Aha! and D'oh! experiences enhance learning for incidental information-new evidence supports the insight memory advantage.

Research on creative problem-solving finds that solutions achieved via spontaneous insight (i.e., Aha! moment) are better remembered than solutions reached without this sense of epiphany, referred to as an "insight memory advantage." We hypothesized that the insight memory advantage can spread to incidental information encoded in the moments surrounding insight as well. Participants (N = 291) were first given Rebus puzzles. After they indicated that they had found a solution, but before they could submit this solution, they were presented with scholastic facts that were incidental and unrelated to the problem at hand. Participants indicated whether they reached the solution via either insight or a step-by-step analysis. Memory results showed better performance for incidental scholastic facts presented when problem solving was accompanied by a spontaneous (Aha! experience) and induced (D'oh! experience) insight compared with solutions reached with analysis. This finding suggests that the memory advantage for problems solved via insight spreads to other unrelated information encoded in close temporal proximity and has implications for novel techniques to enhance learning in educational settings.

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.

Facilitation of fear extinction by novelty is modulated by ß-adrenergic and 5-HT1A serotoninergic receptors in hippocampus.

Extinction is the learned inhibition of retrieval of a previously acquired memory and is a major component of exposure therapy, which has attracted much attention because of the use in the treatment of drug addiction, phobias and particularly fear disorders such as post-traumatic stress disorder (PTSD). Exposure to a novel environment before or after extinction training can enhance the extinction of contextual fear conditioning, however the cellular and molecular substrates are still unclear. Here, we investigated the participation of H2-histaminergic, ß-adrenergic and 5-HT1A-serotonergic receptors of the hippocampus on the enhancement of extinction memory caused by novelty. The infusion into the CA1 region of the serotonin 5-HT1A-receptor agonist, 8-OH-DPAT and the ß-adrenergic blocker, Timolol, after the exposure to the novelty hindered the enhancement of extinction by novelty, while Timolol also hindered the extinction consolidation when infused post-extinction. These impairments were abolished by the coinfusion of 8-OH-DPAT plus the 5-HT1A receptor antagonist, NAN-190 and Timolol plus ß-adrenergic agonist, Isoproterenol. However, Dimaprit and Ranitidine blocked the retrieval of CFC, but did not prevented the extinction learning. Here we elucidated some of the molecular mechanisms that are involved on the enhancement of extinction by novelty, demonstrating that the ß-adrenoreceptors and 5-HT1A serotonergic receptors participate on this process alongside with dopaminergic D1 receptors previously described, while histamine H2 receptors, so ubiquitous in learning-related functions in hippocampus are not involved.

Behavioral, cellular, and synaptic tagging frameworks.

Behavioral tagging is the transformation of a short-term memory induced by a weak experience into a long-term memory through temporal association with a novel experience. This phenomenon was discovered to recapitulate synaptic tagging and capture at the behavioral level. Significant progress has been made in determining the molecular machinery associated with synaptic tagging and capture and behavioral tagging theories. However, the tag setting and recruitment of plasticity-related proteins that occur within the spatiotemporally constrained cell ensemble at the network level (cellular tagging) in the brain where multimodal sensory information is input are just beginning to be understood. Here, we review the evidence for behavioral tagging and the mechanism underlying memory allocation at the network level leading to the overlap of cell ensembles. We also discuss the functional significance of overlapping cell ensembles in association of standard Pavlovian conditioning and distinct memories. Finally, we describe the role of neuronal ensemble overlap in behavioral tagging.

Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus.

Extinction is the learned inhibition of retrieval. Recently it was shown that a brief exposure to a novel environment enhances the extinction of contextual fear in rats, an effect explainable by a synaptic tagging-and-capture process. Here we examine whether this also happens with the extinction of another fear-motivated task, inhibitory avoidance (IA), and whether it depends on dopamine acting on D1 or D5 receptors. Rats were trained first in IA and then in extinction of this task. The retention of extinction was measured 24 h later. A 5-min exposure to a novel environment 30 min before extinction training enhanced its retention. Right after exposure to the novelty, animals were given bilateral intrahippocampal infusions of vehicle (VEH), of the protein synthesis inhibitor anisomycin, of the D1/D5 dopaminergic antagonist SCH23390, of the PKA inhibitor Rp-cAMP or of the PKC inhibitor Gö6976, and of the PKA stimulator Sp-cAMP or of the PKC stimulator PMA. The novelty increased hippocampal dopamine levels and facilitated the extinction, which was inhibited by intrahippocampal protein synthesis inhibitor anisomysin, D1/D5 dopaminerdic antagonist SCH23390, or PKA inhibitor Rp-cAMP and unaffected by PKC inhibitor Gö6976; additionally, the hippocampal infusion of PKA stimulator Sp-cAMP reverts the effect of D1/D5 dopaminergic antagonist SCH 23390, but the infusion of PKC stimulator PMA does not. The results attest to the generality of the novelty effect on fear extinction, suggest that it relies on synaptic tagging and capture, and show that it depends on hippocampal dopamine D1 but not D5 receptors.

Evidence of VTA and LC control of protein synthesis required for the behavioral tagging process.

Several works have shown that the formation of different long-term memories relies on a behavioral tagging process. In other words, to establish a lasting memory, at least two parallel processes must occur: the setting of a learning tag (triggered during learning) that defines where a memory could be stored, and the synthesis of proteins, that once captured at tagged sites will effectively allow the consolidation process to occur. This work focused in studying which brain structures are responsible of controlling the synthesis of those proteins at the brain areas where memory is being stored. It combines electrical activation of the ventral tegmental area (VTA) and/or the locus coeruleus (LC), with local pharmacological interventions and weak and strong behavioral trainings in the inhibitory avoidance and spatial object recognition tasks in rats. The results presented here strongly support the idea that the VTA is a brain structure responsible for regulating the consolidation of memories acting through the D1/D5 dopaminergic receptors of the hippocampus to control the synthesis of new proteins required for this process. Moreover, they provide evidence that the LC may be a second structure with a similar role, acting independently and complementary to the VTA, through the ß-adrenergic receptors of the hippocampus.

Novelty-retrieval-extinction paradigm to decrease high-intensity fear memory recurrence.

BACKGROUND: The retrieval-extinction paradigm based on memory reconsolidation can prevent fear memory recurrence more effectively than the extinction paradigm. High-intensity fear memories tend to resist reconsolidation. Novelty-retrieval-extinction can promote the reconsolidation of fear memory lacking neuroplasticity in rodents; however, whether it could effectively promote high-intensity fear memory reconsolidation in humans remains unclear. METHODS: Using 120 human participants, we implemented the use of the environment (novel vs. familiar) with the help of virtual reality technology. Novelty environment exploration was combined with retrieval-extinction in fear memory of two intensity levels (normal vs. high) to examine whether novelty facilitates the reconsolidation of high-intensity fear memory and prevents recurrence. Skin conductance responses were used to clarify novelty-retrieval-extinction effects at the behavioral level across three experiments. RESULTS: Retrieval-extinction could prevent the reinstatement of normal-intensity fear memory; however, for high-intensity fear memory, only the novelty-retrieval-extinction could prevent recurrence; we further validated that novelty-retrieval-extinction may be effective only when the environment is novel. LIMITATIONS: Although the high-intensity fear memory is higher than normal-intensity in this study, it may be insufficient relative to fear experienced in real-world contexts or by individuals with mental disorders. CONCLUSIONS: To some extent, these findings indicate that the novelty-retrieval-extinction paradigm could prevent the recurrence of high-intensity fear memory, and we infer that novelty of environment may play an important role in novelty-retrieval-extinction paradigm. The results of this study have positive implications for the existing retrieval extinction paradigm and the clinical treatment of phobia.

Exercise and Fear and Safety Learning.

Fear conditioning paradigms have been studied for over 100 years and are of great interest to the behavioral and clinical sciences given that several safety learning processes (e.g., extinction learning and recall) are thought to be fundamental to the success of exposure-based therapies for anxiety and related disorders. This chapter provides an overview of preclinical and clinical investigations that examined the effects of exercise on initial fear acquisition, fear extinction learning and consolidation, and return of fear outcomes. This chapter highlights the collective body of evidence suggesting that exercise administered after extinction learning enhances the consolidation and subsequent recall of extinction memories to a greater extent than exercise administered prior to extinction learning. This suggests that the addition of exercise after exposure therapy sessions may improve treatment outcomes for people with anxiety and related disorders. Potential mechanisms are discussed in addition to suggestions for future research to improve our understanding of the effects of exercise on fear conditioning and extinction outcomes.

Novelty facilitates the persistence of aversive memory extinction by dopamine regulation in the hippocampus and ventral tegmental area.

Aversive memory extinction comprises a novel learning that blocks retrieving a previously formed traumatic memory. In this sense, aversive memory extinction is an excellent tool for decreasing fear responses. However, this tool it's not effective in the long term because of original memory spontaneous recovery. Thus, searching for alternative strategies that strengthen extinction learning is essential. In the current study, we evaluated the effects of a novel context (i.e., novelty) exposure on aversive memory extinction enhancement over days and the dopaminergic system requirement. Given the purpose, experiments were conducted using 3-month-old male Wistar rats. Animals were trained in inhibitory avoidance (IA). Twenty-four hours later, rats were submitted to a weak extinction protocol. Still, 30 min before the first extinction session, animals were submitted to an exploration of a novel context for 5 min. After, memory retention and persistence were evaluated 24 h, 3, 7, 14, and 21 days later. The exposition of a novel context caused a decrease in aversive responses in all days analyzed and an increase in dopamine levels in the hippocampus. The intrahippocampal infusion of dopamine in the CA1 area or the stimulation of the ventral tegmental area (VTA) by a glutamatergic agonist (NMDA) showed similar effects of novelty. In contrast, VTA inhibition by a gabaergic agonist (muscimol) impaired the persistence of extinction learning induced by novelty exposition and caused a decrease in hippocampal dopamine levels. In summary, we show that novel context exposure promotes persistent aversive memory extinction, revealing the significant role of the dopaminergic system.

Aerobic exercise after extinction learning reduces return of fear and enhances memory of items encoded during extinction learning.

Fear conditioning paradigms are widely used in laboratory settings to discover treatments that enhance memory consolidation and various fear processes (extinction learning, limit return of fear) that are relevant targets of exposure-based therapies. However, traditional lab-based paradigms often use the exact same conditioned stimuli for acquisition and extinction (typically differentiated with a context manipulation), whereas the opposite is true in clinical settings, as exposure therapy rarely (if ever) uses precisely the exact same stimuli from an individual's learning history. Accordingly, this study utilized a novel three-day category-based fear conditioning protocol (that uses categories of non-repeating objects [animals and tools] as conditioned stimuli during fear conditioning and extinction) to determine if aerobic exercise enhances the consolidation of extinction learning (reduces return of fear) and memory (for items encoded during extinction) during subsequent tests of extinction recall. Participants (n=40) completed a fear acquisition (day 1), fear extinction (day 2), and extinction recall (day 3) protocol. On day 1, participants completed a fear acquisition task in which they were trained to associate a category of conditioned stimuli (CS+) with the occurrence of an unconditioned stimulus (US). On day 2, participants were administered a fear extinction procedure during which CS+ and CS- categorical stimuli were presented in absence of the occurrence of the US. After completing the task, participants were randomly assigned to either receive moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition. On day 3, participants completed fear recall tests (during which day 1, day 2, and novel CS+ and CS- stimuli were presented). Fear responding was assessed via threat expectancy ratings and skin conductance responses (SCR). During the fear recall tests, the EX group reported significantly lower threat expectancy ratings to the CS+ and CS- and exhibited greater memory of CS+ and CS- stimuli that were previously presented during day 2. There were no significant group differences for SCR. These results suggests that administration of moderate-intensity aerobic exercise following extinction learning contributes to reduced threat expectancies during tests of fear recall and enhanced memory of items encoded during extinction.

Making memories last using the peripheral effect of direct current stimulation.

Most memories that are formed are forgotten, while others are retained longer and are subject to memory stabilization. We show that non-invasive transcutaneous electrical stimulation of the greater occipital nerve (NITESGON) using direct current during learning elicited a long-term memory effect. However, it did not trigger an immediate effect on learning. A neurobiological model of long-term memory proposes a mechanism by which memories that are initially unstable can be strengthened through subsequent novel experiences. In a series of studies, we demonstrate NITESGON's capability to boost the retention of memories when applied shortly before, during, or shortly after the time of learning by enhancing memory consolidation via activation and communication in and between the locus coeruleus pathway and hippocampus by plausibly modulating dopaminergic input. These findings may have a significant impact for neurocognitive disorders that inhibit memory consolidation such as Alzheimer's disease.

Is there selective retroactive memory enhancement in humans?: a meta-analysis.

Memory is an adaptive and flexible system that preferentially stores motivationally relevant information. However, in some cases information that is initially irrelevant can become relevant at a later time. The question arises whether and to what extent the memory system can retroactively boost memories of the initially irrelevant information. Experimental studies in animals and humans have provided evidence for such retroactive memory boosting. Additionally, these studies suggest that retroactive memory enhancement (RME) can be selective to the semantic meaning of the material. Nonetheless, recent experimental work could not replicate these findings, posing the question whether the selective RME effect is reliable. To synthesize the available evidence, we conducted meta-analyses of 14 experiments. Although the classical meta-analytic procedure suggested a small selective RME effect, Cohen's dz = 0.16, when accounting for small-study bias using robust Bayesian meta-analysis the null hypothesis was supported, Cohen's dz = 0.02, BF01 = 3.03. Furthermore strong evidence was found for a bias due to small-study effects, BF10 = 11.39. Together, this calls the reliability of a selective RME effect into question.

Aerobic exercise in the treatment of PTSD: An examination of preclinical and clinical laboratory findings, potential mechanisms, clinical implications, and future directions.

Posttraumatic stress disorder (PTSD) is associated with heightened emotional responding, avoidance of trauma related stimuli, and physical health concerns (e.g., metabolic syndrome, type 2 diabetes, cardiovascular disease). Existing treatments such as exposure-based therapies (e.g., prolonged exposure) aim to reduce anxiety symptoms triggered by trauma reminders, and are hypothesized to work via mechanisms of extinction learning. However, these conventional gold standard psychotherapies do not address physical health concerns frequently presented in PTSD. In addition to widely documented physical and mental health benefits of exercise, emerging preclinical and clinical evidence supports the hypothesis that precisely timed administration of aerobic exercise can enhance the consolidation and subsequent recall of fear extinction learning. These findings suggest that aerobic exercise may be a promising adjunctive strategy for simultaneously improving physical health while enhancing the effects of exposure therapies, which is desirable given the suboptimal efficacy and remission rates. Accordingly, this review 1) encompasses an overview of preclinical and clinical exercise and fear conditioning studies which form the basis for this claim; 2) discusses several plausible mechanisms for enhanced consolidation of fear extinction memories following exercise, and 3) provides suggestions for future research that could advance the understanding of the potential importance of incorporating exercise into the treatment of PTSD.

Behavioral and Cellular Tagging in Young and in Early Cognitive Aging.

The ability to maintain relevant information on a daily basis is negatively impacted by aging. However, the neuronal mechanism manifesting memory persistence in young animals and memory decline in early aging is not fully understood. A novel event, when introduced around encoding of an everyday memory task, can facilitate memory persistence in young age but not in early aging. Here, we investigated in male rats how sub-regions of the hippocampus are involved in memory representation in behavioral tagging and how early aging affects such representation by combining behavioral training in appetitive delayed-matching-to-place tasks with the "cellular compartment analysis of temporal activity by fluorescence in situ hybridization" technique. We show that neuronal assemblies activated by memory encoding were also partially activated by novelty, particularly in the distal CA1 and proximal CA3 subregions in young male rats. In early aging, both encoding- and novelty-triggered neuronal populations were significantly reduced with a more profound effect in encoding neurons. Thus, memory persistence through novelty facilitation engages overlapping hippocampal assemblies as a key cellular signature, and cognitive aging is associated with underlying reduction in neuronal activation.

Neuropsin-dependent and -independent behavioral tagging.

AIM: The consolidation of short-term memories into long-term memories is promoted by associations with novel environmental stimuli. This phenomenon is known as behavioral tagging. Neuropsin, a plasticity-related serine protease in the hippocampus and amygdala, is involved in memory formation. This study investigated how neuropsin affects associative long-term memory. METHODS: Short-term and long-term memory were assessed in control and neuropsin-deficient mice by investigating their performance in inhibitory avoidance and spatial object recognition tasks. The effect of exposure to novelty on the conversion of short-term memory to associative long-term memory was also examined. RESULTS: The consolidation of task-related short-term memories into long-term memories was facilitated by exposing the animals to a novel environment 1 hour before training. However, this long-term memory conversion was impaired in neuropsin-deficient mice performing the inhibitory avoidance task but not the spatial object recognition task. CONCLUSION: Behavioral tagging occurs via neuropsin-dependent and neuropsin-independent processes for different behavioral tasks.

Exposure to Novelty Promotes Long-Term Contextual Fear Memory Formation in Juvenile Mice: Evidence for a Behavioral Tagging.

Episodic memories acquired early in life are fragile and rapidly forgotten in both humans and nonhuman animals. However, early life experiences have been documented to profoundly affect brain function and physiology throughout life, suggesting that in certain circumstances, the developing brain is capable of producing long-term memory (LTM). In this study, we asked whether exposure to a novel environment, a process named "behavioral tagging," may promote the persistence of weak memories in male juvenile mice. Using a contextual fear conditioning (CFC) paradigm, we found that a weak training protocol, which typically induces a transient form of memory, results in LTM when paired with an exploration to a novel but not a familiar environment that occurs close in time to the training session. The promoting effect of the novel context exploration (NCE) on CFC-LTM formation is dependent on the activation of dopamine D1/D5 receptors and requires novel protein synthesis in the dorsal hippocampus. Moreover, NCE increases the size of overlapping CA1 neuronal ensembles engaged by CFC and NCE. These results provide direct support for the existence of a behavioral tagging process, in which exposure to novelty provides newly synthesized proteins to stabilize the contextual fear memory trace in juvenile mice.

PKM-ζ Expression Is Important in Consolidation of Memory in Prelimbic Cortex Formed by the Process of Behavioral Tagging.

Memories are acquired and stored in two forms, short-term memory (STM) and long-term memory (LTM). For the consolidation of LTM, de novo protein synthesis is required, which are also known as plasticity related proteins. Long-term potentiation is a form of synaptic plasticity and it is considered as a cellular model of learning and memory. One of the Long-term potentiation specific plasticity related proteins, PKM-ζ, is required for the formation of LTM as well as for the maintenance of Long-term potentiation. In our study, we have shown that for the consolidation of LTM, in addition to Long-term potentiation -specific plasticity related proteins, synaptic tags are required to interact with each other. In the present study, we investigated the involvement of Long-term potentiation -specific PKM-ζ and learning tags within a critical time window, which are required for the formation of LTM without affecting STM. Behavioral tagging is an established model for the assessment of some forms of learning and memory. Despite being studied for LTM formation for many years, no studies so far have investigated the role of PKM-ζ in Behavioral tagging model. Hence, by using these two different memories based tasks (i.e., Inhibitory avoidance and Novel object recognition tasks), we observed how PKM-ζ activated by exposing a novel arena after a weak training and led to the consolidation of memory. These findings thus show how the process of behavioral tagging activates Long-term potentiation -specific PKM-ζ for the formation of LTM.

Behavioral tagging: Plausible involvement of PKMζ, Arc and role of neurotransmitter receptor systems.

There are many evidences in support of Behavioral Tagging hypothesis that relies on the setting of a learning tag and the synthesis of plasticity related proteins (PRPs). It explains that how a learning tag produced as a result of weak training can be paired up with PRPs that arrive as a result of novelty and consequently lead to long lasting memories. In the following review we have focused on possible involvement of PKMζ, Arc as PRPs and neurotransmitter receptor systems ACh, metabotropic glutamate in behavioral tagging along with evidences in support of involvement of dopamine, NMDA glutamate and ß-adrenergic receptor systems in behavioral tagging.