Nour El Houda MAHDI
Learning and memorizing are two of the most magical capabilities of our mind. Learning refers to a change in behavior that results from acquiring knowledge about the world, whereas memorizing refers to the processes by which that knowledge is encoded, stored, and later retrieved. During the past several decades, researchers have made significant progress in the analysis and understanding of memory. This paper discusses briefly three items that are central to it, its different types, their corresponding dysfunctions and their molecular physiology.
Memory is the ability of our mind to capture information, store it, and later restore it in form of souvenirs, knowledge or skills. Our past shapes our memory through which it influences our perception of the present, allowing us to anticipate and adapt to different circumstances of life in order to survive. When we reflect on the nature of memory, we generally think about it as a single mental faculty, but results of experimental and biologic inquiries in the mid-20th century have revealed that there are different kinds of memory, which are supported by different brain systems.
The most common structural model of memory is built of two interconnected subsystems: short-term memory and long-term memory. As their names suggest, the first is relatively brief and limited while the other is considered a system with an unlimited capacity that lasts years 1.
Short term memory
Also known as working memory, is considered to be the record of conscious thought in humans.
It refers to the active maintenance of verbal and nonverbal information in the mind for potential utilization in the near future to complete goal-directed tasks and behaviors 2. This buffer system works as a sort of intermediary storage space for new information that have never been encountered before, whether they are new word sequences or new combinations of visual features 3.
Working memory consists of two subsystems: one system for verbal information and another for visuospatial information. The former is used when attempting to hold speech-based information into consciousness, as when we mentally rehearse a password before entering it. It depends on posterior parietal cortices, and articulatory processes in Broca’s area 4.The latter subsystem preserves mental images of visual objects and of their location in space. The rehearsal of visuo-spatial information is thought to involve modulation of this information in the parietal, inferior temporal, and occipital cortices 5.
Because working memory depends on a wide network of activity, this makes it a vulnerable target to many disorders such as degenerative, traumatic, vascular, tumoral and inflammatory diseases that would cause its dysfunction. In addition, since phonological working memory involves silent repetition of verbal information, almost any type of aphasia can also impair it. These disorders can present in several ways. Most commonly, the patient will show an inability to concentrate and difficulty performing a new task involving multistep instructions 6.
Working memory is evaluated through bedside mental status screening. It tests the extent with which recent verbal and visual information is recalled. For instance, we can ask a patient to repeat a series of numbers and further increase the number of digits with each trial until the patient fails to remember them correctly (digit span). The test can be made more complex by asking the patient to recite numbers in reverse 7.
Treatment of working memory deficiency is the treatment of the underlying cause.
Long term memory
It is the memory which allows us to retain, in an unlimited way, information over very long periods of time. It consists of several forms as shown in studies as early as the mid-1950s. These forms can be grouped into at least two general categories each with its own properties : explicit and implicit memory 8.
First, explicit (or declarative) memory which is the conscious recall of knowledge about people, places, and objects. It is particularly well developed in the vertebrate brain and it is critically dependent on structures in the medial temporal lobe of the cerebral cortex, including the hippocampal formation.
Explicit memory consists of episodic memory and semantic memory. On one hand, episodic memory refers to the ability to remember rich details about specific times, including information about what happened, when, and where 9. It is unique among memory systems because it is distinctly related to both notions of self and time 2. An example of that is recalling a birthday party, who was there, where it occurred, and our own personal interactions there.
Semantic memory, on the other hand, refers to all our knowledge of the world not related to specific episodic memories, that means our general store of conceptual and factual knowledge, such as the English prime minister during World war II or the shape of our planet 6.
Furthermore, the explicit memory is mediated by at least four related but distinct types of processing: encoding, storage, consolidation and retrieval. Encoding is the initial experience of perceiving and learning information. It is necessary to be attentive to the information and to associate it with knowledge already anchored in the memory. Memory encoding is more effective when the person is well ambitious to learn 4.
Next, there is storage. It refers to mechanisms of memory conservation in their correspondent neural sites over time. it is followed by consolidation, the process that transforms temporarily and recently stored and still labile information into a more stable form. Consolidation involves expression of genes and protein synthesis that gives rise to structural changes at synapses, a phenomenon called long-term potentiation 8.
Finally, retrieval, the process by which stored information is recalled consciously. It involves bringing back to mind different kinds of information that are stored in different sites 10. Retrieving information depends upon contextual information or cues and how effectively the information was encoded and stored into memory. For example, in a classic behavioral experiment, Craig Barclay and colleagues asked some subjects to encode sentences such as “The man lifted the piano.” On a later retrieval test, “something heavy” was a more effective cue for recalling piano than “something with a nice sound.” Other subjects, however, encoded the sentence “The man tuned the piano.” For them, “something with a nice sound” was a more effective retrieval cue for piano than “something heavy” as it reflected better the initial experience. In consequence, explicit memory is partially dependent on working memory 4.
Many neurogenic dysfunctions have adverse repercussions on episodic memory, as seen in neurodegenerative diseases (Alzheimer’s), traumatic brain injury, stroke (especially of the posterior cerebral artery) … etc. They are responsible for prolonged episodic memory dysfunction. On the other hand, transient impairment of memory can accompany seizures 2. In general, any pathology affecting the limbic system and its associated structures can affect encoding, retrieval, and retention of episodic memory. It is important to stress that anxiety, mood, and psychotic disorders can also affect memory formation at any stage 7.
Acute semantic knowledge impairment can be seen in strokes involving dominant temporal and parietal cortices. It is the case of traumatic brain injury, inflammatory and infectious conditions (i.e. herpetic encephalitis) involving these regions 7.
Semantic memory impairments are seen in a variety of disease states, with the most common cause being the semantic variant of primary progressive aphasia (svPPA), which is characterized by anomic, fluent aphasia preceding a general loss of object knowledge with increasingly repetitive speech and eventual mutism. Semantic memory deficits are also common in Alzheimer’s disease and in a post-acute outcome of central nervous system infection (herpes simplex virus encephalitis) 2,11. These disorders affect naming, language comprehension, expressive and receptive vocabulary, and fact retrieval 11; patients demonstrate impaired knowledge of objects, words, and concepts. Language becomes empty of meaning. They also frequently demonstrate two-way naming deficits: they are unable to either name the object or point to the correct object when prompted. They begin using superordinate category names for specific objects (e.g. referring to a dog as an animal) or using semantic paraphasias as a substitution for an actual name such as saying “son” instead of “daughter” or “orange” instead of “apple” 2 .
Effective evaluation of patients with episodic or semantic memory deficits requires a collateral history (i.e. interrogating a close relative or a personal healthcare companion instead of the patient because they are mentally or neurologically impaired therefore unable to give an adequate or appropriate answer). Bedside mental status screening and formal neuropsychological testing are used. Tests of delayed recall of verbal and visual information and tests of general knowledge and naming confirm episodic and semantic memory problems respectively 2 .
Neuroimaging is useful to confirm the neuroanatomical regions involved. Targeted cognitive rehabilitation is beneficial in the spectrum of episodic memory dysfunction and targeted speech therapy for compensatory strategies and alternative communication devices may be beneficial for semantic memory problems 2.
Second, implicit (or non-declarative) memory that refers to a collection of abilities that are expressed through performance without requiring conscious memory content. It includes the procedural memory for skills and habits (e.g., riding a bicycle, driving a car), and priming 9. Implicit memory involves the cerebellum, the striatum, the amygdala, and in the simplest cases, the sensory and motor pathways recruited for particular perceptual or motor skills utilized during the learning process 12. It emerges automatically during perception, thought and action. It tends to be inflexible and expresses itself in the performance of tasks 4.
Priming is a type of implicit memory, where exposure to one stimulus influences a response to a subsequent one, without conscious guidance or intention.
Two major categories of priming have been identified: conceptual and perceptual priming 13. First, conceptual priming, which is associated with the stimuli’s form and is enhanced by links between early and late stimuli. For example, a person wouldn’t recognize the picture of a puzzle until a large part of it is built, however if the test is repeated weeks later, the person would recognize the picture much earlier. Therefore, conceptual priming provides easier access to task-relevant semantic knowledge since that knowledge has been used before 14.
Perceptual priming however depends on the meaning of stimuli. For instance, the words « toilette » and « bathroom » relate to each other as the brain stores them in the same category. Perceptual priming occurs within a specific sensory modality. It depends on cortical modules that operate on sensory information about the form and structure of words and objects. Perceptual learning improves the ability to make sense of novel sensory inputs, as in learning to read mirror-reversed text or recognizing novel objects by reference to familiar categories 14.
In addition to priming, procedural memory is another type of implicit memory that refers to the ability to learn cognitive and behavioral skills and algorithms that operate at an automatic and unconscious level. Varying examples include tying your shoes, reading, riding a bicycle, driving a car or even flying an airplane 6. In general, this form of implicit memory is characterized by incremental learning, which proceeds gradually with repetition until all of the relevant neural systems work together to automatically reproduce the activity 4. Critical brain regions for procedural memory are the basal ganglia, cerebellum, and supplementary motor area 15.
Additionally, procedural memory is independent from the declarative one. Cohen and al have showed this in a comparative study: a group of amnesic patients with severely impaired long-term memory, and another of healthy subjects, were asked to solve a puzzle several times. Both groups showed similar improvements over time, although some participants said they did not even remember seeing the puzzle before 16.
Procedural memory deficits are reported in patients with Parkinson’s disease, Huntington’s disease and cerebellar degeneration syndromes. Their evaluation will also require a collateral history and neuropsychological testing. Unfortunately, it is tested less frequently in clinical settings. As previously mentioned, neuroimaging is valuable for identifying the neuroanatomical substrate of the dysfunction 2.
Mechanisms of the Memory Trace
Researching the mechanisms of learning in the brain has spanned more than a century. It is now clear that memory formation and storage involves structural changes in the connectivity between neurons. This process is termed long term potentiation (LTP) : it is a persistent strengthening of synapses based on patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons 17. The mechanisms are studied traditionally by replacing the learning experience with high frequency electrical stimulation of an excitatory neuron in the hippocampus 18.
On a molecular level, when we apply a stimulation to a pre-synaptic neuron as if we were learning new information and storing it in the short-term memory, there will be an increase in the release of pre-synaptic glutamate. That leads to the stimulation of the post-synaptic glutaminergic receptors and a following increase in calcium influx. Post-synaptic calcium influx and the subsequent phosphorylation and activation of calcium/calmodulin dependent kinase (CaMKII) and protein kinase C (PKC) leads to the increase of the number of glutaminergic receptors and the retrograde release of messengers, such as nitric oxide (NO). NO activates protein kinases in the presynaptic terminal subsequently inducing the increase of glutamate release. These synaptic modifications constitute the early LTP 4.
By contrast, the acquisition of long-term memories is represented by late LTP that require de novo gene transcription, new protein translation and synaptic growth at postsynaptic terminals 19,20. If we have repeated stimuli in a pre-synaptic surface, as in training, there will be a massive and prolonged entry of calcium which activates protein kinase A (PKA). This leads to activation and translocation of mitogen-activated protein kinase (MAP kinase) to the nucleus and ultimate phosphorylation of CREB-1(cAMP-response element binding) protein, an intracellular protein that regulates the expression of genes. It activates in turn the transcription of targets that induce the formation of a new membranous protrusion of the neuronal dendrite, called a spine. Repeated stimulation also activates the translation of mRNA encoding protein kinase M (PKM), a constitutively active isoform of PKC, which leads to a sustained increase in the number of glutamate receptors in the postsynaptic membrane. This process strengthens synaptic connections and consequently allows memory to last longer 4.
The study of these molecular phenomena illuminated us on how a signal originating from an activated synapse, triggers a specific intracellular signaling cascade that alters nuclear function and synaptic connectivity to consolidate a memory 20.These findings may help in the development of targeted therapies that potentiate these pathways to alleviate some memory dysfunctions.
In conclusion, memory is the canvas on which we paint the picture of our lives, in both a conscious and unconscious way. It is an important part of what makes us truly human. Unfortunately, it is susceptible to widespread damage. The evergrowing understanding of its neurobiology is key to developing new approaches that alleviate memory disorders, and perhaps even definitively treating them in the future.
1. Squire LR, Dede AJO. Conscious and Unconscious Memory Systems. Cold Spring Harb Perspect Biol. 2015 Mar;7(3):a021667.
2. Matthews BR. Memory Dysfunction: CONTINUUM: Lifelong Learning in Neurology. 2015 Jun;21:613–26.
3. Norris D. Short-term memory and long-term memory are still different. Psychological Bulletin. 2017 Sep;143(9):992–1009.
4. Kandel ER, Koester JD, Mack SH, Siegelbaum SA, editors. Principles of neural science. 6th ed. New York: McGraw Hill; 2021.
5. Milner B, Squire LR, Kandel ER. Cognitive Neuroscience and the Study of Memory. Neuron. 1998 Mar;20(3):445–68.
6. Wolk DA, Budson AE. MEMORY SYSTEMS: CONTINUUM: Lifelong Learning in Neurology. 2010 Aug;16:15–28.
7. Gliebus GP. Memory Dysfunction. CONTINUUM: Lifelong Learning in Neurology. 2018 Jun;24(3):727–44.
8. Squire LR, Stark CEL, Clark RE. THE MEDIAL TEMPORAL LOBE. Annu Rev Neurosci. 2004 Jul 21;27(1):279–306.
9. Tulving E. Episodic Memory: From Mind to Brain. Annu Rev Psychol. 2002 Feb;53(1):1–25.
10. Eldridge LL, Knowlton BJ, Furmanski CS, Bookheimer SY, Engel SA. Remembering episodes: a selective role for the hippocampus during retrieval. Nat Neurosci. 2000 Nov;3(11):1149–52.
11. Bauer R, Gaynor L, Moreno C, Kuhn T. Episodic and semantic memory disorders. In: Handbook on the Neuropsychology of Aging and Dementia [Internet]. 2nd ed. Springer Science+Business Media, LLC; 2019. p. 619–39.
12. Hawkins RD, Kandel ER, Bailey CH. Molecular Mechanisms of Memory Storage in Aplysia. The Biological Bulletin. 2006 Jun;210(3):174–91.
13. Schacter DL, Buckner RL. Priming and the Brain. Neuron. 1998 Feb;20(2):185–95.
14. Kandel ER, Dudai Y, Mayford MR. The Molecular and Systems Biology of Memory. Cell. 2014 Mar;157(1):163–86.
15. Markowitsch HJ, Staniloiu A. Amnesic disorders. The Lancet. 2012 Oct;380(9851):1429–40.
16. Cohen NJ, Eichenbaum H, Deacedo BS, Corkin S. Different Memory Systems Underlying Acquisition of Procedural and Declarative Knowledge. Ann NY Acad Sci. 1985 May;444(1 Memory Dysfun):54–71.
17.Cooke SF. Plasticity in the human central nervous system. Brain. 2006 Jul 1;129(7):1659–73.
18. Abraham WC, Jones OD, Glanzman DL. Is plasticity of synapses the mechanism of long-term memory storage? npj Sci Learn. 2019 Dec;4(1):9.
19. Bailey CH, Chen M. Structural plasticity at identified synapses during long-term memory inAplysia. J Neurobiol. 1989 Jul;20(5):356–72.
20. Asok A, Leroy F, Rayman JB, Kandel ER. Molecular Mechanisms of the Memory Trace. Trends in Neurosciences. 2019 Jan;42(1):14–22.