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Studying the episodes with the most elevated electron density (Ne) values provides valuable information about spatial distribution and drivers of intense energetic electron (EE) precipitation, which has important space weather implications. By combining EISCAT‐Tromso UHF observations in different modes made in 2001–2021, we survey Ne occurrences and study statistical properties of EE precipitation, producing the highest 10% and 1% of Ne values at the altitudes between 100 and 75 km (corresponding to EE energies of ∼20–∼200 keV). We found that the highest Ne values occur in the nightside‐morning local time sector at the altitudes 90–100 km and in the morning‐noon sector at low altitudes (75–85 km). Although this bimodal pattern could partly be contributed by the suppressed Ne in the dark ionosphere, by analyzing measurements in the twilight conditions at all MLTs together with published patterns of EE precipitation, we argue that a dominance of pre‐noon maximum at low altitudes reflects the enhanced precipitation of >100 keV electrons in this local time sector. At all altitudes (especially below 90 km), the appearance of the highest Ne values favors enhanced auroral activity and shows a strong correlation with fast solar wind (V > 550 km/s) events. These properties mimic the well‐known driving characteristics of energetic electrons. From the correlation of Ne with integral magnetic activity indexes we found that the memory of preceding magnetic activity increases with decreasing altitude, reaching roughly one day at H = 75 km. We discuss the advantages of exploring Ne data at specific altitudes (compared to direct measurements of EE precipitation) to investigate statistically the effects of specific precipitated energy components and the evolution of EE energy spectra. Key Points: Occurrence of high Ne events in D‐region between 75 and 100 km caused by energetic electron precipitation and their activity driversSpatial patterns of extreme ionization differ in the upper (h > 90 km) and low (h < 85 km) D‐region consistent with known precipitation patternsMemory length of preceding magnetic activity increases with decreasing altitude reaching roughly 1 day at h = 75 km [ABSTRACT FROM AUTHOR]

Plasticity, the term we use to describe the ability of a nervous system to change with experience, is the evolutionary adaptation that freed animal behavior from the confines of genetic determinism. This capacity, which increases with brain complexity, is nowhere more evident than in vertebrates, especially mammals. Though the scientific study of brain plasticity dates back at least to the mid-19th century, the last several decades have seen unprecedented advances in the field afforded by new technologies. Olfaction is one system that has garnered particular attention in this realm because it is the only sensory modality with a lifelong supply of new neurons, from two niches no less! Here, we review some of the classical and contemporary literature dealing with the role of the stimulus or lack thereof in olfactory plasticity. We have restricted our comments to studies in mammals that have used dual tools of the field: stimulus deprivation and stimulus enrichment. The former manipulation has been implemented most frequently by unilateral naris occlusion and, thus, we have limited our comments to research using this technique. The work reviewed on deprivation provides substantial evidence of activity-dependent processes in both developing and adult mammals at multiple levels of the system from olfactory sensory neurons through to olfactory cortical areas. However, more recent evidence on the effects of deprivation also establishes several compensatory processes with mechanisms at every level of the system, whose function seems to be the restoration of information flow in the face of an impoverished signal. The results of sensory enrichment are more tentative, not least because of the actual manipulation: What odor or odors? At what concentrations? On what schedule? All of these have frequently not been sufficiently rationalized or characterized. Perhaps it is not surprising, then, that discrepant results are common in sensory enrichment studies. Despite this problem, evidence has accumulated that even passively encountered odors can "teach" olfactory cortical areas to better detect, discriminate, and more efficiently encode them for future encounters. We discuss these and other less-established roles for the stimulus in olfactory plasticity, culminating in our recommended "aspirations" for the field going forward. [ABSTRACT FROM AUTHOR]

Plasticity, the term we use to describe the ability of a nervous system to change with experience, is the evolutionary adaptation that freed animal behavior from the confines of genetic determinism. This capacity, which increases with brain complexity, is nowhere more evident than in vertebrates, especially mammals. Though the scientific study of brain plasticity dates back at least to the mid-19th century, the last several decades have seen unprecedented advances in the field afforded by new technologies. Olfaction is one system that has garnered particular attention in this realm because it is the only sensory modality with a lifelong supply of new neurons, from two niches no less! Here, we review some of the classical and contemporary literature dealing with the role of the stimulus or lack thereof in olfactory plasticity. We have restricted our comments to studies in mammals that have used dual tools of the field: stimulus deprivation and stimulus enrichment. The former manipulation has been implemented most frequently by unilateral naris occlusion and, thus, we have limited our comments to research using this technique. The work reviewed on deprivation provides substantial evidence of activity-dependent processes in both developing and adult mammals at multiple levels of the system from olfactory sensory neurons through to olfactory cortical areas. However, more recent evidence on the effects of deprivation also establishes several compensatory processes with mechanisms at every level of the system, whose function seems to be the restoration of information flow in the face of an impoverished signal. The results of sensory enrichment are more tentative, not least because of the actual manipulation: What odor or odors? At what concentrations? On what schedule? All of these have frequently not been sufficiently rationalized or characterized. Perhaps it is not surprising, then, that discrepant results are common in sensory enrichment studies. Despite this problem, evidence has accumulated that even passively encountered odors can “teach” olfactory cortical areas to better detect, discriminate, and more efficiently encode them for future encounters. We discuss these and other less-established roles for the stimulus in olfactory plasticity, culminating in our recommended “aspirations” for the field going forward.

During development, cortical circuits are remodeled by spontaneous and sensory-evoked activity via alteration of the expression of wiring molecules. An intriguing question is how physiological neuronal activity modifies the expression of these molecules in developing cortical networks. Here, we addressed this issue, focusing on brain-derived neurotrophic factor (BDNF), one of the factors underlying cortical wiring. Real-time imaging of BDNF promoter activity in organotypic slice cultures revealed that patterned stimuli differentially regulated the increase and the time course of the promoter activity in upper layer neurons. Calcium imaging further demonstrated that stimulus-dependent increases in the promoter activity were roughly proportional to the increase in intracellular Ca2+ concentration per unit time. Finally, optogenetic stimulation showed that the promoter activity was increased efficiently by patterned stimulation in defined cortical circuits. These results suggest that physiological stimulation patterns differentially tune activity-dependent gene expression in developing cortical neurons via cortical circuits, synaptic responses, and alteration of intracellular calcium signaling. [ABSTRACT FROM AUTHOR]

During development, cortical circuits are remodeled by spontaneous and sensory-evoked activity via alteration of the expression of wiring molecules. An intriguing question is how physiological neuronal activity modifies the expression of these molecules in developing cortical networks. Here, we addressed this issue, focusing on brain-derived neurotrophic factor (BDNF), one of the factors underlying cortical wiring. Real-time imaging of BDNF promoter activity in organotypic slice cultures revealed that patterned stimuli differentially regulated the increase and the time course of the promoter activity in upper layer neurons. Calcium imaging further demonstrated that stimulus-dependent increases in the promoter activity were roughly proportional to the increase in intracellular Ca2+ concentration per unit time. Finally, optogenetic stimulation showed that the promoter activity was increased efficiently by patterned stimulation in defined cortical circuits. These results suggest that physiological stimulation patterns differentially tune activity-dependent gene expression in developing cortical neurons via cortical circuits, synaptic responses, and alteration of intracellular calcium signaling.

In the era of Internet and big data, contemporary workflows become increasingly large in scale and complex in structure, introducing greater challenges for workflow modeling. Workflows are not with maximized concurrency and block-structuredness in terms of control flow, though languages supporting block-structuredness (e.g., BPEL) are employed. Existing workflow refactoring approaches mostly focus on maximizing concurrency according to dependences between activities, but do not consider the block-structuredness of the refactored workflow. It is easier to comprehend and analyze a workflow that is block-structured and to transform it into BPEL-like processes. In this paper, we aim at maximizing both concurrency and block-structuredness. Nevertheless, not all workflows can be refactored with a block-structured representation, and it is intractable to make sure that the refactored workflows are as block-structured as possible. We first define a well-formed dependence pattern of activities. The control flow among the activities in this pattern can be represented in block-structured forms with maximized concurrency. Then, we propose a greedy heuristics-based graph reduction approach to recursively find such patterns. In this way, the resulting workflow is with maximized concurrency and its block-structuredness approximates optimality. We show the effectiveness and efficiency of our approach with real-world scientific workflows. [ABSTRACT FROM AUTHOR]

The development of sensory circuits is partially guided by sensory experience. In the medial superior olive (MSO), these refinements generate precise coincidence detection to localize sounds in the azimuthal plane. Glycinergic inhibitory inputs to the MSO, which tune the sensitivity to interaural time differences, undergo substantial structural and functional refinements after hearing onset. Whether excitation and calcium signaling in the MSO are similarly affected by the onset of acoustic experience is unresolved. To assess the time window and m echanism of excitatory and calcium-dependent refinements during late postnatal development, we quantified EPSCs and calcium entry in MSO neurons of Mongolian gerbils of either sex raised in a normal and in an activity altered, omnidirectional white noise environment. Global dendritic calcium transients elicited by action potentials disappeared rapidly after hearing onset. Local synaptic calcium transients decreased, leaving a GluR2 lacking AMPAR-mediated influx as the only activity-dependent source in adulthood. Exposure to omnidirectional white noise accelerated the decrease in calcium entry, leaving membrane properties unaffected. Thus, sound-driven activity accelerates the excitatory refinement and shortens the period of activity-dependent calcium signaling around hearing onset. Together with earlier reports, our findings highlight that excitation, inhibition, and biophysical properties are differentially sensitive to distinct features of sensory experience. [ABSTRACT FROM AUTHOR]

Injury to the supraspinal motor systems, especially the corticospinal tract, leads to movement impairments. In addition to direct disruption of descending motor pathways, spinal motor circuits that are distant to and not directly damaged by the lesion undergo remodeling that contributes significantly to the impairments. Knowing which spinal circuits are remodeled and the underlying mechanisms are critical for understanding the functional changes in the motor pathway and for developing repair strategies. Here, we target spinal premotor cholinergic interneurons (IN) that directly modulate motoneuron excitability via their cholinergic C-bouton terminals. Using a model of unilateral medullary corticospinal tract lesion in male rats, we found transneuronal downregulation of the premotor cholinergic pathway. Phagocytic microglial cells were upregulated in parallel with cholinergic pathway downregulation and both were blocked by minocycline, a microglia activation inhibitor. Additionally, we found a transient increase in interneuronal complement protein Clq expression that preceded cell loss. 3D reconstructions showed ongoing phagocytosis of Clq-expressing cholinergic INs by microglia 3 d after injury, which was complete by 10 d after injury. Unilateral motor cortex inactivation using the GABAa receptor agonist muscimol replicated the changes detected at 3 d after lesion, indicating activity dependence. The neuronal loss after the lesion was rescued by increasing spinal activity using cathodal trans-spinal direct current stimulation. Our finding of activity-dependent modulation of cholinergic premotor INs after GST injury provides the mechanistic insight that maintaining activity, possibly during a critical period, helps to protect distant motor circuits from further damage and, as a result, may improve motor functional recovery and rehabilitation. [ABSTRACT FROM AUTHOR]

ABSTRACT The canine knee is morphologically similar to the human knee and thus dogs have been used in experimental models to study human knee pathology. To date, there is limited data of normal canine 3D knee kinematics during daily activities. The objective of this study was to characterize 3D in-vivo femorotibial kinematics in normal dogs during commonly performed daily activities. Using single-plane fluoroscopy, six normal dogs were imaged performing walk, trot, sit, and stair ascent activities. CT-generated bone models were used for kinematic measurement using a 3D-to-2D model registration technique. Increasing knee flexion angle was typically associated with increasing tibial internal rotation, abduction and anterior translation during all four activities. The precise relationship between flexion angle and these movements varied both within and between activities. Significant differences in axial rotation and coronal angulation were found at the same flexion angle during different phases of the walk and trot. This was also found with anterior tibial translation during the trot only. Normal canine knees accommodate motion in all planes; precise kinematics within this envelope of motion are activity dependent. This data establishes the characteristics of normal 3D femorotibial joint kinematics in dogs that can be used as a comparison for future studies. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1603-1610, 2015. [ABSTRACT FROM AUTHOR]

Abstract: Glial cell line-derived neurotrophic factor (GDNF) is widely recognized as a potent survival factor for dopaminergic neurons of the nigrostriatal pathway that degenerate in Parkinson''s disease (PD). In animal models of PD, GDNF delivery to the striatum or the substantia nigra protects dopaminergic neurons against subsequent toxin-induced injury and rescues previously damaged neurons, promoting recovery of the motor function. Thus, GDNF was proposed as a potential therapy to PD aimed at slowing down, halting or reversing neurodegeneration, an issue addressed in previous reviews. However, the use of GDNF as a therapeutic agent for PD is hampered by the difficulty in delivering it to the brain. Another potential strategy is to stimulate the endogenous expression of GDNF, but in order to do that we need to understand how GDNF expression is regulated. The aim of this review is to do a comprehensive analysis of the state of the art on the control of endogenous GDNF expression in the nervous system, focusing mainly on the nigrostriatal pathway. We address the control of GDNF expression during development, in the adult brain and after injury, and how damaged neurons signal glial cells to up-regulate GDNF. Pharmacological agents or natural molecules that increase GDNF expression and show neuroprotective activity in animal models of PD are reviewed. We also provide an integrated overview of the signalling pathways linking receptors for these molecules to the induction of GDNF gene, which might also become targets for neuroprotective therapies in PD. [Copyright &y& Elsevier]

Activity-dependent competition between the corticospinal (CS) systems in each hemisphere drives postnatal development of motor skills and stable CS tract connections with contralateral spinal motor circuits. Unilateral restriction of motor cortex (M1) activity during an early postnatal critical period impairs contralateral visually guided movements later in development and in maturity. Silenced M1 develops aberrant connections with the contralateral spinal cord whereas the initially active M1, in the other hemisphere, develops bilateral connections. In this study, we determined whether the aberrant pattern of CS tract terminations and motor impairments produced by early postnatal M1 activity restriction could be abrogated by reducing activity-dependent synaptic competition from the initially active M1 later in development. We first inactivated M1 unilaterally between postnatal weeks 5-7. We next inactivated M1 on the other side from weeks 7-11 (alternate inactivation), to reduce the competitive advantage that this side may have over the initially inactivated side. Alternate inactivation redirected aberrant contralateral CS tract terminations from the initially silenced M1 to their normal spinal territories and reduced the density of aberrant ipsilateral terminations from the initially active side. Normal movement endpoint control during visually guided locomotion was fully restored. This reorganization of CS terminals reveals an unsuspected late plasticity after the critical period for establishing the pattern of CS terminations in the spinal cord. Our findings show that robust bilateral interactions between the developing CS systems on each side are important for achieving balance between contralateral and ipsilateral CS tract connections and visuomotor control. [ABSTRACT FROM AUTHOR]

Long-term facilitation (LTF) of sensory neuron synapses in Aplysia is produced by either nonassociative or associative stimuli. Nonassociative LTF can be produced by five spaced applications of serotonin (5-HT) and requires a phosphoinosotide 3-kinase (PI3K)- dependent and rapamycin-sensitive increase in the local synthesis of the sensory neuron neuropeptide sensorin and a protein kinase A (PKA)-dependent increase in the secretion of the newly synthesized sensorin. We report here that associative LTF produced by a single pairing of a brief tetanus with one application of 5-HT requires a rapid protein kinase C (PKC)-dependent and rapamycin-sensitive increase in local sensorin synthesis. This rapid increase in sensorin synthesis does not require PI3K activity or the presence of the sensory neuron cell body but does require the presence of the motor neuron. The secretion of newly synthesized sensorin by 2 h after stimulation requires both PKA and PKC activities to produce associative LTF because incubation with exogenous anti-sensorin antibody or the kinase inhibitors after tetanus plus 5-HT blocked LTF. The secreted sensorin leads to phosphorylation and translocation of p42/44 mitogenactivated protein kinase (MAPK) into the nuclei of the sensory neurons. Thus, different stimuli activating different signaling pathways converge by regulating the synthesis and release of a neuropeptide to produce long-term synaptic plasticity. [ABSTRACT FROM AUTHOR]

We have shown previously that the corticospinal tract (CST) with functional connections can be reconstructed in vitro in slice cocultures. Using that system, we stimulated the deep cortical layer and recorded field EPSPs (fEPSPs) along a 100 µm-interval lattice in the spinal gray matter. The specific, spatial synapse distribution on the dorsal side at 14 d in vitro (DIV) basically corresponded to the in vivo area in which CST axons terminate. Anterograde labeling of corticospinal axons with biocytin showed a similar terminal distribution on that side. In vitro development of synapse spatial distribution was investigated, fEPSPs were recorded all across the gray matter at 7 DIV, but amplitudes began to decrease on the ventral side at 9 DIV, dorsal-dominant distribution being nearly complete at 14 DIV. Anterograde labeling showed that the decrease in fEPSP amplitudes was associated with a decrease in the number of axon terminals on the ventral area. Decreases in the synaptic responses and terminals were blocked by applications of D-2-amino-5-phosphonovaleric acid and tetrodotoxin, whereas 6-cyano-7-nitroquinoxaline-2,3-dione had a partial effect. These findings suggest that this regressive event, which occurs during development, is activity and NMDA dependent. Retrograde labeling with two colors of beads and an electrophysiological study that investigated the axon reflex showed that at 7 DIV most corticospinal neurons project to both the ventral and dorsal spinal cord, indicating that synapse decrease on the ventral side is attributable primarily to axon branch elimination rather than to death of cortical cells that send axons solely to that side. [ABSTRACT FROM AUTHOR]

Summary Dendritic spines are the major transmitter reception compartments of glutamatergic synapses in most principal neurons of the mammalian brain and play a key role in the function of nerve cell circuits. The formation of functional spine synapses is thought to be critically dependent on presynaptic glutamatergic signaling. By analyzing CA1 pyramidal neurons in mutant hippocampal slice cultures that are essentially devoid of presynaptic transmitter release, we demonstrate that the formation and maintenance of dendrites and functional spines are independent of synaptic glutamate release. [ABSTRACT FROM AUTHOR]

Injury to the supraspinal motor systems, especially the corticospinal tract, leads to movement impairments. In addition to direct disruption of descending motor pathways, spinal motor circuits that are distant to and not directly damaged by the lesion undergo remodeling that contributes significantly to the impairments. Knowing which spinal circuits are remodeled and the underlying mechanisms are critical for understanding the functional changes in the motor pathway and for developing repair strategies. Here, we target spinal premotor cholinergic interneurons (IN) that directly modulate motoneuron excitability via their cholinergic C-bouton terminals. Using a model of unilateral medullary corticospinal tract lesion in male rats, we found transneuronal downregulation of the premotor cholinergic pathway. Phagocytic microglial cells were upregulated in parallel with cholinergic pathway downregulation and both were blocked by minocycline, a microglia activation inhibitor. Additionally, we found a transient increase in interneuronal complement protein C1q expression that preceded cell loss. 3D reconstructions showed ongoing phagocytosis of C1q-expressing cholinergic INs by microglia 3 d after injury, which was complete by 10 d after injury. Unilateral motor cortex inactivation using the GABA A receptor agonist muscimol replicated the changes detected at 3 d after lesion, indicating activity dependence. The neuronal loss after the lesion was rescued by increasing spinal activity using cathodal trans -spinal direct current stimulation. Our finding of activity-dependent modulation of cholinergic premotor INs after CST injury provides the mechanistic insight that maintaining activity, possibly during a critical period, helps to protect distant motor circuits from further damage and, as a result, may improve motor functional recovery and rehabilitation. SIGNIFICANCE STATEMENT Supraspinal injury to the motor system disrupts descending motor pathways, leading to movement impairments. Whether and how intrinsic spinal circuits are remodeled after a brain injury is unclear. Using a rat model of unilateral corticospinal tract lesion in the medulla, we show activity-dependent, transneuronal downregulation of the spinal premotor cholinergic system, which is mediated by microglial phagocytosis, possibly involving a rapid and transient increase in neuronal C1q before neuronal loss. Spinal cord neuromodulation after injury to augment spinal activity rescued the premotor cholinergic system. Our findings provide the mechanistic insight that maintaining activity, possibly during an early critical period, could protect distant motor circuits from further damage mediated by microglia and interneuronal complement protein and improve motor functional outcomes., (Copyright © 2018 the authors 0270-6474/18/388329-16$15.00/0.)

Background: Alterations in the development of neuronal connectivity can result in dramatic outcomes for brain function. In the cerebral cortex, most sensorimotor and higher-order functions require coordination between precise regions of both hemispheres through the axons that form the corpus callosum. However, little is known about how callosal axons locate and innervate their contralateral targets., Methods: Here, we use a combination of in utero electroporation, retrograde tracing, sensory deprivation and high-resolution axonal quantification to investigate the development, organisation and activity dependence of callosal axons arising from the primary somatosensory cortex of mice., Results: We show that distinct contralateral projections arise from different neuronal populations and form homotopic and heterotopic circuits. Callosal axons innervate the contralateral hemisphere following a dorsomedial to ventrolateral and region-specific order. Furthermore, we identify two periods of region- and layer-specific developmental exuberance that correspond to initial callosal axon innervation and subsequent arborisation. Early sensory deprivation affects only the latter of these events., Conclusion: Taken together, these results reveal the main developmental events of contralateral callosal targeting and may aid future understanding of the formation and pathologies of brain connectivity., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2017.)