Memory Consolidation

Conscious memory for a new experience is initially dependent on information stored in both the hippocampus and neocortex. Systems consolidation is the process by which the hippocampus guides the reorganization of the information stored in the neocortex such that it eventually becomes independent of the hippocampus. Early evidence for systems consolidation was provided by studies of retrograde amnesia, which found that damage to the hippocampus-impaired memories formed in the recent past, but typically spared memories formed in the more remote past. Systems consolidation has been found to occur for both episodic and semantic memories and for both spatial and nonspatial memories, although empirical inconsistencies and theoretical disagreements remain about these issues. Recent work has begun to characterize the neural mechanisms that underlie the dialogue between the hippocampus and neocortex (e.g., “neural replay,” which occurs during sharp wave ripple activity). New work has also identified variables, such as the amount of preexisting knowledge, that affect the rate of consolidation. The increasing use of molecular genetic tools (e.g., optogenetics) can be expected to further improve understanding of the neural mechanisms underlying consolidation.Memory consolidation refers to the process by which a temporary, labile memory is transformed into a more stable, long-lasting form. Memory consolidation was first proposed in 1900 (Müller and Pilzecker 1900; Lechner et al. 1999) to account for the phenomenon of retroactive interference in humans, that is, the finding that learned material remains vulnerable to interference for a period of time after learning. Support for consolidation was already available in the facts of retrograde amnesia, especially as outlined in the earlier writings of Ribot (1881). The key observation was that recent memories are more vulnerable to injury or disease than remote memories, and the significance of this finding for consolidation was immediately appreciated.

In normal memory a process of organization is continually going on—a physical process of organization and a psychological process of repetition and association. In order that ideas may become a part of permanent memory, time must elapse for these processes of organization to be completed. (Burnham 1903, p. 132)

It is useful to note that the term consolidation has different contemporary usages that derive from the same historical sources. For example, the term is commonly used to describe events at the synaptic/cellular level (e.g., protein synthesis), which stabilize synaptic plasticity within hours after learning. In contrast, systems consolidation, which is the primary focus of this review, refers to gradual reorganization of the brain systems that support memory, a process that occurs within long-term memory itself (Squire and Alvarez 1995; Dudai and Morris 2000; Dudai 2012).Systems consolidation is typically, and accurately, described as the process by which memories, initially dependent on the hippocampus, are reorganized as time passes. By this process, the hippocampus gradually becomes less important for storage and retrieval, and a more permanent memory develops in distributed regions of the neocortex. The idea is not that memory is literally transferred from the hippocampus to the neocortex, for information is encoded in the neocortex as well as in hippocampus at the time of learning. The idea is that gradual changes in the neocortex, beginning at the time of learning, establish stable long-term memory by increasing the complexity, distribution, and connectivity among multiple cortical regions. Recent findings have enriched this perspective by emphasizing the dynamic nature of long-term memory (Dudai and Morris 2013). Memory is reconstructive and vulnerable to error, as in false remembering (Schacter and Dodson 2001). Also, under some conditions, long-term memory can transiently return to a labile state (and then gradually stabilize), a phenomenon termed reconsolidation (Nader et al. 2000; Sara 2000; Alberini 2005). In addition, the rate of consolidation can be influenced by the amount of prior knowledge that is available about the material to be learned (Tse et al. 2007; van Kesteren et al. 2012).Neurocomputational models of consolidation (McClelland et al. 1995; McClelland 2013) describe how the acquisition of new knowledge might proceed and suggest a purpose for consolidation. As originally described, elements of information are first stored in a fast-learning hippocampal system. This information directs the training of a “slow learning” neocortex, whereby the hippocampus gradually guides the development of connections between the multiple cortical regions that are active at the time of learning and that represent the memory. Training of the neocortex by the hippocampus (termed “interleaved” training) allows new information to be assimilated into neocortical networks with a minimum of interference. In simulations (McClelland et al. 1995), rapid learning of new information, which was inconsistent with prior knowledge, was shown to cause interference and disrupt previously established representations (“catastrophic interference”). The gradual incorporation of information into the neocortex during consolidation avoids this problem. In a recent revision of this framework (McClelland 2013), neocortical learning is characterized, not so much as fast or slow, but as dependent on prior knowledge. If the information to be learned is consistent with prior knowledge, neocortical learning can be more rapid.This review considers several types of evidence that illuminate the nature of the consolidation process: studies of retrograde amnesia in memory-impaired patients, studies of healthy volunteers with neuroimaging, studies of sleep and memory, studies of experimental animals, both with lesions or other interventions, and studies that track neural activity as time passes after learning.     

Associative Learning during Early Adulthood Enhances Later Memory Retention in Honeybees

Background

Cognitive experiences during the early stages of life play an important role in shaping the future behavior in mammals but also in insects, in which precocious learning can directly modify behaviors later in life depending on both the timing and the rearing environment. However, whether olfactory associative learning acquired early in the adult stage of insects affect memorizing of new learning events has not been studied yet.

Methodology

Groups of adult honeybee workers that experienced an odor paired with a sucrose solution 5 to 8 days or 9 to 12 days after emergence were previously exposed to (i) a rewarded experience through the offering of scented food, or (ii) a non-rewarded experience with a pure volatile compound in the rearing environment.

Principal Findings

Early rewarded experiences (either at 1–4 or 5–8 days of adult age) enhanced retention performance in 9–12-day-conditioned bees when they were tested at 17 days of age. The highest retention levels at this age, which could not be improved with prior rewarded experiences, were found for memories established at 5–8 days of adult age. Associative memories acquired at 9–12 days of age showed a weak effect on retention for some pure pre-exposed volatile compounds; whereas the sole exposure of an odor at any younger age did not promote long-term effects on learning performance.

Conclusions

The associative learning events that occurred a few days after adult emergence improved memorizing in middle-aged bees. In addition, both the timing and the nature of early sensory inputs interact to enhance retention of new learning events acquired later in life, an important matter in the social life of honeybees.     

Daytime Sleep Enhances Consolidation of the Spatial but Not Motoric Representation of Motor Sequence Memory

Motor sequence learning is known to rely on more than a single process. As the skill develops with practice, two different representations of the sequence are formed: a goal representation built under spatial allocentric coordinates and a movement representation mediated through egocentric motor coordinates. This study aimed to explore the influence of daytime sleep (nap) on consolidation of these two representations. Through the manipulation of an explicit finger sequence learning task and a transfer protocol, we show that both allocentric (spatial) and egocentric (motor) representations of the sequence can be isolated after initial training. Our results also demonstrate that nap favors the emergence of offline gains in performance for the allocentric, but not the egocentric representation, even after accounting for fatigue effects. Furthermore, sleep-dependent gains in performance observed for the allocentric representation are correlated with spindle density during non-rapid eye movement (NREM) sleep of the post-training nap. In contrast, performance on the egocentric representation is only maintained, but not improved, regardless of the sleep/wake condition. These results suggest that motor sequence memory acquisition and consolidation involve distinct mechanisms that rely on sleep (and specifically, spindle) or simple passage of time, depending respectively on whether the sequence is performed under allocentric or egocentric coordinates.     

Blocking Dopaminergic Signaling Soon after Learning Impairs Memory Consolidation in Guinea Pigs

Formation of episodic memories (i.e. remembered experiences) requires a process called consolidation which involves communication between the neocortex and hippocampus. However, the neuromodulatory mechanisms underlying this neocortico-hippocampal communication are poorly understood. Here, we examined the involvement of dopamine D1 receptors (D1R) and D2 receptors (D2R) mediated signaling on memory consolidation using the Novel Object Recognition (NOR) test. We conducted the tests in male Hartley guinea pigs and cognitive behaviors were assessed in customized Phenotyper home cages utilizing Ethovision XT software from Noldus enabled for the 3-point detection system (nose, center of the body, and rear). We found that acute intraperitoneal injections of either 0.25 mg/kg SCH23390 to block D1Rs or 1.0 mg/kg sulpiride to block D2Rs soon after acquisition (which involved familiarization to two similar objects) attenuated subsequent discrimination for novel objects when tested after 5-hours in the NOR test. By contrast guinea pigs treated with saline showed robust discrimination for novel objects indicating normal operational processes undergirding memory consolidation. The data suggests that involvement of dopaminergic signaling is a key post-acquisition factor in modulating memory consolidation in guinea pigs.     

Efficient Partitioning of Memory Systems and Its Importance for Memory Consolidation

Long-term memories are likely stored in the synaptic weights of neuronal networks in the brain. The storage capacity of such networks depends on the degree of plasticity of their synapses. Highly plastic synapses allow for strong memories, but these are quickly overwritten. On the other hand, less labile synapses result in long-lasting but weak memories. Here we show that the trade-off between memory strength and memory lifetime can be overcome by partitioning the memory system into multiple regions characterized by different levels of synaptic plasticity and transferring memory information from the more to less plastic region. The improvement in memory lifetime is proportional to the number of memory regions, and the initial memory strength can be orders of magnitude larger than in a non-partitioned memory system. This model provides a fundamental computational reason for memory consolidation processes at the systems level.     

Memory and Learning

The main principles of information processing in the nervous system of animals and man may be defined as follows:

1. A stimulus acting upon the input of a system is transformed in receptors, where it forms a combination of receptor excitations—the EM-dimensional receptor vector of excitation.     

Causal Contribution of Awake Post-encoding Processes to Episodic Memory Consolidation

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Memory Consolidation in the Cerebellar Cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA_A agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage.     

Structural Components of Synaptic Plasticity and Memory Consolidation

Consolidation of implicit memory in the invertebrate Aplysia and explicit memory in the mammalian hippocampus are associated with remodeling and growth of preexisting synapses and the formation of new synapses. Here, we compare and contrast structural components of the synaptic plasticity that underlies these two distinct forms of memory. In both cases, the structural changes involve time-dependent processes. Thus, some modifications are transient and may contribute to early formative stages of long-term memory, whereas others are more stable, longer lasting, and likely to confer persistence to memory storage. In addition, we explore the possibility that trans-synaptic signaling mechanisms governing de novo synapse formation during development can be reused in the adult for the purposes of structural synaptic plasticity and memory storage. Finally, we discuss how these mechanisms set in motion structural rearrangements that prepare a synapse to strengthen the same memory and, perhaps, to allow it to take part in other memories as a basis for understanding how their anatomical representation results in the enhanced expression and storage of memories in the brain.Santiago Ramón y Cajal (1894) used the insights provided by his remarkable light microscopic observations of neurons selectively stained with the Golgi method to propose the first cellular theory of memory storage as an anatomical change in the functional connections between nerve cells, later called synapses (Sherrington 1897). For most of the last century, chemical synapses were thought to convey information in only one direction—from the presynaptic to the postsynaptic neuron. It now is clear that synaptic transmission is a bidirectional and self-modifiable form of cell–cell communication (Peters et al. 1976; Jessell and Kandel 1993). This appreciation of reciprocal signaling between pre- and postsynaptic elements is consistent with other forms of intercellular communication and provides a conceptual framework for understanding memory-induced changes in the structure of the synapse. Indeed, an increasing body of evidence suggests that trans-synaptic signaling and coordinated recruitment of pre- and postsynaptic mechanisms underlie consolidation of both implicit and explicit forms of memory storage (Marrone 2005; Hawkins et al. 2006; Bailey et al. 2008).Studies in a variety of systems have found that molecular mechanisms of consolidation and long-term storage of memory begin at the level of the synapse. Existing proteins are modified, signals are sent back to the nucleus so that specific genes are expressed, and gene products are transported back to the synapse where the local synthesis of new protein is triggered to allow for the remodeling, addition, and elimination of synapses (Bailey and Kandel 1985; Bailey et al. 1996; Kandel 2001; Bourne and Harris 2008, 2012). These structural components of synaptic plasticity are thought to represent a cellular change that contributes to both implicit and explicit memory consolidation (Greenough and Bailey 1988; Bailey and Kandel 1993; Bailey et al. 2005; Bourne and Harris 2008, 2012). The association between alterations in the structure and/or number of synapses and memory storage has led to numerous studies regarding the signaling pathways that might couple molecular changes to structural changes. In addition, parallel homeostatic mechanisms have been identified that can trigger synaptic scaling, which serves to stabilize the strengthened synapses while weakening or eliminating other synapses, thus providing specificity during memory consolidation (Bourne and Harris 2011; Schacher and Hu 2014).In this review, we compare and contrast structural changes at the synapse during both implicit and explicit memory consolidation, as well as the molecular signaling pathways that initiate the learning-induced structural changes versus those that serve to maintain these changes over time. Toward that end, we will focus on two experimental model systems and several prototypic forms of synaptic plasticity that we have worked on and that have been extensively studied as representative examples of memory storage: long-term habituation and sensitization of the gill-withdrawal reflex in Aplysia. These are examples of implicit memory consolidation and hippocampal-based long-term potentiation (LTP) and long-term depression (LTD), as candidate mechanisms for the synaptic plasticity underlying explicit memory storage in mammals. These will serve as useful points of comparison to consider similarities, differences, and still-existing limitations in our understanding of the functional significance of the structural synaptic plasticity recruited during the consolidation of both implicit and explicit forms of memory.     

Electrical Stimulation Accelerates and Enhances Expression of Regeneration-Associated Genes in Regenerating Rat Femoral Motoneurons

1. In this study we investigated whether electrical stimulation accelerates the upregulation of Talpha1-tubulin and GAP-43 (regeneration-associated genes; RAGs) and the downregulation of the medium-molecular-weight neurofilament (NFM), in concert with stimulation-induced acceleration of BDNF and trkB gene expression and axonal regeneration. 2. Two weeks prior to unilateral femoral nerve transection and suture, fluorogold (Fluorochrome Inc., Denver) or fluororuby (Dextran tetramethylrhodamine, Mol. Probes, D-1817, Eugene, OR) was injected into quadriceps muscles of the left and right hindlimbs to label the femoral motoneuron pools as previously described. Over a period of 7 days, fresh spinal cords were processed for semiquantitation of mRNA by using in situ hybridization. 3. There was an increase in Talpha1-tubulin and GAP-43 mRNA and a decline in the NFM mRNA at 7 days after nerve suture and sham stimulation but not in intact nerves. In contrast, 1-h stimulation of sutured but not intact nerves dramatically accelerated the changes in gene expression: mRNA levels of Talpha1-tubulin and GAP-43 were significantly elevated above control levels by 2 days while NFM mRNA was significantly reduced by 2 days in the sutured nerves. Thereby, the neurofilament/tubulin expression ratio was reduced at 2 days after suture and stimulation, possibly allowing more tubulin to be transported faster into the growing axons to accelerate the elongation rate following stimulation. Importantly, the changes in RAGs and NFM gene expression were delayed relative to the accelerated upregulation of BDNF and trkB mRNA by electrical stimulation. 4. The temporal sequence of upregulation of BDNF and trkB, altered gene expression of RAGs and NFM, and accelerated axonal outgrowth from the proximal nerve stump are consistent with a key role of BDNF and trkB in mediating the altered expression of RAGs and, in turn, the promotion of axonal outgrowth after electrical stimulation.     

Autobiographical Thinking Interferes with Episodic Memory Consolidation

New episodic memories are retained better if learning is followed by a few minutes of wakeful rest than by the encoding of novel external information. Novel encoding is said to interfere with the consolidation of recently acquired episodic memories. Here we report four experiments in which we examined whether autobiographical thinking, i.e. an ‘internal’ memory activity, also interferes with episodic memory consolidation. Participants were presented with three wordlists consisting of common nouns; one list was followed by wakeful rest, one by novel picture encoding and one by autobiographical retrieval/future imagination, cued by concrete sounds. Both novel encoding and autobiographical retrieval/future imagination lowered wordlist retention significantly. Follow-up experiments demonstrated that the interference by our cued autobiographical retrieval/future imagination delay condition could not be accounted for by the sound cues alone or by executive retrieval processes. Moreover, our results demonstrated evidence of a temporal gradient of interference across experiments. Thus, we propose that rich autobiographical retrieval/future imagination hampers the consolidation of recently acquired episodic memories and that such interference is particularly likely in the presence of external concrete cues.     

Sleep-Dependent Consolidation of Value-Based Learning

It has been suggested that sleep selectively enhances memories with future relevance. Given that sleep’s benefits can vary by item within a learning context, the present study investigated whether the amount of sleep-dependent consolidation may vary across items based on the value of the to-be-learned material. For this purpose, we used a value-based learning paradigm in which participants studied words paired with point values. There were two groups; participants either studied the words in the evening and were tested after a 12 hr interval containing a full night of sleep, or studied the words in the morning and were tested after 12 hr of continuous daytime wake. Free recall (F(1,36) = 19.35, p<.001) and recognition accuracy (F(1,36) = 7.59, p = .01) for words were better following sleep relative to wake. However there was no difference in the linear increase in the probability of delayed recall with increasing word value for sleep and wake groups (p = .74). Thus, while encoding may vary with the value of the to-be-learned item, sleep-dependent consolidation does not.     

Untreated Sleep-Disordered Breathing: Links to Aging-Related Decline in Sleep-Dependent Memory Consolidation

Background

Increasing age is associated with a decline in cognition and motor skills, while at the same time exacerbating one''s risk of developing obstructive sleep apnea (OSA). OSA-related cognitive deficits are highly prevalent and can affect various memory systems including overnight memory consolidation on a motor sequence task.Thus, the aim of our study was to examine the effect of aging on sleep-dependent motor memory consolidation in patients with and without OSA.

Methods

We studied 44 patients (19–68 years) who had been referred by a physician for a baseline polysomnography (PSG) evaluation. Based on their PSG, patients were assigned either to the OSA group (AHI>5/h), or control (Non-OSA) group (AHI<5/h).All subjects performed the Psychomotor Vigilance Task (PVT) and the Motor Sequence Learning Task (MST) in the evening and again in the morning after their PSG.

Results

Despite similar learning in the evening, OSA subjects showed significantly less overnight improvement on the MST, both for immediate (OSA −2.7%±2.8% vs. controls 12.2%±3.5%; p = 0.002) and plateau improvement (OSA 4.9%±2.3% vs. controls 21.1%±4.0%; p = 0.001). Within the OSA group, there was a significant negative correlation between overnight MST improvement and age (r² = 0.3; p = 0.01), an effect that was not observed in the Non-OSA group (r² = 0.08; p = 0.23)

Conclusions

Consistent with previous research, healthy sleepers demonstrated a higher degree of sleep-dependent overnight improvement on the MST, an effect not mitigated by increasing age. However, the presence of untreated obstructive sleep apnea is associated with an aging-related cognitive deficit, otherwise not present in individuals without OSA. As other research has linked the presence of OSA to a higher likelihood of developing dementia, future studies are necessary to examine if the inhibition of memory consolidation is tied to the onset of neurodegenerative disease.