α7 nicotinic acetylcholine receptor in memory processing.

Information storage in the brain involves different memory types and stages that are processed by several brain regions. Cholinergic pathways through acetylcholine receptors actively participate on memory modulation, and their disfunction is associated with cognitive decline in several neurological disorders. During the last decade, the role of α7 subtype of nicotinic acetylcholine receptors in different memory stages has been studied. However, the information about their role in memory processing is still scarce. In this review, we attempt to identify brain areas where α7 nicotinic receptors have an essential role in different memory types and stages. In addition, we discuss recent work implicating-or not-α7 nicotinic receptors as promising pharmacological targets for memory impairment associated with neurological disorders.

The late consolidation of an aversive memory is promoted by VTA dopamine release in the dorsal hippocampus.

The hippocampus has been implicated in the processing and storage of aversive memories but the precise mechanisms by which these memories persist in time remain elusive. We have demonstrated that dopaminergic neurotransmission in the dorsal hippocampus regulates the long-term storage of both appetitive and aversive memories at a critical time point known as "late consolidation" (12 hr after the learning experience). This modulation appears to have opposite effects depending on the valence of the stimuli, with hippocampal dopamine release peaking immediately and 13-17 hr after a rewarding experience. Here, we determined the release pattern of hippocampal dopamine following an aversive experience, in order to better understand this opposite modulation process. We observed significant increases in dopamine levels at several times (6-8, 11-12, and 15 hr) after subjecting rats to a conditioned place aversion (CPA) task with the aversive agent lithium chloride (LiCl). Early pharmacological blockade of hippocampal DA receptors impaired CPA memory consolidation. In addition and consistent with previous findings showing that late post-training infusions of dopaminergic agents into the hippocampus modulate the long-term storage of aversive memories, we found that the photostimulation of dopaminergic VTA fibers in the dorsal hippocampus 11-12 hr after CPA training was enough to transform a short-lasting long-term memory into a long-lasting one. The fact that the persistence of an aversive memory can still be affected several hours after the learning experience opens new avenues to develop behavioral and pharmacological strategies for the treatment of a variety of mental disorders.

Functional connectivity of anterior retrosplenial cortex in object recognition memory.

Recognition memory can rely on three components: "what", "where" and "when". Recently we demonstrated that the anterior retrosplenial cortex (aRSC), like the perirhinal cortex (PRH) and unlike the hippocampus (HP), is required for consolidation of the "what" component. Here, we aimed at studying which brain structures interact with the aRSC to process object recognition (OR) memory in rats. We studied the interaction of six brain structures that are connected to the aRSC during OR memory processing: PRH, medial prefrontal cortex (mPFC), anteromedial thalamic nuclei (AM), medial entorhinal cortex (MEC), anterior cingulate cortex (ACC) and the dorsal HP (dHP). We previously described the role of the PRH and dHP, so we first studied the participation of the mPFC, AM, MEC and ACC in OR memory consolidation by bilateral microinfusions of the GABAA receptor agonist muscimol. We observed an impairment in OR long-term memory (LTM) when inactivating the mPFC, the AM and the MEC, but not the ACC. Then, we studied the functional connections by unilateral inactivation of the aRSC and each one of the six structures in the same (ipsilateral) or the opposite (contralateral) hemisphere. Our results showed an amnesic LTM effect in rats with ipsilateral inactivations of aRSC-PRH, aRSC-mPFC, aRSC-AM, or aRSC-MEC. On the other hand, we observed memory impairment when aRSC-ACC were inactivated in opposite hemispheres, and no effect when the aRSC-dHP connection was inactivated. Thus, our ipsilateral inactivation findings reveal that the aRSC and, at least one brain region required in OR LTM processing are essential to consolidate OR memory. In conclusion, our results show that several cortico-cortical and cortico-thalamic pathways are important for OR memory consolidation.

Requirement of an Early Activation of BDNF/c-Fos Cascade in the Retrosplenial Cortex for the Persistence of a Long-Lasting Aversive Memory.

During the past few years, there has been growing interest in the role of the retrosplenial cortex (RSC) in memory processing. However, little is known about the molecular changes that take place in this brain region during memory formation. In the present work, we studied the early post-training participation of RSC in the formation of a long-lasting memory in rats. We found an increase in c-Fos levels in the anterior part of the RSC (aRSC) after inhibitory avoidance (IA) training. Interestingly, this increase was associated with memory durability, since blocking c-Fos expression using specific antisense oligonucleotides (ASO) impaired long-lasting retention 7 days after training without affecting memory expression 2 days after training. In addition, we showed that BDNF is one of the upstream signals for c-Fos expression required for memory persistence, since blocking BDNF synthesis prevents IA training-induced increase in c-Fos levels in aRSC and affects memory persistence. In addition, we found that injection of BDNF into aRSC around training was sufficient to establish a persistent memory and that this effect was prevented by c-fos ASO infusion into the same structure. These findings reveal an early post-training involvement of aRSC in the processing of a long-lasting aversive memory.

Requirement for BDNF in the reconsolidation of fear extinction.

Therapies based on the impairment of reconsolidation or the enhancement of extinction offer the possibility of decreasing the persistent recollection of distressing memories. However, the direct interplay between reconsolidation and extinction has rarely been considered. Previously, we reported that reactivation induces reconsolidation of fear extinction memory. Here, using a step-down inhibitory avoidance learning paradigm in rats, we show that intrahippocampus infusion of function-blocking anti-BDNF antibody immediately or 6 h after extinction memory reactivation impairs the reconsolidation of extinction. Extinction memory reactivation increases proBDNF, BDNF, and tropomyosin receptor kinase B (TrkB) phosphorylation levels in dorsal CA1, while blocking BDNF maturation in the hippocampus with plasminogen activator inhibitor 1 hinders the persistence of extinction and induces the recurrence of fear. Moreover, coinfusion of recombinant BDNF (0.25 µg/side) after extinction memory reactivation impedes the recovery of the avoidance response induced by inhibiting gene expression and protein synthesis in the dorsal hippocampus. Our findings unravel a new role for BDNF, suggesting that this neurotrophin is necessary and sufficient to maintain the reactivated fear extinction engram.

Dorsal medial prefrontal cortex contributes to conditioned taste aversion memory consolidation and retrieval.

The medial prefrontal cortex (mPFC) is known for its role in decision making and memory processing, including the participation in the formation of extinction memories. However, little is known regarding its contribution to aversive memory consolidation. Here we demonstrate that neural activity and protein synthesis are required in the dorsal mPFC for memory formation of a conditioned taste aversion (CTA) task and that this region is involved in the retrieval of recent and remote long-term CTA memory. In addition, both NMDA receptor and CaMKII activity in dorsal mPFC are needed for CTA memory consolidation, highlighting the complexity of mPFC functions.

Evidence of Maintenance Tagging in the Hippocampus for the Persistence of Long-Lasting Memory Storage.

The synaptic tagging and capture (STC) hypothesis provides a compelling explanation for synaptic specificity and facilitation of long-term potentiation. Its implication on long-term memory (LTM) formation led to postulate the behavioral tagging mechanism. Here we show that a maintenance tagging process may operate in the hippocampus late after acquisition for the persistence of long-lasting memory storage. The proposed maintenance tagging has several characteristics: (1) the tag is transient and time-dependent; (2) it sets in a late critical time window after an aversive training which induces a short-lasting LTM; (3) exposing rats to a novel environment specifically within this tag time window enables the consolidation to a long-lasting LTM; (4) a familiar environment exploration was not effective; (5) the effect of novelty on the promotion of memory persistence requires dopamine D1/D5 receptors and Arc expression in the dorsal hippocampus. The present results can be explained by a broader version of the behavioral tagging hypothesis and highlight the idea that the durability of a memory trace depends either on late tag mechanisms induced by a training session or on events experienced close in time to this tag.

Dopamine D1/D5 receptors in the dorsal hippocampus are required for the acquisition and expression of a single trial cocaine-associated memory.

The role of the hippocampus in memory supporting associative learning between contexts and unconditioned stimuli is well documented. Hippocampal dopamine neurotransmission modulates synaptic plasticity and memory processing of fear-motivated and spatial learning tasks. Much less is known about the involvement of the hippocampus and its D1/D5 dopamine receptors in the acquisition, consolidation and expression of memories for drug-associated experiences, more particularly, in the processing of single pairing cocaine conditioned place preference (CPP) training. To determine the temporal dynamics of cocaine CPP memory formation, we trained rats in a one-pairing CPP paradigm and tested them at different time intervals after conditioning. The cocaine-associated memory lasted 24 h but not 72 h. Then, we bilaterally infused the dorsal hippocampus with the GABA A receptor agonist muscimol or the D1/D5 dopamine receptor antagonist SCH 23390 at different stages to evaluate the mechanisms involved in the acquisition, consolidation or expression of cocaine CPP memory. Blockade of D1/D5 dopamine receptors at the moment of training impaired the acquisition of cocaine CPP memories, without having any effect when administered immediately or 12 h after training. The expression of cocaine CPP memory was also affected by the administration of SCH 23390 at the moment of the test. Conversely, muscimol impaired the consolidation of cocaine CPP memory only when administered 12 h post conditioning. These findings suggests that dopaminergic inputs to the dorsal hippocampus are required for the acquisition and expression of one trial cocaine-associated memory while neural activity of this structure is required for the late consolidation of these types of memories.

Functional integrity of the retrosplenial cortex is essential for rapid consolidation and recall of fear memory.

Memory storage is a temporally graded process involving different phases and different structures in the mammalian brain. Cortical plasticity is essential to store stable memories, but little is known regarding its involvement in memory processing. Here we show that fear memory consolidation requires early post-training macromolecular synthesis in the anterior part of the retrosplenial cortex (aRSC), and that reversible pharmacological inactivation of this cortical region impairs recall of recent as well as of remote memories. These results challenge the generally accepted idea that neocortical areas are slow encoding systems that participate in the retrieval of remote memories only.

Nicotine modulates the long-lasting storage of fear memory.

Late post-training activation of the ventral tegmental area (VTA)-hippocampus dopaminergic loop controls the entry of information into long-term memory (LTM). Nicotinic acetylcholine receptors (nAChR) modulate VTA function, but their involvement in LTM storage is unknown. Using pharmacological and behavioral tools, we found that α7-nAChR-mediated cholinergic interactions between the pedunculopontine tegmental nucleus and the medial prefrontal cortex modulate the duration of fear-motivated memories, maybe by regulating the activation state of VTA-hippocampus dopamine connections.

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.

On the role of retrosplenial cortex in long-lasting memory storage.

The retrosplenial cortex (RSC) is involved in a range of cognitive functions. However, its precise involvement in memory processing is unknown. Pharmacological and behavioral experiments demonstrate that protein synthesis and c-Fos expression in the anterior part of RSC (aRSC) are necessary late after training to maintain for many days a fear-motivated memory. Long-lasting memory storage is regulated by D1/D5 dopamine receptors in aRSC and depends on the functional interplay between dorsal hippocampus and aRSC. These results suggest that the RSC recapitulates some of the molecular events that occur in the hippocampus to maintain memory trace over time.

Molecular signatures and mechanisms of long-lasting memory consolidation and storage.

A body of evidence emerged in the last decade regarding late posttraining memory processing. Most of this new information comes from aversively motivated learning tasks that mainly depend on hippocampus, amygdala and insular cortex, and points to the involvement of long-lasting changes in gene expression and protein synthesis in late stages of memory consolidation and storage. Here, we describe recent advances in this field and discuss how recurrent rounds of macromolecular synthesis and its regulation might impact long-term memory storage.

Medial prefrontal cortex is a crucial node of a rapid learning system that retrieves recent and remote memories.

The neocortex is thought to be a distributed learning system that gradually integrates semantic information into the initial mnemonic representation rapidly formed by the hippocampus after acquisition. Nevertheless, an emerging view suggests that some cortical regions, in particular the medial prefrontal cortex (mPFC), may also have a role during the initial steps of memory consolidation as well as in the recall of recent memories. Here, we show that mPFC plays a critical role during the first few hours of inhibitory avoidance memory consolidation and is necessary for the normal retrieval of both recent and remote memories, supporting the idea that involvement of neocortical areas in memory processing is not restricted to the late post-training consolidation phase.

Consolidation of object recognition memory requires simultaneous activation of dopamine D1/D5 receptors in the amygdala and medial prefrontal cortex but not in the hippocampus.

The mesocorticolimbic dopaminergic system includes the ventral tegmental area (VTA) and its projections to the amygdala (AMY), the hippocampus (HIP) and the medial prefrontal cortex (mPFC), among others. Object recognition (OR) long-term memory (LTM) processing requires dopaminergic activity but, although some of the brain regions mentioned above are necessary for OR LTM consolidation, their possible dopamine-mediated interplay remains to be analyzed. Using adult male Wistar rats, we found that posttraining microinjection of the dopamine D1/D5 receptor antagonist SCH23390 in mPFC or AMY, but not in HIP, impaired OR LTM. The dopamine D2 receptor agonist quinpirole had no effect on retention. VTA inactivation also hindered OR LTM, and even though this effect was unaffected by co-infusion of the dopamine D1/D5 receptor agonist SKF38393 in HIP, mPFC or AMY alone, it was reversed by simultaneous activation of D1/D5 receptors in the last two regions. Our results demonstrate that the mesocorticolimbic dopaminergic system is indeed essential for OR LTM consolidation and suggest that the role played by some of its components during this process is much more complex than previously thought.

Retrieval induces reconsolidation of fear extinction memory.

The nonreinforced expression of long-tem memory may lead to two opposite protein synthesis-dependent processes: extinction and reconsolidation. Extinction weakens consolidated memories, whereas reconsolidation allows incorporation of additional information into them. Knowledge about these two processes has accumulated in recent years, but their possible interaction has not been evaluated yet. Here, we report that inhibition of protein synthesis in the CA1 region of the dorsal hippocampus after retrieval of fear extinction impedes subsequent reactivation of the extinction memory trace without affecting its storage or that of the initial fear memory. Our results suggest that extinction memory is susceptible to a retrieval-induced process similar to reconsolidation in the hippocampus.

Delayed wave of c-Fos expression in the dorsal hippocampus involved specifically in persistence of long-term memory storage.

Memory formation is a temporally graded process during which transcription and translation steps are required in the first hours after acquisition. Although persistence is a key characteristic of memory storage, its mechanisms are scarcely characterized. Here, we show that long-lasting but not short-lived inhibitory avoidance long-term memory is associated with a delayed expression of c-Fos in the hippocampus. Importantly, this late wave of c-Fos is necessary for maintenance of inhibitory avoidance long-term storage. Moreover, inhibition of transcription in the dorsal hippocampus 24 h after training hinders persistence but not formation of long-term storage. These findings indicate that a delayed phase of transcription is essential for maintenance of a hippocampus-dependent memory trace. Our results support the hypothesis that recurrent rounds of consolidation-like events take place late after learning in the dorsal hippocampus to maintain memories.

Time-dependent inhibition of Rac1 in the VTA enhances long-term aversive memory: implications in active forgetting mechanisms.

The fate of memories depends mainly on two opposing forces: the mechanisms required for the storage and maintenance of memory and the mechanisms underlying forgetting, being the latter much less understood. Here, we show the effect of inhibiting the small Rho GTPase Rac1 on the fate of inhibitory avoidance memory in male rats. The immediate post-training micro-infusion of the specific Rac1 inhibitor NSC23766 (150 ng/0.5 µl/ side) into the ventral tegmental area (VTA) enhanced long-term memory at 1, 7, and 14 days after a single training. Additionally, an opposed effect occurred when the inhibitor was infused at 12 h after training while no effect was observed immediately after testing animals at 1 day. Control experiments ruled out the possibility that post-training memory enhancement was due to facilitation of memory formation since no effect was found when animals were tested at 1 h after acquisition and no memory enhancement was observed after the formation of a weak memory. Immediate post-training micro-infusion of Rac1 inhibitor into the dorsal hippocampus, or the amygdala did not affect memory. Our findings support the idea of a Rac1-dependent time-specific active forgetting mechanism in the VTA controlling the strength of a long-term aversive memory.

α7 nicotinic acetylcholine receptors in the medial prefrontal cortex control rewarding but not aversive memory expression in a dopamine-sensitive manner.

Emotional learning involves the association between sensory cues and rewarding or aversive stimuli, and this stored information can be recalled during memory retrieval. In this process, the medial prefrontal cortex (mPFC) plays an essential role. We have previously shown that the antagonism of α7 nicotinic acetylcholine receptors (nAChRs) by methyllycaconitine (MLA) in the mPFC blocked cue-induced cocaine memory retrieval. However, little is known about the involvement of prefrontal α7 nAChRs in the retrieval of aversive memories. Here, by using pharmacology and different behavioral tasks, we found that MLA did not affect aversive memory retrieval, indicating a differential effect of cholinergic prefrontal control of appetitive and aversive memories. Despite being shown that acetylcholine modulates dopamine release in the mPFC, it remains unknown if those modulatory systems act together to control reward-based behavior. We examined that question and found that dopamine type 1 receptor (D1R) activation prevented MLA-induced blockade of cocaine CPP retrieval. Our results suggest that α7 nAChRs and D1R signaling interact in the mPFC to modulate cocaine-associated memory retrieval.

Maintenance of long-term memory storage is dependent on late posttraining Egr-1 expression.

Expression of immediate-early genes, like Egr-1, has been shown to be induced by activity-dependent synaptic plasticity or behavioral training and is widely thought to play an important role in long-term memory (LTM) formation. However, little is known about the role of Egr-1 in the maintenance of memory storage. Here we show that dorsal hippocampal Egr-1 protein expression is upregulated between 12 and 24 h after strong inhibitory avoidance (IA) training in rats. Local infusion of antisense oligodeoxynucleotide (ASO) to specifically knockdown Egr-1 in the dorsal hippocampus 8 h posttraining impairs LTM tested 7 days, but not 1 day after training, indicating that a delayed learning-associated expression of Egr-1 is necessary for the persistence of LTM storage. In addition, we show that consolidation of the IA memory is accompanied by an increase in Egr-1 protein levels 3 h, but not immediately or 1 h after training. Local infusion of egr-1 ASO 30 min before training in the dorsal hippocampus persistently hinders memory formation measured 1 and 7 days after IA training, indicating the crucial role of Egr-1 in memory formation. Our findings demonstrate that there are at least two waves of Egr-1 expression in the dorsal hippocampus after IA training, an early wave which is involved in IA LTM formation, and a lasting late wave that peaks around 12-24 h after a strong training protocol which is specifically involved in the maintenance of LTM storage.