An ultra-short-acting benzodiazepine in thalamic nucleus reuniens undermines fear extinction via intermediation of hippocamposeptal circuits.

Benzodiazepines, commonly used for anxiolytics, hinder conditioned fear extinction, and the underlying circuit mechanisms are unclear. Utilizing remimazolam, an ultra-short-acting benzodiazepine, here we reveal its impact on the thalamic nucleus reuniens (RE) and interconnected hippocamposeptal circuits during fear extinction. Systemic or RE-specific administration of remimazolam impedes fear extinction by reducing RE activation through A type GABA receptors. Remimazolam enhances long-range GABAergic inhibition from lateral septum (LS) to RE, underlying the compromised fear extinction. RE projects to ventral hippocampus (vHPC), which in turn sends projections characterized by feed-forward inhibition to the GABAergic neurons of the LS. This is coupled with long-range GABAergic projections from the LS to RE, collectively constituting an overall positive feedback circuit construct that promotes fear extinction. RE-specific remimazolam negates the facilitation of fear extinction by disrupting this circuit. Thus, remimazolam in RE disrupts fear extinction caused by hippocamposeptal intermediation, offering mechanistic insights for the dilemma of combining anxiolytics with extinction-based exposure therapy.

Dexmedetomidine Alleviates Microglia-Induced Spinal Inflammation and Hyperalgesia in Neonatal Rats by Systemic Lipopolysaccharide Exposure.

Noxious stimulus and painful experience in early life can induce cognitive deficits and abnormal pain sensitivity. As a major component of the outer membrane of gram-negative bacteria, lipopolysaccharide (LPS) injection mimics clinical symptoms of bacterial infections. Spinal microglial activation and the production of pro-inflammatory cytokines have been implicated in the pathogenesis of LPS-induced hyperalgesia in neonatal rats. Dexmedetomidine (DEX) possesses potent anti-neuroinflammatory and neuroprotective properties through the inhibition of microglial activation and microglial polarization toward pro-inflammatory (M1) phenotype and has been widely used in pediatric clinical practice. However, little is known about the effects of DEX on LPS-induced spinal inflammation and hyperalgesia in neonates. Here, we investigated whether systemic LPS exposure has persistent effects on spinal inflammation and hyperalgesia in neonatal rats and explored the protective role of DEX in adverse effects caused by LPS injection. Systemic LPS injections induced acute mechanical hyperalgesia, increased levels of pro-inflammatory cytokines in serum, and short-term increased expressions of pro-inflammatory cytokines and M1 microglial markers in the spinal cord of neonatal rats. Pretreatment with DEX significantly decreased inflammation and alleviated mechanical hyperalgesia induced by LPS. The inhibition of M1 microglial polarization and microglial pro-inflammatory cytokines expression in the spinal cord may implicate its neuroprotective effect, which highlights a new therapeutic target in the treatment of infection-induced hyperalgesia in neonates and preterm infants.

Correlation of cardiac output measured by non-invasive continuous cardiac output monitoring (NICOM) and thermodilution in patients undergoing off-pump coronary artery bypass surgery.

PURPOSE: This observational study was designed to evaluate the clinical value of cardiac output (CO) obtained via bioreactance (NICOM™) as compared with values of CO obtained via thermodilution (using pulmonary artery catheter, Vigilance™) and the thoracic bioimpedance (BioZ.com™), in patients undergoing off-pump coronary artery bypass surgery. METHODS: Fifty American Society of Anesthesiologists physical status I-III patients, aged 38-81 years, scheduled for off-pump coronary artery bypass surgery were enrolled in this study. CO data (NCO, BCO, PCO) were recorded during the operative period at ten time points after stable hemodynamic conditions were achieved. RESULTS: The equation of the relationship between the PCO and NCO is PCO = 0.945 × NCO + 0.328 (r = 0.77), and that of PCO and BCO is PCO = 0.965 × BCO + 0.729 (r = 0.63). Furthermore, no statistical difference was found between PCO versus NCO (mean (SD): 4.4 (1.1) versus 4.4 (0.9), p = 0.431). A significant correlation was found between PCO and NCO (r = 0.77, p < 0.001). Correlation was also found between PCO and BCO (r = 0.63, p < 0.001). CONCLUSIONS: The NICOM device is a safe, convenient, and reliable device for measuring continuous non-invasive cardiac output and cardiac index, and the trends of change in CO during the surgery are similar between NICOM and PAC.