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In this study, we tested the hypothesis that the Piezo1/Ca 2+ /calpain pathway of the basal forebrain (BF) modulates impaired fear conditioning caused by sleep deprivation. Adult male Wistar rats were subjected to 6 h of total sleep deprivation using the gentle handling protocol. Step-down inhibitory avoidance tests revealed that sleep deprivation induced substantial short- and long-term fear memory impairment in rats, which was accompanied by increased Piezo1 protein expression (P < 0.01) and increased cleavage of full-length tropomyocin receptor kinase B (TrkB-FL) (P < 0.01) in the BF area. Microinjection of the Piezo1 activator Yoda1 into the BF mimicked these sleep deprivation-induced phenomena; TrkB-FL cleavage was increased (P < 0.01) and short- and long-term fear memory was impaired (both P < 0.01) by Yoda1. Inhibition of Piezo1 by GsMTx4 in the BF area reduced TrkB-FL degradation (P < 0.01) and partially reversed short- and long-term fear memory impairments in sleep-deprived rats (both P < 0.01). Inhibition of calpain activation, downstream of Piezo1 signaling, also improved short- and long-term fear memory impairments (P = 0.038, P = 0.011) and reduced TrkB degradation (P < 0.01) in sleep-deprived rats. Moreover, sleep deprivation induced a lower pain threshold than the rest control, which was partly reversed by microinjection of GsMTx4 or PD151746. Neither sleep deprivation nor the abovementioned drugs affected locomotion and sedation. Taken together, these results indicate that BF Piezo1/Ca 2+ /calpain signaling plays a role in sleep deprivation-induced TrkB signaling disruption and fear memory impairments in rats., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: The mechanisms underlying sleep deprivation-induced memory impairments and relevant compensatory signaling pathways remain elusive. We tested the hypothesis that increased brain-derived neurotrophic factor (BDNF) expression in the basal forebrain following acute sleep deprivation was a compensatory mechanism to maintain fear memory performance., Methods: Adult male Wistar rats were deprived of 6-hr total sleep from the beginning of the light cycle. The effects of sleep deprivation on BDNF protein expression and activation of downstream tropomyosin receptor kinase B (TrkB)/phospholipase C-γ1 (PLCγ1) signaling in the basal forebrain and fear memory consolidation were examined. BDNF or selective downstream TrkB receptor antagonist ANA-12 was further injected into the basal forebrain bilaterally to observe the changes in fear memory consolidation in response to modulation of the BDNF/TrkB signaling., Results: Six hours of sleep deprivation-induced both short- and long-term fear memory impairments. Increased BDNF protein expression and TrkB and PLCγ1 phosphorylation in the basal forebrain were observed after sleep deprivation. Microinjection of BDNF into the basal forebrain partly reversed fear memory deficits caused by sleep deprivation, which were accompanied by increased BDNF protein levels and TrkB/PLCγ1 activation. After ANA-12 microinjection, sleep deprivation-induced activation of the BDNF/TrkB pathway was inhibited and impairments of fear memory consolidation were further aggravated., Conclusions: Acute sleep deprivation induces compensatory increase of BDNF expression in the basal forebrain. Microinjection of BDNF into the basal forebrain mitigates the fear memory impairments caused by sleep deprivation by activating TrkB/PLCγ1 signaling., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.)

Introduction: Regulation of brain‐derived neurotrophic factor (BDNF) in the basal forebrain ameliorates sleep deprivation‐induced fear memory impairments in rodents. Antisense oligonucleotides (ASOs) targeting ATXN2 was a potential therapy for spinocerebellar ataxia, whose pathogenic mechanism associates with reduced BDNF expression. We tested the hypothesis that ASO7 targeting ATXN2 could affect BDNF levels in mouse basal forebrain and ameliorate sleep deprivation‐induced fear memory impairments. Methods: Adult male C57BL/6 mice were used to evaluate the effects of ASO7 targeting ATXN2 microinjected into the bilateral basal forebrain (1 μg, 0.5 μL, each side) on spatial memory, fear memory and sleep deprivation‐induced fear memory impairments. Spatial memory and fear memory were detected by the Morris water maze and step‐down inhibitory avoidance test, respectively. Immunohistochemistry, RT‐PCR, and Western blot were used to evaluate the changes of levels of BDNF, ATXN2, and postsynaptic density 95 (PSD95) protein as well as ATXN2 mRNA. The morphological changes in neurons in the hippocampal CA1 region were detected by HE staining and Nissl staining. Results: ASO7 targeting ATXN2 microinjected into the basal forebrain could suppress ATXN2 mRNA and protein expression for more than 1 month and enhance spatial memory but not fear memory in mice. BDNF mRNA and protein expression in basal forebrain and hippocampus was increased by ASO7. Moreover, PSD95 expression and synapse formation were increased in the hippocampus. Furthermore, ASO7 microinjected into the basal forebrain increased BDNF and PSD95 protein expression in the basal forebrain of sleep‐deprived mice and counteracted sleep deprivation‐induced fear memory impairments. Conclusion: ASOs targeting ATXN2 may provide effective interventions for sleep deprivation‐induced cognitive impairments. [ABSTRACT FROM AUTHOR]