CRF regulates pain sensation by enhancement of corticoaccumbal excitatory synaptic transmission.

Both peripheral and central corticotropin-releasing factor (CRF) systems have been implicated in regulating pain sensation. However, compared with the peripheral, the mechanisms underlying central CRF system in pain modulation have not yet been elucidated, especially at the neural circuit level. The corticoaccumbal circuit, a structure rich in CRF receptors and CRF-positive neurons, plays an important role in behavioral responses to stressors including nociceptive stimuli. The present study was designed to investigate whether and how CRF signaling in this circuit regulated pain sensation under physiological and pathological pain conditions. Our studies employed the viral tracing and circuit-, and cell-specific electrophysiological methods to label the CRF-containing circuit from the medial prefrontal cortex to the nucleus accumbens shell (mPFCCRF-NAcS) and record its neuronal propriety. Combining optogenetic and chemogenetic manipulation, neuropharmacological methods, and behavioral tests, we were able to precisely manipulate this circuit and depict its role in regulation of pain sensation. The current study found that the CRF signaling in the NAc shell (NAcS), but not NAc core, was necessary and sufficient for the regulation of pain sensation under physiological and pathological pain conditions. This process was involved in the CRF-mediated enhancement of excitatory synaptic transmission in the NAcS. Furthermore, we demonstrated that the mPFCCRF neurons monosynaptically connected with the NAcS neurons. Chronic pain increased the protein level of CRF in NAcS, and then maintained the persistent NAcS neuronal hyperactivity through enhancement of this monosynaptic excitatory connection, and thus sustained chronic pain behavior. These findings reveal a novel cell- and circuit-based mechanistic link between chronic pain and the mPFCCRF → NAcS circuit and provide a potential new therapeutic target for chronic pain.

Disinhibition of Mesolimbic Dopamine Circuit by the Lateral Hypothalamus Regulates Pain Sensation.

Our recent study demonstrated the critical role of the mesolimbic dopamine (DA) circuit and its brain-derived neurotropic factor (BDNF) signaling in mediating neuropathic pain. The present study aims to investigate the functional role of GABAergic inputs from the lateral hypothalamus (LH) to the ventral tegmental area (VTA; LHGABA→VTA) in regulating the mesolimbic DA circuit and its BDNF signaling underlying physiological and pathologic pain. We demonstrated that optogenetic manipulation of the LHGABA→VTA projection bidirectionally regulated pain sensation in naive male mice. Optogenetic inhibition of this projection generated an analgesic effect in mice with pathologic pain induced by chronic constrictive injury (CCI) of the sciatic nerve and persistent inflammatory pain by complete Freund's adjuvant (CFA). Trans-synaptic viral tracing revealed a monosynaptic connection between LH GABAergic neurons and VTA GABAergic neurons. Functionally, in vivo calcium/neurotransmitter imaging showed an increased DA neuronal activity, decreased GABAergic neuronal activity in the VTA, and increased dopamine release in the NAc, in response to optogenetic activation of the LHGABA→VTA projection. Furthermore, repeated activation of the LHGABA→VTA projection was sufficient to increase the expression of mesolimbic BDNF protein, an effect seen in mice with neuropathic pain. Inhibition of this circuit induced a decrease in mesolimbic BDNF expression in CCI mice. Interestingly, the pain behaviors induced by activation of the LHGABA→VTA projection could be prevented by pretreatment with intra-NAc administration of ANA-12, a TrkB receptor antagonist. These results demonstrated that LHGABA→VTA projection regulated pain sensation by targeting local GABAergic interneurons to disinhibit the mesolimbic DA circuit and regulating accumbal BDNF release.SIGNIFICANCE STATEMENT The mesolimbic dopamine (DA) system and its brain-derived neurotropic factor (BDNF) signaling have been implicated in pain regulation, however, underlying mechanisms remain poorly understood. The lateral hypothalamus (LH) sends different afferent fibers into and strongly influences the function of mesolimbic DA system. Here, utilizing cell type- and projection-specific viral tracing, optogenetics, in vivo calcium and neurotransmitter imaging, our current study identified the LHGABA→VTA projection as a novel neural circuit for pain regulation, possibly by targeting the VTA GABA-ergic neurons to disinhibit mesolimbic pathway-specific DA release and BDNF signaling. This study provides a better understanding of the role of the LH and mesolimbic DA system in physiological and pathological pain.

Influence of Perioperative Anesthesia on Cancer Recurrence: from Basic Science to Clinical Practice.

PURPOSEOF REVIEW: In this review, we will summarize the effects of these perioperative anesthetics and anesthetic interventions on the immune system and tumorigenesis as well as address the related clinical evidence on cancer-related mortality and recurrence. RECENT FINDINGS: Cancer remains a leading cause of morbidity and mortality worldwide. For many solid tumors, surgery is one of the major therapies. Unfortunately, surgery promotes angiogenesis, shedding of circulating cancer cells, and suppresses immunity. Hence, the perioperative period has a close relationship with cancer metastases or recurrence. In the perioperative period, patients require multiple anesthetic management including anesthetics, anesthetic techniques, and body temperature control. Preclinical and retrospective studies have found that these anesthetic agents and interventions have complex effects on cancer outcomes. Therefore, well-planned, prospective, randomized controlled trials are required to explore the effects of different anesthetics and techniques on long-term outcomes after cancer surgery. Due to the conflicting effects of anesthetic management on cancer recurrence, further preclinical and clinical trials are required and beneficial to the development of systemic cancer therapies.

Contralateral Projection of Anterior Cingulate Cortex Contributes to Mirror-Image Pain.

Long-term limb nerve injury often leads to mirror-image pain (MIP), an abnormal pain sensation in the limb contralateral to the injury. Although it is clear that MIP is mediated in part by central nociception processing, the underlying mechanisms remain poorly understood. The anterior cingulate cortex (ACC) is a key brain region that receives relayed peripheral nociceptive information from the contralateral limb. In this study, we induced MIP in male mice, in which a unilateral chronic constrictive injury of the sciatic nerve (CCI) induced a decreased nociceptive threshold in both hind limbs and an increased number of c-Fos-expressing neurons in the ACC both contralateral and ipsilateral to the injured limb. Using viral-mediated projection mapping, we observed that a portion of ACC neurons formed monosynaptic connections with contralateral ACC neurons. Furthermore, the number of cross-callosal projection ACC neurons that exhibited c-Fos signal was increased in MIP-expressing mice, suggesting enhanced transmission between ACC neurons of the two hemispheres. Moreover, selective inhibition of the cross-callosal projection ACC neurons contralateral to the injured limb normalized the nociceptive sensation of the uninjured limb without affecting the increased nociceptive sensation of the injured limb in CCI mice. In contrast, inhibition of the non-cross-callosal projection ACC neurons contralateral to the injury normalized the nociceptive sensation of the injured limb without affecting the MIP exhibited in the uninjured limb. These results reveal a circuit mechanism, namely, the cross-callosal projection of ACC between two hemispheres, that contributes to MIP and possibly other forms of contralateral migration of pain sensation.SIGNIFICANCE STATEMENT Mirror-image pain (MIP) refers to the increased pain sensitivity of the contralateral body part in patients with chronic pain. This pathology requires central processing, yet the mechanisms are less known. Here, we demonstrate that the cross-callosal projection neurons in the anterior cingulate cortex (ACC) contralateral to the injury contribute to MIP exhibited in the uninjured limb, but do not affect nociceptive sensation of the injured limb. In contrast, the non-cross-callosal projection neurons in the ACC contralateral to the injury contribute to nociceptive sensation of the injured limb, but do not affect MIP exhibited in the uninjured limb. Our study depicts a novel cross-callosal projection of ACC that contributes to MIP, providing a central mechanism for MIP in chronic pain state.

Cortical and Thalamic Interaction with Amygdala-to-Accumbens Synapses.

The nucleus accumbens shell (NAcSh) regulates emotional and motivational responses, a function mediated, in part, by integrating and prioritizing extensive glutamatergic projections from limbic and paralimbic brain regions. Each of these inputs is thought to encode unique aspects of emotional and motivational arousal. The projections do not operate alone, but rather are often activated simultaneously during motivated behaviors, during which they can interact and coordinate in shaping behavioral output. To understand the anatomic and physiological bases underlying these interprojection interactions, the current study in mice of both sexes focused on how the basolateral amygdala projection (BLAp) to the NAcSh regulates, and is regulated by, projections from the medial prefrontal cortex (mPFCp) and paraventricular nucleus of the thalamus (PVTp). Using a dual-color SynaptoTag technique combined with a backfilling spine imaging strategy, we found that all three afferent projections primarily targeted the secondary dendrites of NAcSh medium spiny neurons, forming putative synapses. We detected a low percentage of BLAp contacts closely adjacent to mPFCp or PVTp presumed synapses, and, on some rare occasions, the BLAp formed heterosynaptic interactions with mPFCp or PVTp profiles or appeared to contact the same spines. Using dual-rhodopsin optogenetics, we detected signs of dendritic summation of BLAp with PVTp and mPFCp inputs. Furthermore, high-frequency activation of BLAp synchronous with the PVTp or mPFCp resulted in a transient enhancement of the PVTp, but not mPFCp, transmission. These results provide anatomic and functional indices that the BLAp interacts with the mPFCp and PVTp for informational processing within the NAcSh.SIGNIFICANCE STATEMENT The nucleus accumbens regulates emotional and motivational responses by integrating extensive glutamatergic projections, but the anatomic and physiological bases on which these projections integrate and interact remain underexplored. Here, we used dual-color synaptic markers combined with backfilling of nucleus accumbens medium spiny neurons to reveal some unique anatomic alignments of presumed synapses from the basolateral amygdala, medial prefrontal cortex, and paraventricular nucleus of thalamus. We also used dual-rhodopsin optogenetics in brain slices, which reveal a nonlinear interaction between some, but not all, projections. These results provide compelling anatomic and physiological mechanisms through which different glutamatergic projections to the nucleus accumbens, and possibly different aspects of emotional and motivational arousal, interact with each other for final behavioral output.

[Calpain-2 and calcineurin protein expression in right atrial appendages from patients underwent valve replacement with or without atrial fibrillation].

OBJECTIVE: To investigate the relationship between the protein expression of calpain-2 and calcineurin (CaN) and atrial fibrillation (AF) in patient with valvular heart disease (VHD). METHODS: A total of 40 patients who underwent valve replacement surgery in our hospital from March 2013 to March 2014, right atrial appendages were excised during operation and patients were divided into sinus rhythm (SR) group (n = 17) and AF group (n = 23). The protein expression of calpain-2 and the α-isoform of CaN catalytic subunit (CnA) in the right atrial appendages were determined by Western blot. RESULTS: The protein levels of the full-length CnAa (60,000), the 45,000 fragment of CnAa without autoinhibitory domain, and calpain-2 were significantly upregulated in the AF group compared to the SR group (1.25 ± 0.51 vs. 0.76 ± 0.37, 1.08 ± 0.37 vs. 0.76 ± 0.25, and 0.82 ± 0.44 vs. 0.51 ± 0.19, respectively, all P < 0.05). CONCLUSION: Activated calpain-2-CaN signal pathway might be involved in the pathogenesis of AF.

A novel olfactory biosensor based on ZIF-8@SWCNT integrated with nanosome-AuNPs/Prussian blue for sensitive detection of hexanal.

Hexanal is considered as an important volatile compound indicator for the assessment of freshness and maturity of foods. Therefore, sensitive and stable monitoring of hexanal is highly desired. Herein, an efficient receptor immobilization strategy based on ZIF-8@ Single-walled carbon nanotube (SWCNT) and nanosomes-AuNPs/Prussian blue (PB) was proposed for the development of olfactory biosensors. ZIF-8@SWCNT as dual support materials provided a high density of active sites for nanosomes loading. Moreover, the co-electrodeposition of nanosomes-AuNPs and PB on the sensor interface effectively amplified the electrochemical signal and maintained the activity of the receptor. The combination of ZIF-8@SWCNT with AuNPs/PB imparts excellent sensing performance of the biosensor with a wide detection range of 10-16-10-9 M, a low detection limit of 10-16 M for hexanal, and a long storage stability of 15 days. These results indicate that our biosensor can be a powerful tool for versatile applications in food and other related industries.

Expression levels of ERCC1 and RRM1 mRNA and clinical outcome of advanced non-small cell lung cancer.

OBJECTIVE: We conducted a study to understand the genetic effect of ERCC1 and RRM1 on the chemotherapy response and clinical outcome of Non-Small Cell Lung Cancer (NSCLC). METHODS: The relative cDNA quantification for ERCC1 and RRM1 was conducted using a fluorescence-based real-time detection method among 294 NSCLC patients. RESULTS: Compared with the internal reference gene ß-action, the median levels of ERCC1 and RRM1 expression were 2.43×10(-2) and 0.11×10(-2), respectively. Our study showed response to platinum-containing regimen chemotherapy was high in those with high ERCC1 expression, and the OR (95% CI) were 1.73(1.06-2.81). An apparently high response to chemotherapy was decreased when patients were carrying both high expression of ERCC1 and RRM1, with OR (95% CI) of 2.57(1.21-4.90). Patients with high expression of ERCC1 were associated with a longer OS by multivariate Cox proportional hazards model. Moreover, those carrying both high levels of ERCC1 and RRM1 were seem to have a longer OS when compared with those with low expression (HR=0.31, 95% CI=0.13-0.62 for OS). CONCLUSION: This observation could be used in personalized chemotherapy, increase the response rate and prolonged survival time, and could encourage to explore the predictive value of other genes.

Neuropathic pain generates silent synapses in thalamic projection to anterior cingulate cortex.

ABSTRACT: Pain experience can change the central processing of nociceptive inputs, resulting in persistent allodynia and hyperalgesia. However, the underlying circuit mechanisms remain underexplored. Here, we focus on pain-induced remodeling of the projection from the mediodorsal thalamus (MD) to the anterior cingulate cortex (ACC), a projection that relays spinal nociceptive input for central processing. Using optogenetics combined with slice electrophysiology, we detected in male mice that 7 days of chronic constriction injury (CCI; achieved by loose ligation of the sciatic nerve) generated AMPA receptor (AMPAR)-silent glutamatergic synapses within the contralateral MD-to-ACC projection. AMPAR-silent synapses are typically GluN2B-enriched nascent glutamatergic synapses that mediate the initial formation of neural circuits during early development. During development, some silent synapses mature and become "unsilenced" by recruiting and stabilizing AMPARs, consolidating and strengthening the newly formed circuits. Consistent with these synaptogenic features, pain-induced generation of silent synapses was accompanied by increased densities of immature dendritic spines in ACC neurons and increased synaptic weight of GluN2B-containing NMDA receptors (NMDARs) in the MD-to-ACC projection. After prolonged (∼30 days) CCI, injury-generated silent synapses declined to low levels, which likely resulted from a synaptic maturation process that strengthens AMPAR-mediated MD-to-ACC transmission. Consistent with this hypothesis, viral-mediated knockdown of GluN2B in ACC neurons, which prevented pain-induced generation of silent synapses and silent synapse-mediated strengthening of MD-to-ACC projection after prolonged CCI, prevented the development of allodynia. Taken together, our results depict a silent synapse-mediated mechanism through which key supraspinal neural circuits that regulate pain sensitivity are remodeled to induce allodynia and hyperalgesia.

Chronic Pain Impairs Memory Formation via Disruption of Neurogenesis Mediated by Mesohippocampal Brain-Derived Neurotrophic Factor Signaling.

BACKGROUND: Chronic pain patients often complain of their poor memory. The mechanisms underlying chronic pain-related memory impairment remain elusive, and there are few clinical therapeutic strategies available for this condition. METHODS: In a neuropathic pain model induced by chronic constrictive injury of the sciatic nerve in male mice, we used circuit-specific electrophysiological recording, combined with chemogenetic, molecular, and pharmacologic methods, to examine the circuit and molecular mechanisms underlying chronic pain-related memory impairment. RESULTS: Our current results show that chronic neuropathic pain impaired the acquisition of spatial memory and, meanwhile, reduced adult neurogenesis in the dentate gyrus. Experimentally reducing dentate gyrus neurogenesis mimicked this pain-induced effect on spatial memory formation in naïve mice. Furthermore, pain-associated impairments of both hippocampal neurogenesis and memory formation were rescued or mimicked by chemogenetic activation or deactivation, respectively, of the ventral tegmental area dopaminergic projection, through which ventral tegmental area-released brain-derived neurotrophic factor was required. Importantly, we found that chronic, but not acute, systematic administration of subanesthetic doses of ketamine, while without relieving pain, ameliorated chronic pain-related impairment of spatial memory formation, potentially by rescuing brain-derived neurotrophic factor-mediated dentate gyrus neurogenesis. CONCLUSIONS: These findings provide a novel, circuit-based mechanistic link between chronic pain and memory formation deficit, and potential new therapeutic options for chronic pain-related learning deficit and memory impairment.