Emerging byte-addressable non-volatile memory devices attract much attention. A non-volatile main memory (NVMM) built on them enables larger memory size and lower power consumption than a traditional ...DRAM main memory. To fully utilize an NVMM, both software and hardware must be cooperatively optimized. Simultaneously, even focusing on a memory module, its micro architecture is still being developed though real non-volatile memory modules, such as Intel Optane DC persistent memory (DCPMM), have been on the market. Looking at existing NVMM evaluation environments, software simulators can evaluate various micro architectures with their long simulation time. Emulators can evaluate the whole system fast with less flexibility in their configuration than simulators. Thus, an NVMM emulator that can realize flexible and fast system evaluation still has an important role to explore the optimal system. In this paper, we introduce an NVMM emulator for embedded systems and explore a direction of optimization techniques for NVMMs by using it. It is implemented on an SoC-FPGA board employing three NVMM behaviour models: coarse-grain, fine-grain and DCPMM-based. The coarse and fine models enable NVMM performance evaluations based on extensions of traditional DRAM behaviour. The DCPMM-based model emulates the behaviour of a real DCPMM. Whole evaluation environment is also provided including Linux kernel modifications and several runtime functions. We first validate the developed emulator with an existing NVMM emulator, a cycle-accurate NVMM simulator and a real DCPMM. Then, the program behavior differences among three models are evaluated with SPEC CPU programs. As a result, the fine-grain model reveals the program execution time is affected by the frequency of NVMM memory requests rather than the cache hit ratio. Comparing with the fine-grain model and the coarse-grain model under the condition of the former's longer total write latency than the latter's, the former shows lower execution time for four of fourteen programs than the latter because of the bank-level parallelism and the row-buffer access locality exploited by the former model.
Primary afferents are known to be inhibited by kappa opioid receptor (KOR) signaling. However, the specific types of somatosensory neurons that express KOR remain unclear. Here, using a newly ...developed KOR-cre knockin allele, viral tracing, single-cell RT-PCR, and ex vivo recordings, we show that KOR is expressed in several populations of primary afferents: a subset of peptidergic sensory neurons, as well as low-threshold mechanoreceptors that form lanceolate or circumferential endings around hair follicles. We find that KOR acts centrally to inhibit excitatory neurotransmission from KOR-cre afferents in laminae I and III, and this effect is likely due to KOR-mediated inhibition of Ca2+ influx, which we observed in sensory neurons from both mouse and human. In the periphery, KOR signaling inhibits neurogenic inflammation and nociceptor sensitization by inflammatory mediators. Finally, peripherally restricted KOR agonists selectively reduce pain and itch behaviors, as well as mechanical hypersensitivity associated with a surgical incision. These experiments provide a rationale for the use of peripherally restricted KOR agonists for therapeutic treatment.
•KOR is expressed in peptidergic primary afferents in mouse and human•KOR is expressed in LTMRs that form circumferential and lanceolate endings•KOR signaling inhibits nociceptor sensitization and neurogenic inflammation•Peripherally selective KOR agonists inhibit nociception
Snyder et al. identify primary afferents that express the kappa opioid receptor in mouse and human and show that kappa opioid receptor signaling inhibits these cells in physiological and behavioral experiments.
We investigated whether the descending noradrenergic system regulates allergic itch. Mosquito allergy of the hind paw elicited biting, an itch-related response, in sensitized mice. The biting was ...inhibited by intrathecal clonidine and reversed by yohimbine, an α2-adrenoceptor antagonist. The biting was increased by intrathecal pretreatment with the catecholaminergic neurotoxin 6-hydroxydopamine and the α-adrenoceptor antagonist phentolamine but not the serotonergic neurotoxin 5,7-dihydroxytryptamine. We propose that α2-adrenoceptors are involved in the inhibition of allergic itch in the spinal cord and that the descending noradrenergic system exerts a tonic inhibition on the itch signaling. The serotonergic system may not be involved.
The somatosensory input that gives rise to the perceptions of pain, itch, cold and heat are initially integrated in the superficial dorsal horn of the spinal cord. Here, we describe a new approach to ...investigate these neural circuits in mouse. This semi-intact somatosensory preparation enables recording from spinal output neurons, while precisely controlling somatosensory input, and simultaneously manipulating specific populations of spinal interneurons. Our findings suggest that spinal interneurons show distinct temporal and spatial tuning properties. We also show that modality selectivity - mechanical, heat and cold - can be assessed in both retrogradely labeled spinoparabrachial projection neurons and genetically labeled spinal interneurons. Finally, we demonstrate that interneuron connectivity can be determined via optogenetic activation of specific interneuron subtypes. This new approach may facilitate key conceptual advances in our understanding of the spinal somatosensory circuits in health and disease.
This study was conducted to identify the characteristic pharmacological features of GT-0198 that is phenoxymethylbenzamide derivatives. GT-0198 inhibited the function of glycine transporter 2 (GlyT2) ...in human GlyT2-expressing HEK293 cells and did not bind various major transporters or receptors of neurotransmitters in a competitive manner. Thus, GT-0198 is considered to be a comparatively selective GlyT2 inhibitor. Intravenous, oral, and intrathecal injections of GT-0198 decreased the pain-related response in a model of neuropathic pain with partial sciatic nerve ligation. This result suggests that GT-0198 has an analgesic effect. The analgesic effect of GT-0198 was abolished by the intrathecal injection of strychnine, a glycine receptor antagonist. Therefore, GT-0198 is considered to exhibit its analgesic effect via the activation of a glycine receptor by glycine following presynaptic GlyT2 inhibition in the spinal cord. In summary, GT-0198 is a structurally novel GlyT2 inhibitor bearing a phenoxymethylbenzamide moiety with in vivo efficacy in behavioral models of neuropathic pain.
With growing on-device IoT processing, security on edge devices becomes increasingly important. Among Trusted Execution Environment (TEE), an open-source RISC-V Keystone TEE is the expected one. ...However, some issues remain when applying it to various devices: untrusted DRAM, and untrusted path to non-volatile storage. These issues can be resolved by Memory Protection Engine (MPE) based on an integrity tree, and Non-Volatile Main Memory (NVMM), respectively. TEE, MPE, and NVMM must be cooperatively optimized to exploit performance. Despite this demand, there is no widely available platform which enables fast, reliable, and system-wide evaluation. In the paper, we provide an open-source hardware simulator for secure edge devices. We implemented an MPE using SGX-style Integrity Tree on the Keystone compatible RISC-V SoC. Then, we ported the NVMM simulation technique to it. Its whole design was publicized to widely provide a baseline hardware design. The MPE behavior was validated by using micro benchmarks. It revealed that the MPE read/write overhead is <inline-formula><tex-math notation="LaTeX">2.55\times /4.16\times</tex-math> <mml:math><mml:mrow><mml:mn>2</mml:mn><mml:mo>.</mml:mo><mml:mn>55</mml:mn><mml:mo>×</mml:mo><mml:mo>/</mml:mo><mml:mn>4</mml:mn><mml:mo>.</mml:mo><mml:mn>16</mml:mn><mml:mo>×</mml:mo></mml:mrow></mml:math><inline-graphic xlink:href="omori-ieq1-3197777.gif"/> </inline-formula> on DRAM, and <inline-formula><tex-math notation="LaTeX">3.05\times /5.40\times</tex-math> <mml:math><mml:mrow><mml:mn>3</mml:mn><mml:mo>.</mml:mo><mml:mn>05</mml:mn><mml:mo>×</mml:mo><mml:mo>/</mml:mo><mml:mn>5</mml:mn><mml:mo>.</mml:mo><mml:mn>40</mml:mn><mml:mo>×</mml:mo></mml:mrow></mml:math><inline-graphic xlink:href="omori-ieq2-3197777.gif"/> </inline-formula> on NVMM, respectively. Besides, we discuss our work's role by comparing with the gem5 considering TEE evaluation time and impact of the protected NVMM.
This study was conducted to make a new mouse model of neuropathic pain due to injury to a branch of the sciatic nerve. One of three branches (sural, tibial, and common peroneal nerves) of the sciatic ...nerve was tightly ligated, and mechanical and cool stimuli were applied to the medial part (tibial and common peroneal nerve territories) of the plantar skin. The three types of nerve injuries produced behavioral mechanical hypersensitivities, and the extent of the hypersensitivities after sural and tibial nerve ligation was larger than that of common peroneal nerve ligation. Sural nerve ligation did not affect motor function of the affected hind paw, but tibial and common peroneal nerve ligation produced motor dysfunction. These results suggest that the ligation of the sural nerve is the most suitable for behavioral study. Sural nerve ligation induced behavioral hypersensitivities to mechanical and cool stimuli, which were almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation increased spontaneous activity and responses of the wide-dynamic range neurons in the lumbar dorsal horn, which were also almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation provides a new mouse model of neuropathic pain, which is easy to prepare and sensitive to gabapentin.
This study was conducted to identify the mechanosensitive dorsal horn neurons involved in allergic itch. We examined 98 units responsive to cutaneous allergy; 90 showed only immediate responses, ...which subsided before the onset of itch-related behavior and eight showed immediate and sustained responses, the latter of which was similar in duration to itch-related behavior, suggesting the involvement of sustained units in itch signaling. Sustained units were localized in the superficial, but not deep, layers of the dorsal horn. They were wide dynamic range or nociceptive specific, but not low threshold and four of eight were noxious heat sensitive. The results suggest that a small minority of neurons in the superficial dorsal horn are involved in allergic itch signals.
The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain
. Projection neurons of the anterolateral pathway ...are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain. However, the organizational logic of the anterolateral pathway remains poorly understood. Here we show that two populations of projection neurons that express the structurally related G-protein-coupled receptors (GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperate to convey thermal, tactile and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons. Within this nucleus, axons of spinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinct sets of subnuclei, and strong optogenetic stimulation of the axon terminals induces distinct escape behaviours and autonomic responses. Moreover, SPB neurons that express Gpr83 are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Notably, the valence associated with activation of SPB neurons that express Gpr83 can be either positive or negative, depending on stimulus intensity. These findings reveal anatomically, physiologically and functionally distinct subdivisions of the SPB tract that underlie affective aspects of touch and pain.
Wind-up is a frequency-dependent increase in the response of spinal cord neurons, which is believed to underlie temporal summation of nociceptive input. However, whether spinoparabrachial neurons, ...which likely contribute to the affective component of pain, undergo wind-up was unknown. Here, we addressed this question and investigated the underlying neural circuit. We show that one-fifth of lamina I spinoparabrachial neurons undergo wind-up, and provide evidence that wind-up in these cells is mediated in part by a network of spinal excitatory interneurons that show reverberating activity. These findings provide insight into a polysynaptic circuit of sensory augmentation that may contribute to the wind-up of pain's unpleasantness.
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