Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes

Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212−/−) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3–CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212−/− mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3–CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212−/− mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212−/− mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain.

Repercussion of cAMP and EPAC in Memory and Signaling

It is well recognized that cyclic adenosine monophosphate (cAMP) signaling within neurons plays a key role in the foundation of long-term memories. Memory storage is the process that demands the movement of signals, neural plasticity, and the molecules which can transfer the signals from the sensory neuron to the dorsal root ganglion (DRG) neurons and later into the temporal region of the brain. The discovery of cAMP in 1958 as the second messenger also had a role in memory formation and other neural aspects. Further, in 1998 the scientists found that cAMP does not just activate protein kinase A (PKA) but also exchange protein directly activated by cAMP (Epac) which has an active role to play in hyperalgesia, memory, and signaling. The cAMP has three targets, hyperpolarization-activated cyclic nucleotide modulated (HCN) channels, protein kinase A (PKA), and exchange protein activated by cAMP (Epac). Different research has exposed that both PKA and HCN channels are significant for long-term memory creation. Epac is a cAMP-dependent guanine nucleotide exchange factor for the small G proteins including Rap1. However, slight information is there about the role of Epac in this process. The effects of cAMP are predominantly imparted by activating protein kinase A (PKA) and the more newly discovered exchange proteins are directly activated by cAMP 1 and 2 (EPAC1 and EPAC2). This review provides an insight regarding the function and role of both of these secondary messengers in memory and nerve signaling.

Active Working Memory and Simple Cognitive Operations

Working memory is thought to serve as a buffer for ongoing cognitive operations, even in tasks that have no obvious memory requirements. This conceptualization has been supported by dual-task experiments, in which interference is observed between a primary task involving short-term memory storage and a secondary task that presumably requires the same buffer as the primary task. Little or no interference is typically observed when the secondary task is very simple. Here, we test the hypothesis that even very simple tasks require the working memory buffer, but interference can be minimized by using activity-silent representations to store the information from the primary task. We tested this hypothesis using dual-task paradigm in which a simple discrimination task was interposed in the retention interval of a change detection task. We used contralateral delay activity (CDA) to track the active maintenance of information for the change detection task. We found that the CDA was massively disrupted after the interposed task. Despite this disruption of active maintenance, we found that performance in the change detection task was only slightly impaired, suggesting that activity-silent representations were used to retain the information for the change detection task. A second experiment replicated this result and also showed that automated discriminations could be performed without producing a large CDA disruption. Together, these results suggest that simple but non-automated discrimination tasks require the same processes that underlie active maintenance of information in working memory.

Incremental execution of temporal graph queries over runtime models with history and its applications

Modern software systems are intricate and operate in highly dynamic environments for which few assumptions can be made at design-time. This setting has sparked an interest in solutions that use a runtime model which reflects the system state and operational context to monitor and adapt the system in reaction to changes during its runtime. Few solutions focus on the evolution of the model over time, i.e., its history, although history is required for monitoring temporal behaviors and may enable more informed decision-making. One reason is that handling the history of a runtime model poses an important technical challenge, as it requires tracing a part of the model over multiple model snapshots in a timely manner. Additionally, the runtime setting calls for memory-efficient measures to store and check these snapshots. Following the common practice of representing a runtime model as a typed attributed graph, we introduce a language which supports the formulation of temporal graph queries, i.e., queries on the ordering and timing in which structural changes in the history of a runtime model occurred. We present a querying scheme for the execution of temporal graph queries over history-aware runtime models. Features such as temporal logic operators in queries, the incremental execution, the option to discard history that is no longer relevant to queries, and the in-memory storage of the model, distinguish our scheme from relevant solutions. By incorporating temporal operators, temporal graph queries can be used for runtime monitoring of temporal logic formulas. Building on this capability, we present an implementation of the scheme that is evaluated for runtime querying, monitoring, and adaptation scenarios from two application domains.

Flexible Memory Device Composed of Metal-Oxide and Two-Dimensional Material (SnO2/WTe2) Exhibiting Stable Resistive Switching

Two-terminal, non-volatile memory devices are the fundamental building blocks of memory-storage devices to store the required information, but their lack of flexibility limits their potential for biological applications. After the discovery of two-dimensional (2D) materials, flexible memory devices are easy to build, because of their flexible nature. Here, we report on our flexible resistive-switching devices, composed of a bilayer tin-oxide/tungsten-ditelluride (SnO2/WTe2) heterostructure sandwiched between Ag (top) and Au (bottom) metal electrodes over a flexible PET substrate. The Ag/SnO2/WTe2/Au flexible devices exhibited highly stable resistive switching along with an excellent retention time. Triggering the device from a high-resistance state (HRS) to a low-resistance state (LRS) is attributed to Ag filament formation because of its diffusion. The conductive filament begins its development from the anode to the cathode, contrary to the formal electrochemical metallization theory. The bilayer structure of SnO2/WTe2 improved the endurance of the devices and reduced the switching voltage by up to 0.2 V compared to the single SnO2 stacked devices. These flexible and low-power-consumption features may lead to the construction of a wearable memory device for data-storage purposes.

Sleep promotes the formation of dendritic filopodia and spines near learning-inactive existing spines

Changes in synaptic connections are believed to underlie long-term memory storage. Previous studies have suggested that sleep is important for synapse formation after learning, but how sleep is involved in the process of synapse formation remains unclear. To address this question, we used transcranial two-photon microscopy to investigate the effect of postlearning sleep on the location of newly formed dendritic filopodia and spines of layer 5 pyramidal neurons in the primary motor cortex of adolescent mice. We found that newly formed filopodia and spines were partially clustered with existing spines along individual dendritic segments 24 h after motor training. Notably, posttraining sleep was critical for promoting the formation of dendritic filopodia and spines clustered with existing spines within 8 h. A fraction of these filopodia was converted into new spines and contributed to clustered spine formation 24 h after motor training. This sleep-dependent spine formation via filopodia was different from retraining-induced new spine formation, which emerged from dendritic shafts without prior presence of filopodia. Furthermore, sleep-dependent new filopodia and spines tended to be formed away from existing spines that were active at the time of motor training. Taken together, these findings reveal a role of postlearning sleep in regulating the number and location of new synapses via promoting filopodial formation.

460 Assessment of long-term arrhytmic sequelae in patients recovering from COVID-19 infection

Aims COVID-19 has been associated with acute cardiac complications including cardiac arrhythmias. We aimed to assess the prevalence of long-term cardiac arrhythmias in patients recovering from severe COVID-19 infection with proved or suspected of cardiac involvement. Methods and results All patients with COVID-19 infection discharged from the cardiology department of our institution from the 1 March to the 30 April 2020 were considered eligible for this study. Patients were fitted out with an adhesive patch and a wireless single-lead 24-h electrocardiogram (ECG) Holter monitor (Rooti Rx® System, Rooti Labs Ltd, Taipei, Taiwan). RootiRx® is a small device consisting of an integrated sensor system, a microelectronic board with memory storage, and an internal rechargeable battery. This system can provide continuous ECG and was set to monitor heart rhythm for 24 h. The Holter system provides also blood pressure measurements and sleep apnea data which are evaluated through chest wall motion/cyclic variation of heart rate and reported along with the sleep efficiency (percentage of time spent asleep while in bed). Arrhythmic findings, sleep apnea detections, and residual COVID-19 symptoms were reported. The study follow-up was performed 174 (range = 166–190) days after hospital discharge in a cohort of 63 (76% males, median age 66 years) patients. New diagnosis of atrial fibrillation (AF) was performed in three sinus rhythm patients (4.8%). Eleven (18%) patients had asymptomatic bradycardia (<45 b.p.m.) with no pauses lasting more than 3 s. Non-sustained ventricular tachycardia (<30 s) episodes were recorded in two (3.2%) patients, while no sustained ventricular arrhythmia was documented. The Holter system indicated the presence of moderate-to-severe obstructive sleep apnea episodes in 33 (53%) patients without known history of sleep disorders. Some previously unrecognized long-lasting COVID-19 symptoms were also described: fatigue (10, 16%), myalgia (3, 4.8%), and impaired attention (1, 1.6%). Conclusions Six months after the infection, we performed new diagnoses of AF in patients who recovered from severe COVID-19 infection with proved or suspected cardiac involvement using 24-h Holter monitoring. No other arrhythmias were observed, but the Holter system identified obstructive sleep apnea episodes in half of the patients. A relevant percentage of patients also described persisting symptoms of COVID-19 infection. These findings suggest further prospective studies to better describe long-term arrhythmic manifestations and residual symptoms in patients hospitalized with COVID-19 infection.

Olfactory sensory preconditioning in Drosophila: role of memory forgetting in gating S1/S2 associations

Learning and memory storage is a complex process that has proven challenging to tackle. It is likely that, in real nature, the instructive value of reinforcing experiences is acquired rather than innate. The association between seemingly neutral stimuli increases the gamut of possibilities to create meaningful associations and increases the predictive power of moment-by-moment experiences. Here we report physiological and behavioral evidence of olfactory unimodal sensory preconditioning in fruit flies. We show that the presentation of a pair of odors (S1 and S2) before one of them (S1) is associated with electric shocks elicits a conditional response not only to the trained odor (S1) but to the odor previously paired with it (S2). This occurs even if the S2 odor was never presented in contiguity with the aversive stimulus. In addition, we show that inhibition of the small G protein and known forgetting regulator Rac1 facilitates the association between S1/S2 odors. These results indicate that flies can infer value to non-paired odor based on the previous associative structure between odors, and inhibition of Rac1 lengthens the time of olfactory sensory buffer, allowing linking of neutral odors presented in sequence.