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Unlike adult memories that can be remembered for many years, memories that are formed early in life are more fragile and susceptible to being forgotten (a phenomenon known as “infantile” or “childhood” amnesia). Nonetheless, decades of research in both humans and nonhuman animals demonstrate the importance of early life experiences on later physical, mental, and emotional functioning. This raises the question of how early memories can be so influential if they cannot be recalled. This review presents one potential solution to this paradox by considering what happens to an early memory after it has been forgotten. Specifically, we describe evidence showing that these forgotten early-acquired memories have not permanently decayed from storage. Instead, there appears to be a memory “trace” that persists in the face of forgetting which continues to affect a variety of behavioral responses later in life. Excitingly, the discovery of this physical trace will allow us to explore previously untestable issues in new ways, from whether forgetting is due to a failure in retrieval or storage to how memories can be recovered after extended periods of time. A greater understanding of the characteristics of this memory trace will provide novel insights into how some memories are left behind in childhood while others are carried with us, at least in some form, for a lifetime. Memory, along with most other cognitive abilities, develops across the lifespan (Ofen and Shing 2013). While memories acquired in adulthood are generally well remembered and persistent (e.g., Gale et al. 2004), memories formed earlier in development are usually quite fragile and rapidly forgotten (a phenomenon known as “infantile” or “childhood” amnesia [Campbell and Campbell 1962; Spear and Parsons 1976; Hayne 2004; Hayne and Jack 2011]). The fact that early memories are so fragile has resulted in a great deal of controversy over the importance of early experiences on later functioning (e.g., Fraley et al. 2013). Specifically, if early experiences cannot be explicitly recalled, how can they influence an individual's functioning later in life? Although this question remains unanswered, there is an overwhelming amount of evidence supporting the idea that early experiences are critical for later functioning. For example, there is substantial evidence that the quality of maternal care experienced early in life affects the behavioral, neural, and physiological responses of the offspring as they mature. In a striking series of studies, Tottenham and colleagues examined children who experienced maternal deprivation in the first two years of life (i.e., had been reared in an orphanage). In one study it was reported that these individuals were more likely to experience depression in adolescence (Goff et al. 2013). Further, on a neural level, they also exhibited altered maturation of the nucleus accumbens, a structure involved in reward learning. In another study, these individuals exhibited amygdala hyperactivity as well as accelerated maturation of amygdala–prefrontal cortex connectivity (Gee et al. 2013); both of these structures are important for emotion regulation in humans (Hartley and Phelps 2013). Numerous animal studies have also demonstrated the importance of early experiences for later functioning. For example, it has been reported that infant rats whose mothers engaged in a high rate of arched back nursing and licking/grooming exhibit markedly lower hormonal reactions in a stressful situation in adulthood (Liu et al. 1997). In addition, these animals are more exploratory, and perform better at spatial learning and memory tasks (for review, see Champagne and Curley 2009). It has also been suggested that specific early experiences may be the basis of adult psychopathologies (e.g., Jacobs and Nadel 1985; Mineka and Zinbarg 2006). Hence, although early experiences are rapidly forgotten, such experiences do appear to have a lasting impact. Here, we explore some of the ways in which early memories continue to have an influence on later functioning despite being “forgotten.” Traditionally, forgetting is defined as the inability to recall and express a memory on a behavioral level (e.g., free recall in humans, a learned avoidance response in rodents). Although memory loss can be observed in animals of all ages, it is most common in younger and aged animals, each of which exhibit a rapid rate of forgetting compared to adult animals. The faster rate of forgetting in the young is a well-documented phenomenon. For example, in their now-classic study Campbell and Campbell (1962) trained rats ranging in age from 18 d (infants) to 100 d (adults) on an aversively motivated avoidance task. When tested immediately after training animals of all ages showed high, and comparable, levels of avoidance. As the retention interval increased, however, marked age differences in performance were observed. Specifically, the infant rats exhibited substantial forgetting after 7 d and complete forgetting after 21 d. In contrast, the adult rats exhibited perfect retention even after 42 d, the longest interval tested. Similar results have been reported with humans in a nonfear based task. As one example, in a series of experiments Rovee-Collier and colleagues have shown that retention in human infants trained on an operant procedure (e.g., the mobile conjugate reinforcement task, where the infant learns to kick one leg to produce movement in an overhanging mobile, or the train task, where the infant learns to press a manipulandum to cause an electric train to move) increases monotonically with age over the first years of life (for review, see Rovee-Collier and Cuevas 2009). Thus, the studies described above, along with many others, clearly show that memories acquired early in life are forgotten much more quickly than those acquired later in life, at least in terms of conscious recollection or overt behavioral expression of the memory.2 Although we have long been aware of the robust phenomenon of infantile amnesia, in the past 50 years there have been surprisingly few advances in our understanding of the physiological bases of this rapid forgetting. However, several recent papers have suggested potential molecular and structural mechanisms that could be involved in infantile amnesia (e.g., Josselyn and Frankland 2012; Frankland et al. 2013; Callaghan et al. 2014). These potential mechanisms are largely derived from recent studies on the molecular and structural bases of memory in adults. That is, infantile amnesia may be due to the immaturity of one, or more, of these mechanisms in infancy. Determining how the various processes already shown to be important in memory in adulthood change across early development is likely to lead to a much better mechanistic understanding of infantile amnesia. However, in this brief review, we focus on a different approach toward understanding infantile amnesia. This approach focuses on the possibility that at least some part of these apparently forgotten early memories persists beyond the point in time where the memory is overtly expressed. This “trace” of the memory, although not normally expressed in a standard retention test, can still markedly affect the participant's behavior in a number of ways. The following sections explore the various ways through which the lasting influence of this trace on later functioning can be observed. It has long been noted that the pronounced forgetting observed in adult amnesiacs primarily occurs with certain types of memories (for reviews, see Schacter and Buckner 1998; Moscovitch 2010). That is, these individuals typically exhibit difficulties with verbal recall of a past event even though they show altered behavioral responses that could have only resulted from having that experience. For example, an adult amnesiac might not recall learning to play a particular song on a piano, but yet is able to perform it. This distinction is referred to as the difference between explicit and implicit memory. A similar dissociation is observed following forgetting of early memories, where there is a lingering influence of the experience even though it is not explicitly recalled. One example which shows that an enduring memory trace of an early experience can influence subsequent behavior in humans despite a lack of conscious recollection is provided by the research of Newcombe and her colleagues (for review, see Lloyd and Newcombe 2009). In one experiment children were given a recognition test for faces of classmates from preschool. Some children correctly recognized their old classmates while other children did not. Regardless of accuracy in recognition, however, children exhibited a similar skin conductance response to the faces of their old classmates relative to the faces of unfamiliar children. In another study, 3-yr-olds, 5-yr-olds, and adults were shown pictures from a story book. When tested 3 mo later, the 3-yr-olds’ verbal recognition of the pictures was at chance while the 5-yr-olds and adults performed significantly better. Despite this difference in explicit memory of the pictures there was no developmental difference on a perceptual priming task. That is, when asked to name an out-of-focus picture that progressively came into focus, all three age groups performed better (i.e., named the picture sooner) with familiar pictures from the storybook than with novel pictures. Findings like these have led some researchers in the field of human memory development to suggest that early memories leave at least a partial trace that continues to influence later functioning despite not being explicitly recalled (e.g., Sroufe et al. 1990). The idea that an unexpressed memory trace might have an “implicit” effect on later performance in rodents was recently explored by Li and Richardson (2013). In that study, the effect of a memory acquired during infancy, but then forgotten, on the neurobiological mechanisms mediating future learning experiences was examined. In adult animals, it is well-established that the cellular mechanisms underlying initial learning (“acquisition”) involve a series of intracellular signals, one of which is the activation of N-methyl-D-aspartate receptors (NMDArs) (Kandel 2001; Schafe et al. 2001). However, when the same learning experience occurs again (“reacquisition”) NMDArs are no longer required (e.g., Sanders and Fanselow 2003; Wiltgen et al. 2011). This is referred to as a “switch” from NMDAr-dependent acquisition to NMDAr-independent reacquisition. Li and Richardson (2013) explored whether this switch to NMDAr-independent reacquisition still occurred if the original learning had been forgotten. Infant rats were trained at 17 d of age with noise CS-shock US pairings. After 2 wk these infant rats demonstrated complete forgetting by exhibiting negligible levels of conditioned fear (as assessed through CS-elicited freezing). Reacquisition following forgetting was NMDAr-independent regardless of whether reacquisition occurred 2 or 7 wk after training (forgetting was observed at both intervals). Importantly, the switch from NMDAr-dependent acquisition to NMDAr-independent reacquisition only occurred if the experience at 17 d of age was an associative learning experience (i.e., CS–US pairings) and not merely an aversive experience (i.e., unpaired noise-shock presentations). Hence, it appears that early memories can have a long-lasting influence on subsequent learning, altering the cellular mechanisms involved in learning later in life, even though they are no longer overtly expressed at the behavioral level. Interestingly, the transition to NMDAr-independent reacquisition is not observed in adult rats following anisomycin-induced amnesia (Hardt et al. 2009) or following extinction training in conjunction with administration of fibroblast growth factor-2 (Graham and Richardson 2011) as these manipulations appear to permanently alter or erase the original memory trace. Taken together, the results of these studies suggest that the switch from NMDAr-dependent acquisition to NMDAr-independent reacquisition could be a useful procedure for assessing whether some representation of a memory which is forgotten at a behavioral level is still maintained in the brain. The terms “reinstatement” and “reactivation” both refer to a situation where an apparently forgotten memory is recovered (i.e., is now overtly expressed at test). The difference between the two terms is that “reinstatement” usually is used in studies where repeated, periodic reminders are given throughout the retention interval, while “reactivation” usually is used in studies where a single reminder is given at the end of the retention interval (Spear and Parsons 1976). The obvious implication of the findings described immediately above is that infantile forgetting is not due to a loss of the early-acquired memory from storage. In other words, this forgetting must be due to a retrieval failure. Additional evidence for this claim is provided by a study by Campbell and Jaynes (1966) who reported that infantile amnesia in rats could be alleviated by “reminders” given periodically throughout the retention interval. Since that study there has been a plethora of additional studies supporting this finding in a variety of tasks and in both humans and nonhuman subjects. For instance, Spear and Parsons (1976) conditioned 16-d-old rats (infants) to fear a light CS by pairing it with a footshock US. Animals were tested 28 d after training and, as expected, substantial forgetting occurred (i.e., infantile amnesia was observed). However, 24 h prior to test some animals were given a single shock presentation. Animals that received the pretest shock “reminder” exhibited high levels of fear of the light CS at test. To ensure that the reminder shock did not cause any learning by itself, a separate group of animals were not trained but were given the shock prior to test. The light CS did not elicit fear in these animals, demonstrating that the treatment alleviated forgetting by reactivating the original memory rather than producing sufficient new learning to lead to the behavioral response of interest. Although most early studies of this phenomenon used footshock as the reminder cue, later studies showed that infantile amnesia could be attenuated through other pretest treatments, such as hormonal or pharmacological agents (e.g., epinephrine [Haroutunian and Riccio 1977] and FG-7142 [Kim et al. 2006]). All of these studies, as well as those described earlier in the section on explicit/implicit memory, show that some representation of the original memory formed in infancy must still be present later in development despite the fact that the memory is not easily retrieved or overtly expressed. Similar findings have been reported in human infants. For example, Davis and Rovee-Collier (1983) trained 8-wk-old infants on an operant conditioning task where the infant learned to kick their foot in order to move a mobile suspended above them. Two weeks after training, all infants showed complete forgetting of this task. However, infants showed little to no forgetting if they had received a reminder treatment (exposure to the moving mobile) 24 h prior to the long-term retention test. Thus, just like in the rodent studies, even when forgetting occurs on a behavioral level, memories acquired by infant humans are not permanently lost or erased. The studies described in the two preceding sections suggest that there must be some neural representation of the early-acquired memory even when it is not behaviorally expressed. Evidence for such a physical trace was recently provided in a study by Kim et al. (2012). In that study, 16- and 23-d-old rats were given noise CS-shock US pairings. When tested immediately after training, rats at both ages showed similar levels of conditioned fear (as assessed through CS-elicited freezing). When tested 2 d later, however, only the 23-d-old rats continued to exhibit fear to the CS, while the 16-d-old rats showed low levels of CS-elicited freezing, indicating forgetting. Following test, the amount of phosphorylated mitogen-activated protein kinase (pMAPK) in the amygdala was analyzed using immunohistochemistry. Despite failing to behaviorally express the memory, the 16-d-old rats tested at the 2-d interval had heightened pMAPK activity in the amygdala, comparable to that observed in the 23-d-old rats who had exhibited high levels of freezing at test. Importantly, both of these groups differed in levels of amygdala pMAPK activity relative to same-age animals given explicitly unpaired presentations of the CS and US at training and then tested 2 d later; the rats in this unpaired condition did not express fear of the CS. These results suggest that pMAPK levels in the amygdala track past learning history and may be a long-term marker of fear memory storage. That study provided the first neural evidence for a memory trace which persists in the face of infantile forgetting. The discovery of a neural marker of past learning experience that persists despite forgetting on the behavioral level may prove useful in a number of ways. For example, although the studies described above on memory reinstatement/reactivation clearly demonstrate that many instances of infantile forgetting are due to a retrieval failure, this does not mean they always are. That is, forgetting of early memories may go through two phases. In the first phase, the memory is no longer explicitly expressed, but can be recovered if an appropriate reminder treatment is given prior to test. However, if the memory remains in this dormant state (i.e., available but not accessible) long enough, then it may decay sufficiently such that there is no longer a representation of it in the brain (see Callaghan et al. 2014, for a consideration of various neural and molecular processes that could be involved in infantile amnesia). In other words, infantile forgetting, and forgetting more generally, could sometimes be due to a retrieval failure and other times to a storage failure; the presence or absence of the physical trace could potentially distinguish between the two cases. The observation of a successful reinstatement/reactivation effect clearly shows that any observed forgetting was due to a retrieval failure. However, the failure to detect such an effect does not necessarily mean that the memory trace has decayed from storage; rather, such a result could be due to an ineffective reminder cue. This issue has long been noted, but without having any independent evidence of the memory trace, other than successful reactivation, it has not been possible to test these various possibilities. The demonstration of a detectable neural signal resulting from a specific learning experience could be very useful in this situation. That is, if animals fail to recover a memory following a reminder treatment, but they exhibit evidence of the physical trace (e.g., altered pMAPK activity in the amygdala), then a stronger conclusion can be made that the particular reminder treatment used was ineffective in that situation. It will be interesting to determine whether other neural markers of memory can also be used to explore the issue of whether infantile forgetting is due to a storage or retrieval failure. As one example, Han and colleagues took advantage of the finding that changes in cyclic-AMP response element binding protein (CREB) expression plays a role in the formation of a memory trace. Specifically, they reported that experimentally increasing CREB expression in subpopulations of neurons in the lateral amygdala following auditory fear conditioning resulted in the recruitment of those neurons into the memory trace (Han et al. 2007). In a subsequent study they showed that deletion of these CREB-overexpressing neurons reduced memory expression (Han et al. 2009). It is currently unknown whether the same results would be observed in the infant animal. In other words, is CREB expression also important for the formation of a memory trace in the infant animal? If so, then heightened CREB expression in the amygdala, especially at long intervals following initial learning, may be used to predict the success of memory reinstatement/reactivation. The discovery of these various neural markers can help us to distinguish between retrieval- and storage-based failures in memory. However, one issue that requires further investigation is why the animal exhibits forgetting even when there is a neural signature of the memory persisting in the brain. As previously mentioned, it is likely that forgetting occurs in stages. Thus, it is possible that the strength of the memory trace also degrades in stages. For instance, it may be that the behavioral expression or explicit recall of a memory requires the whole (or nearly whole) memory trace to be present in the brain. When an animal forgets but the memory can still be reactivated and retrieved, then a partial memory trace may be observed. The final stage, when an animal forgets and the memory cannot be reactivated, may reflect the complete decay of the memory trace. Future studies could test this possibility by examining the levels of pMAPK expression in the amygdala at different time points following learning. We would expect that the level of pMAPK expression decreases over time until the point where no pMAPK activity is observed, thus reflecting the complete and permanent loss of memory. Although infantile amnesia is one of the strongest, and most frequently observed, characteristics of infant memory, there appear to be some circumstances where infants exhibit much longer-lasting retention of early experiences. A largely ignored area of research has been the interaction between early adversity and the development of memory. This is an important gap in the literature considering that early adversity has been shown to be associated with alterations in the developmental trajectory of neural regions important for memory (e.g., Gee et al. 2013). Whether infantile amnesia remained a characteristic of memory development following early life adverse rearing (i.e., maternal separation) was recently investigated by Callaghan and Richardson (2012). In that study infant rats were given pairings of a noise CS and a shock US, and tested for their fear of the noise CS either 1 or 10 d later. Both standard-reared (SR) and maternally separated (MS) rats learned the association, as both expressed fear at the 1-d interval. However, while the SR rats rapidly forgot the association, expressing negligible levels of CS-elicited freezing just 10 d later, MS infant rats maintained a high level of fear at the 10-d interval. The MS rats trained as infants continued to express conditioned fear up to 30 d after the conditioning episode (i.e., well into the young adult period of development), suggesting that MS drastically enhances retention of infant memories. Enhanced memory retention was also observed if animals were reared by mothers who had their drinking water supplemented with the stress hormone corticosterone across the same period of time (i.e., postnatal days 2–14). Thus, early exposure to stress appears to alter the developmental trajectory of memory, accelerating the emergence of adult-like retention, leading to lasting behavioral expression of learned experiences (also see Cowan et al. 2013). These findings have both clinical and theoretical significance. Clinically, these findings might provide at least a partial explanation for why early life adversity is associated with later anxiety disorders (e.g., McLaughlin et al. 2012) as such individuals may explicitly retain their early experiences much longer than normally occurs. Theoretically, these findings may provide a novel approach toward studying the molecular and structural processes involved in memory (e.g., Callaghan et al. 2014). That is, animals exposed to early life adversity may exhibit a markedly different developmental profile in the maturation of one, or more, of these processes. Another area of future research could be to examine whether these effects of maternal separation on retention are observed for all memories, including appetitive ones or are specific to aversive memories. Infantile amnesia is a robust and ubiquitous phenomenon; however, there are still many unanswered questions about the nature of infant memories. One of those questions is how early memories, despite being forgotten on a behavioral level, continue to have effects on the animal's physical and mental health later in life. In this review, we presented evidence suggesting a neural trace of the experience persists even when memories are no longer recalled or expressed. This finding highlights the importance of considering what the term “forgetting” actually means—is it merely the absence of behavioral expression or is it when even “implicit” effects on later performance are no longer observable? We suggest that forgetting, at least nonreversible and permanent forgetting, occurs when both of these characteristics are observed. In this review, we hypothesized that the “implicit” effects of early memories on later performance are due to the persistence of the neural signature representing that memory. What we currently do not know is how long these physical traces last. Kim et al. (2012) only examined pMAPK levels 2 d after training, and it is possible that heightened pMAPK activity in the amygdala is observed weeks, months, or even years later. This would be exciting on a clinical level because we could reactivate and potentially extinguish aversive or traumatic early memories rather than allowing the memories to persist in their implicit form, with their attendant consequences which are not attributed to a specific experience as that memory is not explicitly recalled. Future research also needs to determine how reactivation/reminder treatments interact with the memory trace. It may be that periodic reminders ward off the decay of the memory by working to stabilize the memory trace. This is of interest clinically because it may explain how some early memories are more resilient to disruption than others. Additional research into these persisting neural markers of memory will hopefully provide us with greater insight into how some memories may, indeed, last a lifetime. Overall, this review shows that while the study of infantile amnesia in the last 50 yr has focused predominantly at the behavioral level, our exploration of the phenomenon on a mechanistic level is only just beginning. Preparation of this manuscript was supported by grants from the Australian Research Council (DP120104925) and the National Health and Medical Research Council (APP1031688) to R.R. Footnotes
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Learning complex skills is driven by reinforcement, which facilitates both online within-session gains and retention of the acquired skills. Yet, in ecologically relevant situations, skills are often acquired when mapping between actions and rewarding outcomes is unknown to the learning agent, resulting in reinforcement schedules of a stochastic nature. Here we trained subjects on a visuomotor learning task, comparing reinforcement schedules with higher, lower, or no stochasticity. Training under higher levels of stochastic reinforcement benefited skill acquisition, enhancing both online gains and long-term retention. These findings indicate that the enhancing effects of reinforcement on skill acquisition depend on reinforcement schedules. Footnotes
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Previous studies have examined the maturation of learning and memory abilities during early stages of development. By comparison, much less is known about the ontogeny of learning and memory during later stages of development, including adolescence. In Experiment 1, we tested the ability of adolescent and adult rats to learn a Pavlovian negative occasion setting task. This procedure involves learning to inhibit a behavioral response when signaled by a cue in the environment. During reinforced trials, a target stimulus (a tone) was presented and immediately followed by a food reward. On nonreinforced trials, a feature stimulus (a light) was presented 5 sec prior to the tone and indicated the absence of reward following presentation of the tone. Both adult and adolescent rats learned to discriminate between two different trial types and withhold responding when the light preceded the tone. However, adolescent rats required more sessions than adults to discriminate between reinforced and nonreinforced trials. The results of Experiment 2 revealed that adolescents could learn the task rules but were specifically impaired in expressing that learning in the form of withholding behavior on nonreinforced trials. In Experiment 3, we found that adolescents were also impaired in learning a different version of the task in which the light and tone were presented simultaneously during the nonreinforced trials. These findings add to existing literature by indicating that impairments in inhibitory behavior during adolescence do not reflect an inability to learn to inhibit a response, but instead reflect a specific deficit in expressing that learning. Footnotes
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The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We find that a single injection of cocaine does not alter LTP. However, pretreatment with nicotine followed by a single injection of cocaine causes a substantial enhancement of LTP. This priming effect of nicotine is unidirectional: There is no enhancement of LTP if cocaine is administrated prior to nicotine. The facilitation induced by nicotine and cocaine can be blocked by oral administration of the dopamine D1/D5 receptor antagonist (SKF 83566) and enhanced by the D1/D5 agonist (SKF 38393). Application of the histone deacetylation inhibitor suberoylanilide hydroxamic acid (SAHA) simulates the priming effect of nicotine on cocaine. By contrast, the priming effect of nicotine on cocaine is blocked in genetically modified mice that are haploinsufficient for the CREB-binding protein (CBP) and possess only one functional CBP allele and therefore exhibit a reduction in histone acetylation. These results demonstrate that the DG of the hippocampus is an important brain region contributing to the priming effect of nicotine on cocaine. Moreover, both activation of dopamine-D1 receptor/PKA signaling pathway and histone deacetylation/CBP mediated transcription are required for the nicotine priming effect in the DG. Footnotes
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Learning-induced modulation of neuronal intrinsic excitability is a metaplasticity mechanism that can impact the acquisition of new memories. Although the amygdala is important for emotional learning and other behaviors, including fear and anxiety, whether learning alters intrinsic excitability within the amygdala has received very little attention. Fear conditioning was combined with intracellular recordings to investigate the effects of learning on the intrinsic excitability of lateral amygdala (LA) neurons. To assess time-dependent changes, brain slices were prepared either immediately or 24-h post-conditioning. Fear conditioning significantly enhanced excitability of LA neurons, as evidenced by both decreased afterhyperpolarization (AHP) and increased neuronal firing. These changes were time-dependent such that reduced AHPs were evident at both time points whereas increased neuronal firing was only observed at the later (24-h) time point. Moreover, these changes occurred within a subset (32%) of LA neurons. Previous work also demonstrated that learning-related changes in synaptic plasticity are also evident in less than one-third of amygdala neurons, suggesting that the neurons undergoing intrinsic plasticity may be critical for fear memory. These data may be clinically relevant as enhanced LA excitability following fear learning could influence future amygdala-dependent behaviors. Footnotes
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The retrosplenial cortex supports navigation, with one role thought to be the integration of different spatial cue types. This hypothesis was extended by examining the integration of nonspatial cues. Rats with lesions in either the dysgranular subregion of retrosplenial cortex (area 30) or lesions in both the granular and dysgranular subregions (areas 29 and 30) were tested on cross-modal object recognition (Experiment 1). In these tests, rats used different sensory modalities when exploring and subsequently recognizing the same test objects. The objects were first presented either in the dark, i.e., giving tactile and olfactory cues, or in the light behind a clear Perspex barrier, i.e., giving visual cues. Animals were then tested with either constant combinations of sample and test conditions (light to light, dark to dark), or changed “cross-modal” combinations (light to dark, dark to light). In Experiment 2, visual object recognition was tested without Perspex barriers, but using objects that could not be distinguished in the dark. The dysgranular retrosplenial cortex lesions selectively impaired cross-modal recognition when cue conditions switched from dark to light between initial sampling and subsequent object recognition, but no impairment was seen when the cue conditions remained constant, whether dark or light. The combined (areas 29 and 30) lesioned rats also failed the dark to light cross-modal problem but this impairment was less selective. The present findings suggest a role for the dysgranular retrosplenial cortex in mediating the integration of information across multiple cue types, a role that potentially applies to both spatial and nonspatial domains. Footnotes
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Though much attention has been given to the neural structures that underlie the long-term consolidation of contextual memories, little is known about the mechanisms responsible for the maintenance of memory precision. Here, we demonstrate a rapid time-dependent decline in memory precision in GABAB(1a) receptor knockout mice. First, we show that GABAB(1a) receptors are required for the maintenance, but not encoding, of a precise fear memory. We then demonstrate that GABAB(1a) receptors are required for the maintenance, but not encoding, of spatial memories. Our findings suggest that GABA-mediated presynaptic inhibition regulates the maintenance of memory precision as a function of memory age. Footnotes
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Research in rats using preferences during exploration as a measure of memory has indicated that sleep is important for the consolidation of episodic-like memory, i.e., memory for an event bound into specific spatio-temporal context. How these findings relate to human episodic memory is unclear. We used spontaneous preferences during visual exploration and verbal recall as, respectively, implicit and explicit measures of memory, to study effects of sleep on episodic memory consolidation in humans. During encoding before 10-h retention intervals that covered nighttime sleep or daytime wakefulness, two groups of young adults were presented with two episodes that were 1-h apart. Each episode entailed a spatial configuration of four different faces in a 3 × 3 grid of locations. After the retention interval, implicit spatio-temporal recall performance was assessed by eye-tracking visual exploration of another configuration of four faces of which two were from the first and second episode, respectively; of the two faces one was presented at the same location as during encoding and the other at another location. Afterward explicit verbal recall was assessed. Measures of implicit and explicit episodic memory retention were positively correlated (r = 0.57, P < 0.01), and were both better after nighttime sleep than daytime wakefulness (P < 0.05). In the sleep group, implicit episodic memory recall was associated with increased fast spindles during nonrapid eye movement (NonREM) sleep (r = 0.62, P < 0.05). Together with concordant observations in rats our results indicate that consolidation of genuinely episodic memory benefits from sleep. Footnotes
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Mechanistically distinct forms of long-lasting plasticity and memory can be induced by a variety of different training patterns. Although several studies have identified distinct molecular pathways that are engaged during these different training patterns, relatively little work has explored potential interactions between pathways when they are simultaneously engaged in the same neurons and circuits during memory formation. Aplysia californica exhibits two forms of intermediate-term synaptic facilitation (ITF) in response to two different training patterns: (1) repeated trial (RT) ITF (induced by repeated tail nerve shocks [TNSs] or repeated serotonin [5HT] application) and (2) activity-dependent (AD) ITF (induced by sensory neuron activation paired with a single TNS or 5HT pulse). RT-ITF requires PKA activation and de novo protein synthesis, while AD-ITF requires PKC activation and has no requirement for protein synthesis. Here, we explored how these distinct molecular pathways underlying ITF interact when both training patterns occur in temporal register (an “Interactive” training pattern). We found that (1) RT, AD, and Interactive training all induce ITF; (2) Interactive ITF requires PKC activity but not de novo protein synthesis; and (3), surprisingly, Interactive training blocks persistent PKA activity 1 h after training, and this block is PKC-independent. These data support the hypothesis that sensory neuron activity coincident with the last RT training trial is sufficient to convert the molecular signaling already established by RT training into an AD-like molecular phenotype. Footnotes
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A common genetic polymorphism that results in increased activity of the dopamine regulating enzyme COMT (the COMT Val158 allele) has been found to associate with poorer cognitive performance and increased susceptibility to develop psychiatric disorders. It is generally assumed that this increase in COMT activity influences cognitive function and psychiatric disease risk by increasing dopamine turnover in cortical synapses, though this cannot be directly measured in humans. Here we explore a novel transgenic mouse model of increased COMT activity, equivalent to the relative increase in activity observed with the human COMT Val158 allele. By performing an extensive battery of behavioral tests, we found that COMT overexpressing mice (COMT-OE mice) exhibit cognitive deficits selectively in the domains that are affected by the COMT Val158 allele, stimulus–response learning and working memory, functionally validating our model of increased COMT activity. Although we detected no changes in the level of markers for dopamine synthesis and dopamine transport, we found that COMT-OE mice display an increase in dopamine release capacity in the striatum. This result suggests that increased COMT activity may not only affect dopamine signaling by enhancing synaptic clearance in the cortex, but may also cause changes in presynaptic dopamine function in the striatum. These changes may underlie the behavioral deficits observed in the mice and might also play a role in the cognitive deficits and increased psychiatric disease risk associated with genetic variation in COMT activity in humans. Footnotes
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Behavioral flexibility is vital for survival in an environment of changing contingencies. The nucleus accumbens may play an important role in behavioral flexibility, representing learned stimulus–reward associations in neural activity during response selection and learning from results. To investigate the role of nucleus accumbens neural activity in behavioral flexibility, we used light-activated halorhodopsin to inhibit nucleus accumbens shell neurons during specific time segments of a bar-pressing task requiring a win–stay/lose–shift strategy. We found that optogenetic inhibition during action selection in the time segment preceding a lever press had no effect on performance. However, inhibition occurring in the time segment during feedback of results—whether rewards or nonrewards—reduced the errors that occurred after a change in contingency. Our results demonstrate critical time segments during which nucleus accumbens shell neurons integrate feedback into subsequent responses. Inhibiting nucleus accumbens shell neurons in these time segments, during reinforced performance or after a change in contingencies, increases lose–shift behavior. We propose that the activity of nucleus shell accumbens shell neurons in these time segments plays a key role in integrating knowledge of results into subsequent behavior, as well as in modulating lose–shift behavior when contingencies change. Footnotes
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Neurotrophins are critically involved in developmental processes such as neuronal cell survival, growth, and differentiation, as well as in adult synaptic plasticity contributing to learning and memory. Our previous studies examining neurotrophins and memory formation in Aplysia showed that a TrkB ligand is required for MAPK activation, long-term synaptic facilitation (LTF), and long-term memory (LTM) for sensitization. These studies indicate that neurotrophin-like molecules in Aplysia can act as key elements in a functionally conserved TrkB signaling pathway. Here we report that we have cloned and characterized a novel neurotrophic factor, Aplysia cysteine-rich neurotrophic factor (apCRNF), which shares classical structural and functional characteristics with mammalian neurotrophins. We show that apCRNF (1) is highly enriched in the CNS, (2) enhances neurite elongation and branching, (3) interacts with mammalian TrkB and p75NTR, (4) is released from Aplysia CNS in an activity-dependent fashion, (5) facilitates MAPK activation in a tyrosine kinase dependent manner in response to sensitizing stimuli, and (6) facilitates the induction of LTF. These results show that apCRNF is a native neurotrophic factor in Aplysia that can engage the molecular and synaptic mechanisms underlying memory formation. Footnotes
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Memories relating to a painful, negative event are adaptive and can be stored for a lifetime to support preemptive avoidance, escape, or attack behavior. However, under unfavorable circumstances such memories can become overwhelmingly powerful. They may trigger excessively negative psychological states and uncontrollable avoidance of locations, objects, or social interactions. It is therefore obvious that any process to counteract such effects will be of value. In this context, we stress from a basic-research perspective that painful, negative events are “Janus-faced” in the sense that there are actually two aspects about them that are worth remembering: What made them happen and what made them cease. We review published findings from fruit flies, rats, and man showing that both aspects, respectively related to the onset and the offset of the negative event, induce distinct and oppositely valenced memories: Stimuli experienced before an electric shock acquire negative valence as they signal upcoming punishment, whereas stimuli experienced after an electric shock acquire positive valence because of their association with the relieving cessation of pain. We discuss how memories for such punishment- and relief-learning are organized, how this organization fits into the threat-imminence model of defensive behavior, and what perspectives these considerations offer for applied psychology in the context of trauma, panic, and nonsuicidal self-injury. Footnotes
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The hippocampal formation receives strong cholinergic input from the septal/diagonal band complex. Although the functional effects of cholinergic activation have been extensively studied in pyramidal neurons within the hippocampus and entorhinal cortex, less is known about the role of cholinergic receptors on dentate gyrus neurons. Using intracellular recordings from rat dentate hilar neurons, we find that activation of m1-type muscarinic receptors selectively increases the excitability of glutamatergic mossy cells but not of hilar interneurons. Following brief stimuli, cholinergic modulation reveals a latent afterdepolarization response in mossy cells that can extend the duration of stimulus-evoked depolarization by >100 msec. Depolarizing stimuli also could trigger persistent firing in mossy cells exposed to carbachol or an m1 receptor agonist. Evoked IPSPs attenuated the ADP response in mossy cells. The functional effect of IPSPs was amplified during ADP responses triggered in the presence of cholinergic receptor agonists but not during slowly decaying simulated ADPs, suggesting that modulation of ADP responses by IPSPs arises from destabilization of the intrinsic currents underlying the ADP. Evoked IPSPs also could halt persistent firing triggered by depolarizing stimuli. These results show that through intrinsic properties modulated by muscarinic receptors, mossy cells can prolong depolarizing responses to excitatory input and extend the time window where multiple synaptic inputs can summate. By actively regulating the intrinsic response to synaptic input, inhibitory synaptic input can dynamically control the integration window that enables detection of coincident inputs and shape the spatial pattern of hilar cell activity. Footnotes
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Forty mice acquired conditioned responses to stimuli presented in a multiple schedule with variable inter-trial intervals (ITIs). In some trials, reinforcement was preceded by a variable conditioned stimulus (CS), while other trials were reinforced following distinctive fixed-duration CS. A third stimulus was presented but never paired with reinforcement. Subjects in five groups experienced ITIs of different durations. Acquisition of responding to each stimulus depended only on the cycle-to-trial ratio (C/T), and thus on the temporal contingency of each stimulus. Acquisition was unaffected by whether CSs were of fixed or variable duration. Footnotes
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An important aspect of goal-directed action selection is differentiating between actions that are more or less likely to be reinforced. With repeated performance or psychostimulant exposure, however, actions can assume stimulus-elicited—or “habitual”—qualities that are resistant to change. We show that selective knockdown of prelimbic prefrontal cortical Brain-derived neurotrophic factor (Bdnf) increases sensitivity to response–outcome associations, blocking habit-like behavioral inflexibility. A history of adolescent cocaine exposure, however, occludes the “beneficial” effects of Bdnf knockdown. This finding highlights a challenge in treating addiction—that drugs of abuse may bias decision-making toward habit systems even in individuals with putative neurobiological resiliencies. Footnotes
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Memory is a dynamic process that allows encoding, storage, and retrieval of information acquired through individual experience. In the honeybee Apis mellifera, olfactory conditioning of the proboscis extension response (PER) has shown that besides short-term memory (STM) and mid-term memory (MTM), two phases of long-term memory (LTM) are formed upon multiple-trial conditioning: an early phase (e-LTM) which depends on translation from already available mRNA, and a late phase (l-LTM) which requires de novo transcription and translation. Here we combined olfactory PER conditioning and neuropharmacological inhibition and studied the involvement of the NO–cGMP pathway, and of specific molecules, such as cyclic nucleotide-gated channels (CNG), calmodulin (CaM), adenylyl cyclase (AC), and Ca2+/calmodulin-dependent protein kinase (CaMKII), in the formation of olfactory LTM in bees. We show that in addition to NO–cGMP and cAMP–PKA, CNG channels, CaM, AC, and CaMKII also participate in the formation of a l-LTM (72-h post-conditioning) that is specific for the learned odor. Importantly, the same molecules are dispensable for olfactory learning and for the formation of both MTM (in the minute and hour range) and e-LTM (24-h post-conditioning), thus suggesting that the signaling pathways leading to l-LTM or e-LTM involve different molecular actors. Footnotes
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We investigated the specific role of zinc present in large amounts in the synaptic vesicles of mossy fibers and coreleased with glutamate in the CA3 region. In previous studies, we have shown that blockade of zinc after release has no effect on the consolidation of spatial learning, while zinc is required for the consolidation of contextual fear conditioning. Although both are hippocampo-dependent processes, fear conditioning to the context implies a strong emotional burden. To verify the hypothesis that zinc could play a specific role in enabling sustainable memorization of a single event with a strong emotional component, we used a neuropharmacological approach combining a glutamate receptor antagonist with different zinc chelators. Results show that zinc is mandatory to allow the consolidation of one-shot memory, thus being the key element allowing the hippocampus submitted to a strong emotional charge to switch from the cognitive mode to a flashbulb memory mode. Individual differences in learning abilities have been known for a long time to be totally or partially compensated by distributed learning practice. Here we show that contextual fear conditioning impairments due to zinc blockade can be efficiently reduced by distributed learning practice. Footnotes
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The proper regulation of translation is required for the expression of long-lasting synaptic plasticity. A major site of translational control involves the phosphorylation of eukaryotic initiation factor 2 α (eIF2α) by PKR-like endoplasmic reticulum (ER) kinase (PERK). To determine the role of PERK in hippocampal synaptic plasticity, we used the Cre-lox expression system to selectively disrupt PERK expression in the adult mouse forebrain. Here, we demonstrate that in hippocampal area CA1, metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) is associated with increased eIF2α phosphorylation, whereas stimulation of early- and late-phase long-term potentiation (E-LTP and L-LTP, respectively) is associated with decreased eIF2α phosphorylation. Interesting, although PERK-deficient mice exhibit exaggerated mGluR-LTD, both E-LTP and L-LTP remained intact. We also found that mGluR-LTD is associated with a PERK-dependent increase in eIF2α phosphorylation. Our findings are consistent with the notion that eIF2α phosphorylation is a key site for the bidirectional control of persistent forms of synaptic LTP and LTD and suggest a distinct role for PERK in mGluR-LTD. Footnotes
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Modulation of cortical network connectivity is crucial for an adaptive response to experience. In the rat barrel cortex, long-term sensory stimulation induces cortical network modifications and neuronal response changes of which the molecular basis is unknown. Here, we show that long-term somatosensory stimulation by enriched environment up-regulates cortical expression of neuropeptide mRNAs and down-regulates immediate-early gene (IEG) mRNAs specifically in the barrel cortex, and not in other brain regions. The present data suggest a central role of neuropeptides in the fine-tuning of sensory cortical circuits by long-term experience. Footnotes
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Protein synthesis is involved in the consolidation of short-term memory into long-term memory. Previous electrophysiological data concerning LTP in CA3 suggest that protein synthesis in that region might also be necessary for short-term memory. We tested this hypothesis by locally injecting the protein synthesis inhibitor anisomycin in hippocampal area CA1 or CA3 immediately after contextual fear conditioning. As previously shown, injections in CA1 impaired long-term memory but spared short-term memory. Conversely, injections in CA3 impaired both long-term and short-term memories. We conclude that early steps of experience-induced plasticity occurring in CA3 and underlying short-term memory require protein synthesis. Footnotes
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Reconsolidation is necessary for the restabilization of reactivated memory traces. However, experimental parameters have been suggested as boundary conditions for this process. Here we investigated the role of a spatial memory trace's age, strength, and update on the reconsolidation process in mice. We first found that protein synthesis is necessary for reconsolidation to occur in the hippocampal CA3 region after reactivation of partially acquired and old memories but not for strongly acquired and recent memories. We also demonstrated that the update of a previously stable memory required, again, a memory reconsolidation in the hippocampal CA3. Finally, we found that the reactivation of a strongly acquired memory requires an activation of the anterior cingulate cortex as soon as 24 h after acquisition. This study demonstrates the importance of the knowledge of the task on the dynamic nature of memory reconsolidation processing. Footnotes
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Seven monkeys performed variants of two short-term memory tasks that others have used to differentiate between selective and nonselective memory mechanisms. The first task was to view a list of sequentially presented images and identify whether a test matched any image from the list, but not a distractor from a preceding list. Performance was best when the test matched the most recently presented image. Response rates depended linearly on recency of repetition whether the test matched a sample from the current list or a distractor from a preceding list, suggesting nonselective memorization of all images viewed instead of just the sample images. The second task was to remember just the first image in a list selectively and ignore subsequent distractors. False alarms occurred frequently when the test matched a distractor presented near the beginning of the sequence. In a pilot experiment, response rates depended linearly on recency of repetition irrespective of whether the test matched the first image or a distractor, again suggesting nonselective memorization of all images instead of just the first image. Modification of the second task improved recognition of the first image, but did not abolish use of recency. Monkeys appear to perform nonspatial visual short-term memory tasks often (or exclusively) using a single, nonselective, memory mechanism that conveys the recency of stimulus repetition. Footnotes
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Extinction training during reconsolidation has been shown to persistently diminish conditioned fear responses across species. We investigated in humans if older fear memories can benefit similarly. Using a Pavlovian fear conditioning paradigm we compared standard extinction and extinction after memory reactivation 1 d or 7 d following acquisition. Participants who underwent extinction during reconsolidation showed no evidence of fear recovery, whereas fear responses returned in participants who underwent standard extinction. We observed this effect in young and old fear memories. Extending the beneficial use of reconsolidation to older fear memories in humans is promising for therapeutic applications. Footnotes
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Infantile amnesia is defined as the lack of memory for experience that occurred prior to what age?
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