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As an emerging framework in neuroscience, brain connectomics is well suited for investigating key questions on brain complexity by combining viral transneuronal tracing and whole brain graphic methodologies using analytical tools of network science. Transsynaptic viral tract-tracing in the toolbox of neural labeling methods has been a significant development in the connectomics field to decipher the circuit-level architecture of the cerebral cortex. In the present work, we reviewed the current methods enabling structural connectivity from the viscera to the cerebral cortex mapping with viral transneuronal tracers and showed how such neuroanatomic connectomic data could be used to infer new structural and functional information in viscera-cerebral cortex circuits., Competing Interests: None., (AJTR Copyright © 2021.)

Propofol is the most common intravenous anesthetic agent for induction and maintenance of anesthesia, and has been used clinically for more than 30 years. However, the mechanism by which propofol induces loss of consciousness (LOC) remains largely unknown. The adenosine A 2A receptor (A 2A R) has been extensively proven to have an effect on physiological sleep. It is, therefore, important to investigate the role of A 2A R in the induction of LOC using propofol. In the present study, the administration of the highly selective A 2A R agonist (CGS21680) and antagonist (SCH58261) was utilized to investigate the function of A 2A R under general anesthesia induced by propofol by means of animal behavior studies, resting-state magnetic resonance imaging and c-Fos immunofluorescence staining approaches. Our results show that CGS21680 significantly prolonged the duration of LOC induced by propofol, increased the c-Fos expression in nucleus accumbens (NAc) and suppressed the functional connectivity of NAc-dorsal raphe nucleus (DR) and NAc-cingulate cortex (CG). However, SCH58261 significantly shortened the duration of LOC induced by propofol, decreased the c-Fos expression in NAc, increased the c-Fos expression in DR, and elevated the functional connectivity of NAc-DR and NAc-CG. Collectively, our findings demonstrate the important roles played by A 2A R in the LOC induced by propofol and suggest that the neural circuit between NAc-DR maybe controlled by A 2A R in the mechanism of anesthesia induced by propofol., (© 2020 International Society for Neurochemistry.)

Background: The outbreak of coronavirus disease 2019 (COVID-19) has spread worldwide and continues to threaten peoples' health as well as put pressure on the accessibility of medical systems. Early prediction of survival of hospitalized patients will help in the clinical management of COVID-19, but a prediction model that is reliable and valid is still lacking., Methods: We retrospectively enrolled 628 confirmed cases of COVID-19 using positive RT-PCR tests for SARS-CoV-2 in Tongji Hospital, Wuhan, China. These patients were randomly grouped into a training (60%) and a validation (40%) cohort. In the training cohort, LASSO regression analysis and multivariate Cox regression analysis were utilized to identify prognostic factors for in-hospital survival of patients with COVID-19. A nomogram based on the 3 variables was built for clinical use. AUCs, concordance indexes (C-index), and calibration curves were used to evaluate the efficiency of the nomogram in both training and validation cohorts., Results: Hypertension, higher neutrophil-to-lymphocyte ratio, and increased NT-proBNP values were found to be significantly associated with poorer prognosis in hospitalized patients with COVID-19. The 3 predictors were further used to build a prediction nomogram. The C-indexes of the nomogram in the training and validation cohorts were 0.901 and 0.892, respectively. The AUC in the training cohort was 0.922 for 14-day and 0.919 for 21-day probability of in-hospital survival, while in the validation cohort this was 0.922 and 0.881, respectively. Moreover, the calibration curve for 14- and 21-day survival also showed high coherence between the predicted and actual probability of survival., Conclusions: We built a predictive model and constructed a nomogram for predicting in-hospital survival of patients with COVID-19. This model has good performance and might be utilized clinically in management of COVID-19., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Cognitive impairment is one of the most common complications associated with chronic pain. Almost 20% of chronic pain patients suffer from cognitive impairment, which may substantially influence their quality of life. Levels of major excitatory neurotransmitters in the central nervous system and alterations in the glutamatergic system may influence cognitive function and the pain sensory pathway. In this study, we adopted the spared nerve injury model to establish the progress of chronic pain and investigated the mechanism underlying the cognitive aspect related to it. At behavioral level, using the novel-object recognition test, mechanical hypersensitivity was observed in peripheral nerve-injured rats because they exhibited recognition deficits. We showed a dramatic decrease in hippocampal glutamate concentration using nuclear magnetic resonance and reduced glutamatergic synaptic transmission using whole-cell recordings. These were associated with deficient hippocampal long-term potentiation induced by high-frequency stimulation of the Schaffer collateral afferent. Ultra-high-performance liquid chromatography revealed lower levels of D-serine in the hippocampus of the spared nerve injury rats and that D-serine treatment could restore synaptic plasticity and cognitive dysfunction. The reduction of excitatory synapses was also increased by administering D-serine. These findings suggest that chronic pain has a critical effect on synaptic plasticity linked to cognitive function and may built up a new target for the development of cognitive impairment under chronic pain conditions.

Functional magnetic resonance imaging (fMRI) has been used extensively to understand the brain function of a wide range of neurological and psychiatric disorders. When applied to animal studies, anesthesia is always used to reduce the movement of the animal and also reduce the impacts on the results of fMRI. Several awake models have been proposed by applying physical animal movement restrictions. However, restraining devices were designed for individual subject which limits the promotion of fMRI in awake animals. Here, a clinical muscle relaxant rocuronium bromide (RB) was introduced to restrain the animal in fMRI scanning time. The fMRI reactions of the animal induced with RB and the other two commonly used anesthesia protocols were investigated. The results of the fMRI showed that there were increased functional connectivity and well-round visual responses in the RB induced state. Furthermore, significant BOLD signal changes were found in the cortex and thalamus regions when the animal revived from isoflurane, which should be essential to further understand the effects of anesthesia on the brain., Competing Interests: None., (AJTR Copyright © 2020.)

Despite the growing knowledge of the mechanisms of chronic pain, the treatment of this disorder in the clinic remains a major challenge. Src-family protein tyrosine kinases (SFKs), a group of non-receptor protein tyrosine kinases, have been implicated in neuronal development and synaptic plasticity. SFKs are critical for the regulate of N-methyl-D-aspartic acid receptor (NMDAR) 2B subunit phosphorylation by various transmembrane receptors, e.g., G-protein coupled receptors (GPCRs), EphB receptors (EphBRs), increased intracellular calcium, epidermal growth factor (EGF) and other growth factors, and thus contribute to the development of chronic pain. SFKs have also been regarded as important points of convergence of intracellular signalling components for the regulation of microglial functions and the immune response. Additionally, the intrathecal administration of SFK inhibitors significantly alleviates mechanical allodynia in different chronic pain models. Here, we reviewed the current evidence for the role of SFKs in the development of chronic pain caused by complete Freund's adjuvant (CFA) injection, peripheral nerve injury (PNI), streptozotocin (STZ) injection and bone metastasis. Moreover, the role of SFKs in the development of morphine tolerance is also discussed. The regulation of SFKs therefore has emerged as a potential therapeutic target for the treatment of chronic pain in terms of safety and efficacy., Competing Interests: Declaration of Competing Interests All authors have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Soups show diverse health functions, which could be linked to their original nutrient profiles and metabolites derived from digestion. NMR spectroscopy is a robust and rapid method that unveils or identifies the chemical composition of food or food-derived metabolites. In the current study, the 1H-NMR spectroscopy approach was applied to identify the differences in metabolic profiling of two kinds of home-cooked freshwater fish soups (crucian carp and snakehead fish) before and after in vitro gastrointestinal digestion. The nutritional profiles of these soups were studied using the 1H-NMR method for the first time. Two metabolomics methods, PCA (Principal Component Analysis) and OPLS-DA (Orthogonal Partial Least Squares Discriminant Analysis), were used to analyze the data. On the whole, levels of amino acid metabolites such as valine (Val), tyrosine, choline, taurine (Tau) and glycine were higher in the crucian carp soup, whereas higher levels of fatty acids and unsaturated fatty acids were found in the snakehead soup. Furthermore, the high content of seven metabolites valine, leucine, EPA C20:5 (PUFA eicosapentaenoic acid), acetic acid, taurine, GPCho (phosphatidylcholine) and creatine showed an upward trend after simulated gastrointestinal digestion. The results demonstrate that the 1H-NMR metabolic profile of different fish soups can shed some light on our understanding of food functional properties and dietary therapy. Furthermore, changes of metabolites in digested fish soups could reveal information about chemical compounds which play important roles in the body.

The accessory olfactory bulb (AOB), located at the posterior dorsal aspect of the main olfactory bulb (MOB), is the first brain relay of the accessory olfactory system (AOS), which can parallelly detect and process volatile and nonvolatile social chemosignals and mediate different sexual and social behaviors with the main olfactory system (MOS). However, due to its anatomical location and absence of specific markers, there is a lack of research on the internal and external neural circuits of the AOB. This issue was addressed by single-color labeling and fluorescent double labeling using retrograde rAAVs injected into the bed nucleus of the stria terminalis (BST), anterior cortical amygdalar area (ACo), medial amygdaloid nucleus (MeA), and posteromedial cortical amygdaloid area (PMCo) in mice. We demonstrated the effectiveness of this AOB projection neuron labeling method and showed that the mitral cells of the AOB exhibited efferent projection dispersion characteristics similar to those of the MOB. Moreover, there were significant differences in the number of neurons projected to different brain regions, which indicated that each mitral cell in the AOB could project to a different number of neurons in different cortices. These results provide a circuitry basis to help understand the mechanism by which pheromone information is encoded and decoded in the AOS.

Efficient viral vectors for mapping and manipulating long-projection neuronal circuits are crucial in structural and functional studies of the brain. The SAD strain rabies virus with the glycoprotein gene deleted pseudotyped with the N2C glycoprotein (SAD-RV(ΔG)-N2C(G)) shows strong neuro-tropism in cell culture, but its in vivo efficiency for retrograde gene transduction and neuro-tropism have not been systematically characterized. We compared these features in different mouse brain regions for SAD-RV-N2C(G) and two other widely-used retrograde tracers, SAD-RV(ΔG)-B19(G) and rAAV2-retro. We found that SAD-RV(ΔG)-N2C(G) enhanced the infection efficiency of long-projecting neurons by ~10 times but with very similar neuro-tropism, compared with SAD-RV(ΔG)-B19(G). On the other hand, SAD-RV(ΔG)-N2C(G) had an infection efficiency comparable with rAAV2-retro, but a more restricted diffusion range, and broader tropism to different types and regions of long-projecting neuronal populations. These results demonstrate that SAD-RV(ΔG)-N2C(G) can serve as an effective retrograde vector for studying neuronal circuits.

Abnormal postoperative neurobehavioral performance (APNP) is a common phenomenon in the early postoperative period. The disturbed homeostatic status of metabolites in the brain after anesthesia and surgery might make a significant contribution to APNP. The dynamic changes of metabolites in different brain regions after anesthesia and surgery, as well as their potential association with APNP are still not well understood. Here, we used a battery of behavioral tests to assess the effects of laparotomy under isoflurane anesthesia in aged mice, and investigated the metabolites in 12 different sub-regions of the brain at different time points using proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy. The abnormal neurobehavioral performance occurred at 6 h and/or 9 h, and recovered at 24 h after anesthesia/surgery. Compared with the control group, the altered metabolite of the model group at 6 h was aspartate (Asp), and the difference was mainly displayed in the cortex; while significant changes at 9 h occurred predominantly in the cortex and hippocampus, and the corresponding metabolites were Asp and glutamate (Glu). All changes returned to baseline at 24 h. The altered metabolic changes could have occurred as a result of the acute APNP, and the metabolites Asp and Glu in the cortex and hippocampus could provide preliminary evidence for understanding the APNP process.

Accumulating evidence suggests that brain metabolic changes may be associated with the pathophysiology of schizophrenia. Both in vivo and in vitro studies have found glutamatergic and GABAergic abnormalities in different brain regions of individuals with schizophrenia. We report a longitudinal behavioral study in a methylazoxymethanol acetate (MAM) rat model of schizophrenia at three different age periods: prepuberty, late-puberty and early-adulthood. MAM-treated rats showed stable hypolocomotive activity, anxiety and cognitive deficits from late-puberty to early-adulthood. Therefore we detected the metabolites changes of adult MAM-treated rats using an in vitro proton nuclear magnetic resonance ( 1 H-NMR) method. In the MAM-treated rats, glutamate was increased in the thalamus and hypothalamus, glutamine was increased in the hippocampus and GABA was increased in the hippocampus and prefrontal cortex, while taurine showed a decrease in the striatum, temporal cortex and parietal cortex. These abnormalities may be helped further understanding the pathophysiology of schizophrenia., Competing Interests: None., (AJTR Copyright © 2019.)

The elucidation of neural networks is essential to understanding the mechanisms of brain functions and brain disorders. Neurotropic virus-based trans-synaptic tracing tools have become an effective method for dissecting the structure and analyzing the function of neural-circuitry. However, these tracing systems rely on fluorescent signals, making it hard to visualize the panorama of the labeled networks in mammalian brain in vivo. One MRI method, Diffusion Tensor Imaging (DTI), is capable of imaging the networks of the whole brain in live animals but without information of anatomical connections through synapses. In this report, a chimeric gene coding for ferritin and enhanced green fluorescent protein (EGFP) was integrated into Vesicular stomatitis virus (VSV), a neurotropic virus that is able to spread anterogradely in synaptically connected networks. After the animal was injected with the recombinant VSV (rVSV), rVSV-Ferritin-EGFP, into the somatosensory cortex (SC) for four days, the labeled neural-network was visualized in the postmortem whole brain with a T2-weighted MRI sequence. The modified virus transmitted from SC to synaptically connected downstream regions. The results demonstrate that rVSV-Ferritin-EGFP could be used as a bimodal imaging vector for detecting synaptically connected neural-network with both ex vivo MRI and fluorescent imaging. The strategy in the current study has the potential to longitudinally monitor the global structure of a given neural-network in living animals., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: The mechanism behind spinal metabolites and myocardial ischemia-reperfusion (IR) injury is not well understood. Proton magnetic resonance spectroscopic analysis of spinal cord extracts provides a quick evaluation of the specific metabolic activity in rats with myocardial IR injury. We investigated the relationship between the IR-related variables and the changes in spinal metabolites., Methods: Proton magnetic resonance spectroscopy ( 1 H-MRS) was used to assess the spinal metabolites of adult rats with and without myocardial IR injury (n = 6 per group). Myocardial IR injury was reproduced using intermittent occlusion of the left anterior descending coronary artery. We studied the relationship between the metabolite ratio measurement and IR-related variables. All rats underwent 1 H-MRS, with the ratio of interest placed in different spinal cord segments to measure levels of twelve metabolites including N-acetylaspartate (NAA), taurine (Tau), glutamate (Glu), gamma amino acid butyric acid (GABA), creatine (Cr), and myoinositol (MI), etc. Results: Rats with myocardial IR injury had higher concentration of Tau in the upper thoracic spinal cord (P < 0.05), and lower concentration of Gly and Glu in the cervical segment of the spinal cord (P < 0.05), when compared to the Control group. The ratios of glutamate/taurine (Glu/Tau), Glu/(GABA + Tau) and Glu/Total were significantly different between the IR group and the Control group in the upper thoracic spinal cord (P < 0.05). So were the ratios of Glu/(GABA + Tau) in the cervical segment (P < 0.05), and Glu/Tau and Glu/(GABA + Tau) in the lower thoracic spinal cord (P < 0.05)., Conclusions: These findings suggest that myocardial IR injury may be related to spinal biochemical alterations. It is speculated that these observed changes in the levels of spinal metabolites may be involved in the pathogenesis and regulation of myocardial IR injury., Competing Interests: None.

Hypertensive patients are more likely to experience latent cerebral ischemia causing regional cerebral oxygen saturation (rSO 2 ) decrease during general anesthesia. The aim of this prospective observational study was to assess the incidence of decreased rSO 2 in hypertensive patients undergoing major abdominal surgery and the perioperative factors affecting this change in rSO 2 . A total of 41 hypertensive patients were enrolled and stratified according to their hypertension as controlled and uncontrolled. The intraoperative rSO 2 and physiological data were routinely collected. The Mini-Mental State Exam (MMSE) was used to test cognitive function before surgery and after 4 days. Cerebral desaturation was defined as a decrease in rSO 2 of more than 20% of the baseline value. There were 20 patients (49%) suffering intraoperative cerebral desaturation classified into cerebral desaturation group (group D) and those 21 without intraoperative desaturation classified into normal group (group N). The area under the curve below 90 and 80% of baseline (AUC rSO2 <90% of baseline and AUC rSO2 <80% of baseline ) was lower in patients of group N (2752.4 ± 1453.3 min% and 0.0 min%) than in patients of group D (6264.9 ± 1832.3 min% and 4486.5 ± 1664.9 min%, P < 0.001). Comparing the two groups, the number of uncontrolled hypertensive individuals in group D (12/20) was significantly more than group N (4/21) (P = 0.007). A significant correlation was observed between relative decrease in MAP and relative decrease in rSO 2 (r 2  = 0.495, P < 0.001). Moreover, nine patients (45%) in group D occurred early postoperative cognitive function decline were more than three patients (14.3%) in group N (P = 0.031). This pilot study showed a large proportion of hypertensive patient experienced cerebral desaturation during major abdominal surgery and uncontrolled hypertension predisposed to this desaturation. NCT02147275 (registered at http://www.clinicaltrials.gov ).

Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients because of our lack of understanding of its mechanisms. Previous studies have shown the vital role of γ-aminobutyric acid B receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats. Our behavioral results show that acute as well as chronic intrathecal treatment with baclofen, a GABABR agonist, significantly attenuated CIBP-induced mechanical allodynia and ambulatory pain. The expression levels of GABABRs were significantly decreased in a time-dependent manner and colocalized mostly with neurons and a minority with astrocytes and microglia. Chronic treatment with baclofen restored the expression of GABABRs and markedly inhibited the activation of cyclic adenosine monophosphate (cAMP)-dependent protein kinase and the cAMP-response element-binding protein signaling pathway., Perspective: Our findings provide, to our knowledge, the first evidence that downregulation of GABABRs contribute to the development and maintenance of CIBP and restored diminished GABABRs attenuate CIBP-induced pain behaviors at least partially by inhibiting the protein kinase/cAMP-response element-binding protein signaling pathway. Therefore, spinal GABABR may become a potential therapeutic target for the management of CIBP., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Major histocompatibility class II (MHC II)-specific activation of CD4 + T helper cells generates specific and persistent adaptive immunity against tumors. Emerging evidence demonstrates that MHC II is also involved in basic pain perception; however, little is known regarding its role in the development of cancer-induced bone pain (CIBP). In this study, we demonstrate that MHC II expression was markedly induced on the spinal microglia of CIBP rats in response to STAT1 phosphorylation. Mechanical allodynia was ameliorated by either pharmacological or genetic inhibition of MHC II upregulation, which was also attenuated by the inhibition of pSTAT1 and pERK but was deteriorated by intrathecal injection of IFNγ. Furthermore, inhibition of ERK signaling decreased the phosphorylation of STAT1, as well as the production of MHC II in vivo and in vitro. These findings suggest that STAT1 contributes to bone cancer pain as a downstream mediator of ERK signaling by regulating MHC II expression in spinal microglia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Previously, we showed that activation of the spinal CXCL9, 10/CXCR3 pathway mediated bone cancer pain (BCP) in rats. However, the cellular mechanism involved is poorly understood. Here, we found that the activated CXCR3 was co-localized with either neurons, microglia, and astrocytes in the spinal cord, or non-peptidergic-, peptidergic-, and A-type neurons in the dorsal root ganglion. The inoculation of Walker-256 mammary gland carcinoma cells into the rat's tibia induced a time-dependent phosphorylation of Akt and extracellular signal-regulated kinase (ERK1/2) in the spinal cord, and CXCR3 was necessary for the phosphorylation of Akt and ERK 1/2. Meanwhile, CXCR3 was co-localized with either pAkt or pERK1/2. Blockage of either Akt or ERK1/2 prevented or reversed the mechanical allodynia in BCP rats. Furthermore, there was cross-activation between PI3K/Akt and Raf/MEK/ERK pathway under the BCP condition. Our results demonstrated that the activation of spinal chemokine receptor CXCR3 mediated BCP through Akt and ERK 1/2 kinase, and also indicated a crosstalk between PI3K/Akt and Raf/MEK/ERK signaling pathways under the BCP condition., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

Aim: To investigate whether the enhanced green fluorescent protein (EGFP) reporter gene could be transferred into human trabecular meshwork (HTM) cells by a HIV-based lentivirus both in vitro and ex vivo., Methods: The HIV-based lentivirus that contains an EF1-α promoter driving EGFP expression cassette was constructed following the standard molecular cloning methods. The cultured HTM cells were transduced at a range of multiplicity of infection (MOI) with HIV-based lentivirus. EGFP positive cell populations were detected by flow cytometry. Human anterior eye segments were cultured with perfusion culture system and transfected by HIV-based lentivirus with a 1×10(8) transducing unit (TU) virus in perfusion liquid. The intraocular pressure was recorded every 8h for 21d. The expression of EGFP in the anterior segment of the human eye was detected by fluorescence microscopy. Furthermore, the distribution of EGFP expression was confirmed by anti-EGFP immunohistochemical staining., Results: The HIV-based lentivirus which contains an EF1-α promoter driving EGFP expression cassette was constructed successfully. After HTM cells were transduced with HIV-based lentivirus containing EGFP in vitro, the ratio of EGFP positive cells to the total cell number reached 92.3%, with the MOI of 15. After the lentivirus containing EGFP were used to transduce human anterior eye segments, the EGFP could be directly detected by fluorescence microscopy in vivo. Immunohistochemistry staining revealed that 88.19% EGFP-positive trabecular meshwork (TM) cells were observed in the human anterior segment. Nevertheless, the intraocular pressure in the lentivirus-transduced group kept constant when compared with control group (P>0.05)., Conclusion: EGFP gene could be efficiently transferred into HTM cells both in vitro and ex vivo by using HIV-based lentivirus.

The etiology of postoperative pain may be different from antigen-induced inflammatory pain and neuropathic pain. However, central neural plasticity plays a key role in incision pain. It is also known that phosphatidylinositol 3-kinase (PI3K) and protein kinase B/Akt (PKB/Akt) are widely expressed in laminae I-IV of the spinal horn and play a critical role in spinal central sensitization. In the present study, we explored the role of PI3K and Akt in incision pain behaviors. Plantar incision induced a time-dependent activation of spinal PI3K-p110γ and Akt, while activated Akt and PI3K-p110γ were localized in spinal neurons or microglias, but not in astrocytes. Pre-treatment with PI3K inhibitors, wortmannin or LY294002 prevented the activation of Akt brought on by plantar incision in a dose-dependent manner. In addition, inhibition of spinal PI3K signaling pathway prevented pain behaviors (dose-dependent) and spinal Fos protein expression caused by plantar incision. These data demonstrated that PI3K signaling mediated pain behaviors caused by plantar incision in mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)