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•Neurons devoid of plasmalogens have impaired excitability.•Plasmalogen deficiency causes a distal repositioning of the axon initial segment (AIS).•Identification of the AKT-ULK1 ...signaling cascade as regulator of AIS positioning•Rescuing plasmalogens or the defective signaling pathway restores normal AIS localization.
The axon initial segment (AIS) is a specialized region in neurons that encompasses two essential functions, the generation of action potentials and the regulation of the axodendritic polarity. The mechanism controlling the position of the axon initial segment to allow plasticity and regulation of neuron excitability is unclear. Here we demonstrate that plasmalogens, the most abundant ether-phospholipid, are essential for the homeostatic positioning of the AIS. Plasmalogen deficiency is a hallmark of Rhizomelic Chondrodysplasia Punctata (RCDP) and Zellweger spectrum disorders, but Alzheimer’s and Parkinson’s disease, are also characterized by plasmalogen defects. Neurons lacking plasmalogens displaced the AIS to more distal positions and were characterized by reduced excitability. Treatment with a short-chain alkyl glycerol was able to rescue AIS positioning. Plasmalogen deficiency impaired AKT activation, and we show that inhibition of AKT phosphorylation at Ser473 and Thr308 is sufficient to induce a distal relocation of the AIS. Pathway analysis revealed that downstream of AKT, overtly active ULK1 mediates AIS repositioning. Rescuing the impaired AKT signaling pathway was able to normalize AIS position independently of the biochemical defect. These results unveil a previously unknown mechanism that couples the phospholipid composition of the neuronal membrane to the positional assembly of the AIS.
Mirror-image pain arises from pathologic alterations in the nociceptive processing network that controls functional lateralization of the primary afferent input. Although a number of clinical ...syndromes related to dysfunction of the lumbar afferent system are associated with the mirror-image pain, its morphophysiological substrate and mechanism of induction remain poorly understood. Therefore, we used
spinal cord preparation of young rats of both sexes to study organization and processing of the contralateral afferent input to the neurons in the major spinal nociceptive projection area Lamina I. We show that decussating primary afferent branches reach contralateral Lamina I, where 27% of neurons, including projection neurons, receive monosynaptic and/or polysynaptic excitatory drive from the contralateral Aδ-fibers and C-fibers. All these neurons also received ipsilateral input, implying their involvement in the bilateral information processing. Our data further show that the contralateral Aδ-fiber and C-fiber input is under diverse forms of inhibitory control. Attenuation of the afferent-driven presynaptic inhibition and/or disinhibition of the dorsal horn network increased the contralateral excitatory drive to Lamina I neurons and its ability to evoke action potentials. Furthermore, the contralateral Aβδ-fibers presynaptically control ipsilateral C-fiber input to Lamina I neurons. Thus, these results show that some lumbar Lamina I neurons are wired to the contralateral afferent system whose input, under normal conditions, is subject to inhibitory control. A pathologic disinhibition of the decussating pathways can open a gate controlling contralateral information flow to the nociceptive projection neurons and, thus, contribute to induction of hypersensitivity and mirror-image pain.
We show that contralateral Aδ-afferents and C-afferents supply lumbar Lamina I neurons. The contralateral input is under diverse forms of inhibitory control and itself controls the ipsilateral input. Disinhibition of decussating pathways increases nociceptive drive to Lamina I neurons and may cause induction of contralateral hypersensitivity and mirror-image pain.
One hundred twenty Siberian lemmings (
Lemmus sibiricus
) were studied from Kotelnyi Island in the eastern sector of the Polar basin. The main habitats, abundance, nutrition, shelters, breeding, and ...sex–age structure were described for the first time in the conditions of the arctic climate and the depleted vegetation of the New Siberian Islands. The morphological parameters confirming the subspecific status of the Siberian lemming on these islands are given. The possibility that the collared lemming (
Dicrostonyx torquatus
) inhabited the archipelago during the Late Pleistocene and in the modern period are discussed. The important roles the Siberian lemming could have played in the vegetation cover, the formation of upper soil horizons, the surface microrelief, the microclimate, and the ecosystem productivity of the island are shown.
Abstract
The paper attempts to consider such economic and legal category as land, in terms of its role as an environmental object. The tendencies of development of this category in the sphere of ...state policy and dynamics of domestic legislation are investigated. The separate attention is devoted to lands of an agricultural purpose - the most important of all categories of ground fund as it includes the most valuable productive earths. As an object of legal relations, this category of land is a unique natural resource, which can be depleted by inappropriate and illiterate use and requiring large costs to restore their fertility.
Although spinal processing of sensory information greatly relies on afferent-driven (AD) presynaptic inhibition (PI), our knowledge about how it shapes peripheral input to different types of ...nociceptive neurons remains insufficient. Here we examined the AD-PI of primary afferent input to spinal neurons in the marginal layer, lamina I, and the layer surrounding the central canal, lamina X; two nociceptive-processing regions with similar patterns of direct supply by Aδ- and C-afferents. Unmyelinated C-fibers were selectively activated by electrical stimuli of negative polarity that induced an anodal block of myelinated Aβ/δ-fibers. Combining this approach with the patch-clamp recording in an
spinal cord preparation, we found that attenuation of the AD-PI by the anodal block of Aβ/δ-fibers resulted in the appearance of new mono- and polysynaptic C-fiber-mediated excitatory postsynaptic current (EPSC) components. Such homosegmental Aβ/δ-AD-PI affected neurons in the segment of the dorsal root entrance as well as in the adjacent rostral segment. In their turn, C-fibers from the L5 dorsal root induced heterosegmental AD-PI of the inputs from the L4 Aδ- and C-afferents to the neurons in the L4 segment. The heterosegmental C-AD-PI was reciprocal since the L4 C-afferents inhibited the L5 Aδ- and C-fiber inputs, as well as some direct L5 Aβ-fiber inputs. Moreover, the C-AD-PI was found to control the spike discharge in spinal neurons. Given that the homosegmental Aβ/δ-AD-PI and heterosegmental C-AD-PI affected a substantial percentage of lamina I and X neurons, we suggest that these basic mechanisms are important for shaping primary afferent input to the neurons in the spinal nociceptive-processing network.
Serotonergic mechanisms play a central role in migraine pathology. However, the region-specific effects of serotonin (5-HT) mediated via multiple types of receptors in the nociceptive system are ...poorly understood. Using extracellular and patch-clamp recordings, we studied the action of 5-HT on the excitability of peripheral and central terminals of trigeminal afferents. 5-HT evoked long-lasting TTX-sensitive firing in the peripheral terminals of meningeal afferents, the origin site of migraine pain. Cluster analysis revealed that in majority of nociceptive fibers 5-HT induced either transient or persistent spiking activity with prevailing delta and theta rhythms. The 5-HT3-receptor antagonist MDL-72222 or 5-HT1B/D-receptor antagonist GR127935 largely reduced, but their combination completely prevented the excitatory pro-nociceptive action of 5-HT. The 5-HT3 agonist mCPBG activated spikes in MDL-72222-dependent manner but the 5HT-1 receptor agonist sumatriptan did not affect the nociceptive firing. 5-HT also triggered peripheral CGRP release in meninges, which was blocked by MDL-72222.5-HT evoked fast membrane currents and Ca2+ transients in a fraction of trigeminal neurons. Immunohistochemistry showed expression of 5-HT3A receptors in fibers innervating meninges. Endogenous release of 5-HT from degranulated mast cells increased nociceptive firing. Low pH but not histamine strongly activated firing. 5-HT reduced monosynaptic inputs from trigeminal Aδ- and C-afferents to the upper cervical lamina I neurons and this effect was blocked by MDL-72222. Consistent with central inhibitory effect, 5-HT reduced CGRP release in the brainstem slices. In conclusion, 5-HT evokes powerful pro-nociceptive peripheral and anti-nociceptive central effects in trigeminal system transmitting migraine pain.
•5-HT induced a robust nociceptive activity in peripheral nerve terminals in meninges.•5-HT3 receptors contributed to pro-nociceptive action 5-HT and CGRP release.•Cluster analysis revealed fibers with remarkably long-lasting firing activity.•In contrast to periphery, 5-HT inhibited central nerve terminals of nociceptors.
The importance of 3D protein structure in proteolytic processing is well known. However, despite the plethora of existing methods for predicting proteolytic sites, only a few of them utilize the ...structural features of potential substrates as predictors. Moreover, to our knowledge, there is currently no method available for predicting the structural susceptibility of protein regions to proteolysis. We developed such a method using data from CutDB, a database that contains experimentally verified proteolytic events. For prediction, we utilized structural features that have been shown to influence proteolysis in earlier studies, such as solvent accessibility, secondary structure, and temperature factor. Additionally, we introduced new structural features, including length of protruded loops and flexibility of protein termini. To maximize the prediction quality of the method, we carefully curated the training set, selected an appropriate machine learning method, and sampled negative examples to determine the optimal positive-to-negative class size ratio. We demonstrated that combining our method with models of protease primary specificity can outperform existing bioinformatics methods for the prediction of proteolytic sites. We also discussed the possibility of utilizing this method for bioinformatics prediction of other post-translational modifications.
The spinal gray matter region around the central canal, lamina X, is critically involved in somatosensory processing and visceral nociception. Although several classes of primary afferent fibers ...terminate or decussate in this area, little is known about organization and functional significance of the afferent supply of lamina X neurons. Using the hemisected ex vivo spinal cord preparation, we show that virtually all lamina X neurons receive primary afferent inputs, which are predominantly mediated by the high-threshold Aδ- fibers and C-fibers. In two-thirds of the neurons tested, the inputs were monosynaptic, implying a direct targeting of the population of lamina X neurons by the primary nociceptors. Beside the excitatory inputs, 48% of the neurons also received polysynaptic inhibitory inputs. A complex pattern of interactions between the excitatory and inhibitory components determined the output properties of the neurons, one-third of which fired spikes in response to the nociceptive dorsal root stimulation. In this respect, the spinal gray matter region around the central canal is similar to the superficial dorsal horn, the major spinal nociceptive processing area. We conclude that lamina X neurons integrate direct and indirect inputs from several types of thin primary afferent fibers and play an important role in nociception.
The most superficial layer of the spinal dorsal horn, lamina I, is a key element of the nociceptive processing system. It contains different types of projection neurons (PNs) and local-circuit ...neurons (LCNs) whose functional roles in the signal processing are poorly understood. This article reviews recent progress in elucidating novel anatomical features and physiological properties of lamina I PNs and LCNs revealed by whole-cell recordings in ex vivo spinal cord.
This article is part of the Special Issue on “Ukrainian Neuroscience”.
•Recording in ex vivo spinal cord reveals novel properties of lamina I neurons.•Most projection neurons have different types of local axon collaterals.•GABAergic local-circuit neurons in lamina I show intrinsic rhythmic firing.•Lamina I neurons integrate broad input from Aβ-, Aδ- and C-afferent fibers.•Lamina I is involved in somatovisceral, trigeminocervical and bilateral integration.
Ruthenocene-based PCP
pincer ligands were used to synthesize novel pincer palladium chloride Rc
PCP
PdCl (
) and two novel palladium tetrahydroborates Rc
PCP
Pd(BH
) (
) and Rc
PCP
Pd(BH
) (
), where ...Rc
PCP
= κ
-{2,5-(tBu
PCH
)
C
H
}Ru(Cp
) (Cp
= C
Me
CF
), and Rc*PCP
= κ
-{2,5-(tBu
PCH
)
C
H
}Ru(Cp*) (Cp* = C
Me
). These coordination compounds were characterized by X-ray, NMR and FTIR techniques. Analysis of the X-ray data shows that an increase of the steric bulk of non-metalated cyclopentadienyl ring in
and
relative to non-substituted RcPCP
Pd(BH
) analogue (
; where RcPCP
= κ
-{2,5-(tBu
PCH
)
C
H
}Ru(Cp), Cp = C
H
) pushes palladium atom from the middle plane of the metalated Cp ring in the direction opposite to the ruthenium atom. This displacement increases in the order
<
<
following the order of the Cp-ring steric volume increase. The analysis of both X-ray and IR data suggests that BH
ligand in both palladium tetrahydroborates
and
has the mixed coordination mode η
. The strength of the BH
bond with palladium atom increases in the order RcPCP
Pd(BH
) < Rc*PCP
Pd(BH
) < Rc
PCP
Pd(BH
) that appears to be affected by both steric and electronic properties of the ruthenocene moiety.
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