Introduction

Memory is a complex brain function to store and retrieve information. In humans, memories of life experiences collectively contribute to represent who we are. It is a function that helps us interact with our environment; similar situations evoke specific responses, known faces evoke reactions, and repeated stimuli help us how to learn and respond.[1] Long-term memories divide into two different groups, procedural and declarative. Procedural memory involves certain activities we learn by practicing and repeated exposure to a series of motor outputs (for example, riding a bicycle or driving a car). Declarative memories, able to be consciously recalled, are comprised of two other groups: semantic memories representing discrete facts such as dates, word definitions, and learned concepts, and episodic memories that represent explicit experiences one has lived through, such as a special birthday or one’s wedding day. The literature sometimes refers to these two groups of long-term memories implicit or explicit, respectively, though these terms aren’t utilized as much because they are more ambiguous. Long-term memory is consolidated from short-term to long-term memories, primarily in the hippocampus and stored throughout the cortex. These interconnected structures help one interpret stimuli to act accordingly, either by retrieving old memories to help us navigate or by storing them so we can start learning more.[2][3][4][5][6]

Cellular Level

Neurons fire all-or-nothing electrical impulses termed action potentials as they become stimulated. Signaling of neurons involved with different sensory modalities is not as easy to study; however, the organization of the cortex is such that signal processing occurs at multiple levels in multiple locations. In primates models, the encoding of stimuli works as groups of neurons fire based on specific stimuli; the more specific the detail, the fewer neurons are involved. For example, a smaller number of neurons would respond with the recognition of your grandmother’s face than with any human or animal face.[1][7][8][9]

Long-term potentiation (LTP) was a groundbreaking discovery in the 1960s that defined a molecular basis for the formation and storage of memories. In LTP, when two neurons repetitively and simultaneously become activated, the strength of the connection between these cells is strengthened. This synaptic strengthening is commonly referred to as ‘cells that fire together, wire together.’[10][11] This phenomenon is the basis for synaptic plasticity and how neurons store and manage our memories in a declarative or procedural way. The strengthening of links between neurons helps us is many ways, such as recognition of places we have been before, recognition of faces we have meet, and information that we can only acquire throughout repeated exposure.[12][13]

Development

The result of LTP is the strengthening of neuronal synapses through increased receptor density on the post-synaptic cell and the expression of growth genes. One of the most studied signaling pathways related to long-term potentiation and memory consolidation is the protein kinase A (PKA) pathway. Continuous or repetitive stimulation to specific neural connections (mediated by realizing repeated stimuli, using certain activities or rewards), activates NMDA receptors that allow the influx of calcium ions. This influx initiates second messenger pathways that are mediated by PKA and cyclic adenosine monophosphate (cAMP). These pathways result in changes to protein synthesis and cell growth, mediated by the cAMP response element-binding protein (CREB), a transcription factor that binds to cAMP response elements (CRE). The binding promotes gene transcription; this has been routinely demonstrated using Aplysia, Drosophila, and rodent animal models. Cell growth and protein synthesis enhance neuronal plasticity and strengthen communication between cells.[14][8][9][15]

Organ Systems Involved

The central nervous system is the main system involved. Specific brain structures have specific tasks within memory development. For example, the hippocampus is required for the consolidation of memories from short-term to long-term, whereas the amygdala adds emotional pertinence to memories. It is the pattern and strength of the connections between cortical structures that permit the storage and retrieval of encoded information.[15][1][16] Encoding and storage of procedural memories also involve multiple brain areas. The cerebellum, basal ganglia, and the association cortices play a part in our learned actions as they are related to motor control and adjustment.[5]

Functional imaging, such as PET or fMRI, has permitted investigation of structures involved in the encoding of stimulus into declarative memory. Certain brain regions may have a specific function in the consolidation of memories. However, most of the cortex works in a combined fashion to enhance the retrieval of memories and learning. "Working memory," temporary memory that does not necessarily get encoded into long term memory, gets defined differently in the literature, with some authors discussing working memory in similar mechanisms as long term memory. In contrast, others discuss it as a different and separate process to store and manipulate information.[2][17]

The hippocampus is a structure related to visuospatial processing, and, in part, to “working” memory. Saturating mechanisms of working memory are possible, with excessive details or quantity of information leading to mistakes in this short-term memory.[18] Dividing the hippocampus in a longitudinal axis also denotes certain functions, for example, the posterior hippocampus has relationships to visuospatial detail in certain memories, while the anterior hippocampus is related to remembering a general concept of a place.[19] The hippocampus is also related to episodic memory, as it helps towards the retrieval of memories lived, and the spaces where they lived.[20]

The amygdala functions in processing emotional components of memory, such as pain, fear, and pleasure. Animals stimulated with a noxious or rewarding stimulus, display increased activity in areas of the amygdala, allowing the animals to differentiate between positive and negative memories. Negative stimuli are more easily stored and remembered, as they tend to create a fight or flight response. In humans, negative stimuli presented during memory formation was associated with the subjects retaining more details about the stimuli (images, words, etc.). Reward stimuli, or “good” stimuli, also may increase retention, but to a lesser degree.[21][22]

The ventral prefrontal cortex correlates with remembering pre-learned schema. It has robust connections with medial temporal structures, and it helps to recognize something that has already happened, while remembering some details associated to it, helping filling gaps in things we think we know already.[23]

The nervous system has deep connections with the endocrine system. For example, the release of cortisol, our primary stress hormone, initiates by signaling within the hypothalamus. Also, there is a correlation between the density of receptors for cortisol, glucocorticoid receptors (GR), within the hippocampus, and the capacity of the neuronal pathways to store information. Upregulation of GRs and corticoids acts in synergy with memory plasticity and memory storage resulting in stressful situations having stronger memories.[24]

Clinical Significance

Korsakoff syndrome is a disease mediated by chronic vitamin B1 (thiamin) deficiency, usually as a complication of alcoholism. Irreversible damage on structures like the prefrontal cortex and the hippocampus can alter information storage. Confabulation is one of the most common signs of this disease, where the patient fills the gaps with false information in the memories they can’t fully recall.[23]

Patients with damage to the medial temporal lobe, the location of the hippocampus, seem to have trouble with the creation of new memories. These patients seem to easily forget or commit mistakes even after receiving similar stimuli many times. Also, their short-term working memory storage is impaired. For example, patients with temporal lobe damage, demonstrate an inability to previous correct mistakes when given repeated exposure to the correct information. The authors suggest this is due to exceeding the working memory capacity of these patients by providing too much information in short retention time.[4][18]

Alzheimer disease is the most common form of dementia, typically known for a loss of short-term memory and the degeneration of the frontal and temporal lobes. Although patients tend to forget where they are, who they are with, or what they are doing at the moment, they may still remember specific details from their past. In the early stages of the disease, episodic and semantic memories, as well as procedural memories, tend to be spared. Semantic memory tends to be more affected than episodic.[25][26]

Memory deficits can appear in other types of prevalent dementia, such as vascular dementia, Parkinson disease, and Lewy body dementia. Vascular dementia may spare or affect memory. It depends on the territory affected by a stroke or by a hemorrhage so that procedural memory may be more intact than declarative memory. Dementia associated with Parkinson disease and dementia with Lewy bodies are two associated types of dementia. Symptomatology and the duration of symptoms separate these diseases. Dementia with Lewy bodies starts with cognitive decline and hallucinations, while Parkinson's starts with motor symptoms like rigidity, bradykinesia, and tremor. Short-term memory is affected, while long-term memory tends to demonstrate relative sparing during the early stages of disease progression (including episodic and semantic).[26]