BackgroundLow oxygen environments like hypobaric hypoxia (HH) are common nodes to various diseases: characterized by neuroinflammation, which is detrimental to the structural and functional aspects of hippocampal circuitry. Various hypoxic conditions also lead to elevation of NLRP3 mediated neuroinflammation that may contribute to cognitive deficits. Components of neurogenic niches like microglia and astrocyte are largely affected by neuroinflammation; however, a systematic investigation of the impact of NLRP3 mediated neuroinflammation on components of neurogenic niche during hypoxia (HH) remains elusive. MethodsIn this study, we simulated cerebral hypoxia via decreasing partial pressure of oxygen(HH). The effect of hypobaric hypoxic (1, 3 and 7 day at 25000 ft) on social memory, anxiety, adult neurogenesis change in the inflammatory milieu in DG was explored in detail. We explored the efficacy of COX-1 inhibitor (Valery salicylate, 5mg/kg/day,i.p), and EP1R antagonist (SC19220, 1mg/kg/day,i.p) on NLRP3 mediated neuroinflammation and associated maladies during HH. ResultsWe observed that HH exposure induced alteration in social and anxiety-like behavior post 7 day exposure along with perturbation in levels of BDNF, Serotonin and adult neurogenesis in the DG right from day 1. Moreover, significant elevated NLRP3, caspase-1, and IL-1β levels are observed during HH from day 1. Concomitantly, a notable increase in the COX-1/EP1 pathway in both activated microglia and astrocyte in DG was evident after 3HH exposure. Pharmacological COX-1 inhibitor and EP1 antagonist counteract the detrimental effects of HH exposure on social memory, adult neurogenesis, and NLRP3 inflammasome induction. ConclusionsThus, our data showed induction of the COX-1/EP1 pathway in glial cells is detrimental to adult neurogenesis and social memory, raising possibility that the COX-1/EP1 pathway as a plausible target for inflammasome related neurogenesis impairment.
Background: Sleep is an indispensable phenomenon in almost every organism’s life. Sleep deprivation (SD) caused by professional demands or lifestyle causing low grade neuroinflammation resulting in physiological and cognitive deficits. However, the impact of neuroinflammation on hippocampal circuitry during sleep deprivation is well-documented, but the temporal events triggering neuroinflammation during SD in the dorsal hippocampus and its effects on fear extinction memory requires further investigation. Objectives: We sought to examine the effect of SD on extinction memory recall and its underlying neuroinflammatory cascades in the hippocampus. We delineated the effect of Adenosine A1 receptor antagonism on TLR4 mediated neuroinflammation elicited by SD and attempted to study the effect of SD on synaptic plasticity, adult neurogenesis, apoptosis, and neuroinflammation in order to understand behavioral deficits. Methods: An automated customized sleep deprivation system with somatosensory stimulation was used to deprive male Sprague Dawley rats of sleep for 48 hours. Adenosine A1 receptor (A1R) antagonist [8-cyclopentyltheophylline (CPT), 12mg/kg/day, i.p.] was administered during SD and brain samples were processed for molecular analysis. Sleep architecture was recorded during baseline, SD, SD+CPT and 24h rebound sleep. Results: SD of 48h after extinction training induced deficits in fear extinction memory recall with a reduction in synaptic plasticity markers PSD95 (p<0.01) and Synaptophysin (p<0.01). Escalation of neuroinflammatory cytokines levels like TNFα, Nf-κB, IL-6 and activation of glial cells was observed in the hippocampal niche. Additionally, an elevation of TLR4 expression in activated microglial cells was evident after 48h SD. These results point to the involvement of A1R receptor in sleep quality, fear extinction memory recall, synaptic plasticity via blunting neuroinflammation and apoptosis in the hippocampus. There was an increase in percent alpha and delta powers in NREM and REM sleep during rebound sleep. After A1R antagonist was administered, percent of NREM, REM sleep stages and delta, theta power during sleep deprivation decreased significantly and did not increase during rebound sleep in comparison to baseline sleep. Conclusion: Our investigation elucidates the role of TLR4 signaling in activated microglia, which disrupts memory recall and neurogenesis. Additionally, we observed that A1R activity modulates TLR4-mediated neuroinflammation triggered by sleep deprivation, suggesting that A1Rs could represent a promising target for regulating memory impairment. Furthermore, we posit that A1Rs regulate REM sleep during sleep deprivation and govern recovery sleep architecture followed by SD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.