Chapter 54

Memory Formation

In this section, we will discuss explicit memory formation with a focus on the role of the hippocampus and specific mechanisms involved in the process.

Explicit Memory

Explicit memory, also known as declarative memory, refers to our knowledge of facts and people. It can be subdivided into two main categories:

1. Episodic Memory - Recall of events or episodes from one’s life, often involving specific contextual details like time, place, and associated emotions. This is considered 'autobiographical' memory.

2. Semantic Memory - Recall of words, meanings, concepts, and general knowledge about the world, independent of personal experience. It's often thought of as a mental encyclopedia.

Role of the Hippocampus

• Explicit memory primarily relies on the hippocampus for the initial formation and consolidation of memories, transferring them from short-term to long-term storage in other cortical areas.

• This region is responsible for various types of memory, including spatial and episodic memory, and plays a role in both pattern separation (dentate gyrus) and pattern completion (CA3).

Memory Formation Mechanisms

Memory storage within the hippocampus is largely mediated through changes in synaptic strength and efficacy, primarily involving:

1. Synaptic Plasticity - Refers to the ability of synapses to strengthen or weaken over time in response to increases or decreases in their activity. These changes can be short-term or long-term and are fundamental to learning and memory.

2. Long-Term Potentiation (LTP) - A persistent strengthening of synapses based on recent patterns of activity. It is a key mechanism for enhancing synaptic strength following high-frequency stimulation of an input, often involving increased AMPA receptor density/efficiency and sometimes structural changes.

3. Long-Term Depression (LTD) - A persistent weakening of synaptic connections, often involving the removal or internalization of AMPA receptors. This process provides a balance to the storage of memories, helping to clear out old or irrelevant information and optimize storage capacity.

• Both LTP and LTD contribute to memory storage through specific signaling pathways involving the NMDA and AMPA receptors, with calcium influx through NMDA receptors acting as a critical trigger, dictating the specific intracellular cascades.

Cell Assemblies

• Memory is thought to be encoded by cell assemblies, a concept proposed by Donald Hebb.

• A cell assembly is a group of neurons that, through repeated synchronous activation, become functionally interconnected, forming a stable neural representation of a specific memory or concept.

• "Neurons that fire together, wire together" describes the principle by which synaptic connections between neurons within an assembly are strengthened via mechanisms like LTP, allowing the assembly to store and retrieve information as a functional unit.

Key Neurotransmitters and Receptors

• Glutamate: The main excitatory neurotransmitter in the central nervous system, critically involved in LTP and LTD.

• NMDA Receptor:

  • Involved in synaptic plasticity and controlling synaptic changes.

  • It is a ligand-gated ion channel that is also voltage-gated due to a magnesium block ($Mg^{2+}$) at resting membrane potential.

  • Requires both glutamate binding and postsynaptic depolarization (to remove the $Mg^{2+}$ block) to open, allowing $Ca^{2+}$ and $Na^{+}$ influx into the neuron. The $Ca^{2+}$ influx is crucial for initiating downstream signaling pathways for LTP and LTD.

• AMPA Receptor:

  • Works alongside NMDA receptors in promoting excitatory responses within the synapse.

  • It is a ligand-gated ion channel that primarily allows $Na^{+}$ influx, causing rapid depolarization of the postsynaptic neuron.

  • Its density and phosphorylation state at the postsynaptic membrane are major determinants of synaptic strength and short-term synaptic plasticity.

Explicit Memory in Media

• Explicit memory is often illustrated in various media, such as movies and TV shows.

• For instance, in movies like Memento, characters display deficits in episodic memory whereby they cannot recall people or places, illustrating a severe form of anterograde amnesia concerning new personal experiences.

• Example: A character struggles to recognize their husband due to memory loss, highlighting a deficit in recalling specific personal information (episodic memory) even if semantic knowledge might be intact.

Hippocampal Anatomy and Memory Storage

• The hippocampus has several key regions involved in memory formation:

1. Dentate Gyrus - Acts as a pattern separator, transforming similar inputs into distinct representations. This is vital for forming unique and distinct memory traces for even similar experiences, preventing interference. It is also a site of adult neurogenesis.

2. CA3 Region - Important for pattern completion, allowing the recall of an entire memory from a partial cue due to its extensive recurrent collateral network that facilitates auto-associative memory.

3. CA1 Region - Receives integrated information from CA3 (via Schaffer collaterals) and the entorhinal cortex. It is crucial for the output of processed information from the hippocampus and plays a significant role in memory consolidation.

Trisynaptic Circuit

This circuit describes how information travels through the hippocampus:

1. Entorhinal Cortex (EC) - The primary interface between the hippocampus and the neocortex, serving as the first point of information entry into the hippocampus via the perforant path. It is functionally segregated into:

   • Medial Entorhinal Cortex (MEC): Primarily processes spatial information, containing grid cells, head direction cells, and border cells, which send input mainly to the dentate gyrus and CA3 region.

   • Lateral Entorhinal Cortex (LEC): Primarily processes non-spatial, contextual information related to objects and sensory features, sending input predominantly to the CA1 region and subiculum.

2. Granule Cells in Dentate Gyrus - These are the principal excitatory neurons of the dentate gyrus that receive input from the entorhinal cortex via the perforant path. They are critical for pattern separation, where distinct neural representations are created for similar experiences, avoiding memory interference. This is achieved through sparse coding and adult neurogenesis.

3. CA3 Neurons (Mossy Fibers) - Receive output from granule cells (via mossy fibers, which are the axons of dentate gyrus granule cells) and communicate to CA1 through Schaffer collaterals. CA3 also has strong recurrent collateral connections crucial for pattern completion.

Long-Term Potentiation in Hippocampus

• Mechanisms:

  • Upon sufficient depolarization of the postsynaptic neuron by AMPA receptors, the $Mg^{2+}$ block is removed from NMDA receptors.

  • This allows $Ca^{2+}$ influx through NMDA receptors, which activates various downstream kinases such as PKA, PKC, and particularly CaMKII (Calcium/calmodulin-dependent protein kinase II).

  • CaMKII is important for inserting new AMPA receptors into the postsynaptic membrane or increasing their conductance, leading to enhanced postsynaptic responsiveness.

  • Activated signaling cascades, such as activation of PKA and CREB (cAMP response element-binding protein), lead to changes in transcriptional activity and protein synthesis, necessary for long-lasting structural changes.

• Early Phase LTP: Lasts minutes to hours; results from post-translational modifications (e.g., phosphorylation of existing proteins) and recruitment of existing AMPA receptors to the synapse. It does not require protein synthesis.

• Late Phase LTP: Lasts days to years; requires changes in gene expression and de novo protein synthesis, leading to structural modifications like the formation of new synapses or remodeling of dendritic spines, making the potentiation enduring.

Induction of Long-Term Potentiation

• Timing of neuronal firing is crucial; the presynaptic neuron must fire before the postsynaptic neuron for LTP induction. This is a core principle of Spike-Timing-Dependent Plasticity (STDP).

  • If the presynaptic neuron fires before the postsynaptic neuron ($\Delta t > 0$), it typically leads to LTP.

• If the postsynaptic neuron fires first ($\Delta t < 0$), it leads to Long-Term Depression (LTD).

• Thus, the synaptic strengths are altered depending on the precise firing order and timing, providing a mechanism for Hebbian learning.

Characteristics of Long-Term Potentiation

1. Cooperativity: Multiple inputs need to converge and sufficiently activate the postsynaptic neuron to achieve the depolarization threshold required to remove the NMDA receptor's $Mg^{2+}$ block, allowing $Ca^{2+}$ influx and LTP induction.

2. Associativity: A weak synaptic input, when activated concurrently with a strong synaptic input on the same postsynaptic neuron, can become potentiated. This is proposed as a cellular mechanism for associative learning, like classical conditioning.

3. Specificity: LTP occurs only at those synapses that were strongly and actively stimulated during the learning process; inactive synapses on the same neuron do not undergo potentiation.

Spatial Memory

• The hippocampus is vital for spatial navigation and memory, housing specialized neurons like place cells.

• Cognitive Map: O'Keefe and Nadel proposed that the hippocampus creates a "cognitive map" of the environment, a neural representation of spatial layouts that animals use for navigation and memory. This map is constructed by integrating input from various specialized cells:

  • Place cells in the hippocampus encode specific locations.

  • Grid cells in the MEC provide a metric, representing distances and directions.

  • Direction cells and border cells contribute to orientation and boundary detection.

• Morris Water Maze: A common behavioral test used to evaluate spatial memory in rodents. Animals must learn to find a submerged platform using visual cues in the environment. Animals without functioning NMDA receptors often take significantly longer to find the platform, indicating deficits in spatial learning and memory.

• Barnes Maze: Another test for spatial memory in rodents, where the animal must find an escape box located under one of many holes on a circular platform, relying on spatial cues to remember the correct location.

Relating Memory to Environment

• The environment can trigger memory recall; spatial memory interacts with sensory inputs to form comprehensive memory traces.

Neural Mechanisms in Spatial Navigation

1. Place Cells: Located in the hippocampus (particularly CA1 and CA3), these neurons activate based on the animal's specific physical location in an environment, encoding a 'cognitive map'.

2. Grid Cells: Found in the medial entorhinal cortex, these neurons create a hexagonal, grid-like representation of the environment, providing a metric for spatial navigation.

3. Direction Cells: Fire based on the animal's head direction, irrespective of its location.

4. Border Cells: Activate at the edges or boundaries of an environment, indicating proximity to physical barriers.

5. Speed Cells: Fire according to the animal's movement speed, providing information essential for navigating and estimating time to reach a location.

Hippocampus and Memory Disorders

• Damage to the hippocampus can lead to amnesia:

  • Anterograde Amnesia: The severe inability to form new explicit long-term memories after the onset of injury or disease. Older memories may remain intact.

  • Retrograde Amnesia: The inability to recall previously formed memories before the onset of the amnesia. The extent can range from recent events to memories from decades past.

• Neurodegenerative disorders like Alzheimer’s disease show significant structural changes and atrophy in the hippocampus, leading to progressive explicit memory deficits. Key pathological features include the accumulation of amyloid-beta plaques (extracellular protein deposits) and neurofibrillary tangles (intracellular aggregates of hyperphosphorylated tau protein), which impair synaptic function and cause neuronal death.

Conclusions and Future Directions

• Exploration of memory mechanisms will help delve into neurodegeneration treatment and understanding unique human experiences in memory formation, offering insights into preventing and treating memory-related diseases.

Next Lecture

• Discussion will shift towards semantic memory, emphasizing knowledge and language storage mechanisms related to memory formation and how they differ from episodic memory.