Retrieval of contextual memory can be predicted by CA3 remapping and is differentially influenced by NMDAR activity in rat hippocampus subregions.

Episodic memory is essential to navigate in a changing environment by recalling past events, creating new memories, and updating stored information from experience. Although the mechanisms for acquisition and consolidation have been profoundly studied, much less is known about memory retrieval. Hippocampal spatial representations are key for retrieval of contextually guided episodic memories. Indeed, hippocampal place cells exhibit stable location-specific activity which is thought to support contextual memory, but can also undergo remapping in response to environmental changes. It is unclear if remapping is directly related to the expression of different episodic memories. Here, using an incidental memory recognition task in rats, we showed that retrieval of a contextually guided memory is reflected by the levels of CA3 remapping, demonstrating a clear link between external cues, hippocampal remapping, and episodic memory retrieval that guides behavior. Furthermore, we describe NMDARs as key players in regulating the balance between retrieval and memory differentiation processes by controlling the reactivation of specific memory traces. While an increase in CA3 NMDAR activity boosts memory retrieval, dentate gyrus NMDAR activity enhances memory differentiation. Our results contribute to understanding how the hippocampal circuit sustains a flexible balance between memory formation and retrieval depending on the environmental cues and the internal representations of the individual. They also provide new insights into the molecular mechanisms underlying the contributions of hippocampal subregions to generate this balance.

Dopamine Modulates Adaptive Forgetting in Medial Prefrontal Cortex.

Active forgetting occurs in many species, but how behavioral control mechanisms influence which memories are forgotten remains unknown. We previously found that when rats need to retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting relies on prefrontal control processes. Dopaminergic input to the prefrontal cortex is important for executive functions and cognitive flexibility. We found that, in a similar way, retrieval-induced forgetting of competing memories in male rats requires prefrontal dopamine signaling through D1 receptors. Blockade of medial prefrontal cortex D1 receptors as animals encountered a familiar object impaired active forgetting of competing object memories as measured on a later long-term memory test. Inactivation of the ventral tegmental area produced the same pattern of behavior, a pattern that could be reversed by concomitant activation of prefrontal D1 receptors. We observed a bidirectional modulation of retrieval-induced forgetting by agonists and antagonists of D1 receptors in the medial prefrontal cortex. These findings establish the essential role of prefrontal dopamine in the active forgetting of competing memories, contributing to the shaping of retention in response to the behavioral goals of an organism.SIGNIFICANCE STATEMENT Forgetting is a ubiquitous phenomenon that is actively promoted in many species. The very act of remembering some experiences can cause forgetting of others, in both humans and rats. This retrieval-induced forgetting process is thought to be driven by inhibitory control signals from the prefrontal cortex that target areas where the memories are stored. Here we started disentangling the neurochemical signals in the prefrontal cortex that are essential to retrieval-induced forgetting. We found that, in rats, the release of dopamine in this area, acting through D1 receptors, was essential to causing active forgetting of competing memories. Inhibition of D1 receptors impaired forgetting, while activation increased forgetting. These findings are important, because the mechanisms of active forgetting and their linkage to goal-directed behavior are only beginning to be understood.

Dentate Gyrus Somatostatin Cells are Required for Contextual Discrimination During Episodic Memory Encoding.

Memory systems ought to store and discriminate representations of similar experiences in order to efficiently guide future decisions. This problem is solved by pattern separation, implemented in the dentate gyrus (DG) by granule cells to support episodic memory formation. Pattern separation is enabled by tonic inhibitory bombardment generated by multiple GABAergic cell populations that strictly maintain low activity levels in granule cells. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the DG. Nonetheless, somatostatin cells have very low connection probability and synaptic efficacy with both granule cells and other interneuron types. Hence, the role of somatostatin cells in DG circuitry, particularly in the context of pattern separation, remains uncertain. Here, by using optogenetic stimulation and behavioral tasks in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.

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.

Molecular mechanisms within the dentate gyrus and the perirhinal cortex interact during discrimination of similar nonspatial memories.

Differentiating between similar memories is a crucial cognitive function that enables correct episodic memory formation. The ability to separate the components of memories into distinct representations is thought to rely on a computational process known as pattern separation, by which differences are amplified to disambiguate similar events. Although pattern separation has been localized to the dentate gyrus (DG) of the hippocampus and shown to occur in a spatial domain, this cognitive function takes place also during processing of other types of information. In particular, there is some debate on whether the DG participates in pattern separation of nonspatial representations. Considering the classic role of the Prh in the acquisition and storage of object memories in general and tasks with similar features in particular, this cognitive function could rely more heavily on perirhinal regions when object-related information is processed. Here we show that two plasticity-related proteins, BDNF, and Arc, are required in the DG for nonspatial mnemonic differentiation. Moreover, we found that the crucial role of the DG is transient since activity of AMPAR is only required in the Prh but not the DG during differentiated object memory retrieval. Additionally, this memory is not modifiable by postacquisition rhBDNF infusions in the DG that are known to improve memory when given in the Prh. This highlights a differential role of Prh and DG during differentiated object memory consolidation. Additionally, we found that these molecular mechanisms actively interact in the DG and Prh for the formation of distinguishable memories, with infusions of rhBDNF in the Prh being able to rescue mnemonic deficits caused by reduced Arc expression in the DG. These results reveal a complex interaction between plasticity mechanisms in the Prh and DG for nonspatial pattern separation and posit the Prh as the key structure where unique object representations are stored.

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.

NMDA receptors and BDNF are necessary for discrimination of overlapping spatial and non-spatial memories in perirhinal cortex and hippocampus.

Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. Discrimination of overlapping representations has been investigated in the dentate gyrus (DG) of the hippocampus and largely in the perirhinal cortex (Prh). In particular, the DG was shown to be important for discrimination of overlapping spatial memories and Prh was shown to be important for discrimination of overlapping object memories. In the present study, we used both a DG-dependent and a Prh-dependent task and manipulated the load of similarity between either spatial or object stimuli during information encoding. We showed that N-methyl-D-aspartate-type glutamate receptors (NMDAr) and BDNF participate of the same cellular network during consolidation of both overlapping object and spatial memories in the Prh and DG, respectively. This argues in favor of conserved cellular mechanisms across regions despite anatomical differences.

Role of medial prefrontal cortex serotonin 2A receptors in the control of retrieval of recognition memory in rats.

Often, retrieval cues are not uniquely related to one specific memory, which could lead to memory interference. Controlling interference is particularly important during episodic memory retrieval or when remembering specific events in a spatiotemporal context. Despite a clear involvement of prefrontal cortex (PFC) in episodic memory in human studies, information regarding the mechanisms and neurotransmitter systems in PFC involved in memory is scarce. Although the serotoninergic system has been linked to PFC functionality and modulation, its role in memory processing is poorly understood. We hypothesized that the serotoninergic system in PFC, in particular the 5-HT2A receptor (5-HT2AR) could have a role in the control of memory retrieval. In this work we used different versions of the object recognition task in rats to study the role of the serotoninergic modulation in the medial PFC (mPFC) in memory retrieval. We found that blockade of 5-HT2AR in mPFC affects retrieval of an object in context memory in a spontaneous novelty preference task, while sparing single-item recognition memory. We also determined that 5-HT2ARs in mPFC are required for hippocampal-mPFC interaction during retrieval of this type of memory, suggesting that the mPFC controls the expression of memory traces stored in the hippocampus biasing retrieval to the most relevant one.

Brain-derived neurotrophic factor interacts with adult-born immature cells in the dentate gyrus during consolidation of overlapping memories.

Successful memory involves not only remembering information over time but also keeping memories distinct and less confusable. The computational process for making representations of similar input patterns more distinct from each other has been referred to as "pattern separation." Although adult-born immature neurons have been implicated in this memory feature, the precise role of these neurons and associated molecules in the processing of overlapping memories is unknown. Recently, we found that brain-derived neurotrophic factor (BDNF) in the dentate gyrus is required for the encoding/consolidation of overlapping memories. In this study, we provide evidence that consolidation of these "pattern-separated" memories requires the action of BDNF on immature neurons specifically.

Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable?

Adult-generated neurons in the dentate gyrus of the hippocampus have been the focus of many studies concerned with learning and memory (L&M). It has been shown that procedures like environmental enrichment (EE) or voluntary physical exercise (Vex) can increase neurogenesis (NG) and also enhance L&M. It is tempting to conclude that improvements in L&M are due to the increased NG; that is, a causal relationship exists between enhancement of NG and enhancement of L&M. However, it remains unclear whether the L&M enhancement observed after these treatments is causally dependent on the increase in newborn neurons in the dentate gyrus. It remains a possibility that some unspecified change--a "third variable"--brought about by EE and/or Vex could be a causal determinant of both NG and L&M. We suggest that this third variable could be neurotrophic and/or plasticity-related factors such as BDNF. Indeed, both EE and Vex can induce expression of such proteins, and BDNF in particular has long been linked with L&M. In addition, we argue that a very likely source of variation in previous experiments was the load on "pattern separation", a process that keeps similar memories distinct, and in which NG has been shown to be critically involved. To attempt to bring these ideas together, we present preliminary evidence that BDNF is also required for pattern separation, which strengthens the case for BDNF as a candidate third variable. Other ways in which BDNF might be involved are also discussed.

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.

Endocytosis is required for consolidation of pattern-separated memories in the perirhinal cortex.

Introduction: The ability to separate similar experiences into differentiated representations is proposed to be based on a computational process called pattern separation, and it is one of the key characteristics of episodic memory. Although pattern separation has been mainly studied in the dentate gyrus of the hippocampus, this cognitive function if thought to take place also in other regions of the brain. The perirhinal cortex is important for the acquisition and storage of object memories, and in particular for object memory differentiation. The present study was devoted to investigating the importance of the cellular mechanism of endocytosis for object memory differentiation in the perirhinal cortex and its association with brain-derived neurotrophic factor, which was previously shown to be critical for the pattern separation mechanism in this structure. Methods: We used a modified version of the object recognition memory task and intracerebral delivery of a peptide (Tat-P4) into the perirhinal cortex to block endocytosis. Results: We found that endocytosis is necessary for pattern separation in the perirhinal cortex. We also provide evidence from a molecular disconnection experiment that BDNF and endocytosis-related mechanisms interact for memory discrimination in both male and female rats. Discussion: Our experiments suggest that BDNF and endocytosis are essential for consolidation of separate object memories and a part of a time-restricted, protein synthesis-dependent mechanism of memory stabilization in Prh during storage of object representations.

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.

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.

Psychological symptoms, mental fatigue and behavioural adherence after 72 continuous days of strict lockdown during the COVID-19 pandemic in Argentina.

BACKGROUND: An early and prolonged lockdown was adopted in Argentina during the first wave of COVID-19. Early reports evidenced elevated psychological symptoms. AIMS: To explore if the prolonged lockdown was associated with elevated anxiety and depressive symptoms; if mental fatigue was associated with lockdown adherence (a phenomenon called 'behavioural fatigue'); and if financial concerns were associated with lockdown adherence and emotional symptoms. METHOD: The survey included standardised questionnaires to assess depressive (PHQ-9) and anxious (GAD-7) symptoms, mental fatigue, risk perception, lockdown adherence, financial concerns, daily stress, loneliness, intolerance to uncertainty, negative repetitive thinking and cognitive problems. LASSO regression analyses were carried out to predict depression, anxiety and lockdown adherence. RESULTS: The survey reached 3617 adults (85.2% female) from all provinces of Argentina after 72 days of lockdown. Data were collected between 21 May 2020 and 4 June 2020. In that period, Argentina had an Oxford stringency index of 85/100. Of those surveyed, 45.6% and 27% met the cut-offs for depression and anxiety, respectively. Mental fatigue, cognitive failures and financial concerns were correlated with psychological symptoms, but not with adherence to lockdown. In regression models, mental fatigue, cognitive failures and loneliness were the most important variables to predict depression, intolerance to uncertainty and lockdown difficulty were the most important for anxiety, and perceived threat was the most important for predicting lockdown adherence. CONCLUSIONS: During the extended lockdown, psychological symptoms increased, being enhanced by mental fatigue, cognitive difficulties and financial concerns. We found no evidence of behavioural fatigue. Thus, feeling mentally fatigued is not the same as being behaviourally fatigued.

Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus.

Persistence is the most characteristic attribute of long-term memory (LTM). To understand LTM, we must understand how memory traces persist over time despite the short-lived nature and rapid turnover of their molecular substrates. It is widely accepted that LTM formation is dependent upon hippocampal de novo protein synthesis and Brain-Derived Neurotrophic Factor (BDNF) signaling during or early after acquisition. Here we show that 12 hr after acquisition of a one-trial associative learning task, there is a novel protein synthesis and BDNF-dependent phase in the rat hippocampus that is critical for the persistence of LTM storage. Our findings indicate that a delayed stabilization phase is specifically required for maintenance, but not formation, of the memory trace. We propose that memory formation and memory persistence share some of the same molecular mechanisms and that recurrent rounds of consolidation-like events take place in the hippocampus for maintenance of the memory trace.

BDNF is essential to promote persistence of long-term memory storage.

Persistence is a characteristic attribute of long-term memories (LTMs). However, little is known about the molecular mechanisms that mediate this process. We recently showed that persistence of LTM requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Here, we show that intrahippocampal delivery of BDNF reverses the deficit in memory persistence caused by inhibition of hippocampal protein synthesis. Importantly, we demonstrate that BDNF induces memory persistence by itself, transforming a nonlasting LTM trace into a persistent one in an ERK-dependent manner. Thus, BDNF is not only necessary, but sufficient to induce a late postacquisition phase in the hippocampus essential for persistence of LTM storage.

Leucine-rich repeats and immunoglobulin-like domains 1 deficiency affects hippocampal dendrite complexity and impairs cognitive function.

Leucine-rich repeat (LRR) transmembrane proteins have been directly linked to neurodevelopmental and cognitive disorders. We have previously shown that the LRR transmembrane protein, leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), is a physiological regulator of dendrite complexity of hippocampal pyramidal neurons and social behavior. In this study, we performed a battery of behavioral tests to evaluate spatial memory and cognitive capabilities in Lrig1 mutant mice. The cognitive assessment demonstrated deficits in recognition and spatial memory, evaluated by novel object recognition and object location tests. Moreover, we found that Lrig1-deficient mice present specific impairments in the processing of similar but not dissimilar locations in a spatial pattern separation task, which was correlated with an enhanced dendritic growth and branching of Doublecortin-positive immature granule cells of the dentate gyrus. Altogether, these findings indicate that Lrig1 plays an essential role in controlling morphological and functional plasticity in the hippocampus.

The spontaneous location recognition task for assessing spatial pattern separation and memory across a delay in rats and mice.

Keeping similar memories distinct from one another is a critical cognitive process without which we would have difficulty functioning in everyday life. Memories are thought to be kept distinct through the computational mechanism of pattern separation, which reduces overlap between similar input patterns to amplify differences among stored representations. At the behavioral level, impaired pattern separation has been shown to contribute to memory deficits seen in neuropsychiatric and neurodegenerative diseases, including Alzheimer's disease, and in normal aging. This protocol describes the use of the spontaneous location recognition (SLR) task in mice and rats to behaviorally assess spatial pattern separation ability. This two-phase spontaneous memory task assesses the extent to which animals can discriminate and remember object locations presented during the encoding phase. Using three configurations of the task, the similarity of the to-be-remembered locations can be parametrically manipulated by altering the spatial positions of objects-dissimilar, similar or extra similar-to vary the load on pattern separation. Unlike other pattern separation tasks, SLR varies the load on pattern separation during encoding, when pattern separation is thought to occur. Furthermore, SLR can be used in standard rodent behavioral facilities with basic expertise in rodent handling. The entire protocol takes ~20 d from habituation to testing of the animals on all three task configurations. By incorporating breaks between testing, and varying the objects used as landmarks, animals can be tested repeatedly, increasing experimental power by allowing for within-subjects manipulations.