Biology subjects

Mathew, J. P.

Publications and source records attributed to Mathew, J. P..

3 recordsLinked to original sources

bioRxiv2024

Noninvasive Assessment of Temporal Dynamics in Sympathetic and Parasympathetic Baroreflex Responses

BackgroundThe baroreflex system is crucial for cardiovascular regulation and autonomic homeostasis. A comprehensive assessment requires understanding the simultaneous temporal dynamics of its multiple functional branches, which traditional methods often overlook. ObjectiveTo develop and validate a noninvasive method for simultaneously assessing the temporal dynamics of sympathetic and parasympathetic baroreflexes using pulse contour analysis and the sequence method. MethodsBeat-to-beat blood pressure and ECG recordings were analyzed from 55 preoperative cardiothoracic surgery patients in the supine position and 21 subjects from the EUROBAVAR dataset in both supine and standing positions. Systolic arterial pressure (SAP), interbeat interval (IBI), cardiac output (CO), myocardial contraction (dP/dtmax), and systemic vascular resistance (SVR) were estimated using pulse contour analysis. Baroreflex sensitivity (BRS) was calculated via the sequence method and correlated with hemodynamic and heart rate variability (HRV) parameters. ResultsParasympathetic BRS for IBI was correlated with the root mean square of successive differences of ECG RR intervals (RMSSD-HRV) at 0-beat delay. Sympathetic BRS for SVR strongly correlated with SVR, CO, and RMSSD-HRV, particularly at 3-beat delay, and was uniquely associated with SAP at 1-beat delay. Sympathetic BRS for dP/dtmax correlated with dP/dtmax at 1-beat delay. In contrast, BRS for CO correlated with CO and SVR at 0- and 3-beat delays. Postural changes mainly affected parasympathetically-mediated BRS for IBI and, to a lesser extent, the sympathetic vascular and myocardial branches. ConclusionsThis method effectively captures multiple baroreflex responses and their temporal dynamics, revealing distinct autonomic mechanisms and the impact of postural changes. Further validation is warranted.

physiology↗

bioRxiv2024

Distinct roles of general anesthesia activated CeA neurons in acute versus late phase of neuropathic pain

A previous study discovered a distinct population of GABAergic neurons in the central amygdala (CeA) that can be activated by general anesthesia (CeAGA) and exert analgesic functions (Hua et al., 2020). To independently reproduce these prior findings and to investigate the electrophysiological properties of CeAGA neurons, we first used 1.2% isoflurane to induce c-Fos activation in the mouse brain and validated the Fos expression by RNAscope in situ hybridization. Indeed, isoflurane induced robust Fos expression in CeA and these Fos+ CeAGA neurons are GABAergic neurons (Vgat+). We next used Fos-TRAP2 method (different from the CANE method used in the prior study) to label CeAGA neurons (tdTomato+). Our ex vivo electrophysiological recordings in brain slices revealed that compared to Fos-negative CeA neurons, CeAGA neurons had significantly higher excitability and exhibited distinct patterns of action potentials. Chemogenetic activation of Fos-TRAPed CeAGA neurons was effective at increasing pain thresholds in naive mice and mice with early-phase neuropathic pain 2 weeks after spared nerve injury (SNI). However, the same chemogenetic activation of CeAGA neurons only had modest analgesia in the late phase of SNI at 8 weeks, although it was highly effective in reducing chronic pain-associated anxiety behaviors at this stage. We found that Fos-negative CeA neurons, but not CeAGA neurons, exhibited increased excitability in the late-phase of SNI, suggesting that chronic pain causes a shift in the relative activity of the CeA microcircuit. Interestingly, Fos-negative neurons exhibited much higher expression of K+-Cl- cotransporter-2 (KCC2), and KCC2 expression was downregulated in the CeA in the late-phase of neuropathic pain. These results support the idea that targeting CeAGA neurons may provide therapeutic benefits for pain relief and chronic pain-associated anxiety. Our findings also suggest distinct roles of CeAGA neurons in regulating physiological pain, acute pain, and chronic pain with a possible involvement of KCC2.

neuroscience↗

bioRxiv2022

Sparcl1/Hevin drives inflammatory and neuropathic pain through astrocyte and NMDA receptor signaling

Hevin/Sparcl1 is an astrocyte-secreted protein and regulates synapse formation in the brain. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared to wild-type mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin is required for the maintenance of nerve injury-induced neuropathic pain (mechanical allodynia), and hevin-null mice have faster recovery than wild-type mice from neuropathic pain after nerve injury. Intrathecal injection of wild-type hevin but not a hevin mutant that is no longer synaptogenic was sufficient to induce persistent mechanical allodynia in naive mice and further enhanced neuropathic pain in animals with nerve injury. In hevin-null mice with nerve injury, AAV-mediated re-expression of hevin, but not mutant hevin, in GFAP-expressing spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling, as NMDA-induced mechanical allodynia and inward currents in spinal cord lamina II neurons is reduced in hevin-null mice. Hevin potentiated NMDA currents mediated by the GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing antibody against hevin alleviated acute inflammatory pain and persistent neuropathic pain. Secreted hevin was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid (< 10 hours) and substantial increases (~20 fold) in HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal antibody may provide a new therapeutic strategy for treating chronic pain and NMDAR-medicated neurodegeneration.

neuroscience↗