The Impact of the Successive Outbreaks of COVID-19, Vaccination, and Physical Activity on Mental Health in the Argentine Population: A Repeated Cross-Sectional Study.

Background and objectives A controversy regarding the duration of generalized anxiety disorders (GAD) and depressive symptoms during the COVID-19 pandemic arose, stating that these symptoms last a short time, perhaps a few months, or that they are more persistent over time. After more than three years of the pandemic, this is still a question that requires an answer. The main goal of this work was to record the levels of self-perceived GAD and depression in the Argentine population at several time points during the pandemic to characterize whether they were transient or persisted over the successive waves of contagion. Furthermore, we studied the association between anti-COVID-19 vaccination and the high frequency of physical activity with GAD and depression levels to evaluate a possible protective role of these factors on mental health. Methods We used a descriptive and correlational research design. We carried out a repeated cross-sectional study performing seven online surveys (collection period: four to 15 days) at different time points in October 2020, May, August, October, and December 2021, and February and April 2022. The participants (24,308) were recruited through Instagram campaigns performed by renowned local scientific communicators and responded to the survey through Google Forms (Google, Mountain View, CA). Generalized anxiety was assessed using the Generalized Anxiety Disorder-7 (GAD-7). Depression was assessed using the Patient Health Questionnaire (PHQ-9). The respondents reported their symptoms using a four-point Likert scale, which led us to calculate the scores and also the prevalence (% of the population with moderate to severe symptoms) for GAD and depression and the frequency they performed physical activity per week. Data were statistically analyzed using the unpaired Mann-Whitney U-test, chi-squared, Spearman correlation, or Tukey's post hoc test after two-way ANOVA. Results Our results show that the highest prevalence for GAD and depression correspond to those of the second wave of infections (May 2021: 57.3% and 54.19%, respectively) and that the lower levels were reported by the end of the third wave (April 2022: 43.21% and 43.65%, respectively). Such levels were even lower than those reported during the first wave at the beginning of our study (October 2020: 45.94% and 48.92%, respectively). In other words, even though the third wave tripled the number of people infected with respect to the second one, its effects on mental health were attenuated. The increment in the vaccine doses inoculated between the last two waves of contagion was associated with a decrease in the GAD score (mean ± SEM: 10.75 ± 0.06 vs. 8.88 ± 0.13) and the depressive symptoms (mean ± SEM: 10.76 ± 0.07 vs. 9.23 ± 0.14). Throughout the entire study period, the fraction of the population that practiced physical activity three or more times per week was self-perceived with lower levels of GAD and depression than those who exercised less frequently. Conclusions Of the three waves of contagion that the Argentine population suffered, the highest rates of GAD and depression were recorded in the second wave, and these symptoms decreased over the months, even during the third wave, which presented the highest number of infections. Our results also suggest that the progress of the vaccination campaign and the practice of physical exercises with high frequency could play a protective role in the mental health of the population during COVID-19.

Modulation of memory reconsolidation by adjacent novel tasks: timing defines the nature of change.

Reconsolidation turns memories into a responsive state that allows their modulation until they stabilize again. This phenomenon attracted remarkable attention due to its potential impact on therapeutics and education. Recent evidence revealed that different memories undergo reconsolidation via a behavioral tagging process. Thus, their re-stabilization involves setting "reconsolidation-tags" and synthesizing plasticity-related proteins for their capture at the tagged sites. Here, we studied the possibility of affecting these fundamental mechanisms to modulate reconsolidation. Our findings, in laboratory rats, indicate that exploring a novel environment 60 min before or after memory reactivation improves spatial object recognition memory by promoting protein synthesis. Conversely, experiencing novelty immediately after reactivation impairs the reconsolidation by affecting the tags. Similar effects, but with a different optimal time window for improvement, occur in inhibitory avoidance memory. These results highlight the possibility of modulating existing memories using non-invasive interventions that selectively affect the fundamental mechanisms of behavioral tagging during their reconsolidation.

Acute and chronic physical activity improves spatial memory in an immersive virtual reality task.

Physical activity benefits both fitness and cognition. However, its effect on long-term memory is unclear. In this study, we evaluated the effect of acute and chronic exercise on long-term spatial memory for a new virtual reality task. Participants were immersed in the virtual environment and navigated a wide arena that included target objects. We assessed spatial memory in two conditions (encoded targets separated by a short or long distance) and found that 25 min of cycling after encoding - but not before retrieval - was sufficient to improve the long-term memory retention for the short, but not for the long distance. Furthermore, we found that participants who engaged in regular physical activity showed memory for the short-distance condition whereas controls did not. Thus, physical activity could be a simple way to improve spatial memories.

Second Wave of COVID-19 Pandemic in Argentinian Population: Vaccination Is Associated With a Decrease in Depressive Symptoms.

Background: Since the irruption of the coronavirus disease 2019 (COVID-19) the planet has submerged in a time of concern and uncertainty, with a direct impact on people's mental health. Moreover, the recurrent outbreaks that periodically harry different regions of the world constantly refocus people's concerns to the pandemic. Yet, each new wave heats the diverse countries in different situations, including the advances in their vaccination campaigns. In this research, we studied the levels of the general anxiety disorder (GAD) and depression in the Argentine population across the first and second waves of infections that occurred in our country. Methods: We conducted an on-line survey, within each peak of the pandemic. People were asked to self-report GAD and depression symptoms using the GAD-7 and PHQ-9 questioners, inform their vaccination status, the frequency they performed physical activity as well as working condition and modality. Here, we identified the more vulnerable groups and evaluated factors that could mitigate the rise of these mental disorders, focusing on vaccination. Results: Our data shows that reported GAD and depression levels were higher during the second wave than during the first one. More importantly, vaccinated people were less depressed than non-vaccinated people, while GAD levels remained equivalent in both groups. Other factors directly associated with lower GAD and depression levels were performing frequent physical activity and being employed, regardless of the employment modality. These observations were replicated in different age ranges and genders. Conclusion: This work evidences GAD and depression in different pandemic waves in Argentina, as well the factors that may contribute to reducing the magnitude of these disorders, including vaccination.

Odor cueing during sleep improves consolidation of a history lesson in a school setting.

Sleep is a key factor in memory consolidation. During sleep, information is reactivated, transferred, and redistributed to neocortical areas, thus favoring memory consolidation and integration. Although these reactivations occur spontaneously, they can also be induced using external cues, such as sound or odor cues, linked to the acquired information. Hence, targeted memory reactivation during sleep represents an advantageous tool for improving memory consolidation in real-life settings. In this study, our goal was to improve the consolidation of complex information such as that of a history lesson, using a school study session in the presence of an odor, and a reactivation round while sleeping at home on the same night of the acquisition, without using additional study sessions. We found that complex information can be associated with an odor in the classroom and that one session of reactivation during the first night of sleep in the students' houses improves its consolidation. These results bring new evidence for the implementation of reactivation during sleep in real-life settings.

A virtual reality platform for memory evaluation: Assessing effects of spatial strategies.

Human spatial memories are usually evaluated using computer screens instead of real arenas or landscapes where subjects could move voluntarily and use allocentric cues to guide their behavior. A possible approach to fill this gap is the adoption of virtual reality, which provides the opportunity to create spatial memory tasks closer to real-life experience. Here we present and evaluate a new software to create experiments using this technology. Specifically, we have developed a spatial memory task that is carried out in a computer-assisted virtual environment where participants walk around a virtual arena using a joystick. This spatial memory task provides an immersive environment where the spatial component is constantly present without the use of virtual reality goggles. The design is similar to that of tasks used for animal studies, allowing a direct comparison across species. We found that only participants who reported using spatial cues to guide their behavior showed significant learning and performed significantly better during a memory test. This tool allows evaluation of human spatial memory in an ecological environment and will be useful to develop a wide range of other tasks to assess spatial cognition.

Nutritional stress timing differentially programs cognitive abilities in young adult male mice.

Objectives: The impact of chronic exposure to environmental adversities on brain regions involved in cognition and mental health depends on whether it occurs during the perinatal period, childhood, adolescence or adulthood. The effects of these adversities on the brain and behavior arise as a function of the timing of the exposure and their co-occurrence with the development of specific regions. Here we aimed to explore the behavioral phenotypes derived from two nutritional stress paradigms which differed in the timing of exposure: a low-protein perinatal diet during gestation and lactation and a low-protein diet during adolescence.Methods: Locomotor and exploratory activity, recognition memory and aversive memory were measured in CF-1 8-week-old male mice subjected to perinatal malnutrition (LP-P) or adolescent malnutrition (LP-A), and their respective controls with normal protein diet (NP-P and NP-A).Results: By using the open field test, we found that LP-P and LP-A mice showed reduced exploratory activity compared to controls, but no alterations in their locomotor activity. Recognition memory was impaired only in LP-P mice. Interestingly, aversive memory was not altered in LP-P mice but was enhanced in LP-A mice. Considering the stress-inoculation theory, we hypothesized that protein malnutrition during adolescence represents a challenging but still moderate stressful environment, which promotes active coping in face of later adversity.Conclusion: Our results indicate that while perinatal malnutrition impairs recognition memory, adolescent malnutrition enhances aversive memory, showing dissimilar adaptive responses.

Behavioral tagging underlies memory reconsolidation.

Memory reconsolidation occurs when a retrieving event destabilizes transiently a consolidated memory, triggering thereby a new process of restabilization that ensures memory persistence. Although this phenomenon has received wide attention, the effect of new information cooccurring with the reconsolidation process has been less explored. Here we demonstrate that a memory-retrieving event sets a neural tag, which enables the reconsolidation of memory after binding proteins provided by the original or a different contiguous experience. We characterized the specific temporal window during which this association is effective and identified the protein kinase A (PKA) and the extracellular signal-regulated kinase 1 and 2 (ERK 1/2) pathways as the mechanisms related to the setting of the reconsolidation tag and the synthesis of proteins. Our results show, therefore, that memory reconsolidation is mediated by a "behavioral tagging" process, which is common to different memory forms. They represent a significant advance in understanding the fate of memories reconsolidated while being adjacent to other events, and provide a tool for designing noninvasive strategies to attenuate (pathological/traumatic) or improve (education-related) memories.

Spatial object recognition memory formation under acute stress.

Stress is known to have a critical impact on memory processes. In the present work, we focus on the effects of an acute stress event closely associated to an unrelated learning task. Here, we show that acute stress (elevated platform [EP] session) experienced 1 hr after a weak spatial object recognition (SOR) training, which only induces a short-term memory (STM), promoted the formation of SOR-long term memory (SOR-LTM) in rats. The effect induced by stress was dependent on the activation of glucocorticoid- and mineralocorticoid-receptors, brain-derived neurotrophic factor (BDNF) and protein synthesis in the dorsal hippocampus. In contrast, EP after a strong SOR impaired SOR-LTM probably by interfering with the use of necessary resources. Moreover, we show that the EP session before training induced anterograde interference, which it was not reversed by a subsequent exposure to an open field. Our findings provide novel insights into the impact of stress on LTM formation in rodents and they are discussed under the behavioral analogue of the synaptic tagging and capture hypothesis.

Memory consolidation and expression of object recognition are susceptible to retroactive interference.

With the aim of analyzing if object recognition long-term memory (OR-LTM) formation is susceptible to retroactive interference (RI), we submitted rats to sequential sample sessions using the same arena but changing the identity of a pair of objects placed in it. Separate groups of animals were tested in the arena in order to evaluate the LTM for these objects. Our results suggest that OR-LTM formation was retroactively interfered within a critical time window by the exploration of a new, but not familiar, object. This RI acted on the consolidation of the object explored in the first sample session because its OR-STM measured 3h after training was not affected, whereas the OR-LTM measured at 24h was impaired. This sample session also impaired the expression of OR memory when it took place before the test. Moreover, local inactivation of the dorsal Hippocampus (Hp) or the medial Prefrontal Cortex (mPFC) previous to the exploration of the second pair of objects impaired their consolidation restoring the LTM for the objects explored in the first session. This data suggests that both brain regions are involved in the processing of OR-memory and also that if those regions are engaged in another process before finishing the first consolidation process its LTM will be impaired by RI.

Behavioral Tagging: A Translation of the Synaptic Tagging and Capture Hypothesis.

Similar molecular machinery is activated in neurons following an electrical stimulus that induces synaptic changes and after learning sessions that trigger memory formation. Then, to achieve perdurability of these processes protein synthesis is required for the reinforcement of the changes induced in the network. The synaptic tagging and capture theory provided a strong framework to explain synaptic specificity and persistence of electrophysiological induced plastic changes. Ten years later, the behavioral tagging hypothesis (BT) made use of the same argument, applying it to learning and memory models. The hypothesis postulates that the formation of lasting memories relies on at least two processes: the setting of a learning tag and the synthesis of plasticity related proteins, which once captured at tagged sites allow memory consolidation. BT explains how weak events, only capable of inducing transient forms of memories, can result in lasting memories when occurring close in time with other behaviorally relevant experiences that provide proteins. In this review, we detail the findings supporting the existence of BT process in rodents, leading to the consolidation, persistence, and interference of a memory. We focus on the molecular machinery taking place in these processes and describe the experimental data supporting the BT in humans.

Retroactive interference of object-in-context long-term memory: role of dorsal hippocampus and medial prefrontal cortex.

Retroactive interference (RI) is a type of amnesia in which a new learning experience can impair the expression of a previous one. It has been studied in several types of memories for over a century. Here, we aimed to study in the long-term memory (LTM) formation of an object-in-context task, defined as the recognition of a familiar object in a context different to that in which it was previously encountered. We trained rats with two sample trials, each taking place in a different context in association with different objects. Test sessions were performed 24 h later, to evaluate LTM for both object-context pairs using separate groups of trained rats. Furthermore, given the involvement of hippocampus (Hp) and medial prefrontal cortex (mPFC) in several recognition memories, we also analyzed the participation of these structures in the LTM formation of this task by the local infusion of muscimol. Our results show that object-in-context LTM formation is sensitive to RI by a different either familiar or novel object-context pair trial, experienced 1 h later. This interference occurs in a restricted temporal window and works on the LTM consolidation phase, leaving intact short-term memory expression. The second sample trial did not affect the object recognition part of the memory. Besides, muscimol treatment before the second sample trial blocks its object-in-context LTM and restores the first sample trial memory. We hypothesized that LTM-RI amnesia is probably caused by resources or cellular machinery competition in these brain regions when they are engaged in memory formation of the traces. In sum, when two different object-in-context memory traces are being processed, the second trace interferes with the consolidation of the first one requiring mPFC and CA1 dorsal Hp activation.

The tagging and capture hypothesis from synapse to memory.

The synaptic tagging and capture theory (STC) was postulated by Frey and Morris in 1997 and provided a strong framework to explain how to achieve synaptic specificity and persistence of electrophysiological-induced plasticity changes. Ten years later, the same argument was applied on learning and memory models to explain the formation of long-term memories, resulting in the behavioral tagging hypothesis (BT). These hypotheses are able to explain how a weak event that induces transient changes in the brain can establish long-lasting phenomena through a tagging and capture process. In this framework, it was postulated that the weak event sets a tag that captures plasticity-related proteins/products (PRPs) synthesized by an independent strong event. The tagging and capture processes exhibit symmetry, and therefore, PRPs can be captured if they are synthesized either before or after the setting of the tag. In summary, the hypothesis provides a wide framework that gives a solid explanation of how lasting changes occur and how the interaction between different events leads to promotion, reinforcement, or impairment of such changes. In this chapter, we will summarize the postulates of STC hypothesis, the common features between synaptic plasticity and memory, as well as a detailed compilation of the findings supporting the existence of BT process. At the end, we pose some questions related to BT mechanism and LTM formation, which probably will be answered in the near future.

Memory in Elementary School Children Is Improved by an Unrelated Novel Experience.

Education is the most traditional means with formative effect on the human mind, learning and memory being its fundamental support. For this reason, it is essential to find different strategies to improve the students performance. Based on previous work, we hypothesized that a novel experience could exert an enhancing effect on learning and memory within the school environment. Here we show that novel experience improved the memory of literary or graphical activities when it is close to these learning sessions. We found memory improvements in groups of students who had experienced a novel science lesson 1 hour before or after the reading of a story, but not when these events were 4 hours apart. Such promoting effect on long-term memory (LTM) was also reproduced with another type of novelty (a music lesson) and also after another type of learning task (a visual memory). Interestingly, when the lesson was familiar, it failed to enhance the memory of the other task. Our results show that educationally relevant novel events experienced during normal school hours can improve LTM for tasks/activities learned during regular school lessons. This effect is restricted to a critical time window around learning and is particularly dependent on the novel nature of the associated experience. These findings provide a tool that could be easily transferred to the classroom by the incorporation of educationally novel events in the school schedule as an extrinsic adjuvant of other information acquired some time before or after it. This approach could be a helpful tool for the consolidation of certain types of topics that generally demand a great effort from the children.

Memory traces compete under regimes of limited Arc protein synthesis: implications for memory interference.

Recently encoded information can be lost in the presence of new information, a process called 'retrograde interference'. Retrograde interference has been extensively described for more than a century; however, little is known about its underlying mechanisms. Different approaches agree on the need of the synthesis of plasticity related proteins (PRPs) to consolidate a long-term memory (LTM). Our hypothesis is that when PRPs are limited, interference of a task over LTM formation of another may be due to the utilization of protein resources common to both tasks. Here, by combining the tasks of inhibitory avoidance (IA) and open field (OF) exploration in rats, we show that memory traces compete for their stabilization if PRPs are limited. As a result, LTM is formed for only one of the tasks with a consequent decrease in the memory for the other. Furthermore, infusing Arc antisense oligonucleotide into the dorsal hippocampus, we found that Arc is necessary for LTM formation of these two types of learning tasks and is one of the PRPs that can be shared between them when animals are trained in both OF and IA. In sum, these findings suggest that under conditions of reduced protein availability, a learning task interferes with LTM formation of another by using the available PRPs.

Identification of transmitter systems and learning tag molecules involved in behavioral tagging during memory formation.

Long-term memory (LTM) consolidation requires the synthesis of plasticity-related proteins (PRPs). In addition, we have shown recently that LTM formation also requires the setting of a "learning tag" able to capture those PRPs. Weak training, which results only in short-term memory, can set a tag to use PRPs derived from a temporal-spatial closely related event to promote LTM formation. Here, we studied the involvement of glutamatergic, dopaminergic, and noradrenergic inputs on the setting of an inhibitory avoidance (IA) learning tag and the synthesis of PRPs. Rats explored an open field (PRP donor) followed by weak (tag inducer) or strong (tag inducer plus PRP donor) IA training. Throughout pharmacological interventions around open-field and/or IA sessions, we found that hippocampal dopamine D1/D5- and ß-adrenergic receptors are specifically required to induce PRP synthesis. Moreover, activation of the glutamatergic NMDA receptors is required for setting the learning tags, and this machinery further required α-Ca(2+)/calmodulin-dependent protein kinase II and PKA but not ERK1/2 activity. Together, the present findings emphasize an essential role of the induction of PRPs and learning tags for LTM formation. The existence of only the PRP or the tag was insufficient for stabilization of the mnemonic trace.

Behavioral tagging is a general mechanism of long-term memory formation.

In daily life, memories are intertwined events. Little is known about the mechanisms involved in their interactions. Using two hippocampus-dependent (spatial object recognition and contextual fear conditioning) and one hippocampus-independent (conditioned taste aversion) learning tasks, we show that in rats subjected to weak training protocols that induce solely short term memory (STM), long term memory (LTM) is promoted and formed only if training sessions took place in contingence with a novel, but not familiar, experience occurring during a critical time window around training. This process requires newly synthesized proteins induced by novelty and reveals a general mechanism of LTM formation that begins with the setting of a "learning tag" established by a weak training. These findings represent the first comprehensive set of evidences indicating the existence of a behavioral tagging process that in analogy to the synaptic tagging and capture process, need the creation of a transient, protein synthesis-independent, and input specific tag.