Neurobiology of memory

Neurobiology of memory

Dr Amit Choughule



  1. Discuss in detail about the neurobiology of memory and practical aspects of this knowledge in clinical settings (RGUHS, 2012) (TNMGR)
  2. Different types of memory?
  3. Assessment of memory in a clinical situation (DNB)


Memory is also of clinical interest because disorders of memory and complaints about memory are common in neurological and psychiatric illness. Memory impairment is also a side effect of certain treatments, such as electroconvulsive therapy. Accordingly, the effective clinician needs to understand something of the biology of memory, the varieties of memory dysfunction, and how memory can be evaluated


Memory neurobiology is defined as the organization of memory systems in terms of the kind of information to be represented, the processes associated with the operation of each system, and the neurobiological substrates including neural structures and mechanisms that sub-serve each system

Definition of Memory:

The process by which, what is experienced or learned is established as a record in the CNS, where it persists with a variable degree of permanence, and can be recalled or recollected from storage at will.

A faculty of learning, storing & retrieval of new information.


Types of memory:

  1. Temporal:
  • Short-term memory (STM) and Long-term memory (LTM).
  1. Form:
  • Visual memory, verbal memory, nonverbal memory
  1. Process:
  • Explicit vs implicit (Tulving, Schacter and Stark, 1982)
  • Declarative vs Non- declarative Cohen and Squire, 1980)

                    Declarative/Explicit                         Non-declarative/Implicit

Facts (semantic)                                  Skills and habits

Events(episodic)                                 Priming

Classical conditioning

Non-associative conditioning


Models of memory:

  1. Information Processing model (Atkinson and Shiffrin 1968)
  2. Levels of processing model (Craig and Lockhart 1972, Craig and Tulving 1975)
  3. Working memory model (Baddley and Hitch 1974)

Explicit Memory:

  • Factual knowledge of people, places, things, and events, along with concepts derived from this knowledge
  • Well developed in vertebrate brain
  • Explicit (declarative) memory is recalled by conscious effort, and can involve assembly and association of many pieces of information in different modalities
  • Dependent on the structures like medial temporal lobe of the cerebral cortex and hippocampus formation
  • Declarative memory can be further classified as episodic or autobiographic memory and semantic memory.

Types of Explicit Memory:

  • Episodic memory:
  • Allows us to remember personal events and experience and, being a link between what we are and what we have been, gives us the sense of our individuality.
  • Semantic memory:
  • Public memory for facts and notions, can be general or autobiographical
  • Over time, autobiographical memory shades into semantic memory so that the experience of an event is remembered as the simple occurrence of such event


Implicit memory:

  • It refers to information storage to perform various reflexive or perceptual tasks
  • Also referred to as non-declarative memory because it is recalled unconsciously
  • Implicit memory is a heterogeneous collection of memory functions and types of learned behaviors such as
    • reflexive learning (sensitization, habituation),
    • classical conditioning
    • fear conditioning
    • Procedural memory (for skills and habits)
    • Priming (the recall of words or objects from a previous unconscious exposure to them).


Nondeclarative / procedural memory:                                      
Declarative memory:
MTL, Diencephalon, Neocortex

    1. Skills and habits: Basal ganglia, Cerebellum, Motor Cortex
    2. Priming: Neocortex
    3. Classical conditioning: Cerebellum;
    4. Emotional response:Amygdala
    5. Non-associative conditioning: Reflex pathways

Working memory:

  1. Central executive: Frontal lobes
  2. Visuo-spatial sketchpad: Neocortex
  • Phonological loop: Perisylivian region




Neuroanatomy of Memory Consolidation:


Amygdala in memory of emotional behaviour:

  1. The amygdala is involved in the regulation of emotional behaviour.
  2. Mediates associative learning of emotional stimuli (e.g., fear conditioning and extinction)
  3. Modulatory effects of projections from the amygdala to the neocortex are responsible for producing enhanced memory for emotional or arousing events compared to neutral events

Frontal Contributions to Memory

Frontal lobes are fundamentally important for declarative memory

Patients with frontal lesions have:

  1. Poor memory for the context in which information was acquired
  2. Difficulty in unaided recall
  3. Difficulty on tests of item recognition


Neurophysiology of memory:

Memory is a special case of the general biological phenomenon of neural plasticity. Plasticity of nerve cells and synapses is the basis of memory


Neurobiological evidence supports two basic conclusions:

  1. Short lasting plasticity, which may last for seconds or minutes, depends on specific synaptic events, including an increase in neurotransmitter release
  2. Long-lasting memory depends on new protein synthesis, physical growth of neural processes, and an increase in the number of synaptic connections




Long-Term Potentiation

The phenomenon of LTP is a candidate mechanism for mammalian long term memory

LTP is observed when a postsynaptic neuron is persistently depolarized after a high-frequency burst of presynaptic neural firing

LTP has a number of properties that make it suitable as a physiological substrate of memory:

  1. It is established quickly and then lasts for a long time
  2. It is associative, in that it depends on the co-occurrence of presynaptic activity and postsynaptic depolarization
  3. It occurs only at potentiated synapses, not all synapses terminating on the postsynaptic cell
  4. LTP occurs prominently in the hippocampus, a structure important for memory

The induction of LTP is known to be mediated postsynaptically and to involve activation of NMDA receptors, which permit the influx of calcium into postsynaptic neurons

LTP is maintained by an increase in the number of postsynaptic AMPA (non-NMDA) receptors and also possibly by increased transmitter release.

Postsynaptic NMDA-mediated changes also support the opposing phenomenon of long-term depression (LTD), which involves temporary decreases in synaptic efficacy following low-frequency synaptic stimulation

The encoding of long-term memories could involve modification of synaptic connections through LTP and LTD.

Associative Learning

The study of classical conditioning has provided many insights into the biology of memory

Classical conditioning has been especially well studied in rabbits using a tone as the conditioned stimulus and an air puff to the eye (which automatically elicits a blink response) as the unconditioned stimulus.

Reversible lesions of the deep nuclei of the cerebellum eliminate the conditioned response without affecting the unconditioned response.

Cerebellum contains essential circuitry for the learned association. The relevant plasticity appears to be distributed between the cerebellar cortex and the deep nuclei.

An analogous pattern of cerebellar plasticity is thought to underlie motor learning in the vestibulo-ocular reflex and, perhaps, associative learning of motor responses in general.

Synaptic changes in the cerebellar cortex are critical for learned timing

Synaptic changes in the deep nuclei are critical for forming an association between a conditioned stimulus and an unconditioned stimulus



  • Priming refers to a facilitation of the ability to detect or to identify a particular stimulus based on a specific recent experience.
  • Perceptual priming is a distinct class of memory that is independent of the medial temporal lobe regions
  • Conceptual priming:
  1. Form of priming reflects improved access to meaning rather than percepts.
  2. Preserved in patients with amnesia, even though they fail to recognize the same words on a conventional memory task


Neuro-chemistry and Neuro-pharmacology of memory:

Evidences are based on neuroimaging and neuropsychological studies. (Linden and Connor 1995)

1.Glutamate:  Two types of glutamate receptors:

  1. a) Linked to ion channel (NMDA, AMPA, and kainite):
  • Induction of LTP is mediated post-synaptically and by activation of NMDA receptor leading to influx of calcium into the postsynaptic cell; increases the pre-synaptic release of neurotransmitter and increase in the number of postsynaptic receptors
  1. b) Linked to G- protein (metebotropic receptors): mediate LTP
  • In mice, by selective deletion of NMDA receptors in the CA1 field of hippocampus, many aspects of CA1 physiology remain intact, but the CA neurons don’t exhibit LTP and memory impairment is observed in behavioral tasks.
  1. c) Glutamate antagonists are beneficial in Alzheimer’s and vascular dementia (prevents glutamate excitotoxicity related neurodegeneration) e.g. memantine


  1. Postsynaptic a2 adrenoceptors have role in prefrontal cognitive functions.
  2. Infusion of a2 agonist Guaifencine into the prefrontal cortex of monkey improves working memory performance and infusion of a2 antagonist Yohimbine into monkey prefrontal cortex impaired the working memory performance.
  3. Administration of high dose of a1 agonist Cirazoline improved working memory by activating PFC, but adminstration of a1 antagonist Prazosin had no effect on working memory


  1. Deficiency in cholinergic functioning, due to degeneration in cholinergic projections from the nucleus basalis of meynert in Alzheimer’s dementia.
  2. Beneficial effect of acetyl cholineesterase which increases the ACh level e.g   Donepezil, Rivastigmine and Galantamine in Alzheimer’s disease.



  1. Regulates excitability of cortical circuitry upon which the working memory function of PFC depends.
  2. It also plays role in LTP (LTP can be blocked by dopamine receptor antagonist)

Other peptides and hormone:

  1. Glucocorticoids: Activation of adrenal steroid receptors in the hippocampus play role in memory storage, also via amygdala.
  2. Opioids: Opioid agonists impair memory and opioid antagonists enhance memory.
  3. GABA: Antagonist enhances memory and agonists impair memory



Studies of brain activity measured using PET and functional MRI have shown that:

  1. Posterior prefrontal regions are involved in strategic processing during retrieval, as well as in working memory
  2. Anterior frontal regions near the frontal poles have been linked with functions such as evaluating the products of retrieval
  3. Frontal connections with posterior neocortical regions support the organization of retrieval and the manipulation of information in working memory
  4. Frontal–posterior networks can be viewed as instrumental in the retrieval of declarative memories and in the online processing of new information.
  5. Multiple parietal regions (including inferior and superior parietal lobules, precuneus, posterior cingulate, and retrosplenial cortex) are activated in conjunction with remembering recent experiences.
  6. Priming differs from declarative memory in that it is signaled by brain activity that occurs more efficiently during memory retrieval and that originates in different brain regions.
  7. Hippocampus appears to be involved in the recollection of recent events




A variety of quantitative methods are available to assess memory functions in neurological and psychiatric patients.  Quantitative methods are useful for evaluating and following patients longitudinally as well as for carrying out a one-time examination to determine the status of memory function. It is desirable to obtain information about the severity of memory dysfunction, as well as to determine whether memory is selectively affected or whether memory problems are occurring, as they often do, against a background of additional intellectual deficits.





A complete assessment of memory usually involves a number of specialized tests that sample:

  1. Intellectual functions
  2. New learning capacity
  3. Remote memory
  4. Memory self-report

Intellectual functions:

  • The assessment of general intellectual functions is central to any neuropsychological examination
  • In the case of memory testing, information about intellectual functions provides information about a patient’s general test-taking ability and a way to assess the selectivity of memory impairment
  • Useful tests include:
  1. Wechsler Adult Intelligence Scale
  2. Test of object naming, such as the Boston Naming Test
  3. A rating scale to assess the possibility of global dementia
  4. A test of word fluency
  5. Specialized tests of frontal lobe function

New Learning Capacity

Memory tests are sensitive to impaired new learning ability when they adhere to either of two important principles:

  1. Tests are sensitive to memory impairment when more information is presented than can be held in immediate memory. The paired-associate learning task is an especially sensitive test of this kind.
  2. Tests are sensitive to memory impairment when a delay, filled with distraction, is interposed between the learning phase and the test phase. examiners typically ask patients to learn a small amount of information and then distract them for several minutes by conversation to prevent rehearsal. Recollection is then assessed for the previously presented material. Memory can be tested by unaided recall of previously studied material (free recall), by presenting a cue for the material to be remembered (cued recall), or by testing recognition memory.

Memory assessment in unilateral cerebral damage:

  1. Damage to medial temporal or diencephalic structures in the left cerebral hemisphere causes difficulty remembering verbal material, such as word lists and stories
  2. Damage to medial temporal or diencephalic structures in the right cerebral hemisphere impairs memory for faces, spatial layouts, and other nonverbal material that is typically encoded without verbal labels
  3. Left medial temporal damage can lead to impaired memory for spoken and written text
  4. Right medial temporal damage can lead to impaired learning of spatial arrays, whether the layouts are examined by vision or by touch
  5. A useful way to test for nonverbal memory is to ask a patient to copy a complex geometric figure and then, after a delay of several minutes, without forewarning, ask the patient to reproduce it.


Remote Memory

  1. Evaluations of retrograde memory loss should attempt to determine the severity of any memory loss and the time period that it covers
  2. Tests have been used that concern news events, photographs of famous persons, or former one season television programs.
  3. Autobiographical memory tests can potentially provide fine grained information about a patient’s retrograde memory
  4. In the word probe task, first used by Francis Galton in 1879, patients are asked to recollect specific episodes from their past in response to single word cues (e.g., bird and ticket) and to date the episodes.

Memory Self-Reports

  1. Tests of the ability to judge one’s own memory abilities are called tests of metamemory
  2. Self-rating scales are available that yield quantitative and qualitative information about memory impairment
  3. As a result, it is possible to distinguish memory complaints associated with depression from memory complaints associated with amnesia


Memory Distortion

  1. Memory distortion can lead to unfortunate consequences, such as when mistaken eyewitness testimony harms an innocent individual
  2. One factor that contributes to memory distortion is that similar brain regions are important both for visual imagery and for the long-term storage of visual memories
  3. Another factor that contributes to memory distortion is that memory functions best in remembering the gist of an event, not the particulars from which the gist is derived.
  4. Studies in adults and in children have documented that illusory memories can be created
  5. Children are particularly susceptible to these effects, especially when subjected to leading questions and false suggestions.
  6. In view of these features of memory, when a memory for childhood abuse is remembered after many years, it is prudent to ask whether the memory is accurate

Infantile Amnesia

  1. Infantile amnesia is the apparent absence of conscious memory for experiences from approximately the first 3 years of life.
  2. Traditional views of infantile amnesia have emphasized repression (psychoanalytic theory) and retrieval failure (developmental psychology)
  3. A common assumption has been that adults retain memories of early events but cannot bring them into consciousness
  4. However, it now appears that the capacity for declarative memory does not become fully available until approximately the third year of life, whereas nondeclarative memory emerges early in infancy (e.g., classical conditioning and skill learning).


  1. Thus, infantile amnesia results not from the adult’s failure to retrieve early memories, but from the child’s failure to store them adequately in the first place.
  2. The perspective consistent with current understanding of the biology of memory is that declarative memories formed very early in life are fragmentary, simple, and tied to the specific context of an infant’s understanding of the world.
  3. They are unlike typical declarative memories in adults, imbued with meaning and a complex understanding of events

Memories and the Unconscious

  1. The existence of multiple memory systems also has implications for issues central to psychoanalytic theory, including the construct of the unconscious
  2. The modern, biological view begins with the distinction between a kind of memory that can be brought to mind—declarative memory—and other kinds of memory that are, by their nature, unconscious.
  3. Stored nondeclarative memories are expressed through performance without affording any conscious memory content
  4. Personalities are shaped by nondeclarative memories in the form of numerous habits and conditioned responses.




Joel L. Voss, and Ken A. Paller. Biology of Memory. In Benjamin James Sadock, Virginia Alcott Sadock, Pedro Ruiz, Editor. Comprehensive textbook of Psychiatry. 10th ed. Wolters Kluwer;2017. P.1916-20



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