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.

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.

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.

Dopamine D1/D5 Receptors in the Retrosplenial Cortex Are Necessary to Consolidate Object Recognition Memory.

The retrosplenial cortex (RSC) has been widely related to spatial and contextual memory. However, we recently demonstrated that the anterior part of the RSC (aRSC) is required for object recognition (OR) memory consolidation. In this study, we aimed to analyze the requirement of dopaminergic inputs into the aRSC for OR memory consolidation in male rats. We observed amnesia at 24-h long-term memory when we infused SCH23390, a D1/D5 dopamine receptors antagonist, into aRSC immediately after OR training session. However, the same infusion had no effect on OR short-term memory. Then, we analyzed whether the ventral tegmental area (VTA) is necessary for OR consolidation. VTA inactivation by intra-VTA administration of muscimol, a GABAA agonist, immediately after an OR training session induced amnesia when animals were tested at 24 h. Moreover, we observed that this VTA inactivation-induced amnesia was reversed by the simultaneous intra-aRSC delivery of SKF38393, a D1/D5 receptor agonist. Altogether, our results suggest that VTA dopaminergic inputs to aRSC play an important modulatory role in OR memory consolidation.

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.

Dopamine neurotransmission in the VTA regulates aversive memory formation and persistence.

Dopamine (DA) neurons in the ventral tegmental area (VTA) innervating several limbic and neocortical regions of the mammalian brain have long been implicated in motivation, rewarding and aversive behaviors, and memory processing. Recently, we demonstrated that somatodendritic release of DA in the VTA regulates the formation and maintenance of appetitive long-term memories (LTM). However, less is known about the impact of DA neurotransmission in the VTA on aversive LTM. Here, we describe the modulation of negative-valence memories by D1/D5-type DA (D1R)-receptor-mediated neurotransmission in the VTA. As aversive stimuli elicit both active and passive behavioral responses, we used two single-trial aversive training protocols: inhibitory avoidance task and conditioned place aversion. We bilaterally microinfused SCH23390, an antagonist of D1R, into the VTA immediately after training and found that DA neurotransmission in the VTA modulates LTM consolidation and persistence of aversive experiences. Together with previous findings demonstrating that D1R-mediated DA neurotransmission in the medial prefrontal cortex and hippocampus is involved in the formation and persistence of LTM for aversive events, our present results indicate that memory processing of environmental stimuli with negative-valence depends on the integration of information mediated by D1R activation in both the VTA region and in selected downstream target areas.

A novel role for the lateral habenula in fear learning.

Fear is an extreme form of aversion that underlies pathological conditions such as panic or phobias. Fear conditioning (FC) is the best-understood model of fear learning. In FC the context and a cue are independently associated with a threatening unconditioned stimulus (US). The lateral habenula (LHb) is a general encoder of aversion. However, its role in fear learning remains poorly understood. Here we studied in rats the role of the LHb in FC using optogenetics and pharmacological tools. We found that inhibition or activation of the LHb during entire FC training impaired both cued and contextual FC. In contrast, optogenetic inhibition of the LHb restricted to cue and US presentation impaired cued but not contextual FC. In either case, simultaneous activation of contextual and cued components of FC, by the presentation of the cue in the training context, recovered the conditioned fear response. Our results support the notion that the LHb is required for the formation of independent contextual and cued fear memories, a previously uncharacterized function for this structure, that could be critical in fear generalization.

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.

AMPA Receptors: A Key Piece in the Puzzle of Memory Retrieval.

Retrieval constitutes a highly regulated and dynamic phase in memory processing. Its rapid temporal scales require a coordinated molecular chain of events at the synaptic level that support transient memory trace reactivation. AMPA receptors (AMPAR) drive the majority of excitatory transmission in the brain and its dynamic features match the singular fast timescales of memory retrieval. Here we provide a review on AMPAR contribution to memory retrieval regarding its dynamic movements along the synaptic compartments, its changes in receptor number and subunit composition that take place in activity dependent processes associated with retrieval. We highlight on the differential regulations exerted by AMPAR subunits in plasticity processes and its impact on memory recall.

Prefrontal cortex nicotinic receptor inhibition by methyllycaconitine impaired cocaine-associated memory acquisition and retrieval.

Cocaine administration has been shown to induce plastic changes in the medial prefrontal cortex (mPFC), which could represent a mechanism by which cocaine facilitates the association between cocaine rewarding effects with contextual cues. Nicotinic acetylcholine receptors (nAChRs) in the mPFC have critical roles in cognitive function including attention and memory and are key players in plasticity processes. However, whether nAChRs in the mPFC are required for the acquisition and maintenance of cocaine-associated memories is still unknown. To assess this question, we used the conditioning place preference (CPP) model to study the effect of intra-mPFC infusion of methyllycaconitine, a selective antagonist of α7 nAChRs, on the acquisition, consolidation and expression of cocaine-associated memory in adult rats. Our findings reveal that mPFC α7 nAChRs activation is necessary for the acquisition and retrieval, but not consolidation, of cocaine induced CPP. Moreover, cocaine-induced sensitization during CPP conditioning sessions was abolished by methyllycaconitine infusion in the mPFC. Together, these results identify mPFC α7 nAChRs as critical players involved in both acquiring and retrieving cocaine-associated memories. Considering that drug seeking often depends on the association between drug-paired cues and the rewarding effects of the drug, α7 nAChRs in the mPFC could be considered as potential targets for the prevention or treatment of cocaine use disorder.

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.

AMPA Receptor Expression Requirement During Long-Term Memory Retrieval and Its Association with mTORC1 Signaling.

Recently, it was reported that mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity during memory retrieval is required for normal expression of aversive and non-aversive long-term memories. Here we used inhibitory-avoidance task to evaluate the potential mechanisms by which mTORC1 signaling pathway participates in memory retrieval. First, we studied the role of GluA-subunit trafficking during memory recall and its relationship with mTORC1 pathway. We found that pretest intrahippocampal infusion of GluR23É£, a peptide that selectively blocks GluA2-containing AMPA receptor (AMPAR) endocytosis, prevented the amnesia induced by the inhibition of mTORC1 during retrieval. Additionally, we found that GluA1 levels decreased and GluA2 levels increased at the hippocampal postsynaptic density subcellular fraction of rapamycin-infused animals during memory retrieval. GluA2 levels remained intact while GluA1 decreased at the synaptic plasma membrane fraction. Then, we evaluated the requirement of AMPAR subunit expression during memory retrieval. Intrahippocampal infusion of GluA1 or GluA2 antisense oligonucleotides (ASO) 3 h before testing impaired memory retention. The memory impairment induced by GluA2 ASO before retrieval was reverted by GluA23É£ infusion 1 h before testing. However, AMPAR endocytosis blockade was not sufficient to compensate GluA1 synthesis inhibition. Our work indicates that de novo GluA1 and GluA2 AMPAR subunit expression is required for memory retrieval with potential different roles for each subunit and suggests that mTORC1 might regulate AMPAR trafficking during retrieval. Our present results highlight the role of mTORC1 as a key determinant of memory retrieval that impacts the recruitment of different AMPAR subunits.

Anterior retrosplenial cortex is required for long-term object recognition memory.

The retrosplenial cortex (RSC) is implicated on navigation and contextual memory. Lesions studies showed that the RSC shares functional similarities with the hippocampus (HP). Here we evaluated the role of the anterior RSC (aRSC) in the "what" and "where" components of recognition memory and contrasted it with that of the dorsal HP (dHP). Our behavioral and molecular findings show functional differences between the aRSC and the dHP in recognition memory. The inactivation of the aRSC, but not the dHP, impairs the consolidation and expression of the "what" memory component. In addition, object recognition task is accompanied by c-Fos levels increase in the aRSC. Interestingly, we found that the aRSC is recruited to process the "what" memory component only if it is active during acquisition. In contrast, both the aRSC and dHP are required for encoding the "where" component, which correlates with c-Fos levels increase. Our findings introduce a novel role of the aRSC in recognition memory, processing not only the "where", but also the "what" memory component.

Dopamine Neurotransmission in the Ventral Tegmental Area Promotes Active Forgetting of Cocaine-Associated Memory.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are well-known components of the brain involved in reward-related behaviors and participate in the generation of new memories. Much attention has been focused to understand how DA neurons integrate a diversity of afferent signals with local excitatory and inhibitory influences regulated by somatodendritic release of dopamine. However, the mechanisms that actively forget rewarding information are still terra incognita. Using rodents in the conditioned place preference (CPP) behavioral task, we show that during acquisition D1-type DA receptors (D1R) in the VTA are crucial components of a neural circuit involving the hippocampus that induces active forgetting of cocaine-associated long-term memory, while VTA and nucleus accumbens (NAc) D1R are required for its formation. Inhibition of VTA D1R results in increased activation of VTA ERK1/2 and in prolonging memory storage of cocaine-place association in an ERK-dependent manner. Moreover, intra-VTA infusion of a specific D1 agonist induces forgetting of cocaine-associated consolidated memory. In contrast, D1R in the NAc shell, medial prefrontal cortex, or amygdala appear not to participate in the maintenance of cocaine-associated memory. Our present results suggest that at the moment of learning D1R-mediated neurotransmission in the VTA actively participates in at least two processes affecting the fate of appetitive memory: its consolidation involving NAc shell DA neurotransmission and its forgetting via DA activation of the hippocampus.

ERK1/2: A Key Cellular Component for the Formation, Retrieval, Reconsolidation and Persistence of Memory.

Extracellular regulated kinase 1/2 (ERK1/2) has been strongly implicated in several cellular processes. In the brain ERK1/2 activity has been primarily involved in long-term memory (LTM) formation and expression. Here, we review earlier evidence and describe recent developments of ERK1/2 signaling in memory processing focusing the attention on the role of ERK1/2 in memory retrieval and reconsolidation, and in the maintenance of the memory trace including mechanisms involving the protection of labile memories. In addition, relearning requires ERK1/2 activity in selected brain regions. Its involvement in distinct memory stages points at ERK1/2 as a core element in memory processing and as one likely target to treat memory impairments associated with neurological disorders.

mTORC1 controls long-term memory retrieval.

Understanding how stored information emerges is a main question in the neurobiology of memory that is now increasingly gaining attention. However, molecular events underlying this memory stage, including involvement of protein synthesis, are not well defined. Mammalian target of rapamycin complex 1 (mTORC1), a central regulator of protein synthesis, has been implicated in synaptic plasticity and is required for memory formation. Using inhibitory avoidance (IA), we evaluated the role of mTORC1 in memory retrieval. Infusion of a selective mTORC1 inhibitor, rapamycin, into the dorsal hippocampus 15 or 40 min but not 3 h before testing at 24 h reversibly disrupted memory expression even in animals that had already expressed IA memory. Emetine, a general protein synthesis inhibitor, provoked a similar impairment. mTORC1 inhibition did not interfere with short-term memory retrieval. When infused before test at 7 or 14 but not at 28 days after training, rapamycin impaired memory expression. mTORC1 blockade in retrosplenial cortex, another structure required for IA memory, also impaired memory retention. In addition, pretest intrahippocampal rapamycin infusion impaired object location memory retrieval. Our results support the idea that ongoing protein synthesis mediated by activation of mTORC1 pathway is necessary for long but not for short term memory.

Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc.

Many psychiatric disorders, despite their specific characteristics, share deficits in the cognitive domain including executive functions, emotional control and memory. However, memory deficits have been in many cases undervalued compared with other characteristics. The expression of Immediate Early Genes (IEGs) such as, c-fos, Egr1 and arc are selectively and promptly upregulated in learning and memory among neuronal subpopulations in regions associated with these processes. Changes in expression in these genes have been observed in recognition, working and fear related memories across the brain. Despite the enormous amount of data supporting changes in their expression during learning and memory and the importance of those cognitive processes in psychiatric conditions, there are very few studies analyzing the direct implication of the IEGs in mental illnesses. In this review, we discuss the role of some of the most relevant IEGs in relation with memory processes affected in psychiatric conditions.

Neural, Cellular and Molecular Mechanisms of Active Forgetting.

The neurobiology of memory formation attracts much attention in the last five decades. Conversely, the rules that govern and the mechanisms underlying forgetting are less understood. In addition to retroactive interference, retrieval-induced forgetting and passive decay of time, it has been recently demonstrated that the nervous system has a diversity of active and inherent processes involved in forgetting. In Drosophila, some operate mainly at an early stage of memory formation and involves dopamine (DA) neurons, specific postsynaptic DA receptor subtypes, Rac1 activation and induces rapid active forgetting. In mammals, others regulate forgetting and persistence of seemingly consolidated memories and implicate the activity of DA receptor subtypes and AMPA receptors in the hippocampus (HP) and related structures to activate parallel signaling pathways controlling active time-dependent forgetting. Most of them may involve plastic changes in synaptic and extrasynaptic receptors including specific removal of GluA2 AMPA receptors. Forgetting at longer timescales might also include changes in adult neurogenesis in the dentate gyrus (DG) of the HP. Therefore, based on relevance or value considerations neuronal circuits may regulate in a time-dependent manner what is formed, stored, and maintained and what is forgotten.

Activation of D1/5 Dopamine Receptors in the Dorsal Medial Prefrontal Cortex Promotes Incubated-Like Aversive Responses.

It is well established that neurons of the mammalian medial prefrontal cortex (mPFC) modulate different behavioral outputs, including several memory types. This behavioral modulation is, at least in part, under the control of the D1-like Dopamine (DA) receptor (D1/5R) which comprises D1 and D5-specific subtypes (D1R and D5R, respectively). Here, combining a set of behavioral assays with pharmacology, we determined whether the activation of D1/5R in the mPFC during almost neutral or weak negative-valence experiences induces aversive behaviors. The intra mPFC bilateral infusion of the D1/5R agonist SKF 38393 (6.25 µg/side) immediately after exposing rats to the white compartment of a place conditioning apparatus promotes a incubated-like aversive memory when tested 7 days thereafter, but it was not seen 24 h after conditioning. No signs of fear or changes in the anxiety state were observed after the exposure to the white compartment. This aversive response is observed only when the experience paired with the mPFC D1/5R activation has a context component involved. By using specific agonists for D1R or D5R subtypes we suggest that D5R mediate the induction of the aversive behavior. No aversive effects were observed when the D1/5R agonist was infused into the dorsal hippocampus (HP), the nucleus accumbens (NAcc) or the basolateral amygdala (BLA) of rats exposed to the white compartment. Taken together, our present findings endorse the idea that activation of mPFC D1/5R is sufficient to induce incubated-like aversive memories after exposing rats to an apparent neutral or weak negative-valence environment and that mPFC might be considered a key brain region involved in providing adaptive emotional behaviors in response to an ever-changing environment.