Memory II

Identifying the Critical Circuits and Cell Types

Summary of Core Concepts

  • Memory Engram: Defined as "the specific ensemble of neurons whose lasting physical and synaptic changes encode a memory and whose reactivation leads to its recall". It is often referred to as a memory trace.
      - Key Researcher: Susumu Tonegawa (MIT, USA)

Approaches Used to Identify Memory Engrams

Different methodologies are employed to identify memory engrams:

  1. Calcium Imaging: Technique utilized to measure the calcium ion concentration, which indicates neuronal activity.
  2. PHluorin Imaging: Involves genetically encoded calcium indicators to visualize activity in living cells.
  3. Single Unit Tetrode Arrays: Microelectrodes used to record the action potentials of individual neurons.
  4. Lesion Chemical Techniques: Methods involving targeted destruction of specific cells to assess the effects on memory.
  5. Silencing Cells: Involves various methods:
       - DTx (Diphtheria toxin): Kills specific neurons through receptor-mediated endocytosis.
       - Inhibitory DREADD (Designer Receptors Exclusively Activated by Designer Drugs): Allows control of neuronal activity via pharmacological agents.
       - Excitatory DREADD: Similar to inhibitory but facilitates neuronal activation.
       - Channelrhodopsin: Light-activated ion channel for cell activation through light exposure.
       - TRPV1 + Capsaicin: Neurons expressing TRPV1 are activated by capsaicin (the component responsible for spiciness in chili peppers).
       - cFos-tTA/TetO-ChR2: A system used for controlling gene expression whereby specific neurons are tagged for manipulation when activated.
       - cFos-tTA/TetO-ChEF: Another system for manipulation based on activity-induced expression.
       - cFos-ChR: Allows optical control of neuronal activity based on cFos expression.

Hippocampal Tri-Synaptic Circuit

  • Circuit Pathway: The tri-synaptic circuit consists of the following key components:
       - Entorhinal Cortex (EC) → Dentate Gyrus (DG) → CA3 → CA1
  • Reference Study: Hainmueller T, Bartos M demonstrate how these circuits are involved in the encoding, retrieval, and discrimination of episodic memories (Nat Rev Neurosci, 2020).

Memory Types Within the Tri-Synaptic Circuit

  • Different Brain Areas: Each region within the hippocampal circuit encodes distinct types of memories:
      - Subiculum
      - Dentate Gyrus (DG): Granule Cells (GC)
      - CA3: Pyramidal Cells (PC)
      - CA1: Pyramidal Cells (PC)
      - The subiculum serves as a significant output structure of the hippocampus.
  • Distinct Cell Types: Each area hosts various cell types that are responsible for storing different kinds of memories.
  • Reference Study: Basu J, Siegelbaum SA (Cold Spring Harb Perspect Biol, 2015).

Observational Studies on Place and Grid Cells

Discovery of Place Cells

  • John O'Keefe: Discovered in 1971 that certain neurons in the hippocampus (referred to as place cells) are activated when a rat is in specific locations, effectively forming an internal map of the environment.
  • Function: Each place cell activates based on the rat's location in the environment.

Discovery of Grid Cells

  • May-Britt and Edvard I. Moser (2005): Identified grid cells in the entorhinal cortex, activated as rats navigate, creating a consistent hexagonal pattern in their activity.
  • Function: Grid cells provide a coordinate system that enhances spatial navigation abilities.

Interaction Between Place and Grid Cells

  • Place Cells: Rapidly form when an animal explores a new environment, with their spatial firing patterns stabilizing as the animal gains experience (contributing to spatial memory).
  • Place Fields: Anchored to visual landmarks, indicating that the visual context influences their firing patterns. Movement of visual cues can also shift the position of place fields.

Loss-of-Function Studies on CA2's Role in Social Memory

Findings Related to CA2 Region

  • Studies utilizing the Amigo2-cre mouse line have shown the following:
      - CA2 Neurons: Essential for recognizing familiar conspecifics; their silencing prevents social memory retrieval, while spatial and object memory remains unaffected.
      - Significant literature: Hitti FL, Siegelbaum SA (Nature, 2014).

Gain-of-Function Studies

Tonegawa et al. (2015) on Memory Engram Cells

  • Outlined advancement in understanding and manipulating memory engrams.

Gain-of-Function Research on Fear Memory

  • Findings from Liu et al. (2012):
      - Hippocampal Engrams: Specific neuronal circuits implicated in the encoding of fear memories.
      - Artificial Activation: Engaging these engrams can trigger fear memory recall independently of the original context.

Summary of Key Points

  • Engram Definition: A group of neurons involved in storing specific memories.
  • Hippocampus Functions: Plays a central role in spatial, social, and fear-related memories.
  • Trisynaptic Circuit Pathway: Summary of the main pathway: EC → DG → CA3 → CA1
  • Subiculum: Acts as the primary output structure of the hippocampus.
  • CA1 Connectivity: Highly interconnected and implicated in conditions like temporal lobe epilepsy.
  • Navigation System: Place cells and grid cells interact to form an individual's navigational framework (akin to a GPS).
  • CA2's Role: Critical for social memory recognition.
  • Genetic Manipulation Tools: New techniques have emerged that enable direct identification and manipulation of memory engrams for research purposes.