Inhibitors of cellular stress overcome acute effects of ethanol on hippocampal plasticity and learning.
TL;DR: It is demonstrated that ethanol's effects on LTP in the CA1 hippocampal region are overcome by agents that inhibit cellular stress responses, including ISRIB, a specific inhibitor of integrated stress response, and GW3965, an agonist that acts at liver X receptors (LXRs) and dampens cellular stress.
About: This article is published in Neurobiology of Disease.The article was published on 2020-07-01 and is currently open access. It has received 10 citations till now. The article focuses on the topics: Metaplasticity & Synaptic plasticity.
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TL;DR: In this article , the effects of N2O on glutamate transmission in the hippocampus and compared its effects to those of ketamine were examined in the CA1 region of hippocampal slices from adult albino rats using standard extracellular recording methods.
8 citations
TL;DR: In this paper, an overview of the current understanding of the molecular mechanisms involved in ethanol-induced damage with endoplasmic reticulum stress, integrated stress response, NLRP3 inflammation and autophagy, while discussing the impact of neurosteroids and oxysterols, including allopregnanolone, 25-hydroxycholesterol and 24S-hydroxylcholesterol, on the central nervous system.
7 citations
TL;DR: Sex differences in synaptic transmission and plasticity in PNCs following application of stress-associated neurotransmitter, norepinephrine, in a rat model of AUD are investigated and selective blockade of α1AR is found to ameliorate CIE-induced deficits in HPA responses to stress in a sex-specific manner.
Abstract: BACKGROUND
Individuals afflicted with alcohol use disorder (AUD) exhibit maladaptive responses of the hypothalamic-pituitary-adrenal (HPA) axis to stress, which has been linked to high relapse rates to drinking during abstinence. Corticotropin-releasing factor (CRF) parvocellular neuroendocrine cells (PNCs) within the paraventricular nucleus of the hypothalamus (PVN) are critical to stress-induced HPA axis activation. Here, we investigate sex differences in synaptic transmission and plasticity in PNCs following application of stress-associated neurotransmitter, norepinephrine (NE) in a rat model of AUD.
METHODS
Adult Sprague-Dawley rats were exposed to 40 days of chronic intermittent ethanol (CIE) vapor and 30-108 days of protracted withdrawal. We measured changes in holding current, evoked synaptic currents, and short-term glutamatergic plasticity (STP) in putative PNCs following NE (10μM) application with and without selective α1 adrenergic receptor (AR) antagonist, prazosin (10μM) or α2AR antagonist, atipamezole (10μM), using whole-cell patch clamp recordings in slices from CIE rats and air-exposed controls.
RESULTS
NE application caused two distinct effects: a depolarizing, inward, postsynaptic current and a reduction in evoked glutamatergic excitatory postsynaptic current (eEPSC) amplitude. Both effects were sex and CIE-specific. Prazosin blocked the postsynaptic inward current, while atipamezole blocked the NE-mediated suppression of eEPSCs. Additionally, STP formation was facilitated following NE application in only stress-naïve males and this response was lost in stressed animals exposed to a 30-minute restraint stress following CIE exposure. Furthermore, NE + prazosin restored STP formation in stressed CIE males.
CONCLUSIONS
NE exerts excitatory and inhibitory effects onto CRF PVN PNCs and both effects are influenced by sex and CIE. Behavioral and hormonal responses to stress are influenced by STP formation within the PVN, which is lost following CIE and restored with pre-application of prazosin. Selective blockade of α1AR may therefore ameliorate CIE-induced deficits in HPA responses to stress in a sex-specific manner.
5 citations
TL;DR: In this paper, the effects of oxysterol positive allosteric modulators (PAMs) on ethanol-mediated inhibition of NMDARs, block of longterm potentiation (LTP) and long-term depression (LTD), and defects in one-trial learning in vivo were examined.
Abstract: Ethanol is a noncompetitive inhibitor of N-methyl-d-aspartate receptors (NMDARs) and acutely disrupts hippocampal synaptic plasticity and learning. In the present study, we examined the effects of oxysterol positive allosteric modulators (PAMs) of NMDARs on ethanol-mediated inhibition of NMDARs, block of long-term potentiation (LTP) and long-term depression (LTD) in rat hippocampal slices, and defects in one-trial learning in vivo. We found that 24S-hydroxycholesterol and a synthetic oxysterol analog, SGE-301, overcame effects of ethanol on NMDAR-mediated synaptic responses in the CA1 region but did not alter acute effects of ethanol on LTD; the synthetic oxysterol, however, overcame acute inhibition of LTP. In addition, both oxysterols overcame persistent effects of ethanol on LTP in vitro, and the synthetic analog reversed defects in one-trial inhibitory avoidance learning in vivo. These results indicate that effects of ethanol on both LTP and LTD arise by complex mechanisms beyond NMDAR antagonism and that oxysterol NMDAR PAMS may represent a novel approach for preventing and reversing acute ethanol-mediated changes in cognition. SIGNIFICANCE STATEMENT: Ethanol acutely inhibits hippocampal NMDARs, LTP, and learning. This study found that certain oxysterols that are NMDAR-positive allosteric modulators can overcome the acute effects of ethanol on NMDARs, LTP, and learning. Oxysterols differ in their effects from agents that inhibit integrated cellular stress responses.
4 citations
TL;DR: In this article , the effects of acrylamide on long-term potentiation (LTP) induction in rat hippocampal slices were investigated using a model of learning and memory, and the results indicated that cognitive impairment is mediated by mechanisms involving microglia and release of cytokines via NLRP3 activation.
Abstract: Acrylamide is a chemical used in various industries and a product following high-temperature cooking of vegetables containing asparagine. Environmental or dietary exposure to acrylamide could impair cognitive function because of its neurotoxicity. Using rat hippocampal slices, we tested whether acrylamide alters induction of long-term potentiation (LTP), a cellular model of learning and memory. We hypothesized that acrylamide impairs cognitive function via activation of pro-inflammatory cytokines because robust upregulation of NLRP3 inflammasome has been reported. Although acrylamide up to 3 mM did not alter basal synaptic transmission, incubation with 10 μM or acute administration of 100 μM acrylamide inhibited induction of LTP. Inhibitors of toll-like receptor 4 (TLR4), and minocycline, an inhibitor of microglial activation, overcame the effects of acrylamide on LTP induction. Furthermore, we observed that acrylamide failed to inhibit LTP after administration of MCC950, an inhibitor of NLRP3, or in the presence of Interleukin-1 receptor antagonist (IL-1Ra). We also found that in vivo acrylamide injection transiently impaired body weight gain and impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by MCC950. These results indicate that cognitive impairment by acrylamide is mediated by mechanisms involving microglia and release of cytokines via NLRP3 activation.
4 citations
References
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TL;DR: It is found that one-trial inhibitory avoidance learning in rats produced the same changes in hippocampal glutamate receptors as induction of LTP with HFS and caused a spatially restricted increase in the amplitude of evoked synaptic transmission in CA1 in vivo.
Abstract: Years of intensive investigation have yielded a sophisticated understanding of long-term potentiation (LTP) induced in hippocampal area CA1 by high-frequency stimulation (HFS). These efforts have been motivated by the belief that similar synaptic modifications occur during memory formation, but it has never been shown that learning actually induces LTP in CA1. We found that one-trial inhibitory avoidance learning in rats produced the same changes in hippocampal glutamate receptors as induction of LTP with HFS and caused a spatially restricted increase in the amplitude of evoked synaptic transmission in CA1 in vivo. Because the learning-induced synaptic potentiation occluded HFS-induced LTP, we conclude that inhibitory avoidance training induces LTP in CA1.
1,818 citations
"Inhibitors of cellular stress overc..." refers background or methods in this paper
...While the contributions of LTP and LTD to different forms of learning are uncertain, the form of one-trial learning we studied has been linked previously to changes in hippocampal LTP (Whitlock et al., 2006; Tokuda et al., 2010) suggesting that the behavioral effects observed here may be most relevant to ethanol-induced changes in LTP....
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...For these studies, we used a one trial inhibitory avoidance learning task, a form of learning dependent upon hippocampal plasticity (Whitlock et al., 2006; Tokuda et al., 2010)....
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...Rats were tested in a one-trial inhibitory avoidance learning task (Whitlock et al., 2006; Tokuda et al., 2010)....
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TL;DR: The hypothesis that naturally occurring oxysterols are physiological ligand for LXRs is supported and a rational, structure-based approach can be used to design potent LXR ligands for pharmacologic use is shown.
Abstract: LXRα and -β are nuclear receptors that regulate the metabolism of several important lipids, including cholesterol and bile acids. Previously, we have proposed that LXRs regulate these pathways through their interaction with specific, naturally occurring oxysterols, including 22(R)-hydroxycholesterol, 24(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol. Using a ligand binding assay that incorporates scintillation proximity technology to circumvent many of the problems associated with assaying extremely hydrophobic ligands, we now demonstrate that these oxysterols bind directly to LXRs at concentrations that occur in vivo. To characterize further the structural determinants required for potent LXR ligands, we synthesized and tested a series of related compounds for binding to LXRs and activation of transcription. These studies revealed that position-specific monooxidation of the sterol side chain is requisite for LXR high-affinity binding and activation. Enhanced binding and activation can also be achieved through the use of 24-oxo ligands that act as hydrogen bond acceptors in the side chain. In addition, introduction of an oxygen on the sterol B-ring results in a ligand with LXRα-subtype selectivity. These results support the hypothesis that naturally occurring oxysterols are physiological ligands for LXRs and show that a rational, structure-based approach can be used to design potent LXR ligands for pharmacologic use.
915 citations
"Inhibitors of cellular stress overc..." refers background in this paper
...Prior studies have found that agonists at liver X receptors (LXRs), a subtype of nuclear receptors, can dampen ER stress via effects on membrane phospholipid composition (Sun et al., 2016; Rong et al., 2013; Janowski et al., 1999)....
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TL;DR: A small molecule is identified, named ISRIB, that potently reverses the effects of eIF2α phosphorylation and promises to contribute to the understanding and treatment of cognitive disorders.
Abstract: Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2α phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders. DOI:http://dx.doi.org/10.7554/eLife.00498.001.
513 citations
Journal Article•
TL;DR: Blackouts are much more common among social drinkers—including college drinkers—than was previously assumed, and have been found to encompass events ranging from conversations to intercourse.
Abstract: Alcohol primarily interferes with the ability to form new long-term memories, leaving intact previously established long-term memories and the ability to keep new information active in memory for brief periods. As the amount of alcohol consumed increases, so does the magnitude of the memory impairments. Large amounts of alcohol, particularly if consumed rapidly, can produce partial (i.e., fragmentary) or complete (i.e., en bloc) blackouts, which are periods of memory loss for events that transpired while a person was drinking. Blackouts are much more common among social drinkers--including college drinkers--than was previously assumed, and have been found to encompass events ranging from conversations to intercourse. Mechanisms underlying alcohol-induced memory impairments include disruption of activity in the hippocampus, a brain region that plays a central role in the formation of new autobiographical memories.
330 citations
"Inhibitors of cellular stress overc..." refers background in this paper
...Greater intoxication (BAL ~ 20–40 mM) results in slowed thinking and altered learning; at BAL above 40 mM some individuals develop acute memory “blackouts” (White, 2003; Abrahao et al., 2017)....
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...Memory blackouts can have devastating personal and societal effects, particularly among adolescents and young adults, and may predict further cognitive difficulties with ongoing alcohol use (White, 2003; Parada et al., 2011)....
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TL;DR: This review highlights current progress in the field of ethanol use and abuse, focusing on recent and emerging molecular, cellular, and circuit effects of the drug that impact ethanol-related behaviors.
265 citations
"Inhibitors of cellular stress overc..." refers background in this paper
...Greater intoxication (BAL ~ 20-40 mM) results in slowed thinking and altered learning; at BAL above 40 mM some individuals develop acute memory "blackouts" (White, 2003; Abrahao et al., 2017)....
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...Prior studies have found that several neuronal stressors including low glucose, ammonia and brief hypoxia inhibit LTP via untimely activation of NMDARs (Zorumski and Izumi, 2012)....
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...Mechanisms contributing to alcohol-induced memory blackouts are likely complex but thought to involve defects in the synaptic plasticity underlying learning and memory, particularly defects in long-term potentiation (LTP) (Abrahao et al., 2017; Chandler et al., 1998; Zorumski et al., 2014)....
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...DISCUSSION Ethanol inhibits NMDARs (Izumi et al., 2005b; Zorumski et al., 2014; Abrahao et al., 2017) and inhibits NMDAR-dependent synaptic plasticity in hippocampal slices (Zorumski et al....
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...Unexpectedly, we found that the LXR agonist but not ISRIB overcomes effects of ethanol on synaptic responses mediated by Nmethyl-D-aspartate receptors (NMDARs)....
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