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PURPOSE: Memory plays an essential role in daily life and is one of the first functions to deteriorate in cognitive impairment and dementia. Transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic method; however, its ability to enhance memory is underexplored, especially considering long-term stimulation. We aimed to investigate the effect of a 2-week course of auricular tVNS (taVNS) on memory in a non-clinical population. METHODS: This single-blind randomized placebo-wait-list controlled trial recruited 76 participants (30 men; mean age 48.32 years) and randomized them into four groups: early active/sham taVNS and late active/sham taVNS. Participation in the study lasted 4 weeks; early groups underwent 2 weeks intervention immediately following the first study site visit (days 0-13) and late groups 2 weeks after the first study site visit (days 14-27). Active and sham taVNS included 2 weeks of daily 4-h neurostimulation at the tragus or earlobe, respectively. To assess memory, we used the Rey Auditory Verbal Learning Test. RESULTS: Two weeks of active taVNS, but not sham taVNS, improved immediate recall and short-term memory score both in early and late groups. Furthermore, the improvements persisted over subsequent follow-up in early active taVNS. Importantly, the effect of active taVNS was superior to sham for immediate recall in both early and late groups. There were no statistical differences in delayed recall. CONCLUSION: Our findings suggest that taVNS has potential to improve memory, particularly immediate recall, and may be an effective method in preventing memory loss and mitigating cognitive aging.

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The amygdala has been implicated in a variety of functions linked to emotions. One popular view is that the amygdala modulates consolidation in other brain systems thought to be mainly involved in learning and memory processes. This series of experiments represents a further exploration into the role of the amygdala in memory modulation and consolidation. One interesting line of research has shown that drugs of abuse, like amphetamine, produce dendritic changes in select brain regions and these changes are thought to be equivalent to a usurping of normal plasticity processes. We were interested in the possibility that this modulation of plasticity processes would be dependent on interactions with the amygdala. According to the modulation view of amygdala function, amphetamine would activate modulation mechanisms in the amygdala that would alter plasticity processes in other brain regions. If the amygdala was rendered dysfunctional, these effects should not occur. Accordingly, this series of experiments evaluated the effects of extensive neurotoxic amygdala damage on amphetamine-induced dendritic changes in the nucleus accumbens and prefrontal cortex. The results showed that rats with large lesions of the amygdala showed the normal pattern of dendritic changes in these brain regions. This pattern of results suggests that the action of not all memory modulators, activated during emotional events, require the amygdala to impact memory.

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Cognitive decline in spatial memory is seen in aging. Understanding affected processes in aging is vital for developing methods to improve wellbeing. Daily memory persistence can be influenced by events around the time of learning or by prior experiences in early life. Fading memories in young can last longer if a novel event is introduced around encoding, a process called behavioral tagging. Based on this principle, we asked what processes are affected in aging and if prior training can rescue them. Two groups of aged rats received training in an appetitive delayed matching-to-place task. One of the groups additionally received prior training of the same task in young and in mid-life, constituting a longitudinal study. The results showed long-term memory decline in late aging without prior training. This would reflect affected encoding and consolidation. On the other hand, short-term memory was preserved and novelty at memory reactivation and reconsolidation enabled memory maintenance in aging. Prior training improved cognition through facilitating task performance, strengthening short-term memory and intermediate memory, and enabling encoding-boosted long-term memory. Implication of these findings in understanding brain mechanisms in cognitive aging and in beneficial effects of prior training is discussed.

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The re-ignition of memory reconsolidation research sparked by Karim Nader in the early 2000s led to great excitement that 'reconsolidation-based' interventions might be developed for mental health disorders such as post-traumatic stress disorder and substance use disorder. Two decades on, it is clear that reconsolidation-based interventions have been more challenging to translate to the clinic than initially thought. We argue that this challenge could be addressed with a better understanding of how prior expectations interact with information presented in a putative memory reactivation / cue reminder session, and through the identification of non-invasive biomarkers for memory destabilisation that would allow reminder sessions to be 'tuned' to enhance memory lability in an ad hoc manner.

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[This corrects the article DOI: 10.3389/fnins.2020.00255.].

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Olfaction is an evolutionary ancient sense, but it remains unclear to what extent it can influence routine human behavior. We examined whether a threat-relevant predator odor (2-methyl-2-thiazoline) would contextually enhance the formation of human fear memory associations. Participants who learned to associate visual stimuli with electric shock in this predator odor context later showed stronger fear responses to the visual stimuli than participants who learned in an aversiveness-matched control odor context. This effect generalized to testing in another odor context, even after extinction training. Results of a separate experiment indicate that a possible biological mechanism for this effect may be increased cortisol levels in a predator odor context. These results suggest that innate olfactory processes can play an important role in human fear learning. Modulatory influences of odor contexts may partly explain the sometimes maladaptive persistence of human fear memory, e.g., in post-traumatic stress disorders.

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BACKGROUND: Despite its potential to revolutionize the treatment of memory dysfunction, the efficacy of direct electrical hippocampal stimulation for memory performance has not yet been well characterized. One of the main challenges to cross-study comparison in this area of research is the diversity of the cognitive tasks used to measure memory performance. OBJECTIVE: We hypothesized that the tasks that differentially engage the hippocampus may be differentially influenced by hippocampal stimulation and the behavioral effects would be related to the underlying hippocampal activity. METHODS: To investigate this issue, we recorded intracranial EEG from and directly applied stimulation to the hippocampus of 10 epilepsy patients while they performed two different verbal memory tasks - a word pair associative memory task and a single item memory task. RESULTS: Hippocampal stimulation modulated memory performance in a task-dependent manner, improving associative memory performance, while impairing item memory performance. In addition, subjects with poorer baseline cognitive function improved much more with stimulation. iEEG recordings from the hippocampus during non-stimulation encoding blocks revealed that the associative memory task elicited stronger theta oscillations than did item memory and that stronger theta power was related to memory performance. CONCLUSIONS: We show here for the first time that stimulation-induced associative memory enhancement was linked to increased theta power during retrieval. These results suggest that hippocampal stimulation enhances associative memory but not item memory because it engages more hippocampal theta activity and that, in general, increasing hippocampal theta may provide a neural mechanism for successful memory enhancement.

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Studies of age-related changes in learning and memory often focus on hippocampus-sensitive tasks and reveal age-associated impairments across numerous species and contexts. However, cognitive decline with advanced age is not all-encompassing; for example, forms of striatum-sensitive learning are conserved or enhanced with age. Under certain conditions, hippocampal and striatal memory systems function in opposition. In young adult rodents, disruption of one structure can enhance learning on tasks dependent on the other, suggesting that competitive interactions across memory systems contribute to learning and memory abilities. This report examines whether imbalances across memory systems might contribute to cognitive aging. We inactivated the striatum using central infusions of lidocaine (sodium channel blocker) prior to hippocampus-sensitive spatial (place) training in young (3-4-month-old) and old (24-25-month-old) F344 male rats. Consistent with prior work, vehicle-infused old rats exhibited place learning impairments relative to young rats. Additionally, striatal inactivation enhanced learning in old rats, but not young rats, abolishing the age-related impairment. These findings suggest that age-related declines in learning tasks thought to engage the hippocampus may stem from exaggerated interference from other memory systems and that interventions to target the striatum may reverse some age-related learning decrements.

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Experience-dependent neuronal plasticity is a fundamental substrate of learning and memory. Intrinsic excitability is a form of neuronal plasticity that can be altered by learning and indicates the pattern of neuronal responding to external stimuli (e.g. a learning or synaptic event). Associative fear conditioning is one form of learning that alters intrinsic excitability, reflecting an experience-dependent change in neuronal function. After fear conditioning, intrinsic excitability changes are evident in brain regions that are a critical part of the fear circuit, including the amygdala, hippocampus, retrosplenial cortex, and prefrontal cortex. Some of these changes are transient and/or reversed by extinction as well as learning-specific (i.e. they are not observed in neurons from control animals). This review will explore how intrinsic neuronal excitability changes within brain structures that are critical for fear learning, and it will also discuss evidence promoting intrinsic excitability as a vital mechanism of associative fear memories. This work has raised interesting questions regarding the role of fear learning in changes of intrinsic excitability within specific subpopulations of neurons, including those that express immediate early genes and thus demonstrate experience-dependent activity, as well as in neurons classified as having a specific firing type (e.g. burst-spiking vs. regular-spiking). These findings have interesting implications for how intrinsic excitability can serve as a neural substrate of learning and memory, and suggest that intrinsic plasticity within specific subpopulations of neurons may promote consolidation of the memory trace in a flexible and efficient manner.

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Memory reactivation has been shown to open a time window for memory modulation. The majority of the methodological or pharmacological approaches target disruption of reconsolidation to weaken aversive memories. However, methods to improve appetitive memory persistence through reconsolidation or to reverse drug-induced reconsolidation impairment are limited. To improve memory persistence, previous studies show that a novel event, introduced around the time of memory encoding, enables the persistence of an otherwise decayed memory. This is mainly through a memory consolidation process. The current study first investigated if a novel event introduced during memory reactivation improves memory persistence through reconsolidation. Using a rodent appetitive spatial paradigm, similar to the human everyday experience of recalling where an item is located, a novel event around memory reactivation facilitated the persistence of spatial memory. This facilitation did not occur when the novel event was omitted and the protein synthesis-dependent reconsolidation was not affected by zif268 anti-sense in the dorsal hippocampus. Furthermore, beta-adrenergic antagonists, propranolol, impaired reconsolidation of appetitive spatial memory and contextual fear conditioning. A novel event after memory reactivation could reverse this impairment due to propranolol. Together, this study provides methods and confirmation for improving memory persistence during memory reactivation and reconsolidation.

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Decline in cognitive functions, including hippocampus-dependent spatial memory, is commonly observed at a later stage of aging (e.g., >20 months old in rodents) and typically studied after a discrete learning event. How normal aging, particularly at an early stage, affects the modulatory aspect of memory persistence is underinvestigated. Previous studies in young animals show that weak, fading memories can last longer if a modulating event, such as spatial novelty, is introduced around memory encoding. This is known as behavioral tagging and capture (BTC). Here, we investigated how early aging (10-13 months old) affects BTC in an appetitive delayed-matching-to-place task. We trained rats when they were young and middle aged and found that novelty facilitated long-term memory persistence in young but not in middle-aged rats. However, re-exposure to the encoded environment after learning improved memory persistence in middle-aged rats. BTC, combined with memory reactivation, facilitated memory persistence through reconsolidation. Our results point toward a weakened tagging and capture mechanism before reduction of plasticity-related proteins at an early stage of aging.

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The nucleus accumbens shell is a site of converging inputs during memory processing for emotional events. The accumbens receives input from the nucleus of the solitary tract (NTS) regarding changes in peripheral autonomic functioning following emotional arousal. The shell also receives input from the amygdala and hippocampus regarding affective and contextual attributes of new learning experiences. The successful encoding of affect or context is facilitated by activating noradrenergic systems in either the amygdala or hippocampus. Recent findings indicate that memory enhancement produced by activating NTS neurons, is attenuated by suppressing accumbens functioning after learning. This finding illustrates the significance of the shell in integrating information from the periphery to modulate memory for arousing events. However, it is not known if the accumbens shell plays an equally important role in consolidating information that is initially processed in the amygdala and hippocampus. The present study determined if the convergence of inputs from these limbic regions within the nucleus accumbens contributes to successful encoding of emotional events into memory. Male Sprague-Dawley rats received bilateral cannula implants 2 mm above the accumbens shell and a second bilateral implant 2 mm above either the amygdala or hippocampus. The subjects were trained for 6 days to drink from a water spout. On day 7, a 0.35 mA footshock was initiated as the rat approached the spout and was terminated once the rat escaped into a white compartment. Subjects were then given intra-amygdala or hippocampal infusions of PBS or a dose of norepinephrine (0.2 µg) previously shown to enhance memory. Later, all subjects were given intra-accumbens infusion of muscimol to functionally inactivate the shell. Muscimol inactivation of the accumbens shell was delayed to allow sufficient time for norepinephrine to activate intracellular cascades that lead to long-term synaptic modifications involved in forming new memories. Results show that memory improvement produced by infusing norepinephrine in either the amygdala or hippocampus is attenuated by interrupting neuronal activity in the shell 1 or 7 7 h following amygdala or hippocampus activation. These findings suggest that the accumbens shell plays an integral role modulating information initially processed by the amygdala and hippocampus following exposure to emotionally arousing events. Additionally, results demonstrate that the accumbens is involved in the long-term consolidation processes lasting over 7 h.

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Brief experiences while a memory is consolidated may capture the consolidation, perhaps producing a maladaptive memory, or may interrupt the consolidation. Since consolidation occurs during sleep, even fleeting experiences when animals are awakened may produce maladaptive long-term memory, or may interrupt consolidation. In a learning paradigm affecting Aplysia feeding, when animals were trained after being awakened from sleep, interactions between new experiences and consolidation were prevented by blocking long-term memory arising from the new experiences. Inhibiting protein synthesis eliminated the block and allowed even a brief, generally ineffective training to produce long-term memory. Memory formation depended on consolidative proteins already expressed before training. After effective training, long term memory required subsequent transcription and translation. Memory formation during the sleep phase was correlated with increased CREB1 transcription, but not CREB2 transcription. Increased C/EBP transcription was a correlate of both effective and ineffective training and of treatments not producing memory.

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Direct vagus nerve stimulation (dVNS) is known to improve mood, epilepsy, and memory. Memory improvements have been observed in Alzheimer's disease patients after long-term stimulation. The potential of transcutaneous vagus nerve stimulation (tVNS), a noninvasive alternative to dVNS, to alter memory performance remains unknown. We aimed to investigate the effect of a single-session tVNS on associative memory performance in healthy older individuals. To investigate this, we performed a single-blind sham-controlled randomized crossover pilot study in healthy older individuals (n = 30, 50% female). During the stimulation or sham condition, participants performed an associative face-name memory task. tVNS enhanced the number of hits of the memory task, compared with the sham condition. This effect was specific to the experimental task. Participants reported few side effects. We conclude that tVNS is a promising neuromodulatory technique to improve associative memory performance in older individuals, even after a single session. More research is necessary to investigate its underlying neural mechanisms, the impact of varying stimulation parameters, and its applicability in patients with cognitive decline.

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The role of norepinephrine (NE) in the consolidation of inhibitory avoidance learning (IA) in rats is known to involve α1- and ß-adrenoceptor systems in the basolateral nucleus of the amygdala (BLA). However, the amygdala also contains α2-adrenoceptor subtypes, and local microinfusions of the selective α2-adrenoceptor antagonist idazoxan and agonist UK 14,304 respectively into the BLA enhance and inhibit IA performances when administered before acquisition. The present study investigated whether the effects of idazoxan and UK 14,304 on IA were associated with changes in NE release within the BLA before and after one-trial inhibitory avoidance training. Male Sprague-Dawley rats were unilaterally implanted with a microdialysis probe in the BLA and were administered idazoxan (0.1mM) or UK 14,304 (10 µM) by retrodialysis infusion 15 min before the acquisition of IA. Dialysates were collected every 15 min for analysis of NE. Retrodialysis of idazoxan potentiated the release of NE induced by footshock application, whereas UK 14,304 decreased NE release to the extent that the footshock failed to induce any measurable effect on NE levels. Idazoxan infusion enhanced IA retention tested 24h later and this effect was directly related to the level of NE release in the BLA measured during IA acquisition. In contrast, the infusion of UK 14,304 did not modify IA performances in comparison to control animals, possibly due to compensatory activity of the contralateral BLA. These results are consistent with previous evidence that amygdala NE is involved in modulating memory consolidation, and provide evidence for an involvement of presynaptic α2-autoceptors in the BLA in this process.

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This review describes the role of cytokines and their downstream signaling cascades on the modulation of learning and memory. Immune proteins are required for many key neural processes and dysregulation of these functions by systemic inflammation can result in impairments of memory that persist long after the resolution of inflammation. Recent research has demonstrated that manipulations of individual cytokines can modulate learning, memory, and synaptic plasticity. The many conflicting findings, however, have prevented a clear understanding of the precise role of cytokines in memory. Given the complexity of inflammatory signaling, understanding its modulatory role requires a shift in focus from single cytokines to a network of cytokine interactions and elucidation of the cytokine-dependent intracellular signaling cascades. Finally, we propose that whereas signal transduction and transcription may mediate short-term modulation of memory, long-lasting cellular and molecular mechanisms such as epigenetic modifications and altered neurogenesis may be required for the long lasting impact of inflammation on memory and cognition.

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Arousing events are better remembered than mundane events. Indeed, manipulation of arousal, such as by muscle tension, can influence memory even when it occurs shortly after learning. Indeed, our founding study showed this approach can raise delayed memory performance in older adults to a level comparable to that of unaided young adults. Yet, systematic studies, especially those investigating different modalities or types of memory, have not been done. This study investigated the effects of a brief bout of isometric exercise via handgrip on narrative and visuospatial episodic memory in healthy elders. Forty-seven participants completed the Logical Memory subtest of the Wechsler Memory Scales III (LM) and the Benton Visual Retention Test (BVRT), followed alternately by no treatment and by moderately squeezing a sand-filled latex ball for 1-min (counterbalanced order and test forms). Isometric exercise significantly increased both positive and negative affect ratings. Retention was tested 2 weeks later. Delayed recall and recognition of LM was enhanced by arousal relative to control, as was recognition of the BVRT. The results extend past findings that muscle tension induced after learning modulates memory consolidation, extending findings in elders to suggest that a simple form of isometric exercise can have practical effects, such as aiding memory for stories and images.

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Extensive evidence indicates that endocannabinoids modulate cognitive processes in animal models and human subjects. However, the results of endocannabinoid system manipulations on cognition have been contradictory. As for anxiety behavior, a duality has indeed emerged with regard to cannabinoid effects on memory for emotional experiences. Here we summarize findings describing cannabinoid effects on memory acquisition, consolidation, retrieval and extinction. Additionally, we review findings showing how the endocannabinoid system modulates memory function differentially, depending on the level of stress and arousal associated with the experimental context. Based on the evidence reviewed here, we propose that the endocannabinoid system is an emotional buffer that moderates the effects of environmental context and stress on cognitive processes.

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Norepinephrine is released in the amygdala following negatively arousing learning conditions. This event initiates a cascade of changes including the transcription of activity-regulated cytoskeleton-associated protein (Arc) expression, an early-immediate gene associated with memory encoding. Recent evidence suggests that the valence of emotionally laden encounters may generate lateralized, as opposed to symmetric release of this transmitter in the right or left amygdala. It is currently not clear if valence-induced patterns of selective norepinephrine output across hemispheres are also reproduced in downstream pathways of cellular signaling necessary for memory formation. This question was addressed by determining if Arc expression is differentially distributed across the right and left amygdala following exposure to positively or negatively valenced learning conditions respectively. Male Sprague Dawley rats were randomly assigned to groups exposed to the Homecage only, five auditory tones only, or five auditory tones paired with footshock (0.35 mA) during Pavlovian fear conditioning. Western blot analysis revealed that Arc expression in the right amygdala was elevated significantly above that observed in the left amygdala 60 and 90 min following fear conditioning. Similarly, subjects exposed to a negatively valenced outcome consisting of an unexpected reduction in food rewards showed a greater level of Arc expression in only the right, but not left basolateral amygdala. Presenting a positively valenced event involving an unexpected increase in food reward magnitude following bar pressing, resulted in significantly greater Arc expression in the left, but not right basolateral amygdala (p < 0.01). These findings indicate that the valence of emotionally arousing learning conditions is reflected at later stages of synaptic plasticity involving the transcription of immediate early genes such as Arc.

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"Use it or lose it" is a popular adage often associated with use-dependent enhancement of cognitive abilities. Much research has focused on understanding exactly how the brain changes as a function of experience. Such experience-dependent plasticity involves both structural and functional alterations that contribute to adaptive behaviors, such as learning and memory, as well as maladaptive behaviors, including anxiety disorders, phobias, and posttraumatic stress disorder. With the advancing age of our population, understanding how use-dependent plasticity changes across the lifespan may also help to promote healthy brain aging. A common misconception is that such experience-dependent plasticity (e.g., associative learning) is synonymous with synaptic plasticity. Other forms of plasticity also play a critical role in shaping adaptive changes within the nervous system, including intrinsic plasticity - a change in the intrinsic excitability of a neuron. Intrinsic plasticity can result from a change in the number, distribution or activity of various ion channels located throughout the neuron. Here, we review evidence that intrinsic plasticity is an important and evolutionarily conserved neural correlate of learning. Intrinsic plasticity acts as a metaplasticity mechanism by lowering the threshold for synaptic changes. Thus, learning-related intrinsic changes can facilitate future synaptic plasticity and learning. Such intrinsic changes can impact the allocation of a memory trace within a brain structure, and when compromised, can contribute to cognitive decline during the aging process. This unique role of intrinsic excitability can provide insight into how memories are formed and, more interestingly, how neurons that participate in a memory trace are selected. Most importantly, modulation of intrinsic excitability can allow for regulation of learning ability - this can prevent or provide treatment for cognitive decline not only in patients with clinical disorders but also in the aging population.

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