[HD 202] E01-T05-Neuroscience of Memory and Learning - Hippocampus

• These are study notes on neuroscience of memory and learning

Brain Neuroanatomy

• Lateral ventricles are C-shaped cavities present within each cerebral hemisphere
• The central part, or body, resides within the parietal lobe, with the roof consisting of the inferior surface of the corpus callosum
• Inferior horns exist in the temporal lobe, positioned laterally to the hippocampus
• The third ventricle is located medially between the two thalami and part of the hypothalamus
• Mammillary bodies extend from the undersurface of the hypothalamus

Hippocampus and Related Structures

• The parahippocampal gyrus (PHG) is mostly neocortex and connects to the hippocampus
• The hippocampus is not part of the neocortex because it does not contain 6 layers of neurons, characteristic of the neocortex
• The hippocampal formation includes the hippocampus proper and the dentate gyrus

Hippocampus Function Discovery

• Patient H.M.'s case (1953) revealed the role of the hippocampus in memory
• H.M. had intractable seizures and underwent bilateral resection of the medial temporal lobe to treat the condition
• This resulted in severe anterograde amnesia, preventing the formation of new memories
• Limited retrograde amnesia caused loss of events up to 2 years before the surgery

Amnesia Types and Memory Processing

• Anterograde amnesia prevents new memories after surgery
• Retrograde amnesia causes loss of pre-surgery events up to 2 years
• This case suggested the hippocampus is needed to form new memories & process old memories

Declarative Memory

• Declarative memory is a type of long-term memory
• It is the memory of facts and events
• Declarative memory was the type lost in patient H.M.
• Examples include memory for events, small and large, doctor's names, family events, etc

Further Experiments with Patient H.M.

• Dr. Howard tested H.M. by introducing and inviting him to lunch over multiple days
• Despite repeated meetings, H.M. did not remember previous encounters
• This indicated that memory was not retrievable or consolidated

Patient H.M.'s Brain Analysis and Surgical Practices

• Patient H.M. died in 2008, after which his brain was analyzed further
• Resection was stopped following patient H.M.'s case, but unilateral resections can occur in those with epilepsy

Preserved Memory Abilities in Patient H.M.

• Patient H.M. retained short-term memory (0-5 minutes) and remote long-term memory, like name, place of birth, and family members
• Non-hippocampal abilities preserved included learning of skilled movements, priming & conditioning

Mirror-Drawing Task and Procedural Memory

• Despite his amnesia, H.M. learned and improved on the mirror-drawing task
• He retained the motor skills over multiple days without conscious memory of the task or experimenters
• Case demonstrates a distinction between procedural memory (intact) and declarative memory (impaired), meaning procedural learning depends on brain systems outside the medial temporal lobe

Scientific Implications of H.M.'s Case

• H.M.'s performance provided strong evidence that different brain systems support different types of memory
• It also fundamentally advanced an understanding of human memory organization.

Encephalitis Case Study

• A 51-year-old male with herpes simplex encephalitis developed amnesia due to bilateral medial temporal lobe damage
• He kept a journal documenting his repeated experience of waking up for the first time each day highlighting the impact of anterograde amnesia

Long-Term Memory Divisions

• Declarative memory includes facts (semantic memory) and events (episodic memory)
• Both are dependent on the hippocampus, nearby cortical areas, and the diencephalon
• Procedural memory involves skills and habits, relying on the striatum, motor areas of cortex, and cerebellum

Memory and Associations

• Emotional associations involve fear memory and the amygdala
• Conditioned reflexes are associated with the cerebellum
• Working memory is dependent on the prefrontal cortex
• It is not the growth of new neurons

Electroconvulsive Treatment (ECT) and Memory Disruption

• Recent memories (programs aired 1-2 years prior) were more susceptible to disruption following ECT
• Older memories (programs aired 4-15 years prior) were less affected
• Recent memories are more vulnerable to disruption than older memories following ECT, supporting the idea that older memories are more stable and resistant to memory loss after trauma or treatment.

Hippocampus and Memory Vulnerability

• The hippocampus is essential for forming and retrieving recent declarative memories
• Recent memories are more vulnerable to disruption by ECT
• Older memories are stored in the neocortex and are no longer dependent on the hippocampus
• ECT may temporarily impair hippocampal function, leading to a greater loss of recent memories

Circuitry of the Hippocampus

• The entorhinal Cortex (EC) sends sensory and spatial information to the hippocampus, acting as a gateway for memory processing
• The dentate Gyrus (DG) filters and organizes incoming information, separates between similar experiences
• CA3 integrates information and forms associative memories
• CA1 refines memory output, essential for long-term memory storage and retrieval
• The Subiculum bridges the hippocampus with other cortical areas with involvement in memory consolidation

Neocortex Communication and Memory

• The hippocampus integrates/consolidates/stores long-term memories and retrieves them when needed
• Unimodal/Polymodal association cortexes process sensory data
• The perirhinal Cortex does object recognition
• The parahippocampal Cortex analyzes and adds context to object memory
• The entorhinal Cortex relays processed sensory, object, and contextual information to the hippocampus

Ischemia-Induced Cell Death and Memory Loss

• CA1 is highly sensitive to oxygen and glucose deprivation, brief ischemic episode can disrupt its normal function
• Stroke or even a brief ischemic episode can reduce blood flow leading to a lack of oxygen and glucose which are essential to neuronal function
• Therefore, the tricepic pathway is broken & memory loss occurs (interferes with the memory pathway).

Memory Formation and Synaptic Change

• Memories are stored as a set of synaptic weights
• New patterns in the cortex change how information flows through a network
• Learning causes Cell A projects to Cell B with a strong connection
• Synaptic strength reflects the timing or co-occurrence of events

Synaptic Strengthening and Long-Term Potentiation (LTP)

• Cell A projects to Cell B, releasing glutamate, which binds with amper receptor -> depolarizes Cell B
• Glutamate also binds with NMDA receptors -> Sodium can't enter (membrane is not depolarized -> Calcium enters instead -> Ca activates kinases inserts receptors into membrane -> strengthened synapse
• Mg is highly positive, postsynaptic cell is depolarized, Mg is pushed out, Calcium can now enter
• Two factors are required for Ca to enter NMDA channel: release of glutamate (firing of cell A) and depolarization of call B to relieve Mg block (firing of cell B)

Hebb's Rule

• Hebb's Rule states "Neurons that fire together wire together, Neurons that never fire together weaken"
• NMDA receptors can detect the association between the event firing cell A and the event firing cell B

Long-Term Potentiation (LTP)

• LTP involves the growth of new synapses and doubling of synaptic spines
• AMPA and NMDA receptor activation
• Synaptic strengthening, induced by high-frequency stimulation is what underlies long-term memory

Hippocampus and Mental Illness

• The hippocampus is involved in severe mental illness and experiences volume reduction in schizophrenia, PTSD and depression
• It is a site of adult neurogenesis, though new cells do not necessarily correlate to new memories

Korsakoff's Syndrome

• The degeneration of mammillary bodies and MD causes severe anterograde amnesia
• Often results from thiamine deficiency or chronic alcoholism
• Patients tend to confabulate, to cover up memory deficit

Working Memory

• Working memory lasts seconds to minutes and is important for consciousness and stream of thought
• This allows people to hold information for only a limited time Ex. Telephone
• It is encoded and activated in the lateral area of the prefrontal cortex

Prefrontal Disinhibition: Phineas Gage

• Phineas Gage was a railroad worker with brain injury from a railroad spike
• The railroad spike severed his cheek and penetrated his prefrontal cortex, through the head
• Gage survived but had personality changes, becoming more aggressive and gambling.
• This famous case suggested the prefrontal cortex is tied to higher reasoning

Alzheimer's Disease

• In Alzheimer's disease, tangles and plaques develop within the cell and can destroy the cell and originates in the anterior cortex

Alzheimer's Progression

• The hippocampus does not receive information properly leading to memory problems, and as the disease progresses, the damage spreads to other cortical areas
• Alzheimer's does not affect sensory or motor areas because Alzheimer's preferentially affects association (thinking) cortex
• Ascending cholinergic fibers are lost in Alzheimer's

Tau Protein and Axonal Projections

• Tau Proteins: Alzheimer spread in the brain moves along the axonal projections and synaptic connections
• Damaged tau 1st strikes the entorhinal cortex then the neighboring parahippocampal cortex then the hippocampus, and so forth.
• Vaccines can be used against beta-amyloid or tau

Approaches to Alzheimer's

• New potential treatments are focused on neuroinflammation, Fyn kinase, Tau aggregation inhibitors
• Lowering modifiable heart disease could improve Alzheimer's