Demarcating the boundary conditions of memory reconsolidation: An unsuccessful replication.

Disrupting memory reconsolidation provides an opportunity to abruptly reduce the behavioural expression of fear memories with long-lasting effects. The success of a reconsolidation intervention is, however, not guaranteed as it strongly depends on the destabilization of the memory. Identifying the necessary conditions to trigger destabilization remains one of the critical challenges in the field. We aimed to replicate a study from our lab, showing that the occurrence of a prediction error (PE) during reactivation is necessary but not sufficient for destabilization. We tested the effectiveness of a reactivation procedure consisting of a single PE, compared to two control groups receiving no or multiple PEs. All participants received propranolol immediately after reactivation and were tested for fear retention 24 h later. In contrast to the original results, we found no evidence for a reconsolidation effect in the single PE group, but a straightforward interpretation of these results is complicated by the lack of differential fear retention in the control groups. Our results corroborate other failed reconsolidation studies and exemplify the complexity of experimentally investigating this process in humans. Thorough investigation of the interaction between learning and memory reactivation is essential to understand the inconsistencies in the literature and to improve reconsolidation interventions.

Intranasal calcitonin gene-related peptide administration impairs fear memory retention in mice through the PKD/p-HDAC5/Npas4 pathway.

The calcitonin gene-related peptide (CGRP) suppresses fear memory retention in mice. Although intracerebroventricular administration of CGRP alters the fear memory processes, making it a promising therapeutic strategy for post-traumatic stress disorder (PTSD), direct brain injection into patients is not practical. Therefore, we propose that intranasal application may be an effective way to deliver CGRP to the brain. This study tested whether CGRP nasal administration exerts the same effect as intracerebroventricular administration using C57BL6J mice. The amount of CGRP in the cerebrospinal fluid and hippocampus 30 min after nasal administration of CGRP was significantly higher when compared with saline. Intranasal CGRP also elicited photophobic behaviors similar to intracerebroventricular injection. Moreover, intranasal CGRP decreased fear memory retention but did not affect reactivation and extinction of fear memory. We found intranasal CGRP significantly increased the expression of protein kinase D (PKD), phosphorylated histone deacetylase 5 (p-HDAC5) and neuronal PAS domain protein 4 (Npas4) in the hippocampus. CGRP-mediated impairment of fear memory and Npas4 expression increases were attenuated significantly by the CGRP receptor antagonist BIBN4096. Together, our data demonstrate that intranasal CGRP delivery activates the PKD/p-HDAC5/Npas4 pathway, decreases fear memory retention.

Retention rate and effectiveness of secukinumab vs TNF inhibitor in ankylosing spondylitis patients with prior TNF inhibitor exposure.

OBJECTIVES: The choice of second-line biologics for AS patients previously treated with a TNF inhibitor (TNFi) remains unclear. Here, we compared drug retention and clinical efficacy between AS patients who switched biologics to secukinumab and those who switched to a different TNFi. METHODS: AS patients enrolled in the Korean College of Rheumatology BIOlogics registry were included, and patients with non-radiographic axial spondyloarthritis were excluded. Patients with previous TNFi exposure were divided into the secukinumab group and the TNFi switching group. Drug retention and clinical efficacy [BASDAI50, Assessment of Spondylo-Arthritis International Society (ASAS)20, ASAS40, AS disease activity score (ASDAS) <2.1, ASDAS clinically important improvement and ASDAS major improvement] were assessed at the 1 year follow-up. Propensity score (PS)-matched and covariate-adjusted logistic regression analyses were performed. RESULTS: Two hundred and forty-six had available 1 year follow-up data. Secukinumab as third- or later-line biologic was more frequent than alternative TNFi (54% vs 14%). PS-matched and multiple covariate-adjusted analyses showed that the odds ratio (OR) for drug discontinuation was comparable between the secukinumab and TNFi switching groups [OR 1.136 (95% CI 0.843, 1.531) and 1.000 (95% CI 0.433-2.308), respectively]. The proportion of patients who achieved BASDAI50 was also comparable between the two groups [OR 0.833 (95% CI 0.481, 1.441) in PS-matched analysis]. Other clinical efficacy parameters were also comparable. In the subgroup analysis of AS patients with previous TNFi discontinuation due to ineffectiveness, all clinical efficacy parameters were comparable between the two groups. CONCLUSION: In AS patients with previous exposure to a TNFi, switching biologics to secukinumab and switching to an alternative TNFi resulted in comparable drug retention and clinical efficacy.

Apparent reconsolidation interference without generalized amnesia.

Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of memory (i.e., amnesia). Such drug-induced post-reactivation amnesia has traditionally been studied in AAA experimental designs, where a memory is initially created for a stimulus A (be it a singular cue or a context) and later reactivated and tested through exposure to the exact same stimulus. Using a contextual fear conditioning procedure in rats and midazolam as amnestic agent, we recently demonstrated that drug-induced amnesia can also be obtained when memories are reactivated through exposure to a generalization stimulus (GS, context B) and later tested for that same generalization stimulus (ABB design). However, this amnestic intervention leaves fear expression intact when at test animals are instead presented with the original training stimulus (ABA design) or a novel generalization stimulus (ABC design). The underlying mechanisms of post-reactivation memory malleability and of MDZ-induced amnesia for a generalization context remain largely unknown. Here, we evaluated whether, like typical CS-mediated (or AAA) post-reactivation amnesia, GS-mediated (ABB) post-reactivation amnesia displays key features of a destabilization-based phenomenon. We first show that ABB post-reactivation amnesia is critically dependent on prediction error at the time of memory reactivation and provide evidence for its temporally graded nature. In line with the known role of GluN2B-NMDA receptor activation in memory destabilization, we further demonstrate that pre-reactivation administration of ifenprodil, a selective antagonist of GluN2B-NMDA receptors, prevents MDZ-induced ABB amnesia. In sum, our data reveal that ABB MDZ-induced post-reactivation amnesia exhibits the hallmark features of a destabilization-dependent phenomenon. Implication of our findings for a reconsolidation-based account of post-reactivation amnesia are discussed.

Resolvin D1 Prevents the Impairment in the Retention Memory and Hippocampal Damage in Rats Fed a Corn Oil-Based High Fat Diet by Upregulation of Nrf2 and Downregulation and Inactivation of p66Shc.

This study investigated the effect of a high-fat diet rich in corn oil (CO-HFD) on the memory retention and hippocampal oxidative stress, inflammation, and apoptosis in rats, and examined if the underlying mechanisms involve modulating Resolvin D1 (RvD1) levels and activation of p66Shc. Also, we tested if co-administration of RvD1 could prevent these neural adverse effects induced by CO-HFD. Adult male Wistar rats were divided into 4 groups (n = 18/each) as control fed standard diet (STD) (3.82 kcal/g), STD + RvD1 (0.2 µg/Kg, i.p/twice/week), CO-HFD (5.4 kcal/g), and CO-HFD + RvD1. All treatments were conducted for 8 weeks. With normal fasting glucose levels, CO-HFD induced hyperlipidemia, hyperinsulinemia, increased HOMA-IRI and reduced the rats' memory retention. In parallel, CO-HFD increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), cytoplasmic cytochrome-c, and cleaved caspase-3 and significantly decreased levels of glutathione (GSH), Bcl-2, and manganese superoxide dismutase (MnSOD) in rats' hippocampi. Besides, CO-HFD significantly reduced hippocampal levels of docosahexaenoic acid (DHA) and RvD1, as well as total protein levels of Nrf2 and significantly increased nuclear protein levels of p-NF-κB. Concomitantly, CO-HFD increased hippocampal protein levels of p-JNK, p53, p66Shc, p-p66Shc, and NADPH oxidase. However, without altering plasma and serum levels of glucose, insulin, and lipids, co-administration of RvD1 to CO-HFD completely reversed all these events. It also resulted in similar effects in the STD fed-rats. In conclusion, CO-HFD impairs memory function and induces hippocampal damage by reducing levels of RvD1 and activation of JNK/p53/p66Shc/NADPH oxidase, effects that are prevented by co-administration of RvD1.

Opposite effects of noradrenergic and glucocorticoid activation on accuracy of an episodic-like memory.

Stressful and emotionally arousing experiences activate hormonal systems that create strong memories. It remains unclear, however, how this strengthening affects the quality of such memories. In the present study, we examined whether the noradrenergic and glucocorticoid hormonal systems affect accuracy of episodic-like memory. We trained male Sprague-Dawley rats on an episodic-like association task, termed inhibitory avoidance discrimination task, in which they explored two different contexts, but shock was given only in the latter context. Forty-eight hours later, retention latencies were tested in the two training contexts as well as in a novel context. The noradrenergic stimulant yohimbine, administered systemically immediately after the training session, enhanced both accuracy and strength of the memory, as shown by long latencies specific to the shock context. By contrast, the glucocorticoid corticosterone induced a generalized strengthening of memory and enhanced latencies in both the shock and non-shock training contexts. Retention latencies in the novel context were not significantly affected. These findings indicate that the noradrenergic and glucocorticoid systems, while both strengthening memory of the shock experience per se, produce opposite effects on accuracy of the shock-context association.

NMDA receptors and the ontogeny of post-shock and retention freezing during contextual fear conditioning.

The ontogeny and NMDA-receptor (NMDAR) mechanisms of context conditioning were examined during standard contextual fear conditioning (sCFC) - involving context and context-shock learning in the same trial - as a comparison with our previous reports on the Context Preexposure Facilitation Effect (CPFE), which separates these two types of learning by 24 hr. In Experiment 1, systemic administration of the NMDAR antagonist, MK-801, prior to conditioning disrupted retention but not post-shock freezing during sCFC in PD31 rats. Experiment 2 replicated and extended this effect to PD17 versus PD31 rats. Consistent with Experiment 1, pre-training MK-801 spared post-shock freezing but impaired retention freezing in PD31 rats. In contrast, pre-training MK-801 disrupted post-shock freezing in PD17 rats, which showed no retention freezing regardless of drug. These results reveal developmental differences in the role of NMDAR activity in the acquisition versus retention of a context-shock association during sCFC in pre-weanling and adolescent rats.

Modeling psychiatric comorbid symptoms of epileptic seizures in zebrafish.

Epilepsy is a debilitating neurological disorder characterized by recurrent unprovoked seizures. Anxiety, cognitive deficits, depressive-like symptoms, and social dysfunction are psychiatric comorbidities with high prevalence in epileptic patients. Due to the genetic and behavioral tractability, the zebrafish is a promising model organism to understand the neural bases involved in epilepsy-related comorbidities. Here, we aimed to characterize some behavioral phenotypes paralleling those observed in epilepsy-related comorbidities after a single pentylenetetrazole (PTZ) exposure in zebrafish. We also analyzed the influence of whole-body cortisol levels in the behavioral responses measured. Fish were exposed to 10 mM PTZ for 20 min to induce epileptic seizures. After 24 h recovery period, locomotion and anxiety-like responses (novel tank and light-dark tests), social interaction (shoaling behavior task), and memory retention (inhibitory avoidance protocol) were assessed. Basically, PTZ impaired habituation to novelty stress, evoked anxiogenic-like behaviors, disrupted shoaling, and caused memory consolidation deficits in zebrafish without changing whole-body cortisol levels. In conclusion, our novel findings further validate the use of zebrafish as a suitable tool for modeling epilepsy-related comorbidities in translational neuropsychiatric research.

D-578, an orally active triple monoamine reuptake inhibitor, displays antidepressant and anti-PTSD like effects in rats.

Significant unmet needs exist for development of better pharmacotherapeutic agents for major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) as the current drugs are inadequate. Our goal in this study is to investigate behavioral pharmacological characterization of a novel triple reuptake inhibitor (TRI) D-578 which exhibits nanomolar potency at all three monoamine transporters (Ki; 16.2. 16.2, 3.23 nM, and 29.6, 20.6, 6.10 nM for the rat brain and cloned human dopamine, serotonin and norepinephrine transporters, respectively) and exhibited little to no affinity for other off-target CNS receptors. In a rat forced swim test, compound D-578 upon oral administration displayed high efficacy and not stimulating in locomotor behavior. The effects of D-578 and paroxetine were next evaluated in a rat model for traumatic stress exposure - the single prolonged stress (SPS) model - which has been shown to have construct, predictive, and behavioral validity in modeling aspects of PTSD. Our results show that SPS had no effect on the acquisition of conditioned fear, but impaired extinction learning and extinction retention of fear behavior compared to sham treatment. D-578, but not paroxetine, attenuated the extinction and extinction-retention deficit induced by SPS. These findings suggest that D-578 has greater efficacy in normalizing traumatic stress-induced extinction-retention learning in a model for PTSD compared to paroxetine. Overall these results suggest that D-578, in addition to producing a robust and efficacious antidepressant effect, may attenuate maladaptive retention of fearful memories and support further testing of this agent for the pharmacotherapy of depression and PTSD.

Working Memory Capacity Is Negatively Associated with Memory Load Modulation of Alpha Oscillations in Retention of Verbal Working Memory.

Working memory capacity (WMC) measures the amount of information that can be maintained online in the face of distraction. Past work has shown that the efficiency with which the frontostriatal circuit filters out task-irrelevant distracting information is positively correlated with WMC. Recent work has demonstrated a role of posterior alpha oscillations (8-13 Hz) in providing a sensory gating mechanism. We investigated the relationship between memory load modulation of alpha power and WMC in two verbal working memory experiments. In both experiments, we found that posterior alpha power increased with memory load during memory, in agreement with previous reports. Across individuals, the degree of alpha power modulation by memory load was negatively associated with WMC, namely, the higher the WMC, the less alpha power was modulated by memory load. After the administration of topiramate, a drug known to affect alpha oscillations and have a negative impact on working memory function, the negative correlation between memory load modulation of alpha power and WMC was no longer statistically significant but still somewhat detectable. These results suggest that (1) individuals with low WMC demonstrate stronger alpha power modulation by memory load, reflecting possibly an increased reliance on sensory gating to suppress task-irrelevant information in these individuals, in contrast to their high WMC counterparts who rely more on frontal areas to perform this function and (2) this negative association between memory load modulation of alpha oscillations and WMC is vulnerable to drug-related cognitive disruption.

Calcineurin is involved in retrieval of passive avoidance memory and synaptic plasticity impairment induced by Nandrolone administration in adolescent male rats.

In spite of evidence about negative effects of Nandrolone Decanoate (ND) on cognitive and memory performance, the underlying mechanisms are complex and have remained unclear. This research examines the role of Calcineurin in synaptic plasticity and memory storage impairment in ND administrated adolescent male rats. For behavioral study by passive avoidance learning and memory (PAL), adolescent male rats were treated with ND or ND plus selective Calcineurin antagonist (Tacrolimus), before retention test. ND significantly decreased the retrieval of PAL, whereas Tacrolimus plus ND had no significant effect on PAL. For electrophysiological study hippocampal slices were perfused by ND or ND plus Tacrolimus. The magnitude of fEPSP-LTP of ND perfused slices was less than the control and a reduction of fEPSP-PS (E-S) coupling was observed, while pre-administration of Tacrolimus abolished the ND impairment effect on fEPSP-LTP and E-S coupling. This study showed that ND may induce impairing effects on hippocampal area CA1 activity and plasticity and PAL memory storage through changes in the function of the Calcineurin.

Influence of Δ9-tetrahydrocannabinol on long-term neural correlates of threat extinction memory retention in humans.

The neural mechanisms and durability of Δ9-tetrahydrocannabinol (THC) impact on threat processing in humans are not fully understood. Herein, we used functional MRI and psychophysiological tools to examine the influence of THC on the mechanisms of conditioned threat extinction learning, and the effects of THC on extinction memory retention when assessed 1 day and 1 week from learning. Healthy participants underwent threat conditioning on day 1. On day 2, participants were randomized to take one pill of THC or placebo (PBO) 2-h before threat extinction learning. Extinction memory retention was assessed 1 day and 1 week after extinction learning. We found that THC administration increased amygdala and ventromedial prefrontal cortex (vmPFC) activation during early extinction learning with no significant impact on skin conductance responses (SCR). When extinction memory retention was tested 24 h after learning, the THC group exhibited lower SCRs to the extinguished cue with no significant extinction-induced activations within the extinction network. When extinction memory retention was tested 1 week after learning, the THC group exhibited significantly decreased responses to the extinguished cues within the vmPFC and amygdala, but significantly increased functional coupling between the vmPFC, hippocampus, and dorsal anterior cingulate cortex during this extinction retention test. Our results are the first to report a long-term impact of one dose of THC on the functional activation of the threat extinction network and unveil a significant change in functional connectivity emerging after a week from engagement. We highlight the need for further investigating the long-term impact of THC on threat and anxiety circuitry.

MLC901 during sleep deprivation rescues fear memory disruption in rats.

Several lines of evidence suggest that sleep deprivation disrupts cognitive and emotional abilities and changes the expression of distinctive categories of genes in the brain. In the present study, saline- or MLC901 (a traditional Chinese medicine)-treated male Wistar rats were first submitted to a modified water box (for 24-h sleep deprivation) and then trained in contextual and tone fear conditioning tasks with the purpose to evaluate the effect of MLC901 during sleep deprivation on fear memory retention. Hippocampal mRNA measurement was performed by reverse transcription-polymerase chain reaction (RT-PCR). We found that the exposure of rats to 24 h of sleep deprivation impaired contextual and tone fear memory retention, while administration of MLC901 (0.2, 0.4, and 0.8 mg/kg, once/12 h; i.p.) during sleep deprivation abolished memory deficits. Meanwhile, different doses of MLC901 alone had no effect on performance in both tasks. We observed that MLC901 increased the expression levels of pro-apoptotic BAD, anti-apoptotic Bcl-xL, and Tfam as an index of mitochondrial biogenesis compared to sleep-deprived rats, while MLC901 during sleep deprivation increased BAX, BAD, and Bcl-xL compared to the control group. Sleep deprivation decreased BAX and Tfam, by itself. MLC901 only decreased BAX and Tfam and increased BAD level compared to the non-sleep-deprived control group. It is suggested that MLC901 might be a therapeutic option for memory impairment during sleep deprivation.

Transient inactivation of the visual-associative nidopallium frontolaterale (NFL) impairs extinction learning and context encoding in pigeons.

Extinction learning is a fundamental learning process that enables organisms to continuously update knowledge about their ever-changing environment. When using visual cues as conditioned stimuli (CS), visual cortical areas of mammals are known to participate in extinction learning. The aim of the present study was to test whether similar processes can also be observed in birds. With pigeons as an animal model, we therefore investigated the role of the nidopallium frontolaterale (NFL), a key avian visual associative area, in an extinction learning task. We adopted a within-subject extinction task design with context manipulation, and tested the animals for extinction memory retention and renewal. Before extinction, the NFL was transiently inactivated by intracerebral tetrodotoxin (TTX) injections. Our data suggest that inactivation of NFL indeed produces a slowing of extinction learning. Importantly, NFL also plays a key role in context encoding, as indicated by an abolishment of the renewal effect. This is not due to an overall perceptual decrement, since the ability to distinguish between the different visual stimuli was unaltered, but might be caused by an impaired formation of the context-CS-configuration during extinction. Taken together, our experiment not only reveals similarities of neural substrates of extinction learning in birds and mammals, but also provides strong evidence for a specific contribution of the NFL in context encoding.

Early memory consolidation window enables drug induced state-dependent memory.

It is well established that newly acquired information is stabilized over time by processes underlying memory consolidation, these events can be impaired by many drug treatments administered shortly after learning. The consolidation hypothesis has been challenged by a memory integration hypothesis, which suggests that the processes underlying new memories are vulnerable to incorporation of the neurobiological alterations induced by amnesic drugs generating a state-dependent memory. The present experiments investigated the effects of amnesic drugs infused into the insular cortex of male Wistar rats on memory for object recognition training. The findings provide evidence that infusions of several amnesic agents including a protein synthesis inhibitor, an RNA synthesis inhibitor, or an NMDA receptor antagonist administered both after a specific period of time and before retrieval induce state-dependent recognition memory. Additionally, when amnesic drugs were infused outside the early consolidation window, there was amnesia, but the amnesia was not state-dependent. Data suggest that amnesic agents can induce state-dependent memory when administered during the early consolidation window and only if the duration of the drug effect is long enough to become integrated to the memory trace. In consequence, there are boundary conditions in order to induce state-dependent memory.

Pretraining hippocampal stimulation of melatonin type 2 receptors can improve memory acquisition in rats.

BACKGROUND: Learning and memory are among the most important cognitive functions of the brain. Melatonin receptor type 2 (MT2R) is located in the hippocampus and participates in learning and memory processes. In the present study, we examined the role of hippocampal MT2R activation in the acquisition, consolidation, and retrieval of learning and memory in novel object recognition (NOR) and passive avoidance (PA) tasks. METHODS: IIK7 (0.03, 0.3, and 3 µg/µl/side), as a selective MT2R agonist, or vehicle was injected bilaterally into the dentate gyrus (DG) region of the hippocampus in rats five minutes before training, immediately after training, and five minutes before the retrieval-behavioral tasks, respectively. The discrimination index (DI) was measured in the NOR task, while step-through latency in acquisition (STLa), number of trials to acquisition (NOT), step-through latency in the retention trial (STLr), and time spent in the dark compartment (TDC) were determined in the PA task. RESULTS: The pretraining intrahippocampal injection of IIK7 at all doses significantly improved acquisition in the PA task. On the other hand, the posttraining intrahippocampal administration of IIK7 had no significant effects on consolidation. The preretrieval intrahippocampal injection of IIK7 at different doses attenuated the retrieval of memory. However, the NOR data showed that the intrahippocampal injection of IIK7 at different doses had no significant effects on the acquisition, consolidation, or retrieval in this task. DISCUSSION: Based on the findings, stimulation of MT2R could improve acquisition, whereas it had no effects on consolidation. It could impair retrieval in the PA task, while it had no effects on object recognition in rats.

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction.

The extinction of conditioned fear responses entrains the formation of safe new memories to decrease those behavioral responses. The knowledge in neuronal mechanisms of extinction is fundamental in the treatment of anxiety and fear disorders. Interestingly, the use of pharmacological compounds that reduce anxiety and fear has been shown as a potent co-adjuvant in extinction therapy. However, the efficiency and mechanisms by which pharmacological compounds promote extinction of fear memories remains still largely unknown and would benefit from a validation based on functional neuronal circuits, and the neurotransmitters that modulate them. From this perspective, oxytocin receptor signaling, which has been shown in cortical and limbic areas to modulate numerous functions (Eliava et al. Neuron 89(6):1291-1304, 2016), among them fear and anxiety circuits, and to enhance the salience of social stimuli (Stoop Neuron 76(1):142-59, 2012), may offer an interesting perspective. Experiments in animals and humans suggest that oxytocin could be a promising pharmacological agent at adjusting memory consolidation to boost fear extinction. Additionally, it is possible that long-term changes in endogenous oxytocin signaling can also play a role in reducing expression of fear at different brain targets. In this review, we summarize the effects reported for oxytocin in cortico-limbic circuits and on fear behavior that are of relevance for the modulation and potential extinction of fear memories.

Post-retrieval oxytocin facilitates next day extinction of threat memory in humans.

RATIONALE: Memories can return to a labile state and become amenable to modification by pharmacological and behavioral manipulations after retrieval. This process may reduce the impact of aversive memories and provide a promising therapeutic technique for the treatment of anxiety disorders. A growing body of evidence suggests that the mammalian neuropeptide oxytocin (OT) plays a role in the regulation of emotional memories in animals. However, the effects of OT on threat memory in humans remain largely unknown. OBJECTIVES: This study aimed to investigate the effects of OT administration following threat memory retrieval on subsequent memory expression in human participants. METHODS: In a double-blind, randomized, placebo-controlled, between-subject design, 61 healthy human individuals completed a 3-day experiment. All the participants underwent threat conditioning on day 1. On day 2, the participants were randomized to receive an intranasal dose of OT (40 IU) or placebo after memory retrieval, or an intranasal dose of OT (40 IU) without retrieval. On day 3, the participants were tested for extinction and reinstatement. RESULTS: On day 3, all groups showed equivalent stimulus discrimination during the early phase of extinction. However, the group that received OT following a memory reminder showed a greater decline in stimulus discrimination by the late phase of extinction relative to the two other groups. CONCLUSIONS: The results indicate that OT did not block reconsolidation to prevent the return of threat memory but rather interacted with post-retrieval processes to facilitate next day extinction. The study provides novel preliminary evidence for the role of OT in human threat memory.

K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression.

BACKGROUND: Alzheimer's disease, which is pathologically characterized by an excessive accumulation of amyloid beta (Aß) fibrils, is a degenerative brain disease and the most common cause of dementia. In a previous study, it was reported that an increased level of CHI3L1 in plasma was found in AD patients. We investigated the inhibitory effect of 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), an inhibitor of chitinase 3 like 1 (CHI3L1), on memory impairment in Aß1-42-infused mice, and microglial BV-2 cells and astrocytes. METHODS: We examined whether K284-6111 (3 mg/kg given orally for 4 weeks) prevents amyloidogenesis and memory loss in Aß1-42-induced AD mice model. After intracerebroventrical (ICV) infusion of Aß1-42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. K284-6111 treatment was found to reduce Aß1-42-induced memory loss. RESULTS: A memory recovery effect was found to be associated with the reduction of Aß1-42-induced expression of inflammatory proteins (iNOS, COX-2, GFAP, and Iba-1) and the suppression of CHI3L1 expression in the brain. Additionally, K284-6111 reduced Aß1-42-induced ß-secretase activity and Aß generation. Lipopolysaccharide (LPS)-induced (1 µg/mL) expression of inflammatory (COX-2, iNOS, GFAP, Iba-1) and amyloidogenic proteins (APP, BACE1) were decreased in microglial BV-2 cells and cultured astrocytes by the K284-6111 treatment (0.5, 1, and 2 µM). Moreover, K284-6111 treatment suppressed p50 and p65 translocation into the nucleus, and phosphorylation of IκB in vivo and in vitro. CONCLUSION: These results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB.

Pharmacological Dopamine Manipulation Does Not Alter Reward-Based Improvements in Memory Retention during a Visuomotor Adaptation Task.

Motor adaptation tasks investigate our ability to adjust motor behaviors to an ever-changing and unpredictable world. Previous work has shown that punishment-based feedback delivered during a visuomotor adaptation task enhances error-reduction, whereas reward increases memory retention. While the neural underpinnings of the influence of punishment on the adaptation phase remain unclear, reward has been hypothesized to increase retention through dopaminergic mechanisms. We directly tested this hypothesis through pharmacological manipulation of the dopaminergic system. A total of 96 young healthy human participants were tested in a placebo-controlled double-blind between-subjects design in which they adapted to a 40° visuomotor rotation under reward or punishment conditions. We confirmed previous evidence that reward enhances retention, but the dopamine (DA) precursor levodopa (LD) or the DA antagonist haloperidol failed to influence performance. We reason that such a negative result could be due to experimental limitations or it may suggest that the effect of reward on motor memory retention is not driven by dopaminergic processes. This provides further insight regarding the role of motivational feedback in optimizing motor learning, and the basis for further decomposing the effect of reward on the subprocesses known to underlie motor adaptation paradigms.