Glia-derived adenosine in the ventral hippocampus drives pain-related anxiodepression in a mouse model resembling trigeminal neuralgia.

Glial activation and dysregulation of adenosine triphosphate (ATP)/adenosine are involved in the neuropathology of several neuropsychiatric illnesses. The ventral hippocampus (vHPC) has attracted considerable attention in relation to its role in emotional regulation. However, it is not yet clear how vHPC glia and their derived adenosine regulate the anxiodepressive-like consequences of chronic pain. Here, we report that chronic cheek pain elevates vHPC extracellular ATP/adenosine in a mouse model resembling trigeminal neuralgia (rTN), which mediates pain-related anxiodepression, through a mechanism that involves synergistic effects of astrocytes and microglia. We found that rTN resulted in robust activation of astrocytes and microglia in the CA1 area of the vHPC (vCA1). Genetic or pharmacological inhibition of astrocytes and connexin 43, a hemichannel mainly distributed in astrocytes, completely attenuated rTN-induced extracellular ATP/adenosine elevation and anxiodepressive-like behaviors. Moreover, inhibiting microglia and CD39, an enzyme primarily expressed in microglia that degrades ATP into adenosine, significantly suppressed the increase in extracellular adenosine and anxiodepressive-like behaviors. Blockade of the adenosine A2A receptor (A2AR) alleviated rTN-induced anxiodepressive-like behaviors. Furthermore, interleukin (IL)-17A, a pro-inflammatory cytokine probably released by activated microglia, markedly increased intracellular calcium in vCA1 astrocytes and triggered ATP/adenosine release. The astrocytic metabolic inhibitor fluorocitrate and the CD39 inhibitor ARL 67156, attenuated IL-17A-induced increases in extracellular ATP and adenosine, respectively. In addition, astrocytes, microglia, CD39, and A2AR inhibitors all reversed rTN-induced hyperexcitability of pyramidal neurons in the vCA1. Taken together, these findings suggest that activation of astrocytes and microglia in the vCA1 increases extracellular adenosine, which leads to pain-related anxiodepression via A2AR activation. Approaches targeting astrocytes, microglia, and adenosine signaling may serve as novel therapies for pain-related anxiety and depression.

Toward Antifragility: Social Defeat Stress Enhances Learning and Memory in Young Mice Via Hippocampal Synaptosome Associated Protein 25.

Social adversity not only causes severe psychological diseases but also may improve people's ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 (SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A+ neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility.

Distinct Function of Estrogen Receptors in the Rodent Anterior Cingulate Cortex in Pain-related Aversion.

BACKGROUND: Brain-derived estrogen is implicated in pain-related aversion; however, which estrogen receptors mediate this effect remains unclear. This study hypothesized that the different estrogen receptors in the rostral anterior cingulate cortex play distinct roles in pain-related aversion. METHODS: Formalin-induced conditioned place avoidance and place escape/avoidance paradigms were used to evaluate pain-related aversion in rodents. Immunohistochemistry and Western blotting were used to detect estrogen receptor expression. Patch-clamp recordings were used to examine N-methyl-D-aspartate-mediated excitatory postsynaptic currents in rostral anterior cingulate cortex slices. RESULTS: The administration of the estrogen receptor-ß antagonist 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP) or the G protein-coupled estrogen receptor-1 antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15) but not the estrogen receptor-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) into the rostral anterior cingulate cortex blocked pain-related aversion in rats (avoidance score, mean ± SD: 1,3-bis [4-hydroxyphenyl]-4-methyl-5-(4-[2-piperidinylethoxy] phenol)-1H-pyrazole dihydrochloride (MPP): 47.0 ± 18.9%, 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP): -7.4 ± 20.6%, and [3aS*,4R*,9bR*]-4-[6-bromo-1,3-benzodioxol-5-yl]-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15): -4.6 ± 17.0% vs. vehicle: 46.5 ± 12.2%; n = 7 to 9; P < 0.0001). Consistently, estrogen receptor-ß knockdown but not estrogen receptor-α knockdown by short-hairpin RNA also inhibited pain-related aversion in mice (avoidance score, mean ± SD: estrogen receptor-α-short-hairpin RNA: 26.0 ± 7.1% and estrogen receptor-ß-short-hairpin RNA: 6.3 ± 13.4% vs. control short-hairpin RNA: 29.1 ± 9.1%; n = 7 to 10; P < 0.0001). Furthermore, the direct administration of the estrogen receptor-ß agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein-coupled estrogen receptor-1 agonist (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1) into the rostral anterior cingulate cortex resulted in conditioned place avoidance (avoidance score, mean ± SD: 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN): 35.3 ± 9.5% and (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1): 43.5 ± 22.8% vs. vehicle: 0.3 ± 14.9%; n = 8; P < 0.0001) but did not affect mechanical or thermal sensitivity. The activation of the estrogen receptor-ß/protein kinase A or G protein-coupled estrogen receptor-1/protein kinase B pathway elicited the long-term potentiation of N-methyl-D-aspartate-mediated excitatory postsynaptic currents. CONCLUSIONS: These findings indicate that estrogen receptor-ß and G protein-coupled estrogen receptor-1 but not estrogen receptor-α in the rostral anterior cingulate cortex contribute to pain-related aversion by modulating N-methyl-D-aspartate receptor-mediated excitatory synaptic transmission.

Monitoring of Gas Emboli During Hysteroscopic Surgery: A Prospective Study.

OBJECTIVES: Previous studies have demonstrated a high frequency of gas emboli during hysteroscopy, but guidelines for the prevention, early detection, and intervention of gas embolism during hysteroscopic procedures are still lacking. This study aimed to gain a clearer understanding of risk factors and specific signs and symptoms associated with gas emboli. METHODS: This prospective study enrolled 120 women scheduled for hysteroscopy using 5% glucose as distension medium. The gas bubbles were monitored sequentially in internal iliac vein, common iliac vein, inferior vena cava, superior vena cava, heart, and pulmonary artery under the gray-scale imaging of Doppler ultrasound. The frequency, extent, and the hemodynamic and respiratory effects of gas emboli were evaluated. The interventions and outcomes were recorded. The risk factors associated with gas emboli, and their relationship with the frequency and extent of gas emboli, were assessed. RESULTS: In our study, evidence of gas emboli under Doppler ultrasound monitoring was observed in 44 (36.7%) patients. The operation was continued and finished as soon as possible for patients presenting with stable vital signs or transient hemodynamic and respiratory changes, which resolved spontaneously without intervention. The operation was paused for patients presenting with significant hemodynamic changes or loss of consciousness, and the operation was resumed shortly after resumption of stable vital signs following symptomatic treatment. All patients in our study finished the operation and recovered without developing serious complications. Data analysis showed prolonged procedure duration and increased bleeding volume were both positively correlated with the frequency and extent of gas emboli. CONCLUSION: Our study demonstrated a high frequency of gas emboli during hysteroscopy. Doppler ultrasonic monitoring combined with a clearer understanding of specific signs, symptoms, and risk factors will facilitate early detection and intervention of gas emboli during hysteroscopy.

[Treatment of Sepsis-associated Encephalopathy by Xingnaojing Injection: a Clinical Observation].

OBJECTIVE: To observe the efficacy of Xingnaojing Injection (XI) in treatment of sepsis-associated encephalopathy (SAE). METHODS: Totally 65 SAE patients were retrospectively analyzed at EICU from September 2010 to September 2013. They were assigned to the control group (32 cases) and the treatment group (33 cases) according to whether they received XI. Patients in the control group received anti-infection and symptomatic support, while those in the treatment group were intravenously injected with XI at 20 mL per day for additional 7-10 days. The fever clearance time, Glasgow coma scale (GCS), C-reactive protein (CRP), neuron-specific enolase (NSE), and improvement of electroen-cephalogram (EEG) were observed in the two groups. RESULTS: Compared with the control group, the fever clearance time was shortened, CRP levels decreased, GCS score and efficacy of EEG was alleviated in the treatment group after treatment with statistical difference (P < 0.05). No adverse reaction occurred during medication. CONCLUSION: X1 was safe and effective in treatment of SAE.

Characteristics of patients with initial diagnosis of systemic lupus erythematosus in emergency department and their outcomes: a retrospective single-center study.

STUDY OBJECTIVE: This study aims to investigate the characteristics of patients with an initial diagnosis of systemic lupus erythematosus (SLE) in an emergency department (ED) and their outcomes. METHODS: A total of 147 SLE patients (119 females and 28 males, mean age 26 ± 19 years) who visited the ED of the Peking University People's Hospital between January 2017 and June 2022 were enrolled in the study. Data on demographic information, clinical characteristics, comorbidities, therapy, and outcomes were collected. RESULTS: Most patients visit ED because of symptoms related to SLE (74.8%, 110/147). The remaining 37 patients (25.2%) visited ED due to infection (43.2%, 16/37), gastrointestinal bleeding (10.8%, 4/37), coronary heart or cerebrovascular disease (18.9%, 7/37), macrophage activation syndrome or thrombotic microangiopathy (18.9%, 7/37), leukemia (5.4%, 2/37), and hepatic encephalopathy (2.7%, 1/37). Of the patients, 54.4% (80/147) were first diagnosed with SLE at the time of their ED visit. Thrombocytopenia events occurred significantly more frequently in this group of patients (OR 3.664, 95% CI 1.586-8.464, p = 0.002). Pulse steroid therapy was administered to 32.5% (26/80) of the patients with an initial diagnosis of SLE, and 26.3% (21/80) of these patients also received IVIG therapy during their ED visit. SLEDAI scores were significantly decreased after 6 months of therapy. The rate of mortality was 6.8% (10/147) in the 6-month follow-up period, and all the ten deaths happened in patients with disease-established SLE. The main causes of death were infections (two patients) and SLE flare (four patients). CONCLUSION: Understanding disease patterns can contribute to physicians providing accurate diagnosis and efficient care for SLE patients in ED. Key Points • Systemic lupus erythematosus, a complex autoimmune disorder, can have either a chronic or a relapsing and remitting disease course. The disease can involve acute events or severe comorbidities, and frequent visits to the emergency department (ED) are inevitable. • It is essential to better understand which comorbidities can lead to emergency department visits. Accurate clinical diagnosis and appropriate interventions from ED physicians can have a strong impact on the prognosis of the disease. • Hematologic compromise attributed to SLE flare is the most common reason for ED visits. Owing to aggressive treatments, the clinical outcomes in patients with initial diagnosis of SLE have improved notably. • Our study highlights that early recognition and appropriate management of SLE-related conditions and other comorbidity in ED are crucial.

Corticotropin-releasing hormone neurons control trigeminal neuralgia-induced anxiodepression via a hippocampus-to-prefrontal circuit.

Anxiety and depression are frequently observed in patients suffering from trigeminal neuralgia (TN), but neural circuits and mechanisms underlying this association are poorly understood. Here, we identified a dedicated neural circuit from the ventral hippocampus (vHPC) to the medial prefrontal cortex (mPFC) that mediates TN-related anxiodepression. We found that TN caused an increase in excitatory synaptic transmission from vHPCCaMK2A neurons to mPFC inhibitory neurons marked by the expression of corticotropin-releasing hormone (CRH). Activation of CRH+ neurons subsequently led to feed-forward inhibition of layer V pyramidal neurons in the mPFC via activation of the CRH receptor 1 (CRHR1). Inhibition of the vHPCCaMK2A-mPFCCRH circuit ameliorated TN-induced anxiodepression, whereas activating this pathway sufficiently produced anxiodepressive-like behaviors. Thus, our studies identified a neural pathway driving pain-related anxiodepression and a molecular target for treating pain-related psychiatric disorders.

Asymmetric activation of microglia in the hippocampus drives anxiodepressive consequences of trigeminal neuralgia in rodents.

BACKGROUND AND PURPOSE: Patients suffering from trigeminal neuralgia are often accompanied by anxiety and depression. Microglia-mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in trigeminal neuralgia-induced anxiodepression remains unclear. EXPERIMENTAL APPROACH: Unilateral constriction of the infraorbital nerve (CION) was performed to establish trigeminal neuralgia in rat and mouse models. Mechanical allodynia and anxiodepressive-like behaviours were measured. Optogenetic and pharmacological manipulations were employed to investigate the role of hippocampal microglia in anxiety and depression caused by trigeminal neuralgia. KEY RESULTS: Trigeminal neuralgia activated ipsilateral but not contralateral hippocampal microglia, up-regulated ipsilateral hippocampal ATP and interleukin-1ß (IL-1ß) levels, impaired ipsilateral hippocampal long-term potentiation (LTP) and induced anxiodepressive-like behaviours in a time-dependent manner in rodents. Pharmacological or optogenetic inhibition of ipsilateral hippocampal microglia completely blocked trigeminal neuralgia-induced anxiodepressive-like behaviours. Activation of unilateral hippocampal microglia directly elicited an anxiodepressive state and impaired hippocampal LTP. Knockdown of ipsilateral hippocampal P2X7 receptors prevented trigeminal neuralgia-induced microglial activation and anxiodepressive-like behaviours. Furthermore, we demonstrated that microglia-derived IL-1ß mediated microglial activation-induced anxiodepressive-like behaviours and LTP impairment. CONCLUSION AND IMPLICATIONS: These findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviours via IL-1ß. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia-induced anxiety and depression was uncovered. The approaches targeting microglia and P2X7 signalling might offer novel therapies for trigeminal neuralgia-related anxiety and depressive disorder.

Green light analgesia in mice is mediated by visual activation of enkephalinergic neurons in the ventrolateral geniculate nucleus.

Green light exposure has been shown to reduce pain in animal models. Here, we report a vision-associated enkephalinergic neural circuit responsible for green light-mediated analgesia. Full-field green light exposure at an intensity of 10 lux produced analgesic effects in healthy mice and in a model of arthrosis. Ablation of cone photoreceptors completely inhibited the analgesic effect, whereas rod ablation only partially reduced pain relief. The analgesic effect was not modulated by the ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are atypical photoreceptors that control various nonvisual effects of light. Inhibition of the retino-ventrolateral geniculate nucleus (vLGN) pathway completely abolished the analgesic effects. Activation of this pathway reduced nociceptive behavioral responses; such activation was blocked by the inhibition of proenkephalin (Penk)-positive neurons in the vLGN (vLGNPenk). Moreover, green light analgesia was prevented by knockdown of Penk in the vLGN or by ablation of vLGNPenk neurons. In addition, activation of the projections from vLGNPenk neurons to the dorsal raphe nucleus (DRN) was sufficient to suppress nociceptive behaviors, whereas its inhibition abolished the green light analgesia. Our findings indicate that cone-dominated retinal inputs mediated green light analgesia through the vLGNPenk-DRN pathway and suggest that this signaling pathway could be exploited for reducing pain.

Activation of ventrolateral orbital cortex improves mouse neuropathic pain-induced anxiodepression.

Depression and anxiety are frequently observed in patients suffering from neuropathic pain. The underlying mechanisms remained unclear. The ventrolateral orbital cortex (VLO) has attracted considerable interest in its role in antidepressive effect in rodents. In the present study, we further investigated the role of the VLO in the anxiodepressive consequences of neuropathic pain in a chronic constriction injury of infraorbital nerve-induced trigeminal neuralgia (TN) mouse model. Elevated plus maze, open field, forced swimming, tail suspension, and sucrose preference tests were used to evaluate anxiodepressive-like behaviors. The results show that chemogenetic activation of bilateral VLO neurons, especially CaMK2A+ pyramidal neurons, blocked the TN-induced anxiodepressive-like behaviors. Chemogenetic and optogenetic activation of VGLUT2+ or inhibition of VGAT+ VLO neurons was sufficient to produce an antianxiodepressive effect in TN mice. Pharmacological activation of D1-like receptors (D1Rs) but not D2Rs in the VLO significantly alleviated TN-induced depressive-like behaviors. Electrophysiological recordings revealed a decreased excitability of VLO excitatory neurons following neuropathic pain. Furthermore, activation of submedius thalamic nucleus-VLO (Sm-VLO) projection mimicked the antianxiodepressive effect of VLO excitation. Conversely, activation of VLO-periaqueductal gray matter (PAG) projection had no effect on TN-induced anxiodepressive behaviors. This study provides a potentially novel mechanism-based therapeutic strategy for the anxiodepressive consequences of neuropathic pain.

Overexpression of Thellungiella halophila H(+)-PPase (TsVP) in cotton enhances drought stress resistance of plants.

An H(+)-PPase gene, TsVP from Thellungiella halophila, was transferred into two cotton (Gossypium hirsutum) varieties (Lumianyan19 and Lumianyan 21) and southern and northern blotting analysis showed the foreign gene was integrated into the cotton genome and expressed. The measurement of isolated vacuolar membrane vesicles demonstrated that the transgenic plants had higher V-H(+)-PPase activity compared with wild-type plants (WT). Overexpressing TsVP in cotton improved shoot and root growth, and transgenic plants were much more resistant to osmotic/drought stress than the WT. Under drought stress conditions, transgenic plants had higher chlorophyll content, improved photosynthesis, higher relative water content of leaves and less cell membrane damage than WT. We ascribe these properties to improved root development and the lower solute potential resulting from higher solute content such as soluble sugars and free amino acids in the transgenic plants. In this study, the average seed cotton yields of transgenic plants from Lumianyan 19 and Lumianyan 21 were significantly increased compared with those of WT after exposing to drought stress for 21 days at flowering stage. The average seed cotton yields were 51 and 40% higher than in their WT counterparts, respectively. This study benefits efforts to improve cotton yields in arid and semiarid regions.

Induction of apoptosis by d-limonene is mediated by a caspase-dependent mitochondrial death pathway in human leukemia cells.

Using K562 and HL60 cell lines, we have investigated the anti-tumoral activity of d-limonene, a monocyclic monoterpene, in human leukemia cells. Apoptosis was evaluated by Hoechst staining and by the annexin V/propidium iodide binding assay. d-Limonene induced apoptosis in a dose- and time-dependent manner in both cell lines. Our findings and data, demonstrating an increase in Bax protein expression, the release of cytochrome c from mitochondria, and an increase in caspase-9 and cleaved caspase-3, but not caspase-8, after the treatment of d-limonene, all suggest that the mitochondrial death pathway is primarily involved in the development of d-limonene-induced apoptosis.