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Thursday, August 27, 2026

Encoding (memory)

From Wikipedia, the free encyclopedia
 

Memory has the ability to encode, store and recall information. Memories give an organism the capability to learn and adapt from previous experiences as well as build relationships. Encoding allows a perceived item of use or interest to be converted into a construct that can be stored within the brain and recalled later from long-term memory. Working memory stores information for immediate use or manipulation, which is aided through hooking onto previously archived items already present in the long-term memory of an individual.

History

Hermann Ebbinghaus
Hermann Ebbinghaus (1850–1909)

Encoding is still relatively new and unexplored but the origins of encoding date back to age-old philosophers such as Aristotle and Plato. A major figure in the history of encoding is Hermann Ebbinghaus (1850–1909). Ebbinghaus was a pioneer in the field of memory research. Using himself as a subject he studied how we learn and forget information by repeating a list of nonsense syllables to the rhythm of a metronome until they were committed to his memory. These experiments led him to suggest the learning curve. He used these relatively meaningless words so that prior associations between meaningful words would not influence learning. He found that lists that allowed associations to be made and semantic meaning to be apparent were easier to recall. Ebbinghaus' results paved the way for experimental psychology in memory and other mental processes.

During the 1900s, further progress in memory research was made. Ivan Pavlov began research about classical conditioning. His research demonstrated the ability to create a semantic relationship between two unrelated items. In 1932, Frederic Bartlett proposed the idea of mental schemas. This model proposed that whether new information would be encoded was dependent on its consistency with prior knowledge (mental schemas). This model also suggested that information not present at the time of encoding would be added to memory if it was based on schematic knowledge of the world. In this way, encoding was found to be influenced by prior knowledge. With the advance of Gestalt theory came the realization that memory for encoded information was often perceived as different from the stimuli that triggered it. It was also influenced by the context in which the stimuli were embedded in.

With advances in technology, the field of neuropsychology emerged and with it a biological basis for theories of encoding. In 1949, Donald Hebb looked at the neuroscience aspect of encoding and stated that "neurons that fire together wire together," implying that encoding occurred as connections between neurons were established through repeated use. The 1950s and 60s saw a shift to the information processing approach to memory based on the invention of computers, followed by the initial suggestion that encoding was the process by which information is entered into memory. In 1956, George Armitage Miller wrote his paper on how short-term memory is limited to seven items, plus-or-minus two, called The Magical Number Seven, Plus or Minus Two. This number was appended when studies done on chunking revealed that seven, plus or minus two could also refer to seven "packets of information". In 1974, Alan Baddeley and Graham Hitch proposed their model of working memory, which consists of the central executive, visuo-spatial sketchpad, and phonological loop as a method of encoding. In 2000, Baddeley added the episodic buffer. Simultaneously Endel Tulving (1983) proposed the idea of encoding specificity whereby context was again noted as an influence on encoding.

Types

There are two main approaches to analyzing how the brain encodes information: the physiological approach, and the mental approach. The physiological approach looks at how a stimulus is represented by neurons firing in the brain, while the mental approach looks at how the stimulus is represented in the mind.

There are many types of mental encoding that are used, such as visual, elaborative, organizational, acoustic, and semantic. However, this is not an extensive list.

Visual encoding

Visual encoding is the process of converting images and visual sensory information to memory stored in the brain. This means that people can convert the new information that they stored into mental pictures (Harrison, C., Semin, A.,(2009). Psychology. New York p. 222) Visual sensory information is temporarily stored within our iconic memory and working memory before being encoded into permanent long-term storage. Baddeley's model of working memory suggests that visual information is stored in the visuo-spatial sketchpad. The visuo-spatial sketchpad is connected to the central executive, which is a key area of working memory. The amygdala is another complex structure that has an important role in visual encoding. It accepts visual input in addition to input, from other systems, and encodes the positive or negative values of conditioned stimuli.

Elaborative encoding

Elaborative encoding is the process of actively relating new information to knowledge that is already in memory. Memories are a combination of old and new information, so the nature of any particular memory depends as much on the old information already in our memories as it does on the new information coming in through our senses. In other words, how we remember something depends on how we think about it at the time. Many studies have shown that long-term retention is greatly enhanced by elaborative encoding.

Semantic encoding

Semantic encoding is the processing and encoding of sensory input that has particular meaning or can be applied to a context. Various strategies can be applied such as chunking and mnemonics to aid in encoding, and in some cases, allow deep processing, and optimizing retrieval.

Words studied in semantic or deep encoding conditions are better recalled as compared to both easy and hard groupings of nonsemantic or shallow encoding conditions with response time being the deciding variable. Brodmann's areas 45, 46, and 47 (the left inferior prefrontal cortex or LIPC) showed significantly more activation during semantic encoding conditions compared to nonsemantic encoding conditions regardless of the difficulty of the nonsemantic encoding task presented. The same area showing increased activation during initial semantic encoding will also display decreasing activation with repetitive semantic encoding of the same words. This suggests the decrease in activation with repetition is process specific occurring when words are semantically reprocessed but not when they are nonsemantically reprocessed. Lesion and neuroimaging studies suggest that the orbitofrontal cortex is responsible for initial encoding and that activity in the left lateral prefrontal cortex correlates with the semantic organization of encoded information.

Acoustic encoding

Acoustic encoding is the encoding of auditory impulses. According to Baddeley, processing of auditory information is aided by the concept of the phonological loop, which allows input within our echoic memory to be sub vocally rehearsed in order to facilitate remembering. When we hear any word, we do so by hearing individual sounds, one at a time. Hence the memory of the beginning of a new word is stored in our echoic memory until the whole sound has been perceived and recognized as a word. Studies indicate that lexical, semantic and phonological factors interact in verbal working memory. The phonological similarity effect (PSE), is modified by word concreteness. This emphasizes that verbal working memory performance cannot exclusively be attributed to phonological or acoustic representation but also includes an interaction of linguistic representation. What remains to be seen is whether linguistic representation is expressed at the time of recall or whether the representational methods used (such as recordings, videos, symbols, etc.) participate in a more fundamental role in encoding and preservation of information in memory. The brain relies primarily on acoustic (aka phonological) encoding for use in short-term storage and primarily semantic encoding for use in long-term storage.

Other senses

Tactile encoding is the processing and encoding of how something feels, normally through touch. Neurons in the primary somatosensory cortex (S1) react to vibrotactile stimuli by activating in synchronization with each series of vibrations. Odors and tastes may also lead to encode.

Organizational encoding is the course of classifying information permitting to the associations amid a sequence of terms.

Long-term potentiation

Early LPT Mechanism

Encoding is a biological event that begins with perception. All perceived and striking sensations travel to the brain's thalamus where all these sensations are combined into one single experience. The hippocampus is responsible for analyzing these inputs and ultimately deciding if they will be committed to long-term memory; these various threads of information are stored in various parts of the brain. However, the exact way in which these pieces are identified and recalled later remains unknown.

Encoding is achieved using a combination of chemicals and electricity. Neurotransmitters are released when an electrical pulse crosses the synapse which serves as a connection from nerve cells to other cells. The dendrites receive these impulses with their feathery extensions. A phenomenon called long-term potentiation allows a synapse to increase strength with increasing numbers of transmitted signals between the two neurons. For that to happen, NMDA receptor, which influences the flow of information between neurons by controlling the initiation of long-term potentiation in most hippocampal pathways, need to come to the play. For these NMDA receptors to be activated, there must be two conditions. Firstly, glutamate has to be released and bound to the NMDA receptor site on postsynaptic neurons. Secondly, excitation has to take place in postsynaptic neurons. These cells also organize themselves into groups specializing in different kinds of information processing. Thus, with new experiences the brain creates more connections and may 'rewire'. The brain organizes and reorganizes itself in response to one's experiences, creating new memories prompted by experience, education, or training. Therefore, the use of a brain reflects how it is organised. This ability to re-organize is especially important if ever a part of the brain becomes damaged. Scientists are unsure of whether the stimuli of what we do not recall are filtered out at the sensory phase or if they are filtered out after the brain examines their significance.

Mapping activity

Positron emission tomography (PET) demonstrates a consistent functional anatomical blueprint of hippocampal activation during episodic encoding and retrieval. Activation in the hippocampal region associated with episodic memory encoding has been shown to occur in the rostral portion of the region whereas activation associated with episodic memory retrieval occurs in the caudal portions. This is referred to as the Hippocampal memory encoding and retrieval model or HIPER model.

One study used PET to measure cerebral blood flow during encoding and recognition of faces in both young and older participants. Young people displayed increased cerebral blood flow in the right hippocampus and the left prefrontal and temporal cortices during encoding and in the right prefrontal and parietal cortex during recognition. Elderly people showed no significant activation in areas activated in young people during encoding, however they did show right prefrontal activation during recognition. Thus it may be concluded that as we grow old, failing memories may be the consequence of a failure to adequately encode stimuli as demonstrated in the lack of cortical and hippocampal activation during the encoding process.

Recent findings in studies focusing on patients with post traumatic stress disorder demonstrate that amino acid transmitters, glutamate and GABA, are intimately implicated in the process of factual memory registration, and suggest that amine neurotransmitters, norepinephrine-epinephrine and serotonin, are involved in encoding emotional memory.

Molecular perspective

The process of encoding is not yet well understood, however key advances have shed light on the nature of these mechanisms. Encoding begins with any novel situation, as the brain will interact and draw conclusions from the results of this interaction. These learning experiences have been known to trigger a cascade of molecular events leading to the formation of memories. These changes include the modification of neural synapses, modification of proteins, creation of new synapses, activation of gene expression and new protein synthesis. One study found that high central nervous system levels of acetylcholine during wakefulness aided in new memory encoding, while low levels of acetylcholine during slow-wave sleep aided in consolidation of memories. However, encoding can occur on different levels. The first step is short-term memory formation, followed by the conversion to a long-term memory, and then a long-term memory consolidation process.

Synaptic plasticity

Synaptic plasticity is the ability of the brain to strengthen, weaken, destroy and create neural synapses and is the basis for learning. These molecular distinctions will identify and indicate the strength of each neural connection. The effect of a learning experience depends on the content of such an experience. Reactions that are favored will be reinforced and those that are deemed unfavorable will be weakened. This shows that the synaptic modifications that occur can operate either way, in order to be able to make changes over time depending on the current situation of the organism. In the short term, synaptic changes may include the strengthening or weakening of a connection by modifying the preexisting proteins leading to a modification in synapse connection strength. In the long term, entirely new connections may form or the number of synapses at a connection may be increased, or reduced.

Encoding process

A significant short-term biochemical change is the covalent modification of pre-existing proteins in order to modify synaptic connections that are already active. This allows data to be conveyed in the short term, without consolidating anything for permanent storage. From here a memory or an association may be chosen to become a long-term memory, or forgotten as the synaptic connections eventually weaken. The switch from short to long-term is the same concerning both implicit memory and explicit memory. This process is regulated by a number of inhibitory constraints, primarily the balance between protein phosphorylation and dephosphorylation. Finally, long term changes occur that allow consolidation of the target memory. These changes include new protein synthesis, the formation of new synaptic connections, and finally the activation of gene expression in accordance with the new neural configuration. The encoding process has been found to be partially mediated by serotonergic interneurons, specifically in regard to sensitization as blocking these interneurons prevented sensitization entirely. However, the ultimate consequences of these discoveries have yet to be identified. Furthermore, the learning process has been known to recruit a variety of modulatory transmitters in order to create and consolidate memories. These transmitters cause the nucleus to initiate processes required for neuronal growth and long-term memory, mark specific synapses for the capture of long-term processes, regulate local protein synthesis, and even appear to mediate attentional processes required for the formation and recall of memories.

Encoding and genetics

Human memory, including the process of encoding, is known to be a heritable trait that is controlled by more than one gene. In fact, twin studies suggest that genetic differences are responsible for as much as 50% of the variance seen in memory tasks. Proteins identified in animal studies have been linked directly to a molecular cascade of reactions leading to memory formation, and a sizable number of these proteins are encoded by genes that are expressed in humans as well. In fact, variations within these genes appear to be associated with memory capacity and have been identified in recent human genetic studies.

Complementary processes

The idea that the brain is separated into two complementary processing networks (task positive and task negative) has recently become an area of increasing interest. The task positive network deals with externally oriented processing whereas the task negative network deals with internally oriented processing. Research indicates that these networks are not exclusive and some tasks overlap in their activation. A study done in 2009 shows encoding success and novelty detection activity within the task-positive network have significant overlap and have thus been concluded to reflect common association of externally oriented processing. It also demonstrates how encoding failure and retrieval success share significant overlap within the task negative network indicating common association of internally oriented processing. Finally, a low level of overlap between encoding success and retrieval success activity and between encoding failure and novelty detection activity respectively indicate opposing modes or processing. In sum task positive and task negative networks can have common associations during the performance of different tasks.

Depth of processing

Different levels of processing influence how well information is remembered. This idea was first introduced by Craik and Lockhart (1972). They claimed that the level of processing information was dependent upon the depth at which the information was being processed; mainly, shallow processing and deep processing. According to Craik and Lockhart, the encoding of sensory information would be considered shallow processing, as it is highly automatic and requires very little focus. Deeper level processing requires more attention being given to the stimulus and engages more cognitive systems to encode the information. An exception to deep processing is if the individual has been exposed to the stimulus frequently and it has become common in the individual’s life, such as the person’s name. These levels of processing can be illustrated by maintenance and elaborate rehearsal.

Maintenance and elaborative rehearsal

Maintenance rehearsal is a shallow form of processing information which involves focusing on an object without thought to its meaning or its association with other objects. For example, the repetition of a series of numbers is a form of maintenance rehearsal. In contrast, elaborative or relational rehearsal is a process in which you relate new material to information already stored in Long-term memory. It's a deep form of processing information and involves thought of the object's meaning as well as making connections between the object, past experiences and the other objects of focus. Using the example of numbers, one might associate them with dates that are personally significant such as your parents' birthdays (past experiences) or perhaps you might see a pattern in the numbers that helps you to remember them.

American Penny

Due to the deeper level of processing that occurs with elaborative rehearsal it is more effective than maintenance rehearsal in creating new memories. This has been demonstrated in people's lack of knowledge of the details in everyday objects. For example, in one study where Americans were asked about the orientation of the face on their country's penny few recalled this with any degree of certainty. Despite the fact that it is a detail that is often seen, it is not remembered as there is no need to because the color discriminates the penny from other coins. The ineffectiveness of maintenance rehearsal, simply being repeatedly exposed to an item, in creating memories has also been found in people's lack of memory for the layout of the digits 0-9 on calculators and telephones.

Maintenance rehearsal has been demonstrated to be important in learning but its effects can only be demonstrated using indirect methods such as lexical decision tasks, and word stem completion which are used to assess implicit learning. In general, however previous learning by maintenance rehearsal is not apparent when memory is being tested directly or explicitly with questions like " Is this the word you were shown earlier?"

Intention to learn

Studies have shown that the intention to learn has no direct effect on memory encoding. Instead, memory encoding is dependent on how deeply each item is encoded, which could be affected by intention to learn, but not exclusively. That is, intention to learn can lead to more effective learning strategies, and consequently, better memory encoding, but if one learns something incidentally (i.e. without intention to learn), but still processes and learns the information effectively, it will get encoded just as well as something learned with intention.

The effects of elaborative rehearsal or deep processing can be attributed to the number of connections made while encoding that increase the number of pathways available for retrieval.

Optimal encoding

Organization

Organization is key to memory encoding. Researchers have discovered that our minds naturally organize information if the information received is not organized. One natural way information can be organized is through hierarchies. For example, the grouping mammals, reptiles, and amphibians is a hierarchy of the animal kingdom.

Depth of processing is also related to the organization of information. For example, the connections that are made between the to-be-remembered item, other to-be-remembered items, previous experiences, and context generate retrieval paths for the to-be-remembered item and can act as retrieval cues. These connections create organization on the to-be-remembered item, making it more memorable.

Visual images

Another method used to enhance encoding is to associate images with words. Gordon Bower and David Winzenz (1970) demonstrated the use of imagery and encoding in their research while using paired-associate learning. Researchers gave participants a list of 15-word-pairs, showing each participant the word pair for 5 seconds for each pair. One group was told to create a mental image of the two words in each pair in which the two items were interacting. The other group was told to use maintenance rehearsal to remember the information. When participants were later tested and asked to recall the second word in each word pairing, researchers found that those who had created visual images of the items interacting remembered over twice as many of the word pairings than those who used maintenance rehearsal.  

Mnemonics

 Red Orange Yellow Green Blue Indigo Violet
The mnemonic "Roy G. Biv" can be used to remember the colors of the rainbow.

When memorizing simple material such as lists of words, mnemonics may be the best strategy, while "material already in long-term store [will be] unaffected". Mnemonic Strategies are an example of how finding organization within a set of items helps these items to be remembered. In the absence of any apparent organization within a group, organization can be imposed with the same memory enhancing results. An example of a mnemonic strategy that imposes organization is the peg-word system which associates the to-be-remembered items with a list of easily remembered items. Another example of a mnemonic device commonly used is the first letter of every word system or acronyms. When learning the colours in a rainbow most students learn the first letter of every color and impose their own meaning by associating it with a name such as Roy. G. Biv which stands for red, orange, yellow, green, blue, indigo, violet. In this way mnemonic devices not only help the encoding of specific items but also their sequence. For more complex concepts, understanding is the key to remembering. In a study done by Wiseman and Neisser in 1974 they presented participants with a picture (the picture was of a Dalmatian in the style of pointillism making it difficult to see the image). They found that memory for the picture was better if the participants understood what was depicted.

Chunking

Chunking is a memory strategy used to maximize the amount of information stored in short term memory in order to combine it into small, meaningful sections.  By organizing objects into meaningful sections, these sections are then remembered as a unit rather than separate objects. As larger sections are analyzed and connections are made, information is weaved into meaningful associations and combined into fewer, but larger and more significant pieces of information. By doing so, the ability to hold more information in short-term memory increases. To be more specific, the use of chunking would increase recall from 5 to 8 items to 20 items or more as associations are made between these items.

Words are an example of chunking, where instead of simply perceiving letters we perceive and remember their meaningful wholes: words. The use of chunking increases the number of items we are able to remember by creating meaningful "packets" in which many related items are stored as one. The use of chunking is also seen in numbers. One of the most common forms of chunking seen on a daily basis is that of phone numbers. Generally speaking, phone numbers are separated into sections. An example of this would be 909 200 5890, in which numbers are grouped together to make up one whole. Grouping numbers in this manner, allows them to be recalled with more facility because of their comprehensible acquaintanceship.

State-dependent learning

For optimal encoding, connections are not only formed between the items themselves and past experiences, but also between the internal state or mood of the encoder and the situation they are in. The connections that are formed between the encoders internal state or the situation and the items to be remembered are State-dependent. In a 1975 study by Godden and Baddeley the effects of State-dependent learning were shown. They asked deep sea divers to learn various materials while either under water or on the side of the pool. They found that those who were tested in the same condition that they had learned the information in were better able to recall that information, i.e. those who learned the material under water did better when tested on that material under water than when tested on land. Context had become associated with the material they were trying to recall and therefore was serving as a retrieval cue. Results similar to these have also been found when certain smells are present at encoding.

However, although the external environment is important at the time of encoding in creating multiple pathways for retrieval, other studies have shown that simply creating the same internal state that was present at the time of encoding is sufficient to serve as a retrieval cue. Therefore, being in the same mindset as in at the time of encoding will help with recalling in the same way that being in the same situation helps recall. This effect called context reinstatement was demonstrated by Fisher and Craik 1977 when they matched retrieval cues with the way information was memorized.

Transfer-appropriate processing

Transfer-appropriate processing is a strategy for encoding that leads to successful retrieval. An experiment conducted by Morris and coworkers in 1977 proved that successful retrieval was a result of matching the type of processing used during encoding. During their experiment, their main findings were that an individual's ability to retrieve information was heavily influenced on whether the task at encoding matched the task during retrieval. In the first task, which consisted of the rhyming group, subjects were given a target word and then asked to review a different set of words. During this process, they were asked whether the new words rhymed with the target word. They were solely focusing on the rhyming rather than the actual meaning of the words. In the second task, individuals were also given a target word, followed by a series of new words. Rather than identify the ones that rhymed, the individual was to focus more on the meaning. As it turns out, the rhyming group, who identified the words that rhymed, was able to recall more words than those in the meaning group, who focused solely on their meaning. This study suggests that those who were focusing on rhyming in the first part of the task and on the second, were able to encode more efficiently. In transfer-appropriate processing, encoding occurs in two different stages. This helps demonstrate how stimuli were processed. In the first phase, the exposure to stimuli is manipulated in a way that matches the stimuli. The second phase then pulls heavily from what occurred in the first phase and how the stimuli was presented; it will match the task during encoding.

Encoding specificity

An ambiguous figure which can be perceived as either a vase or a pair of faces.
Vase or faces?

The context of learning shapes how information is encoded. For instance, Kanizsa in 1979 showed a picture that could be interpreted as either a white vase on a black background or 2 faces facing each other on a white background. The participants were primed to see the vase. Later they were shown the picture again but this time they were primed to see the black faces on the white background. Although this was the same picture as they had seen before, when asked if they had seen this picture before, they said no. The reason for this was that they had been primed to see the vase the first time the picture was presented, and it was therefore unrecognizable the second time as two faces. This demonstrates that the stimulus is understood within the context it is learned in as well the general rule that what really constitutes good learning are tests that test what has been learned in the same way that it was learned. Therefore, to truly be efficient at remembering information, one must consider the demands that future recall will place on this information and study in a way that will match those demands.

Generation effect

Another principle that may have the potential to aid encoding is the generation effect. The generation effect implies that learning is enhanced when individuals generate information or items themselves rather than reading the content. The key to properly apply the generation effect is to generate information, rather than passively selecting from information already available like in selecting an answer from a multiple-choice question In 1978, researchers Slameka and Graf conducted an experiment to better understand this effect. In this experiment, the participants were assigned to one of two groups, the read group or the generate group. The participants assigned to the read group were asked to simply read a list of paired words that were related, for example, horse-saddle. The participants assigned to the generate group were asked to fill in the blank letters of one of the related words in the pair. In other words, if the participant was given the word horse, they would need to fill in the last four letters of the word saddle.The researchers discovered that the group that was asked to fill in the blanks had better recall for these word pairs than the group that was asked to simply remember the word pairs.

Self-reference effect

Research illustrates that the self-reference effect aids encoding. The self-reference effect is the idea that individuals will encode information more effectively if they can personally relate to the information. For example, some people may claim that some birth dates of family members and friends are easier to remember than others. Some researchers claim this may be due to the self-reference effect. For example, some birth dates are easier for individuals to recall if the date is close to their own birth date or any other dates they deem important, such as anniversary dates.

Research has shown that after being encoded, self-reference effect is more effective when it comes to recalling memory than semantic encoding. Researchers have found that the self-reference effect goes more hand and hand with elaborative rehearsal. Elaborative rehearsal is more often than not, found to have a positive correlation with the improvement of retrieving information from memories. Self-reference effect has shown to be more effective when retrieving information after it has been encoded when being compared to other methods such as semantic encoding. Also, it is important to know that studies have concluded that self-reference effect can be used to encode information among all ages. However, they have determined that older adults are more limited in their use of the self-reference effect when being tested with younger adults.

Salience

When an item or idea is considered "salient", it means the item or idea appears to noticeably stand out. When information is salient, it may be encoded in memory more efficiently than if the information did not stand out to the learner. In reference to encoding, any event involving survival may be considered salient. Research has shown that survival may be related to the self-reference effect due to evolutionary mechanisms. Researchers have discovered that even words that are high in survival value are encoded better than words that are ranked lower in survival value. Some research supports evolution, claiming that the human species remembers content associated with survival. Some researchers wanted to see for themselves whether or not the findings of other research was accurate. The researchers decided to replicate an experiment with results that supported the idea that survival content is encoded better than other content. The findings of the experiment further suggested that survival content has a higher advantage of being encoded than other content.

Retrieval practice

Studies have shown that an effective tool to increase encoding during the process of learning is to create and take practice tests. Using retrieval in order to enhance performance is called the testing effect, as it actively involves creating and recreating the material that one is intending to learn and increases one’s exposure to it. It is also a useful tool in connecting new information to information already stored in memory, as there is a close association between encoding and retrieval. Thus, creating practice tests allows the individual to process the information at a deeper level than simply reading over the material again or using a pre-made test. The benefits of using retrieval practice have been demonstrated in a study done where college students were asked to read a passage for seven minutes and were then given a two-minute break, during which they completed math problems. One group of participants was given seven minutes to write down as much of the passage as they could remember while the other group was given another seven minutes to reread the material. Later all participants were given a recall test at various increments (five minutes, 2 days, and one week) after the initial learning had taken place. The results of these tests showed that those who had been assigned to the group that had been given a recall test during their first day of the experiment were more likely to retain more information than those that had simply reread the text. This demonstrates that retrieval practice is a useful tool in encoding information into long term memory.

Computational models of memory encoding

Computational models of memory encoding have been developed in order to better understand and simulate the mostly expected, yet sometimes wildly unpredictable, behaviors of human memory. Different models have been developed for different memory tasks, which include item recognition, cued recall, free recall, and sequence memory, in an attempt to accurately explain experimentally observed behaviors.

Item recognition

In item recognition, one is asked whether or not a given probe item has been seen before. The recognition of an item can include context. That is, one can be asked whether an item has been seen in a study list. So even though one may have seen the word "apple" sometime during their life, if it was not on the study list, it should not be recalled.

Item recognition can be modeled using Multiple trace theory and the attribute-similarity model. In brief, every item that one sees can be represented as a vector of the item's attributes, which is extended by a vector representing the context at the time of encoding, and is stored in a memory matrix of all items ever seen. When a probe item is presented, the sum of the similarities to each item in the matrix (which is inversely proportional to the sum of the distances between the probe vector and each item in the memory matrix) is computed. If the similarity is above a threshold value, one would respond, "Yes, I recognize that item." Given that context continually drifts by nature of a random walk, more recently seen items, which each share a similar context vector to the context vector at the time of the recognition task, are more likely to be recognized than items seen longer ago.

Cued recall

In cued recall, an individual is presented with a stimulus, such as a list of words and then asked to remember as many of those words as possible. They are then given cues, such as categories, to help them remember what the stimuli were. An example of this would be to give a subject words such as meteor, star, space ship, and alien to memorize. Then providing them with the cue of "outer space" to remind them of the list of words given. Giving the subject cues, even when never originally mentioned, helped them recall the stimulus much better. These cues help guide the subjects to recall the stimuli they could not remember for themselves prior to being given a cue. Cues can essentially be anything that will help a memory that is deemed forgotten to resurface. An experiment conducted by Tulvig suggests that when subjects were given cues, they were able to recall the previously presented stimuli.

Cued recall can be explained by extending the attribute-similarity model used for item recognition. Because in cued recall, a wrong response can be given for a probe item, the model has to be extended accordingly to account for that. This can be achieved by adding noise to the item vectors when they are stored in the memory matrix. Furthermore, cued recall can be modeled in a probabilistic manner such that for every item stored in the memory matrix, the more similar it is to the probe item, the more likely it is to be recalled. Because the items in the memory matrix contain noise in their values, this model can account for incorrect recalls, such as mistakenly calling a person by the wrong name.

Free recall

In free recall, one is allowed to recall items that were learned in any order. For example, you could be asked to name as many countries in Europe as you can. Free recall can be modeled using SAM (Search of Associative Memory) which is based on the dual-store model, first proposed by Atkinson and Shiffrin in 1968. SAM consists of two main components: short-term store (STS) and long-term store (LTS). In brief, when an item is seen, it is pushed into STS where it resides with other items also in STS, until it displaced and put into LTS. The longer the item has been in STS, the more likely it is to be displaced by a new item. When items co-reside in STS, the links between those items are strengthened. Furthermore, SAM assumes that items in STS are always available for immediate recall.

SAM explains both primacy and recency effects. Probabilistically, items at the beginning of the list are more likely to remain in STS, and thus have more opportunities to strengthen their links to other items. As a result, items at the beginning of the list are made more likely to be recalled in a free-recall task (primacy effect). Because of the assumption that items in STS are always available for immediate recall, given that there were no significant distractors between learning and recall, items at the end of the list can be recalled excellently (recency effect).

Studies have shown that free recall is one of the most effective methods of studying and transferring information from short term memory to long term memory compared to item recognition and cued recall as greater relational processing is involved.

Incidentally, the idea of STS and LTS was motivated by the architecture of computers, which contain short-term and long-term storage.

Sequence memory

Sequence memory is responsible for how we remember lists of things, in which ordering matters. For example, telephone numbers are an ordered list of one digit numbers. There are currently two main computational memory models that can be applied to sequence encoding: associative chaining and positional coding.

Associative chaining theory states that every item in a list is linked to its forward and backward neighbors, with forward links being stronger than backward links, and links to closer neighbors being stronger than links to farther neighbors. For example, associative chaining predicts the tendencies of transposition errors, which occur most often with items in nearby positions. An example of a transposition error would be recalling the sequence "apple, orange, banana" instead of "apple, banana, orange."

Positional coding theory suggests that every item in a list is associated to its position in the list. For example, if the list is "apple, banana, orange, mango" apple will be associated to list position 1, banana to 2, orange to 3, and mango to 4. Furthermore, each item is also, albeit more weakly, associated to its index ± 1, even more weakly to ± 2, and so forth. So banana is associated not only to its actual index 2, but also to 1, 3, and 4, with varying degrees of strength. For example, positional coding can be used to explain the effects of recency and primacy. Because items at the beginning and end of a list have fewer close neighbors compared to items in the middle of the list, they have less competition for correct recall.

Although the models of associative chaining and positional coding are able to explain a great amount of behavior seen for sequence memory, they are far from perfect. For example, neither chaining nor positional coding is able to properly illustrate the details of the Ranschburg effect, which reports that sequences of items that contain repeated items are harder to reproduce than sequences of unrepeated items. Associative chaining predicts that recall of lists containing repeated items is impaired because recall of any repeated item would cue not only its true successor but also the successors of all other instances of the item. However, experimental data have shown that spaced repetition of items resulted in impaired recall of the second occurrence of the repeated item. Furthermore, it had no measurable effect on the recall of the items that followed the repeated items, contradicting the prediction of associative chaining. Positional coding predicts that repeated items will have no effect on recall, since the positions for each item in the list act as independent cues for the items, including the repeated items. That is, there is no difference between the similarity between any two items and repeated items. This, again, is not consistent with the data.

Because no comprehensive model has been defined for sequence memory to this day, it makes for an interesting area of research.

Wednesday, August 26, 2026

Epigenetics in learning and memory

While the cellular and molecular mechanisms of learning and memory have long been a central focus of neuroscience, it is only in recent years that attention has turned to the epigenetic mechanisms behind the dynamic changes in gene transcription responsible for memory formation and maintenance. Epigenetic gene regulation often involves the physical marking (chemical modification) of DNA or associated proteins to cause or allow long-lasting changes in gene activity. Epigenetic mechanisms such as DNA methylation and histone modifications (methylation, acetylation, and deacetylation) have been shown to play an important role in learning and memory.

DNA methylation

DNA methylation involves the addition of a methyl group to a 5' cytosine residue. This usually occurs at cytosines that form part of a cytosine-guanine dinucleotide (CpG sites). Methylation can lead to activation or repression of gene transcription and is mediated through the activity of DNA methyltransferases (DNMTs). DNMT3A and DNMT3B regulate de novo methylation of CpG sites, while DNMT1 maintains established methylation patterns. S-adenosyl methionine acts as the methyl donor.

One current hypothesis for how DNA methylation contributes to the storage of memories is that dynamic DNA methylation changes occur temporally to activate transcription of genes that encode for proteins whose role is to stabilize memory. Another hypothesis is that changes in DNA methylation that occur even early in life can persist through adulthood, affecting how genes are able to be activated in response to different environmental cues.

The first demonstration about the role of epigenetics in learning in memory was the landmark work of Szyf and Meaney (PMID 15220929) where they showed that licking and grooming by mother rats (maternal care) prevented methylation of the glucocorticoid receptor gene. When these pups become adults, they respond better to stressors than rats who, as pups, were not licked and groomed by their mothers and instead had a buildup of methylation in the glucocorticoid receptor gene.

DNMTs and memory

Miller and Sweatt demonstrated that rats trained in a contextual fear conditioning paradigm had elevated levels of mRNA for DNMT3a and DNMT3b in the hippocampus. Fear conditioning is an associative memory task where a context, like a room, is paired with an aversive stimulus, like a foot shock; animals who have learned the association show higher levels of freezing behavior when exposed to the context even in the absence of the aversive stimulation. However, when rats were treated with the DNMT inhibitors zebularine or 5-aza-2′-deoxycytidine immediately after fear-conditioning, they demonstrated reduced learning (freezing behavior). When treated rats were re-trained 24 hours later, they performed as well as non-treated rats. Furthermore, it was shown that when these DNMT inhibitors were given 6 hours after training, and the rats were tested 24 hours later, the rats displayed normal fear memory, indicating that DNMTs are involved specifically in memory consolidation. These findings reveal the importance of dynamic changes in methylation status in memory formation.

Feng et al. created double conditional knock out (DKO) mice for the genes DNMT3a and DNMT1. These mice were shown to have significantly weakened long-term potentiation (LTP) and much more easily stimulated long-term depression (LTD) in the hippocampus. When tested in the Morris water navigation task, which is used to study hippocampus-dependent spatial memory, the DNMT3a/DNMT1 DKO mice took longer to find the platform than control mice. Single knock-out mice (SKO) for either DNMT3a or DNMT1 performed normally. DKO mice were also unable to consolidate memory after fear-conditioning. Since SKO mice did not exhibit the same learning and memory defects as the DKO mice, it was concluded that DNMT3a and DNMT1 play redundant roles in regulating learning and memory.

When DNMTs are inhibited in the prefrontal cortex, recall of existing memories is impaired, but not the formation of new ones. This indicates that DNA methylation may be circuit-specific when it comes to regulating the formation and maintenance of memories.

DNA methylation targets

The memory suppressor gene, protein phosphatase 1 (PP1), was shown to have increased CpG island methylation after contextual-fear conditioning. This corresponded to decreased levels of PP1 mRNA in the hippocampus of the trained rats. When DNMTs were inhibited, increased methylation at the PP1 gene was no longer observed. These data suggest that during memory consolidation in associative learning tasks, CpG methylation is used to inhibit the expression of PP1, a gene that negatively inhibits memory formation.

Demethylation and memory

While DNA methylation is necessary to inhibit genes involved in memory suppression, DNA demethylation is important in activating genes whose expression is positively correlated with memory formation. Sweatt and Miller also showed that the gene reelin, which is involved in long term potentiation induction, had a reduced methylation profile and increased reelin mRNA in fear-conditioned versus control rats. Brain-derived neurotrophic factor (BDNF), another important gene in neural plasticity, has also been shown to have reduced methylation and increased transcription in animals that have undergone learning. While these studies have been linked to the hippocampus, recent evidence has also shown increased demethylation of reelin and BDNF in the medial prefrontal cortex (mPFC), an area involved in cognition and emotion.

The mechanism behind this experience-dependent demethylation response was previously not fully understood, with some evidence showing that DNMTs may be involved in demethylation. It was also suggested that members of the DNA damage repair GADD45 family may contribute to this demethylation process. However, more recently, the pathways illustrated in the Figure below, titled "Demethylation of 5-Methylcytosine (5mC) in neuron DNA," especially the TET dependent pathway, have been confirmed as pathways of DNA demethylation. A role for GADD45 has also recently been indicated, since GADD45 physically interacts with thymine-DNA glycosylase (TDG) and GADD45 may promote the activity of TDG in its role(s) during conversion of 5mC to cytosine.

Methyl-binding domain proteins (MBDs)

Mice that have genetic disruptions for CpG binding protein 2 (MeCP2) have been shown to have significant problems in hippocampus#Role in memory-dependent memory and have impaired hippocampal LTP.

Methylation and learning and memory disorders

Changes in expression of genes associated with post-traumatic stress disorder (PTSD), which is characterized by an impaired extinction of traumatic memory, may be mediated by DNA methylation. In people with schizophrenia, it has been shown that reelin is down-regulated through increased DNA methylation at promoter regions in GABAergic interneurons. DNMT1 has also been shown to be upregulated in these cells.

Histone methylation

Methylation of histones may either increase or decrease gene transcription depending on which histone is modified, the amino acid that is modified, and the number of methyl groups added. In the case of lysine methylation, three types of modifications exist: monomethylated, dimethylated, or trimethylated lysines. The di- or trimethylation of histone H3 at lysine 9 (H3K9) has been associated with transcriptionally silent regions, while the di- or trimethylation of histone H3 at lysine 4 (H3K4) is associated with transcriptionally active genes.

Histone 3 lysine 4 trimethylation and memory formation

The hippocampus is an important brain region in memory formation. H3K4 trimethylation is associated with active transcription. In contextual fear conditioning experiments in rats, it was found that levels of H3K4 trimethylation increases in the hippocampus after fear conditioning. In these experiments by Gupta et al., a connection was made between changes in histone methylation and active gene expression during the consolidation of associative memories. In this same study, it was also found that these histone methylations were reversible, as the levels of trimethylation of H3K4 returned to basal levels after a period of 24 hours. This indicated that active demethylation was occurring following memory consolidation. To further explore the role of methyltransferases in long-term memory formation, this study applied the same fear conditioning tests on rats deficient in Mll, a H3K4-specific methyltransferase. The rats with a heterozygous mutant Mll+/− gene showed a significant reduction in their ability to form long-term memories compared to normal rats with an intact Mll gene. Therefore, H3K4 methyltransferases, such as Mll, must have an essential role in long-term memory formation in the hippocampus.

The change in methylation state of histones at the location of specific gene promoters, as opposed to just genome-wide, is also involved in memory formation. Zif268 and BDNF genes are critical for memory consolidation. H3K4 trimethylation increases around both of the Zif268 and BDNF promoters following contextual fear conditioning, when these genes are transcriptionally active. This demonstrates that at the time of memory consolidation, the transcription of memory formation genes such as Zif268 and bdnf is regulated by histone methylation.

Histone 3 lysine 9 dimethylation and memory formation

Histone H3 lysine 9 dimethylation is associated with transcriptional silencing. The G9a/G9a-like protein (GLP) complex is a methyltransferase specific for producing this modification. One study examined the role of G9a/GLP-mediated transcriptional silencing in the hippocampus and entorhinal cortex (EC) during memory consolidation. It was found that the inhibition of G9a/GLP in the EC, but not in the hippocampus, results in the enhancement of long-term memory formation. In addition, G9a/GLP inhibition in the entorhinal cortex altered histone H3 lysine 9 dimethylation in the Cornu Ammonis area 1 of the hippocampus, suggesting the importance of this complex in mediating connectivity between these two brain regions. Therefore, the G9a/GLP complex plays an important role in histone methylation and long-term memory formation in the hippocampus and the EC.

Histone methylation and other epigenetic modifications

Histone methylation marks are also correlated with other epigenetic modifications, such as histone deacetylation and DNA methylation, in the context of learning and memory. Reduced histone deacetylation is correlated with an increase in H3K9 dimethylation, a modification associated with transcriptional silencing. Therefore, histone deacetylase inhibitors may be applied to increase histone acetylation and suppress H3K9 dimethylation, thereby increasing gene transcription. In the case of DNA methylation, it was found that increases in H3K4 trimethylation correlate with altered DNA methylation of CpG sites at the promoter of Zif268, a gene involved in memory formation, after fear conditioning. Gupta et al. showed that DNA methylation at the Zif268 promoter increased after fear conditioning, correlating with an increase in Zif268 gene expression. This finding was surprising, since it was previously thought that DNA methylation resulted in transcriptional silencing.

Histone acetylation

Acetylation involves the replacement of a hydrogen with an acetyl group. In a biological context, acetylation is most often associated with the modification of proteins, specifically histones. The acetylation reaction is most often catalyzed by enzymes that contain histone acetyltransferase (HAT) activity.

Histone acetyltransferases (HATs)

HATs are enzymes responsible for the acetylation of amino acids. HATs acetylate by converting the lysine side group of amino acids with the addition of an acetyl group from an acetyl CoA molecule, creating acetyl lysine. HAT enzymes are most often associated with histone proteins and work to regulate the interaction between histones and the DNA that is wrapped around them. HATs are not only restricted to the acetylation of histone but can also acetylate many other proteins implicated in the manipulation of gene expression like that of transcription factors and receptor proteins.

Chromatin remodeling

Acetylation is one of the main mechanisms implicated in the process of chromatin remodeling. Chromatin remodeling affects the regulation of gene expression by altering the relationship between nucleosomes and DNA. Acetylation of histones removes positive charge, which reduces the level of interaction between the formerly positively charged histone and the negatively charged phosphate groups of the DNA wrapped around the nucleosome complex. This alteration in charges causes a relaxation of DNA from the nucleosome, this relaxed section is seen to have higher levels of gene expression than non acetylated regions.

Acetylation as an epigenetic marker

Patterns of histone acetylation have been useful as a source of epigenetic information due to their ability to reflect changes in transcription rates and the maintenance of gene expression patterns. This acetylation code can then be read and provide generous information for the study of inheritance patterns of epigenetic changes like that of learning, memory and disease states.

Acetlylation as a mechanism for learning and memory

The role of epigenetic mechanisms and chromatin remodeling has been implicated in both synaptic plasticity and neuronal gene expression. Studies with histone deactylase complex inhibitors like SAHA, toluene, garcinol, trichostatin A and sodium butyrate have shown that acetylation is important for the synaptic plasticity of the brain; by inhibiting deactylase complexes total acetylation rates in the brain increased leading to increased rates of transcription and enhanced memory consolidation. By using various learning assays like the Morris water maze test and fear conditioning assays in conjunction with acetylation influencing drugs it was shown that acetylation patterns in the hippocampus are integral to memory association and learning behavior. Studies with various HDAC inhibitors and neural development have shown increased learning and memory, as a result of an increased acetylation state. Conversely studies conducted with HAT inhibitors yielded impairment of memory consolidation and an overall decrease in learning.

ERK/MAPK cascade

Studies have shown that the ERK/MAPK cascade is important for the regulation of lysine acetylation in the insular cortex of the brain (A part of the brain implicated in the formation of taste memories). The activation of the ERK/MAPK cascade was seen in mice after the introduction of a new taste, the cascade was shown to be necessary for the memory of the taste to be formed. The proposed mechanism for how this cascade works is that MAPK regulates histone acetylation and subsequent chromatin remodeling by means of downstream effectors, such as the CREB binding protein (which has HAT activity). By observing the rates of acetylation in the insular cortex researchers were able to determine which patterns of acetylation were due to deacetylase or acetylase activity and which were a result of lysine acetyltransferase activity.

Long term potentiation

Long term potentiation (LTP) is the enhancement of signal strength between neurons. LTP is the basis of synaptic plasticity and plays a pivotal role in memory formation. LTP is dependent on the activity of NMDA receptors in the brain and it has been shown that NMDA activity influences acetylation. When NMDA receptors are activated they cause an influx of calcium into the cell which in turn activates various signal pathways that ultimately activate the ERK pathway which then modulates transcription factors like CREB. CREB then recruits a HAT to help create and stabilize the long term formation of memory, often through the self-perpetuation of acetylated histones. Studies done on Acetylation of histone H3 in the CA1 region of the hippocampus show that the activation of NMDA receptors increased the acetylation of H3 and conversely inhibition of the ERK pathway in the CA1 region resulted in a decrease in acetylation of H3. In summary:

  • NMDA-R activation increases phosphorylation of ERK and Acetylation of Histone H3
  • Memory requires proper NMDA-R function
  • Memory conditioning increases phosphorylation of ERK and acetylation of Histone H3
  • ERK is regulated by phosphorylation
  • Histone H3 acetylation is regulated by ERK
  • Histone H4 is not regulated by ERK
  • HDAC inhibitors enhance LTP, this is dependent on rate of transcription
  • HDAC inhibitors do not affect NMDA-R

Histone deacetylation

HDACs' role in CREBP-dependent transcriptional activation

Figure 1 HDAC inhibition enhances memory and synaptic plasticity through CREB:CBP. Figure adapted from Vecsey et al. (2007)

Histone deacetylases (HDAC) remove acetyl groups (-COCH3) from histones altering chromatin structures and decreasing accessibility of transcriptional factors to DNA, thereby reducing transcription of genes. HDACs have shown to play a role in learning and memory through their regulation in the CREB-CBP pathway.

Studies conclude that HDAC inhibitors such as trichostatin A (TSA) increase histone acetylation and improve synaptic plasticity and long-term memory (Fig 1A). CREB, a cAMP response element-binding protein and transcriptional activator, binds CBP forming the CREBP complex. This complex activates genes involved in synaptic formation and long-term memory.(Fig 1B) TSA treatments in the hippocampal CA1 region of mice increased acetylation levels and enhanced long-term potentiation (LTP), a mechanism involved in learning and memory (Fig 1B). However, TSA treatments in CBP mutants lacking KIX domains did not effect LTP in mice (Fig 1D). The KIX domain allows for interaction between CREB and CBP, so knocking out this region disrupts formation of the CREBP complex. Knock outs of CREB produced similar results to those of mutant CBP mice (Fig 1C). Therefore, HDAC inhibition and CREBP association are both necessary for memory development. TSA treatments showed increased expression levels of Nr4a1 and Nra2 genes while other CREB regulated genes were unaffected. HDAC inhibitors improve memory through activation of specific genes regulated by CREBP complex.

HDAC2

The role of individual HDACs in learning and memory is not well understood, but HDAC2 has been shown to negatively regulate memory formation and synaptic plasticity.

Overexpression (OE) of HDAC1 and HDAC2 in mice resulted in decreased levels of acetylated lysines. After exposing these mice to context and tone-dependent fear conditioning experiments, HDAC1 OE mice did not change, but HDAC2 OE mice showed a decrease in freezing behavior, suggesting impairment in memory formation. On the other hand, mice with HDAC2 knockouts (KO) illustrated increased freezing levels compared to wild-type (WT) mice while HDAC1 displayed similar freezing behaviors to WTs. In summary, Guan et al. have shown that:

  • HDAC2, not HDAC1, regulates synaptogenesis and synaptic plasticity. HDAC2 overexpression decreases spine density in CA1 pyramidal neurons and dentate gyrus granule cells but HDAC2 KO show an increase in spine density.
  • Long term potentiation in CA1 neurons was not observed in HDAC2 OE mice but was easily induced in HDAC2 KO mice. LTP was not altered between HDAC1 KO and OE mice.
  • HDAC2 suppresses neuronal gene expression. HDAC2 interacted more than HDAC1 with specific memory-forming promoters such as Bdnf, Egr1, Fos, and GLUR1.
  • CoREST, a co-repressor, associates with HDAC2 not HDAC1.
  • SAHA, a HDAC inhibitor, increased freezing of HDAC2 OE mice in contextual fear and tone dependent experiments, but did not effect HDAC2 KO mice suggesting HDAC2 is major target of SAHA

HDAC3

HDAC3 is also a negative regulator of long term potentiation formation. McQuown et al. have shown that:

  • KOs of HDAC3 in dorsal hippocampus resulted in enhanced memory during object location tests (OLM).
  • RGFP136, HDAC3 inhibitor, enhances LTP for object recognition and location
  • RGFP136 enhances LTP through CBP-dependent mechanism
  • HDAC3 deletions showed increased Nr4a2 and c-Fos expression
  • HDAC3 interacts with NCoR and HDAC4 to perform its role in memory formation

HDACs' role in CNS disorders

Research has shown that HDACs and HATs play a crucial role in central nervous system (CNS) disorders such as Rett syndrome. Rubinstein-Tabyi syndrome causes intellectual disability through possible mutations in CREB-binding protein and p300. However, enhancing expression of CREB-dependent genes or inhibition of HDAC activity partially restore LTP loss and ameliorate late LTP deficits. HDAC inhibitor like TSA may provide a possible therapy for Rubinstein-Tabyi syndrome. Other memory-deficit disorders which may involve HDAC inhibitors as potential therapy are:

Role of DNA topoisomerase II beta in learning and memory

During a new learning experience, a set of genes is rapidly expressed in the brain. This induced gene expression is considered to be essential for processing the information being learned. Such genes are referred to as immediate early genes (IEGs). DNA topoisomerase II beta (TOP2B) activity is essential for the expression of IEGs in a type of learning experience in mice termed associative fear memory. Such a learning experience appears to rapidly trigger TOP2B to induce double-strand breaks in the promoter DNA of IEG genes that function in neuroplasticity. Repair of these induced breaks is associated with DNA demethylation of IEG gene promoters allowing immediate expression of these IEG genes.

Regulatory sequence in a promoter at a transcription start site with a paused RNA polymerase and a TOP2B-induced double-strand break
Brain regions involved in memory formation including medial prefrontal cortex (mPFC)

The double-strand breaks that are induced during a learning experience are not immediately repaired. About 600 regulatory sequences in promoters and about 800 regulatory sequences in enhancers appear to depend on double strand breaks initiated by topoisomerase 2-beta (TOP2B) for activation. The induction of particular double-strand breaks are specific with respect to their inducing signal. When neurons are activated in vitro, just 22 of TOP2B-induced double-strand breaks occur in their genomes.

Such TOP2B-induced double-strand breaks are accompanied by at least four enzymes of the non-homologous end joining (NHEJ) DNA repair pathway (DNA-PKcs, KU70, KU80 and DNA LIGASE IV) (see Figure). These enzymes repair the double-strand breaks within about 15 minutes to two hours. The double-strand breaks in the promoter are thus associated with TOP2B and at least these four repair enzymes. These proteins are present simultaneously on a single promoter nucleosome (there are about 147 nucleotides in the DNA sequence wrapped around a single nucleosome) located near the transcription start site of their target gene.

The double-strand break introduced by TOP2B apparently frees the part of the promoter at an RNA polymerase-bound transcription start site to physically move to its associated enhancer (see regulatory sequence). This allows the enhancer, with its bound transcription factors and mediator proteins, to directly interact with the RNA polymerase paused at the transcription start site to start transcription.

Contextual fear conditioning in the mouse causes the mouse to have a long-term memory and fear of the location in which it occurred. Contextual fear conditioning causes hundreds of DSBs in mouse brain medial prefrontal cortex (mPFC) and hippocampus neurons (see Figure: Brain regions involved in memory formation). These DSBs predominately activate genes involved in synaptic processes, that are important for learning and memory.

Roles of ROS and OGG1 in memory and learning

Initiation of DNA demethylation at a CpG site. In adult somatic cells DNA methylation typically occurs in the context of CpG dinucleotides (CpG sites), forming 5-methylcytosine-pG, or 5mCpG. Reactive oxygen species (ROS) may attack guanine at the dinucleotide site, forming 8-hydroxy-2'-deoxyguanosine (8-OHdG), and resulting in a 5mCp-8-OHdG dinucleotide site. The base excision repair enzyme OGG1 targets 8-OHdG and binds to the lesion without immediate excision. OGG1, present at a 5mCp-8-OHdG site recruits TET1 and TET1 oxidizes the 5mC adjacent to the 8-OHdG. This initiates demethylation of 5mC.
Demethylation of 5-Methylcytosine (5mC) in neuron DNA. As reviewed in 2018, in brain neurons, 5mC is oxidized by the ten-eleven translocation (TET) family of dioxygenases (TET1, TET2, TET3) to generate 5-hydroxymethylcytosine (5hmC). In successive steps TET enzymes further hydroxylate 5hmC to generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Thymine-DNA glycosylase (TDG) recognizes the intermediate bases 5fC and 5caC and excises the glycosidic bond resulting in an apyrimidinic site (AP site). In an alternative oxidative deamination pathway, 5hmC can be oxidatively deaminated by activity-induced cytidine deaminase/apolipoprotein B mRNA editing complex (AID/APOBEC) deaminases to form 5-hydroxymethyluracil (5hmU) or 5mC can be converted to thymine (Thy). 5hmU can be cleaved by TDG, single-strand-selective monofunctional uracil-DNA glycosylase 1 (SMUG1), Nei-Like DNA Glycosylase 1 (NEIL1), or methyl-CpG binding protein 4 (MBD4). AP sites and T:G mismatches are then repaired by base excision repair (BER) enzymes to yield cytosine (Cyt).

As reviewed by Massaad and Klann in 2011 and by Beckhauser et al. in 2016, reactive oxygen species (ROS) are required for normal learning and memory functions.

One of the most frequent DNA oxidation products of ROS is 8-hydroxy-2'-deoxyguanosine (8-OHdG). Removal of oxidized bases in DNA usually occurs in a matter of minutes, with a half-life of 11 minutes for 8-OHdG. Steady-state levels of endogenous DNA damages represent the balance between formation and repair. 8-OHdGs are among the most frequent DNA damages present in the steady-state, with about 2,400 8-OHdG damaged nucleotides in the average mammalian cell. The steady state 8-OHdG level in the brain is similar to that in other tissues.

The occurrence of 8-OHdG in neurons appears to have a role in memory and learning. The DNA glycosylase oxoguanine glycosylase (OGG1) is the primary enzyme responsible for the excision of 8-OHdG in base excision repair. However, OGG1, which targets and associates with 8-OHdG, also has a role in adaptive behavior, which implies a physiologically relevant role for 8-OHdG combined with OGG1 in cognition in the adult brain. In particular, heterozygous OGG1+/- mice, with about half the protein level of OGG1, exhibit poorer learning performance in the Barnes maze compared to wild-type animals.

In adult somatic cells, such as neurons, DNA methylation typically occurs in the context of CpG dinucleotides (CpG sites), forming 5-methylcytosine (5mC). Thus, a CpG site may be methylated to form 5mCpG. The presence of 5mC at CpG sites in gene promoters is widely considered to be an epigenetic mark that acts to suppress transcription. If the guanine at the 5mCpG site is attacked by ROS, leading to 8-OHdG formation, OGG1 binds to the 8-OHdG lesion without immediate excision of the 8-OHdG. When OGG1 is present at a 5mCp-8-OHdG site, it recruits TET1 to the 8-OHdG lesion and TET1 oxidizes the 5mC adjacent to 8-OHdG. This causes the 5mC to enter the DNA demethylation pathway (see Figure titled "Initiation of DNA demethylation at a CpG site"). This pathway is initiated by formation of 5-hydroxymethylcytosine, which may remain in the DNA, or there may be further oxidative reactions followed by base excision repair, to return the nucleoside at that position to cytosine (see Figure "Demethylation of 5-Methylcytosine (5mC) in neuron DNA").

The total number of CpG sites in the human genome is approximately 28 million and the average frequency of CpG sites in the genome is about 1 per hundred base pairs. An intense learning situation can be applied to rats, referred to as contextual fear conditioning. This can result in a life-long fearful memory after a single training event. While the long-term memory of this event appears to be first stored in the hippocampus, this storage is transient and does not remain in the hippocampus. Much of the long-term storage of contextual fear conditioning memory appears to take place in the anterior cingulate cortex. (See Figure: Brain regions involved in memory formation, and also this reference.) When contextual fear conditioning is applied to a rat, more than 5,000 differentially methylated regions (DMRs) of 500 nucleotides each occur in the rat hippocampus neural genome both one hour and 24 hours after the conditioning in the hippocampus. This causes about 500 genes to be up-regulated (often due to hypomethylation of CpG sites) and about 1,000 genes to be down-regulated (often due to newly formed 5mC at CpG sites in a promoter region). The pattern of induced and repressed genes within neurons appears to provide a molecular basis for forming this first transient memory of this training event in the hippocampus of the rat brain. When similar contextual fear conditioning is applied to a mouse, one hour after contextual fear conditioning there were 675 demethylated genes and 613 hypermethylated genes in the hippocampus region of the mouse brain. These changes were transient in the hippocampal neurons, and almost none were present after four weeks. However, in mice subjected to conditional fear conditioning, after four weeks there were more than 1,000 differentially methylated genes and more than 1,000 differentially expressed genes in the anterior cingulate cortex, where long-term memories are stored in the mouse brain.

Big Bounce

From Wikipedia, the free encyclopedia
An animation of the Big Bounce

The Big Bounce hypothesis is a cosmological model for the origin of the known universe. It was originally suggested as a phase of the cyclic model or oscillatory universe interpretation of the Big Bang, where the first cosmological event was the result of the collapse of a previous universe. It receded from serious consideration in the early 1980s after inflation theory emerged as a solution to the horizon problem, which had arisen from advances in observations revealing the large-scale structure of the universe.

Inflation was found to be inevitably eternal, creating an infinity of different universes with typically different properties, suggesting that the properties of the observable universe are a matter of chance. An alternative concept that included a Big Bounce was conceived as a predictive and falsifiable possible solution to the horizon problem. Investigation continued as of 2022.

Expansion and contraction

The concept of the Big Bounce envisions the Big Bang as the beginning of a period of expansion that followed a period of contraction. In this view, one could talk of a "Big Crunch" followed by a "Big Bang" or, more simply, a "Big Bounce". This concept suggests that we could exist at any point in an infinite sequence of universes, or conversely, the current universe could be the very first iteration. However, if the condition of the interval phase "between bounces"—considered the "hypothesis of the primeval atom"—is taken into full contingency, such enumeration may be meaningless because that condition could represent a singularity in time at each instance if such perpetual repeats (cycles) were absolute and undifferentiated.

The main idea behind the quantum theory of a Big Bounce is that, as density approaches infinity, the behavior of quantum foam changes. All the so-called fundamental physical constants, including the speed of light in vacuum, need not remain constant during a Big Crunch, especially in the time interval smaller than that in which measurement may never be possible (one unit of Planck time, roughly 10−43 seconds) spanning or bracketing the point of inflection.

History

Big Bounce models were endorsed on largely aesthetic grounds by cosmologists including Willem de Sitter, Carl Friedrich von Weizsäcker, George McVittie, and George Gamow (who stressed that "from the physical point of view we must forget entirely about the precollapse period").

By the early 1980s, the advancing precision and scope of observational cosmology had revealed that the large-scale structure of the universe is flat, homogeneous, and isotropic, a finding later accepted as the cosmological principle to apply at scales beyond roughly 300 million light-years. This led cosmologists to seek an explanation to the horizon problem, which questioned how distant regions of the universe could have identical properties without ever being in light-like communication. A solution was proposed to be a period of exponential expansion of space in the early universe, which formed the basis of what became known as inflation theory. Following the brief inflationary period, the universe continues to expand at a slower rate.

Various formulations of inflation theory and their detailed implications became the subject of intense theoretical study. Without a compelling alternative, inflation became the leading solution to the horizon problem.

The phrase "Big Bounce" appeared in scientific literature in 1987, when it was first used in the title of a pair of articles (in German) in Stern und Weltraum by Wolfgang Priester and Hans-Joachim Blome. It reappeared in 1988 in Iosif Rozental's Big Bang, Big Bounce, a revised English-language translation of a Russian-language book (by a different title), and in a 1991 English-language article by Priester and Blome in Astronomy and Astrophysics. The phrase originated as the title of a novel by Elmore Leonard in 1969, shortly after increased public awareness of the Big Bang model with of the discovery of the cosmic microwave background by Penzias and Wilson in 1965.

The idea of the existence of a big bounce in the very early universe has found diverse support in works based on loop quantum gravity. In loop quantum cosmology, a branch of loop quantum gravity, the big bounce was first discovered in February 2006 for isotropic and homogeneous models by Abhay Ashtekar, Tomasz Pawlowski, and Parampreet Singh at Pennsylvania State University. This result has been generalized to various other models by different groups, and includes the case of spatial curvature, cosmological constant, anisotropies, and Fock quantized inhomogeneities.

Martin Bojowald, an assistant professor of physics at Pennsylvania State University, published a study in July 2007 detailing work related to loop quantum gravity that claimed to mathematically solve the time before the Big Bang, which would give new weight to the oscillatory universe and Big Bounce theories.

One of the main problems with the Big Bang theory is that there is a singularity of zero volume and infinite energy at the moment of the Big Bang. This is normally interpreted as a breakdown of physics as we know it; in this case, of the theory of general relativity. This is why one expects quantum effects to become important and avoid a singularity.

However, research in loop quantum cosmology purported to show that a previously existing universe collapses not to a singularity, but to a point where the quantum effects of gravity become so strongly repulsive that the universe rebounds back out, forming a new branch. Throughout this collapse and bounce, the evolution is unitary.

Bojowald also claimed that some properties of the universe that collapsed to form ours can be determined; however, other properties are not determinable due to some uncertainty principle. This result has been disputed by different groups, which show that due to restrictions on fluctuations stemming from the uncertainty principle, there are strong constraints on the change in relative fluctuations across the bounce.

While the existence of the Big Bounce has still to be demonstrated from loop quantum gravity, the robustness of its main features has been confirmed using exact results and several studies involving numerical simulations using high performance computing in loop quantum cosmology.

In 2006, it was proposed that the application of loop quantum gravity techniques to Big Bang cosmology can lead to a bounce that need not be cyclic.

In 2010, Roger Penrose advanced a general relativity-based theory which he called the "conformal cyclic cosmology". The theory explains that the universe will expand until all matter decays and ultimately turns to light. Since nothing in the universe would have any time or distance scale associated with it, the universe becomes identical with the Big Bang, resulting in a type of Big Crunch that becomes the next Big Bang, thus perpetuating the next cycle.

In 2011, Nikodem PopÅ‚awski showed that a nonsingular Big Bounce appears naturally in the Einstein–Cartan–Sciama–Kibble theory of gravity. This theory extends general relativity by removing a constraint of the symmetry of the affine connection and regarding its antisymmetric part, the torsion tensor, as a dynamical variable. The minimal coupling between torsion and Dirac spinors generates a spin-spin interaction which is significant in fermionic matter at extremely high densities. Such an interaction avoids the unphysical Big Bang singularity, replacing it with a cusp-like bounce at a finite minimum scale factor, before which the universe was contracting. This scenario also explains why the present Universe at the largest scales appears spatially flat, homogeneous, and isotropic, providing a physical alternative to cosmic inflation.

In 2012, a new theory of a nonsingular Big Bounce was constructed within the frame of standard Einstein gravity. This theory combines the benefits of matter bounce and ekpyrotic cosmology. Particularly, in the homogeneous and isotropic background cosmological solution, the BKL instability is unstable to the growth of anisotropic stress, which is resolved in this theory. Moreover, curvature perturbations seeded in matter contraction can form a nearly scale-invariant primordial power spectrum and thus provide a consistent mechanism to explain the cosmic microwave background (CMB) observations.

Critics

According to a study published in Physical Review Letters in May 2023, the Big Bounce should have left marks in the primordial light, known as the cosmic microwave background (CMB), but comparing observations conducted by the Planck satellite with the simulated CMB in the case the Universe bounced on itself only once, that particular bounce signature was not found.

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