General anesthesia (GA) can produce analgesia (loss of pain) independent of inducing loss of consciousness, but the underlying mechanisms remain unclear. We hypothesized that GA suppresses pain in ...part by activating supraspinal analgesic circuits. We discovered a distinct population of GABAergic neurons activated by GA in the mouse central amygdala (CeA
neurons). In vivo calcium imaging revealed that different GA drugs activate a shared ensemble of CeA
neurons. CeA
neurons also possess basal activity that mostly reflects animals' internal state rather than external stimuli. Optogenetic activation of CeA
potently suppressed both pain-elicited reflexive and self-recuperating behaviors across sensory modalities and abolished neuropathic pain-induced mechanical (hyper-)sensitivity. Conversely, inhibition of CeA
activity exacerbated pain, produced strong aversion and canceled the analgesic effect of low-dose ketamine. CeA
neurons have widespread inhibitory projections to many affective pain-processing centers. Our study points to CeA
as a potential powerful therapeutic target for alleviating chronic pain.
Humans often rank craniofacial pain as more severe than body pain. Evidence suggests that a stimulus of the same intensity induces stronger pain in the face than in the body. However, the underlying ...neural circuitry for the differential processing of facial versus bodily pain remains unknown. Interestingly, the lateral parabrachial nucleus (PB
), a critical node in the affective pain circuit, is activated more strongly by noxious stimulation of the face than of the hindpaw. Using a novel activity-dependent technology called CANE developed in our laboratory, we identified and selectively labeled noxious-stimulus-activated PB
neurons and performed comprehensive anatomical input-output mapping. Surprisingly, we uncovered a hitherto uncharacterized monosynaptic connection between cranial sensory neurons and the PB
-nociceptive neurons. Optogenetic activation of this monosynaptic craniofacial-to-PB
projection induced robust escape and avoidance behaviors and stress calls, whereas optogenetic silencing specifically reduced facial nociception. The monosynaptic circuit revealed here provides a neural substrate for heightened craniofacial affective pain.
How general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown. Previous studies have revealed that ...many GA drugs inhibit neural activity through targeting GABA receptors. Here, using Fos staining, ex vivo brain slice recording, and in vivo multi-channel electrophysiology, we discovered a core ensemble of hypothalamic neurons in and near the supraoptic nucleus, consisting primarily of neuroendocrine cells, which are persistently and commonly activated by multiple classes of GA drugs. Remarkably, chemogenetic or brief optogenetic activations of these anesthesia-activated neurons (AANs) strongly promote slow-wave sleep and potentiates GA, whereas conditional ablation or inhibition of AANs led to diminished slow-wave oscillation, significant loss of sleep, and shortened durations of GA. These findings identify a common neural substrate underlying diverse GA drugs and natural sleep and reveal a crucial role of the neuroendocrine system in regulating global brain states.
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•General-anesthesia-activated neurons (AANs) are identified in hypothalamus•AANs consist mainly of neuroendocrine cells in and near the supraoptic nucleus•Activation of AANs promotes slow-wave sleep and extends general anesthesia•Inhibition of AANs shortens general anesthesia and disrupts natural sleep
Jiang-Xie et al. identified a specific group of hypothalamic neurons (AANs) commonly activated by multiple classes of general anesthetics. Stimulation of AANs potentiates slow-wave sleep and general anesthesia (GA), whereas inhibition of AANs disrupts natural sleep and destabilizes GA.
Acetylcholine is an important neurotransmitter, and the habenulo-interpeduncular projection is a major cholinergic pathway in the brain. To study the physiological properties of cholinergic ...transmission in the interpeduncular nucleus (IPN), we used a transgenic mouse line in which the light-gated cation channel ChannelRhodopsin-2 is selectively expressed in cholinergic neurons. Cholinergic axonal terminals were activated by light pulses, and postsynaptic responses were recorded from IPN neurons. Surprisingly, brief photostimulation produces fast excitatory postsynaptic currents that are mediated by ionotropic glutamate receptors, suggesting wired transmission of glutamate. By contrast, tetanic photostimulation generates slow inward currents that are largely mediated by nicotinic acetylcholine receptors, suggesting volume transmission of acetylcholine. Finally, vesicular transporters for glutamate and acetylcholine are coexpressed on the same axonal terminals in the IPN. These results strongly suggest that adult brain “cholinergic” neurons can corelease glutamate and acetylcholine, but these two neurotransmitters activate postsynaptic neurons via different transmission modes.
► We used optogenetics to study acetylcholine transmission in the adult mouse brain ► Acetylcholine is coreleased with glutamate by habenula cholinergic neurons ► Glutamate transmission follows the “wired transmission” mode ► Acetylcholine transmission follows the “volume transmission” mode
Primary pain and touch sensory neurons not only detect internal and external sensory stimuli, but also receive inputs from other neurons. However, the neuronal derived inputs for primary neurons have ...not been systematically identified. Using a monosynaptic rabies viruses-based transneuronal tracing method combined with sensory-specific Cre-drivers, we found that sensory neurons receive intraganglion, intraspinal, and supraspinal inputs, the latter of which are mainly derived from the rostroventral medulla (RVM). The viral-traced central neurons were largely inhibitory but also consisted of some glutamatergic neurons in the spinal cord and serotonergic neurons in the RVM. The majority of RVM-derived descending inputs were dual GABAergic and enkephalinergic (opioidergic). These inputs projected through the dorsolateral funiculus and primarily innervated layers I, II, and V of the dorsal horn, where pain-sensory afferents terminate. Silencing or activation of the dual GABA/enkephalinergic RVM neurons in adult animals substantially increased or decreased behavioral sensitivity, respectively, to heat and mechanical stimuli. These results are consistent with the fact that both GABA and enkephalin can exert presynaptic inhibition of the sensory afferents. Taken together, this work provides a systematic view of and a set of tools for examining peri- and extrasynaptic regulations of pain-afferent transmission.
Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ...ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4-22 (Δe4-22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4-22(-/-) mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.
Anoikis resistance is a prerequisite for the successful development of osteosarcoma (OS) metastases, whether the expression of anoikis-related genes (ARGs) correlates with OS prognosis remains ...unclear. This study aimed to investigate the feasibility of using ARGs as prognostic tools for the risk stratification of OS.
The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases provided transcriptome information relevant to OS. The GeneCards database was used to identify ARGs. Differentially expressed ARGs (DEARGs) were identified by overlapping ARGs with common differentially expressed genes (DEGs) between OS and normal samples from the GSE16088, GSE19276, and GSE99671 datasets. Anoikis-related clusters of patients were obtained by consistent clustering, and gene set variation analysis (GSVA) of the different clusters was completed. Next, a risk model was created using Cox regression analyses. Risk scores and clinical features were assessed for independent prognostic values, and a nomogram model was constructed. Subsequently, a functional enrichment analysis of the high- and low-risk groups was performed. In addition, the immunological characteristics of OS samples were compared between the high- and low-risk groups, and their sensitivity to therapeutic agents was explored.
Seven DEARGs between OS and normal samples were obtained by intersecting 501 ARGs with 68 common DEGs.
and
were significantly differentially expressed between both clusters (
<0.05) and were identified as prognosis-related genes. The risk model showed that the risk score and tumor metastasis were independent prognostic factors of patients with OS. A nomogram combining risk score and tumor metastasis effectively predicted the prognosis. In addition, patients in the high-risk group had low immune scores and high tumor purity. The levels of immune cell infiltration, expression of human leukocyte antigen (HLA) genes, immune response gene sets, and immune checkpoints were lower in the high-risk group than those in the low-risk group. The low-risk group was sensitive to the immune checkpoint PD-1 inhibitor, and the high-risk group exhibited lower inhibitory concentration values by 50% for 24 drugs, including AG.014699, AMG.706, and AZD6482.
The prognostic stratification framework of patients with OS based on ARGs, such as
and
, may lead to more efficient clinical management.
In this paper, the optimal distributed Kalman filtering fusion with linear equality constraint (LEC) is proposed. When the Kalman filter subject to LEC is applied in state estimation of distributed ...linear dynamic system, all local error covariance matrices are singular, which is a challenge for most of the existing distributed fusion algorithms. However, the new fusion algorithm is rigorously derived with matrix analysis technique on the Moore-Penrose inverse. Updating state estimate and error covariance matrix, the new fusion algorithm only uses local estimates and their corresponding error covariances. We have proved theoretically that the distributed Kalman filtering with LEC (DKF-LEC) just using all local measurements is equivalent to the centralized Kalman filtering with LEC (CKF-LEC), which means it is optimal. Furthermore, we also prove the optimality of the proposed fusion formula for Kalman filtering with LEC and feedback. In addition, the simulation results show that the proposed fusion formula for Kalman filtering with LEC have the same performance of the centralized Kalman filtering with LEC whether considering feedback or not. It is consistent with the theoretical result that the DKF-LEC is equivalent to CKF-LEC as the estimate of CKF-LEC is disassembled into local estimates in distributed system. And the performance of the new fusion formula for Kalman filtering with LEC and feedback is obviously better than those without feedback.
To analyze the association between scoliosis and vertebral refracture after percutaneous kyphoplasty (PKP) in patients with osteoporotic vertebral compression fractures (OVCFs).
A retrospective study ...was conducted on 269 patients meeting the criteria from January 2014 to October 2022. All patients underwent PKP with complete data and were followed-up for > 12 months. First, it was verified that scoliosis was a risk factor in 269 patients. Second, patients with scoliosis were grouped based on the Cobb angle to evaluate the impact of the post-operative angle. The cox proportional hazards regression analysis and survival analysis were used to calculate the hazard ratio and recurrence time.
A total of 56 patients had scoliosis, 18 of whom experienced refractures after PKP. The risk factors for vertebral refractures included a T-score < - 3.0 and presence of scoliosis (both p < 0.001). The results indicated that the vertebral fractured arc (T10 - L4) was highly influential in scoliosis and vertebral fractures. When scoliotic and initially fractured vertebrae were situated within T10 - L4, the risk factors for vertebral refracture included a postoperative Cobb angle of ≥ 20° (p = 0.002) and an increased angle (p = 0.001). The mean recurrence times were 17.2 (10.7 - 23.7) months and 17.6 (7.9 - 27.3) months, respectively.
Osteoporosis combined with scoliosis significantly increases the risk of vertebral refractures after PKP in patients with OVCFs. A postoperative Cobb angle of ≥ 20° and an increased angle are significant risk factors for vertebral refractures when scoliotic and initially fractured vertebrae are situated within T10 - L4.
In some experiments, the levels of some factors are difficult to change; then fractional factorial split-plot (FFSP) designs are suitable for selection. In an FFSP design, the factors are divided ...into two classes—the whole plot (WP) and subplot (SP) factors. In some experiments, the selection of the levels of the WP factors can affect that of the SP factors, which attracts much attention to the WP factors. Paying more attention to the WP factors, a new optimality criterion for selecting such FFSP designs is proposed. The robustness of the proposed method is discussed. The construction method of the optimal designs under the new criterion is studied.
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