L74. Physiology - Mechanics of Memory

• There are three major types of memory categories.
• Memories are established in at least two phases.
• Retrograde amnesia and consolidation are key terms to understand in memory processing.
• Long-term and short-term memory can be distinguished.
• Memory is affected by hypothermia, inhibition of protein synthesis, and blocking cyclic AMP pathways.
• Hippocampal lesions have effects on declarative memories; anterograde amnesia is important to the understanding.
• Specific neuroanatomical sites are important for implicit (non-declarative, procedural, reflexive) memories.
• Working memory storage is mediated by various sites in the frontal lobes.
• The temporal lobe shows early degenerative changes (neurofibrillary tangles) in Alzheimer's Disease.
• In vitro electrophysiological model tissues can study cellular mechanisms of learning.
• In the hippocampal slice long-term potentiation model, NMDA receptors function as sources of calcium influx with strong, sustained depolarizing inputs.
• Elevated calcium, working via other second messengers and kinases, mediates synaptic remodeling.
• Roles of mediators are supported by experimental learning models.
• Protein synthesis changes in learning can be sustained by nuclear factors modifying mRNA transcription and proteins produced by dendritic ribosomes.
• Learning mechanisms are a basic property of the nervous system, studied in cellular models and organisms like invertebrates.
• Few clinical instances of memory dysfunction have proven susceptible to a clear understanding of their mechanisms, treatment, or improvement.
• Reading: Kandel, Schwartz, Jessel, Siegelbaum, & Hudspeth; Principles of Neural Science. 5th Ed. (2012. pp. 350-351, 374-381, 1441-1459, & 1461-1520.

Types of Memory

• Reflexive memory has an automatic quality and is not dependent on awareness, consciousness, or cognitive process.
• Reflexive memory is important in learning perceptual and motor skills.
• Reflexive memory can apply to automatic features of speech.
• Reflexive memory is also called implicit memory.
• Declarative memory depends on conscious reflection for acquisition and recall.
• Autobiographical memory is a form of declarative memory.
• Declarative memory consists of memories of events or actions that can be expressed in declarative statements.
• Driving a car initially has a conscious declarative quality but eventually becomes a reflexive memory.
• Declarative memory is also called explicit memory.
• Working memory is short term memory for temporary use.

Phases of Memory

• Types or phases of memory differ in how long they last and how sensitive they are to disruption.
• Long-term memory is permanent, though it may be hard to retrieve, and is not sensitive to disruption by brain hypothermia or electroconvulsive shock.
• Recent memories are more susceptible to disruption by electroconvulsive shock therapy (ECT).
• Graph data supports that after ECT, patients showed memory loss for recent programs (1-2 years old) but not older programs.
• Long-term memory isn't retained in reverberating circuits.
• Manipulations disrupt recently acquired memories, indicating memories transition from a short term, labile state, to a long-term permanent memory state.
• Short-term memory is temporary, lasting a few hours at most.
• Short-term memory may only last minutes when it is working memory, not intended for long-term storage.
• Short-term memory is easily disrupted, and disruption of recent memories by ECS is known as retrograde amnesia.
• Experimental demonstration: Teach animal two tasks a day apart and give ECS right after the 2nd task. Animal retains first task but lacks memory of 2nd task.
• Converting short-term memories to long-term memories is consolidation.
• Inhibition of protein synthesis or cAMP dependent protein kinase do not block learning, but can disrupt consolidation.
• The molecular mechanisms underlying consolidation involve cyclic AMP and protein synthesis mechanisms.

Memory Consolidation

• Different types of memory have different locations.

Declarative Memory

• Temporal lobe and esp. hippocampus are important for declarative memory.
• Temporal lobe lesion (incl. hippocampus): long-term memory remains intact.
• Short-term memory can be acquired, but consolidation does not occur.
• In the case of H.M., hippocampal system removal in the patient resulted in anterograde amnesia.
• Anterograde amnesia is an inability to transfer events to long-term memory.
• The sufferer will be unable to remember anything that occurs after the onset of this type of amnesia for a few moments.
• Sufferers from "pure" anterograde amnesia can still remember memories from before the onset of anterograde amnesia.
• Anterograde amnesia is usually accompanied by retrograde amnesia.
• Skill learning (reflexive memory) is unimpaired, even with hippocampal damage.
• An example is a hippocampal damaged piano player who could learn new tunes (reflexive memory) but have no memory of learning them (declarative memory).
• Temporal lobes are important for memory trace.
• During brain surgery, stimulation of temporal lobes activates "vivid experiences of past events."
• These stimulations activate the "memory neurons" or places that connect to the memory trace.

Long-term Memory

• Various areas are important in localization.

Declarative Memory

• Initially temporal lobe, but also elsewhere as memories become further consolidated.
• Long-term memory traces are found in medio-temporal, frontal & other areas of neocortex.
• Conditioning reflexes to a neutral stimulus (classical conditioning) is abolished by lesion to medial dentate and lateral interpositus nuclei of the cerebellum.
• Conditioning associated changes in electrical activity in these nuclei have been demonstrated.
• Conditioned fear responses are disrupted by lesions in the amygdala.
• Complex tasks involve more than one area of the brain.
• Tasks with a declarative component to them may also be hippocampal-dependent.
• Localization for different types of memories: multiple forms of long term memory are explicit (declarative) and implicit (nondeclarative), as well as working memory.
• Explicit memory includes facts & events using the temporal lobe, medio-temporal, frontal & other areas of neocortex.
• Implicit memory includes priming, procedural learning, associative conditioning, and nonassociative learning using sensory & prefrontal neocortex, striatum, amygdala & cerebellum, and reflex pathways.
• Working memory uses the frontal lobe.

Working Memory

• In monkeys, delayed spatial response is disrupted by bilateral lesions in the prefrontal cortex association area.
• For delayed alternation, a lesion in the principal sulcus disrupts.
• Neurons in this region are activated by spatial cues and continue to fire during the delay period.
• Dopamine is involved in working memory: Delayed alternation is disrupted by electrical stimulation or destruction of dopaminergic endings by localized application of 6-hydroxydopamine.
• Functional magnetic resonance imaging in human has identified an area in the superior frontal sulcus specialized for spatial working memory
• Dorsolateral prefrontal cortex is an area that functions subnormally in many schizophrenics.
• Dendritic spine density in layer three of dorsolateral prefrontal cortex is reduced in schizophrenics.
• Schizophrenic disorganization symptoms include conceptual disorganization, mannerism and posturing, difficulty abstracting, and poor attention.
• fMRI evaluated change in dIPFC activity during a working memory task.

Alzheimer's Disease

• Neurofibrillary tangles, an early degenerative change, starts early and most severely in the hippocampus, entorhinal cortex, and other temporal lobe areas.

Cellular Mechanisms

• Cellular mechanisms are searching for the physical/biochemical change corresponding to a memory.

Synaptic Theory of Learning

• Neuronal changes underlying learning are due to changes in synaptic efficacy.
• Cellular models to study synaptic modifications include Hippocampal slice, Amygdala slice, Cerebellar cortex, Abdominal ganglion of Aplysia.

Hippocampal Slice: A Electrophysiological Model

• Set up for studying LTP in the CA1 region by stimulating the Schaffer collateral pathway electricity and recording the response of the population pyramidal neurons.
• Appearance of the unpotentiated and potentiated CA3-CA1 synaptic potential.
• Comparison of early and late LTP in a cell in the CA1 region.
• The graph is a plot of the slope of the excitatory postsynaptic potentials (EPSPs) in the cell as a function of time.
• The slope is a measure of synaptic efficacy.
• A test stimulus was given every 60 s to the Schaffer collaterals.
• To elicit early LTP a single train of stimuli is given for 1 s at 100 Hz.
• To elicit the late phase of LTP four trains are given separated by 10 min.
• The resulting early LTP lasts 2-3 hours, whereas the late LTP lasts 24 or more hours.
• High frequency stimulation of the Schaffer collaterals causes a long-lasting increase in post-synaptic potentials in pyramidal cells of the CA 1 region of the hippocampus.
• This activation requires simultaneous activation of several collaterals, giving it an associative property.
• Changes here are similar to mechanisms occurring during declarative learning and when the hippocampus becomes epileptic.
• Repeated stimulation of the limbic system causes changes that lower the threshold for subsequent elicitation of seizures.

Cellular Mechanisms

• The Schaffer collaterals use glutamate as transmitter.
• Glutamate acts on both AMPA- and NMDA types of glutamate receptors.
• Ca² through NMDA receptors is necessary for LTP to occur.
• Non-NMDA glutamate receptors are permeable to only Na+ and K+; whereas NMDA receptors are also permeable to Ca2+.
• NMDA Glutamate receptors are gated by Mg2+ at resting potential.
• NMDA receptors must first be depolarized, e.g., by the receptor of AMPA receptors.
• Elevated calcium, working via other second messengers and kinases can mediate synaptic remodeling.
• [Ca2+]; in the post-synaptic cell activates Ca-calmodulin regulated kinase and C kinase to cause LTP to occur.
• These kinases phosphorylate the glutamate receptors, making them more sensitive.
• The kinases also increase insertion of glutamate receptors on reserve in internal vesicles into the synaptic membrane.
• Synaptic ending feed on the presynaptic ending to enhanced transmitter release.
• Nitric oxide (NO) may be involved.
• NO synthesis in neurons is Ca-calmodulin-dependent: arginine---------> NO+ citrulline
• Nitric oxide synthase can be blocked by LNNA or LNMA.
• LNNA or LNMA blocks LTP.

Mechanisms of Late Phase

• Nuclear pathway: Ca-calmodulin activates Ca-calmodulin-dependent adenylyl cyclase, resulting in increased [cAMP], resulting in activation of cAMP-dependent protein kinase.
• This phosphorylates CREB-1, resulting in increased synthesis of specific proteins, resulting in changes in synaptic structure
• Dendritic pathway: Protein synthesis on dendritic ribosomes synthesizes PKMĘ (the “zeta” form of PK resembles PKC but is constitutively active).
• PKMĘ promotes insertion of new glutamate receptors in the synaptic membrane and also feeds back on the dendritic ribosomes or mRNA to sustain the levels of PKM synthesis.
• CREB-deficient mice: maze- and fear learning is disrupted, impairing long-term not short-term learning
• Aplysia: cAMP, calcium, and for long-term memory, CREB-1, nuclear regulation and protein synthesis on synaptic ribosomes all play a role
• Drosophila mutations or modifications of calcium-calmodulin sensitive adenylyl cyclase, CREB, etc. disrupt memory.
• Rubenstein-Taybi syndrome is caused by mutations in the CREB-binding protein (CBP) that assists CREB in activating transcription at cyclic AMP response elements in the nuclear genome.
• Mental retardation is possibly related to CBP role in memory.