In this study we report an evolutionarily conserved role for NHS in vertebrate retinogenesis. Loss of function of nhs leads to small eye size in both zebrafish and Xenopus tropicalis, marked by reduced proliferation but not cell death. Transcriptome analysis of nhs morphant zebrafish eyes revealed a marked upregulation in Δ113p53, an isoform of p53, concomitant with a selective upregulation of p53 responsive genes that inhibit cell cycle progression but not apoptosis. Our data supports a model where Nhs is a negative regulator of Δ113p53 expression and exerts its function through regulation of the p53 pathway to promote expansive growth of retinal progenitor cells prior to differentiation.

Carrying heavy loads results in biomechanical changes to gait and to an increased risk of injury in soldiers. The aim of this review is to examine the effects of military specific load carriage on the gait of soldiers. The Web of Science, PubMed and CINAHL databases were searched, a total of 1239 records were screened and 20 papers were included in the review. Participant, load and task characteristics and a summary of key findings were extracted. Due to heterogeneity in the reviewed studies, analysis was restricted to qualitative synthesis. There were limited effects on spatio-temporal variables but consistently reported increased trunk, hip and knee flexion and increased hip and knee extension moments. Muscle activation of lower limb and trunk muscles were also increased with loads. However, there were some conflicting findings for most parameters reviewed and apart from spatio-temporal parameters the findings of this review were in line with previous reviews of combined military and civilian populations.

Background Previous reviews have shown balance in older adults to be improved with exercise. However, it is currently unclear whether postural control, indicated by centre of pressure (COP) measurement, can be improved in older adults and thus whether postural control could be a mechanism to improve balance. Objectives The purpose of this systematic review was to assess the effectiveness of force platform COP variables to identify changes in postural control following exercise interventions in older adults. In addition, a secondary purpose was to determine whether the exercise types (balance, resistance or multi-component exercise interventions) are equally effective to improve postural control. Methods Randomised controlled trials were identified using searches of databases and reference lists (PROSPERO registration number CRD42014010617). Trials performing exercise interventions, reporting force platform COP measurements, in participants with a mean age of ≥60 years were included. Risk of bias assessments were performed following the Cochrane guidelines. Data were pooled in meta-analyses, and standardised mean differences (SMDs) with 95 % confidence intervals (CIs) were calculated. Results Twenty-three trials met the inclusion criteria for the systematic review. Twenty-two trials could be defined as either utilising a balance, resistance or multi-component exercise intervention. These 22 trials were used in the meta-analyses. All trials reported measurements of double leg stance; eight trials reported additional stance conditions. The meta-analyses of double leg stance showed that balance exercise interventions significantly decreased total sway path length/velocity [SMD −1.13, 95 % CI −1.75 to −0.51 (eyes open); SMD −0.79, 95 % CI −1.33 to −0.26 (eyes closed)] and anterior-posterior sway path length/velocity [SMD −1.02, 95 % CI −2.01 to −0.02 (eyes open); SMD −0.82, 95 % CI −1.46 to −0.17 (eyes closed)] in both eyes open and eyes closed conditions. Balance exercise interventions also decreased sway area in eyes closed conditions (SMD −0.57, 95 % CI −1.01 to −0.13) and medio-lateral sway path length/velocity in eyes open conditions (SMD −0.8, 95 % CI −1.48 to −0.12). In contrast, neither resistance nor multi-component exercise interventions affected any of the included COP measurements. Conclusions Postural control is improved by balance exercise interventions. In contrast, strength or multi-component exercise interventions did not influence postural control measurements in older adults. In addition, a lack of standardisation in collection protocol and COP variables calculated across trials was identified. Electronic supplementary material The online version of this article (doi:10.1007/s40279-016-0559-0) contains supplementary material, which is available to authorized users.

BACKGROUND Autosomal dominant polycystic kidney disease is the most common monogenetic kidney disorder and is linked to mutations in PKD1 and PKD2. PKD2, a Ca2+ -conducting TRP channel enriched in ciliated cells and gated by extracellular signals, is necessary to activate the multifunctional Ca2+/ calmodulin-dependent protein kinase type 2 (CaMK-II), enabling kidney morphogenesis and cilia stability. RESULTS In this study, antisense morpholino oligonucleotides and pharmacological compounds were employed to investigate the roles of class II HDAC family members (HDAC 4, 5, and 6) in Zebrafish kidney development. While all three class II HDAC genes were expressed throughout the embryo during early development, HDAC5-morphant embryos exhibited anterior cysts and destabilized cloacal cilia, similar to PKD2 and CaMK-II morphants. In contrast, HDAC4-morphant embryos exhibited elongated cloacal cilia and lacked anterior kidney defects. Suppression of HDAC4 partially reversed the cilia shortening and anterior convolution defects caused by CaMK-II deficiency, whereas HDAC5 loss exacerbated these defects. EGFP-HDAC4, but not EGFP-HDAC5, translocated into the nucleus upon CaMK-II suppression in pronephric kidney cells. CONCLUSIONS These results support a model by which activated CaMK-II sequesters HDAC4 in the cytosol to enable primary cilia formation and kidney morphogenesis. Developmental Dynamics 247:807-817, 2018. © 2018 Wiley Periodicals, Inc.

This study aimed to investigate effects of walking direction and speed on gait complexity, symmetry and variability as indicators of neural control mechanisms, and if a period of backward walking has acute effects on forward walking. Twenty-two young adults attended 2 visits. In each visit participants walked forwards at preferred walking speed (PWS) for 3-minutes (pre) followed by 5-minutes walking each at 80%, 100% and 120% of PWS of either forward or backward walking then a further 3-minutes walking forward at PWS (post). The order of walking speed in each visit was randomised and walking direction of each visit was randomised. An inertial measurement unit was placed over L5 vertebra to record tri-axial accelerations. From the trunk accelerations multiscale entropy, harmonic ratio and stride time variability were calculated to measure complexity, symmetry and variability for each walk. Complexity increased with increasing walking speed for all axes in forward and backward walking, and backward walking was less complex than forward walking. Stride time variability was also greater in backward than forward walking. Anterio-posterior and medio-lateral complexity increased following forward and backward walking but there was no difference between forward and backward walking post effects. No effects were found for harmonic ratio. These results suggest during backward walking trunk motion is rigidly controlled but central pattern generators responsible for temporal gait patterns are less refined for backward walking. However, in both directions complexity increased as speed increased suggesting additional constraint of trunk motion, normally characterised by reduced complexity, is not applied as speed increases.

Collective migration depends on cell-cell interactions between neighbors that contribute to their overall directionality, yet the mechanisms that control the coordinated migration of neurons remains to be elucidated. During hindbrain development, facial branchiomotor neurons (FBMNs) undergo a stereotypic tangential caudal migration from their place of birth in rhombomere (r)4 to their final location in r6/7. FBMNs engage in collective cell migration that depends on neuron-to-neuron interactions to facilitate caudal directionality. Here, we demonstrate that Cadherin-2-mediated neuron-to-neuron adhesion is necessary for directional and collective migration of FBMNs. We generated stable transgenic zebrafish expressing dominant-negative Cadherin-2 (Cdh2ΔEC) driven by the islet1 promoter. Cell-autonomous inactivation of Cadherin-2 function led to non-directional migration of FBMNs and a defect in caudal tangential migration. Additionally, mosaic analysis revealed that Cdh2ΔEC-expressing FBMNs are not influenced to migrate caudally by neighboring wild-type FBMNs due to a defect in collective cell migration. Taken together, our data suggest that Cadherin-2 plays an essential cell-autonomous role in mediating the collective migration of FBMNs.

The facial branchiomotor neurons (FBMNs) undergo a characteristic tangential migration in the vertebrate hindbrain. We previously used a morpholino knockdown approach to reveal that zebrafish prickle1b (pk1b) is required for this migration. Here we report that FBMN migration is also blocked in a pk1b mutant with a disruption in the consensus farnesylation motif. We confirmed that this lipid modification is required during FBMN migration by disrupting the function of farnesyl biosynthetic enzymes. Furthermore, farnesylation of a tagged Pk1b is required for its nuclear localization. Using a unique rescue approach, we have demonstrated that Pk1b nuclear localization and farnesylation are required during FBMN migration. Our data suggest that Pk1b acts at least partially independently of core planar cell polarity molecules at the plasma membrane, and might instead be acting at the nucleus. We also found that the neuronal transcriptional silencer REST is necessary for FBMN migration, and we provide evidence that interaction between Pk1b and REST is required during this process. Finally, we demonstrate that REST protein, which is normally localized in the nuclei of migrating FBMNs, is depleted from the nuclei of Pk1b-deficient neurons. We conclude that farnesylation-dependent nuclear localization of Pk1b is required to regulate REST localization and thus FBMN migration.

Here, we investigated the intracellular mechanisms that underlie the relative invulnerability of adult versus developing dorsal root ganglion (DRG) sensory neurons. In culture, adult neurons were resistant to stimuli that caused apoptosis of their neonatal counterparts. In both adult and neonatal neurons, death stimuli induced the apoptotic c-Jun N-terminal protein kinase (JNK) pathway, but JNK activation only caused death of neonatal neurons, indicating that adult neurons have a downstream block to apoptosis. Expression of the dominant-inhibitory p53 family member, ΔNp73, rescued JNK-induced apoptosis of neonatal neurons, suggesting that it might participate in the downstream apoptotic block in adult neurons. To test this possibility, we examined adult DRG neurons cultured from p73+/- mice. Adult p73+/- DRG neurons were more vulnerable to apoptotic stimuli than their p73+/+ counterparts, and invulnerability could be restored to the p73+/- neurons by increased expression of ΔNp73. Moreover, although DRG neuron development was normal in p73+/- animalsin vivo, axotomy caused death of adult p73+/- but not p73+/+ DRG neurons. Thus, one way adult neurons become invulnerable is to enhance endogenous survival pathways, and one critical component of these survival pathways is p73.

The p53 family member, p73, is essential for the survival of sympathetic neurons during the developmental period of naturally occurring neuronal death. Here, we have asked whether ΔNp73, which is the only p73 isoform expressed in sympathetic neurons, mediates this survival by p53-dependent and/or p53-independent mechanisms. Initially, we used a genetic approach and crossed p53+/-and p73+/-mice. Quantitation of neurons in the sympathetic superior cervical ganglion during the period of naturally occurring cell death revealed that the loss of p53 partially rescued the death of neurons seen in p73-/-animals. Moreover, exogenous expression of ΔNp73 in cultured p53-/-sympathetic neurons rescued these neurons from apoptosis after NGF withdrawal. Biochemical studies asking how ΔNp73 inhibited NGF withdrawal-induced apoptosis in wild-type neurons demonstrated that it prevented the upregulation of the direct p53 targets p21 and Apaf-1 as well as cleavage of caspase-3. It also inhibited events at the mitochondrial apoptotic checkpoint, suppressing the induction of BimEL and the release of mitochondrial cytochromec. Interestingly, ΔNp73 expression also inhibited one very early event in the apoptotic cascade, the activation of c-Jun N-terminal protein kinase (JNK), likely by binding directly to JNK. Finally, we show that neuronal cell size is decreased in p73-/-mice, and that this decrease is not rescued by the lack of p53, suggesting a role for p73 in regulating cell size that does not involve interactions with p53. Thus, ΔNp73 promotes neuronal survival via p53-dependent and -independent mechanisms, and it does so at multiple points, including some of the most proximal events that occur after NGF withdrawal.

Elucidating the mechanisms that regulate the life versus death of mammalian neurons is important not only for our understanding of the normal biology of the nervous system but also for our efforts to devise approaches to maintain neuronal survival in the face of traumatic injury or neurodegenerative disorders. Here, we review the emerging evidence that a key survival/death checkpoint in both peripheral and central neurons involves the p53 tumor suppressor and its newly discovered family members, p73 and p63. The full-length isoforms of these proteins function as proapoptotic proteins, whereas naturally occurring N-terminal truncated variants of p73 and p63 act as prosurvival proteins, at least partially by antagonizing the full-length family members. The authors propose that together, these isoforms comprise an upstream rheostat that sums different environmental cues to ultimately determine neuronal survival during development, during neuronal maintenance in adult animals, and even following traumatic injury.

Nerve growth factor (NGF) mediates the survival and differentiation of neurons by stimulating the tyrosine kinase activity of the TrkA/NGF receptor. Here, we identify SHP-1 as a phosphotyrosine phosphatase that negatively regulates TrkA. SHP-1 formed complexes with TrkA at Y490, and dephosphorylated it at Y674/675. Expression of SHP-1 in sympathetic neurons induced apoptosis and TrkA dephosphorylation. Conversely, inhibition of endogenous SHP-1 with a dominant-inhibitory mutant stimulated basal tyrosine phosphorylation of TrkA, thereby promoting NGF-independent survival and causing sustained and elevated TrkA activation in the presence of NGF. Mice lacking SHP-1 had increased numbers of sympathetic neurons during the period of naturally occurring neuronal cell death, and when cultured, these neurons survived better than wild-type neurons in the absence of NGF. These data indicate that SHP-1 can function as a TrkA phosphatase, controlling both the basal and NGF-regulated level of TrkA activity in neurons, and suggest that SHP-1 regulates neuron number during the developmental cell death period by directly regulating TrkA activity.

Neuronal activity and neurotrophins play a central role in the formation, maintenance, and plasticity of dendritic arbors. Here, we show that neuronal activity, mediated by electrical stimulation, KCl depolarization, or cholinergic receptor activation, promotes reversible dendrite formation in sympathetic neurons and that this effect is enhanced by NGF. Activity-dependent dendrite formation is accompanied by increased association of HMW MAP2 with microtubules and increased microtubule stability. Inhibition of either CaMKII or the MEK-ERK pathway, both of which phosphorylate MAP2, inhibits dendrite formation, but inhibition of both pathways simultaneously is required for dendrites to retract. These data indicate that neuronal activity signals via CamKII and the ERKs to regulate MAP2:microtubule interactions and hence reversible dendrite stability, and to provide a mechanism whereby activity and neurotrophins converge intracellularly to dynamically regulate dendritic morphology.

Elevating target-derived levels of nerve growth factor (NGF) in peripheral organs of postnatal mammals is known to enhance the survival of postganglionic sympathetic neurons and to promote the terminal arborization of sympathetic axons within such NGF-rich target tissues. Although increasing levels of NGF in the central nervous system can ameliorate cholinergic function of damaged and aged neurons of the medial septum, it remains undetermined whether the postnatal development of this neuronal population and their projections that innervate the hippocampus are likewise affected by elevated levels of target-derived NGF. To address this question, the cholinergic septohippocampal pathway was examined in adult transgenic mice which display elevated levels of NGF protein production in the dorsal hippocampus during postnatal development. Adult transgenic mice possessed a cholinergic population of septal neurons approximately 15% larger than that seen in age-matched control animals. Despite increased numbers of cholinergic septal neurons, as well as elevated levels of hippocampal NGF, the density of cholinergic septal axons in the outer molecular layer of the hippocampal dentate gyrus of adult transgenic animals was comparable with that found in wild-type controls. These results reveal that elevating levels of target-derived NGF during postnatal development can increase the population size of the cholinergic septal neurons but does not alter their pattern of afferent innervation in the hippocampus of adult mice.

Nerve growth factor (NGF) regulates the expression of the glycoprotein L1 among neural cell populations. The purpose of this investigation was to determine whether NGF equally affects the immunolocalization of L1 on both sympathetic and sensory axons, and whether the functional expression of the p75 neurotrophin receptor (p75NTR) is required for the immunodetection of this glycoprotein on peripheral axons. Two lines of transgenic mice overexpressing NGF among glial cells were used in this study: (1) one line of mice possessing two normal alleles for p75NTR, and (2) another line of mice possessing two mutated alleles for p75NTR. In both types of animals, sensory axons stained immunohistochemically for calcitonin gene-related peptide and sympathetic axons stained immunohistochemically for tyrosine hydroxylase invaded the deep white matter portions of the cerebellum (a central structure containing high levels of transgene expression and synthesis); the cerebella of wild type (C57Bl/6) and p75NTR-deficient mice lacked these sensory and sympathetic fibers. Both lines of transgenic animals also possessed a dense plexus of L1-immunoreactive axons in their cerebella; the spatial distribution of these L1-immunostained axons paralleled that seen for the sensory and sympathetic axons. A unilateral removal of the superior cervical ganglion in both lines of transgenic animals caused a complete reduction of tyrosine hydroxylase-immunopositive axons in the cerebellum but did not affect the density of L1-immunopositive axons. From these in vivo data, we conclude that collateral branches of sensory axons which invade a NGF-rich target area display L1 immunoreactivity, and that such immunodetection does not require the functional expression of p75NTR.

It has been postulated that the aberrant projection of sympathetic axons to individual primary sensory neurons may provide the morphological basis for pain-related behaviors in rat models of chronic pain syndrome. Since nerve growth factor (NGF) can elicit the collateral sprouting of noradrenergic sympathetic terminals, it might be predicted that NGF plays a role in mediating the sprouting of sympathetic axons into sensory ganglia. Using a line of transgenic mice overexpressing NGF among glial cells, it was first found that trigeminal ganglia from adult transgenic mice possessed significantly higher levels of NGF protein in comparison to age-matched wild-type mice; as well, detectable levels of NGF mRNA transgene expression were present in both the ganglia and brain stem. Within the trigeminal ganglia, a small proportion of the sensory neuronal population stained immunohistochemically for NGF; a higher percentage of NGF-positive neurons was evident in transgenic mice. New sympathetic axons extended into the trigeminal ganglia of transgenic mice only and formed perineuronal plexuses surrounding only those neurons immunostained for NGF. In addition, such plexuses were accompanied by glial processes from nonmyelinating Schwann cells. From these data, we propose that accumulation of glial-derived NGF by adult sensory neurons and its putative release into the ganglionic environment induce the directional growth of sympathetic axons to the source of NGF, namely, the cell bodies of primary sensory neurons. © 1998 John Wiley & Sons, Inc. J Neurobiol 34: 347–360, 1998

Components of the planar cell polarity (PCP) pathway are required for the caudal tangential migration of facial branchiomotor (FBM) neurons, but how PCP signaling regulates this migration is not understood. In a forward genetic screen, we identified a new gene, nhsl1b, required for FBM neuron migration. nhsl1b encodes a WAVE-homology domain-containing protein related to human Nance-Horan syndrome (NHS) protein and Drosophila GUK-holder (Gukh), which have been shown to interact with components of the WAVE regulatory complex that controls cytoskeletal dynamics and with the polarity protein Scribble, respectively. Nhsl1b localizes to FBM neuron membrane protrusions and interacts physically and genetically with Scrib to control FBM neuron migration. Using chimeric analysis, we show that FBM neurons have two modes of migration: one involving interactions between the neurons and their planar-polarized environment, and an alternative, collective mode involving interactions between the neurons themselves. We demonstrate that the first mode of migration requires the cell-autonomous functions of Nhsl1b and the PCP components Scrib and Vangl2 in addition to the non-autonomous functions of Scrib and Vangl2, which serve to polarize the epithelial cells in the environment of the migrating neurons. These results define a role for Nhsl1b as a neuronal effector of PCP signaling and indicate that proper FBM neuron migration is directly controlled by PCP signaling between the epithelium and the migrating neurons.

Exposure to Mycobacterium tuberculosis produces varied early outcomes, ranging from resistance to infection to progressive disease. Here we report results from a forward genetic screen in zebrafish larvae that identify multiple mutant classes with distinct patterns of innate susceptibility to Mycobacterium marinum. A hypersusceptible mutant maps to the lta4h locus encoding leukotriene A(4) hydrolase, which catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)), a potent chemoattractant and proinflammatory eicosanoid. lta4h mutations confer hypersusceptibility independent of LTB(4) reduction, by redirecting eicosanoid substrates to anti-inflammatory lipoxins. The resultant anti-inflammatory state permits increased mycobacterial proliferation by limiting production of tumor necrosis factor. In humans, we find that protection from both tuberculosis and multibacillary leprosy is associated with heterozygosity for LTA4H polymorphisms that have previously been correlated with differential LTB(4) production. Our results suggest conserved roles for balanced eicosanoid production in vertebrate resistance to mycobacterial infection.

Developmental sympathetic neuron death is determined by functional interactions between the TrkA/NGF receptor and the p75 neurotrophin receptor (p75NTR). A key question is whether p75NTR promotes apoptosis by directly inhibiting or modulating TrkA activity, or by stimulating cell death independently of TrkA. Here we provide evidence for the latter model. Specifically, experiments presented here demonstrate that the presence or absence of p75NTR does not alter Trk activity or NGF- and NT-3–mediated downstream survival signaling in primary neurons. Crosses of p75NTR−/− and TrkA−/− mice indicate that the coincident absence of p75NTR substantially rescues TrkA−/− sympathetic neurons from developmental death in vivo. Thus, p75NTR induces death regardless of the presence or absence of TrkA expression. These data therefore support a model where developing sympathetic neurons are “destined to die” by an ongoing p75NTR-mediated apoptotic signal, and one of the major ways that TrkA promotes neuronal survival is by silencing this ongoing death signal.

Recent evidence indicates that the p53 tumor suppressor protein, and its related family member, p73, play an essential role in regulating neuronal apoptosis in both the developing and injured, mature nervous system. In the developing nervous system, they do so by regulating naturally-occurring cell death in neural progenitor cells and in postmitotic neurons, acting to ensure the apoptosis of cells that either do not appropriately undergo the progenitor to postmitotic neuron transition, or that fail to compete for sufficient quantities of trophic support. Somewhat surprisingly, in developing postmitotic neurons, p53 plays a proapoptotic role, while a naturally-occurring, truncated form of p73, DeltaNp73, antagonizes p53 and plays an anti-apoptotic role. In the mature nervous system, numerous studies indicate that p53 is essential for the neuronal death in response to a variety of insults, including DNA damage, ischemia and excitotoxicity. It is likely that all of these insults culminate in DNA damage, which may well be a common trigger for neuronal apoptosis. In this regard, the signaling pathways that are responsible for triggering p53-dependent neuronal apoptosis are starting to be elucidated, and involve cell cycle deregulation and activation of the JNK pathway. Finally, accumulating evidence indicates that p53 is perturbed in the CNS in a number of neurodegenerative disorders, leading to the hypothesis that longterm oxidative damage and/or excitotoxicity ultimately trigger p53-dependent apoptosis in the chronically degenerating nervous system.

Axonal growth in the adult mammalian CNS is limited because of inhibitory influences of the glial environment and/or a lack of growth-promoting molecules. Here, we investigate whether supplementation of nerve growth factor (NGF) to the CNS during postnatal development and into adulthood can support the growth of sympathetic axons within myelinated portions of the maturing brain. We have also asked whether p75NTRplays a role in this NGF-induced axon growth. To address these questions we used two lines of transgenic mice overexpressing NGF centrally, with or without functional expression of p75NTR(NGF/p75+/+and NGF/p75−/−mice, respectively). Sympathetic axons invade the myelinated portions of the cerebellum, beginning shortly before the second week of postnatal life, in both lines of NGF transgenic mice. Despite the presence of central myelin, these sympathetic axons continue to sprout and increase in density between postnatal days 14 and 100, resulting in a dense plexus of sympathetic fibers within this myelinated environment. Surprisingly, the growth response of sympathetic fibers into the cerebellar white matter of NGF/p75−/−mice is enhanced, such that both the density and extent of axon ingrowth are increased, compared with age-matched NGF/p75+/+mice. These dissimilar growth responses cannot be attributed to differences in cerebellar levels of NGF protein or sympathetic neuron numbers between NGF/p75+/+and NGF/p75−/−mice. Our data provide evidence demonstrating that growth factors are capable of overcoming the inhibitory influences of central myelin in the adult CNS and that neutralization of the p75NTRmay further enhance this growth response.

Sympathetic axons invade the trigeminal ganglia of mice overexpressing nerve growth factor (NGF) (NGF/p75+/+mice) and surround sensory neurons having intense NGF immunolabeling; the growth of these axons appears to be directional and specific (Walsh and Kawaja, 1998). In this investigation, we provide new insight into the neurochemical features and receptor requirements of this sympathosensory sprouting. Using double-antigen immunohistochemistry, we demonstrate that virtually all (98%) trigeminal neurons that exhibit a sympathetic plexus aretrktyrosine kinase receptor (trkA)-positive. In addition, the majority (86%) of those neurons enveloped by sympathetic fibers is also calcitonin gene-related peptide (CGRP)-positive; a smaller number of plexuses (14%) surrounded other somata lacking this neuropeptide. Our results show that sympathosensory interactions form primarily between noradrenergic sympathetic efferents and the trkA/CGRP-expressing sensory somata. To assess the contribution of the p75 neurotrophin receptor (p75NTR) in sympathosensory sprouting, a hybrid strain of mice was used that overexpresses NGF but lacks p75NTRexpression (NGF/p75−/−mice). The trigeminal ganglia of NGF/p75−/−mice, like those of NGF/p75+/+mice, have increased levels of NGF protein and display a concomitant ingrowth of sympathetic axons. In contrast to the precise pattern of sprouting seen in the ganglia of NGF/p75+/+mice, sympathetic axons course randomly throughout the ganglionic neuropil of NGF/p75−/−mice, forming few perineuronal plexuses. Our results indicate that p75NTRis not required to initiate or sustain the growth of sympathetic axons into the NGF-rich trigeminal ganglia but rather plays a role in regulating the directional patterns of axon growth.

Transgenic mice possessing elevated levels of mRNA expression and synthesis for the neurotrophin nerve growth factor among astrocytes display a robust ingrowth of new sympathetic fibers to the cerebellum. In this investigation, we report that the cerebellum of these mice also possesses a dense plexus of aberrant axons of sensory origin. Axons stained immunohistochemically for calcitonin gene-related peptide were seen in the transgenic cerebellum as early as one week after birth. The density of these axons dramatically increased with age. Immunopositive axons were confined predominantly to the deep white matter of the cerebellum in the adult transgenic mice, with a smaller number of axons seen coursing along blood vessels in the gray matter. Axons stained immunohistochemically for the neurotrophin receptor, p75NTR, displayed a similar pattern of distribution and density as those immunostained for calcitonin gene-related peptide. Wild-type post-natal and adult animals lacked such calcitonin gene-related peptide- and p75NTR-immunoreactive axons in the cerebellum. Retrograde labelling revealed that these axons within the transgenic cerebellum originated from neurons in the sensory trigeminal and dorsal root ganglia (upper cervical levels). This investigation demonstrates that overexpression of nerve growth factor is capable of inducing the directional growth of collateral axons of sensory neurons into the undamaged mammalian central nervous system.

BackgroundThe evaluation and treatment of Jefferson fractures, a burst fracture of the ring of CI, has been well documented in the medical literature. Vertebral artery injury associated with a Jefferson fracture is very rare.MethodsThe case study technique was used to summarize the case. Review of the literature was performed to discuss the case. Retrospective chart review of the 174 patients with cervical fractures admitted to St. Michael’s Hospital from 1989–1994 was also performed.ResultsThe case of a patient with a Jefferson fracture, with bilateral lateral displacement of the lateral masses causing bilateral vertebral artery occlusions resulting in a lateral medullary and cerebellar infarction is reported. A review of the literature is provided.ConclusionA high index of suspicion for this injury is paramount, especially in patients with multiple trauma, where the diagnosis of Jefferson fractures can be delayed.