Spinal morphine but not ziconotide or gabapentin analgesia is affected by alternative splicing of voltage-gated calcium channel CaV2.2 pre-mRNA

Presynaptic voltage-gated calcium CaV2.2 channels play a privileged role in spinal level sensitization following peripheral nerve injury. Direct and indirect inhibitors of CaV2.2 channel activity in spinal dorsal horn are analgesic in chronic pain states. CaV2.2 channels represent a family of splice isoforms that are expressed in different combinations according to cell-type. A pair of mutually exclusive exons in the CaV2.2 encoding Cacna1b gene, e37a and e37b, differentially influence morphine analgesia. In mice that lack exon e37a, which is enriched in nociceptors, the analgesic efficacy of intrathecal morphine against noxious thermal stimuli is reduced. Here we ask if sequences unique to e37a influence: the development of abnormal thermal and mechanical sensitivity associated with peripheral nerve injury; and the actions of two other classes of analgesics that owe part or all of their efficacy to CaV2.2 channel inhibition. We find that: i) the analgesic efficacy of morphine, but not ziconotide or gabapentin, is reduced in mice lacking e37a, ii) the induction and maintenance of behaviors associated with sensitization that accompany peripheral nerve injury, do not require e37a-specific sequence, iii) intrathecal morphine, but not ziconotide or gabapentin analgesia to thermal stimuli is significantly lower in wild-type mice after peripheral nerve injury, iv) the analgesic efficacy of ziconotide and gabapentin to mechanical stimuli is reduced following nerve injury, and iv) intrathecal morphine analgesia to thermal stimuli in mice lacking e37a is not further reduced by peripheral nerve injury. Our findings show that the analgesic action of morphine, but not ziconotide or gabapentin, to thermal stimuli is linked to which Cacna1b exon, e37a or e37b, is selected during alternative pre-mRNA splicing

Competition with primary sensory afferents drives remodeling of corticospinal axons in mature spinal motor circuits

Injury to the mature motor system drives significant spontaneous axonal sprouting instead of axon regeneration. Knowing the circuitlevel determinants of axonal sprouting is important for repairing motor circuits after injury to achieve functional rehabilitation. Competitive interactions are known to shape corticospinal tract axon outgrowth and withdrawal during development. Whether and how competition contributes to reorganization of mature spinal motor circuits is unclear. To study this question, we examined plastic changes in corticospinal axons in response to two complementary proprioceptive afferent manipulations: (1) enhancing proprioceptive afferents activity by electrical stimulation; or (2) diminishing their input by dorsal rootlet rhizotomy. Experiments were conducted in adult rats. Electrical stimulation produced proprioceptive afferent sprouting that was accompanied by significant corticospinal axon withdrawal and a decrease in corticospinal connections on cholinergic interneurons in the medial intermediate zone and C boutons on motoneurons. In contrast, dorsal rootlet rhizotomy led to a significant increase in corticospinal connections, including those on cholinergic interneurons; C bouton density increased correspondingly. Motor cortex-evoked muscle potentials showed parallel changes to those of corticospinal axons, suggesting that reciprocal corticospinal axon changes are functional. Using the two complementary models, we showed that competitive interactions between proprioceptive and corticospinal axons are an important determinant in the organization of mature corticospinal axons and spinal motor circuits. The activity- and synaptic space-dependent properties of the competition enables prediction of the remodeling of spared corticospinal connection and spinal motor circuits after injury and informs the target-specific control of corticospinal connections to promote functional recovery

Nonlinear dynamic response analysis of a cantilever beam with a breathing crack

The nonlinear dynamic characteristics of plane cracked beam subjected to a harmonic load at the tip are researched. A crack opens and closes during vibration that is simulated as a frictionless plane contact problem, and a finite element contact model for a cantilever cracked beam is established. The quarter-point element is used to describe the crack tip singularity. Based on the proposed finite element contact model, the influence of excitation frequency, crack depth and crack position on nonlinear dynamic characteristics are discussed in detail. Relative amplitude of frequency spectrum with respect to different factors is analyzed to realize sub-harmonics or super-harmonics of cracked beam. The research results demonstrate that there is obvious nonlinear dynamic behavior for plane beam with a fatigue crack, and the different feature of frequency spectrum can be used to identify the beam damage in structure. Meanwhile, the strategy of experimental validation to the FEM results is discussed

Global attractivity and permanence of a SVEIR epidemic model with pulse vaccination and time delay

AbstractIn this study, we propose a new SVEIR epidemic disease model with time delay, and analyze the dynamic behavior of the model under pulse vaccination. Pulse vaccination is an effective strategy for the elimination of infectious disease. Using the discrete dynamical system determined by the stroboscopic map, we obtain an ‘infection-free’ periodic solution. We also show that the ‘infection-free’ periodic solution is globally attractive when some parameters of the model under appropriate conditions. The permanence of the model is investigated analytically. Our results indicate that a large vaccination rate or a short pulse of vaccination or a long latent period is a sufficient condition for the extinction of the disease

Impact of high-frequency pumping on anomalous finite-size effects in three-dimensional topological insulators

Lowering of the thickness of a thin-film three-dimensional topological insulator down to a few nanometers results in the gap opening in the spectrum of topologically protected two-dimensional surface states. This phenomenon, which is referred to as the anomalous finite-size effect, originates from hybridization between the states propagating along the opposite boundaries. In this work, we consider a bismuth-based topological insulator and show how the coupling to an intense high-frequency linearly polarized pumping can further be used to manipulate the value of a gap. We address this effect within recently proposed Brillouin-Wigner perturbation theory that allows us to map a time-dependent problem into a stationary one. Our analysis reveals that both the gap and the components of the group velocity of the surface states can be tuned in a controllable fashion by adjusting the intensity of the driving field within an experimentally accessible range and demonstrate the effect of light-induced band inversion in the spectrum of the surface states for high enough values of the pump.Comment: 6 pages, 3 figure

The impact of social comparison on the neural substrates of reward processing: An event-related potential study

Event-related potentials (ERPs) were recorded to explore the electrophysiological correlates of reward processing in the social comparison context when subjects performed a simple number estimation task that entailed monetary rewards for correct answers. Three social comparison stimulus categories (three relative reward levels/self reward related to the other subject\u27s) were mainly prepared: Self:Other=1:2 (Disadvantageous inequity condition); Self:Other=1:1 (Equity condition); and Self:Other=2:1 (Advantageous inequity condition). Results showed that: both Disadvantageous and Advantageous inequity elicited a more negative ERP deflection (N350–550) than did Equity between 350 and 550 ms, and the generators of N350–550 were localized near the parahippocampal gyrus and the medial frontal/anterior cingulate cortex, which might be related to monitor and control reward prediction error during reward processing. Then, Disadvantageous and Advantageous inequity both elicited a more late negative complex (LNC1 and LNC2) than did Equity between 550 and 750 ms. The generators of LNC1 and LNC2 were both localized near the caudate nucleus, which might be related to reward processing under social comparison