Unravelling the role of adenosine A1 receptors (A1R) in toll like receptor-4 mediated neuroinflammation during sleep deprivation and recovery sleep

Abstract

Abstract 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.