Study Notes on Synaptic Plasticity, Memory, and Learning

Synaptic Plasticity Overview

  • Synaptic plasticity refers to the changes in the strengths of synaptic connections in response to experience and neuronal activity.

    • Key forms of synaptic plasticity include:

    • Hebb’s rule (1949): Formulated the idea that an increase in the synaptic strength arises from the repeated and persistent stimulation of one neuron by another.

    • Long-Term Potentiation (LTP) (1970): A long-lasting enhancement in signal transmission between two neurons that results from stimulating them simultaneously.

    • Long-Term Depression (LTD) (1978): A long-lasting decrease in synaptic strength following a pattern of activity.

    • Spike-Timing-Dependent Plasticity (STDP) (1997): A biological learning rule that expresses how the relative timing of spikes from the pre- and postsynaptic neurons determines the sign and magnitude of the change in synaptic strength.

    • Homeostatic plasticity (1998): The ability of neurons to stabilize their activity by adjusting their synaptic strengths in response to changes in overall network activity.

    • Structural plasticity: Changes in the number and structure of synapses in the brain as a response to learning and memory.

Relationship Between Learning and Memory

  • Spatial Learning and Memory

    • The relationship between hippocampal LTP and spatial memory is crucial for understanding memory encoding.

    • Important concepts:

    • Memory engram: The physical embodiment of memory in the brain, often theorized to reside within specific neurons and synapses that undergo plastic changes during learning.

    • Hippocampal LTP is fundamental for spatial learning: For example, experiments show that manipulations that alter hippocampal LTP also impact spatial memory performance.

Research Insights and Methodologies

  • Experimental Methods to Assess Memory:

    • Morris Water Maze: An experimental tool used to measure spatial learning and memory, where rats learn to find a hidden platform within a pool of water, demonstrating learning via time to find the platform.

    • Example data from the Morris Water Maze experiment shows control rats are able to locate the hidden platform faster than hippocampal-lesioned rats, indicating the critical role of the hippocampus in spatial memory.

    • Control rat: Time to find platform is significantly lower (e.g., 60 seconds).

    • Hippocampal-lesioned rat: Longer time, reaching up to 110 seconds in some trials.

  • LTP Mechanisms: Phases and Elements

    • Early Phase of LTP: Triggered by repeated high-frequency stimulation (HFS), increasing Ca2+ influx through NMDA receptors, leading to activation of adenylyl cyclase, and subsequent cAMP and PKA activity.

    • Late Phase of LTP: Involves gene expression changes mediated by CREB and c-FOS, solidifying synaptic changes.

    • Roles of calcium signaling and AMPA receptor insertion in the postsynaptic membrane are emphasized in LTP consolidation.

Molecular Mechanisms of Memory Encoding

  • CaMKII: A critical molecule for memory; acts as a historical record of local calcium signaling within the neuron.

    • Autophosphorylated CaMKII can phosphorylate AMPA receptors, increasing their availability on the postsynaptic membrane, potentially enhancing synaptic strength and efficacy.

Hypotheses on Memory and Synaptic Connections

  • Hypothesis I: Memory is stored in the strength of synaptic connections within neural circuits.

    • The synaptic weight matrix model could theoretically store vast amounts of information by linking specific input patterns (events) to particular output patterns (memories).

  • Hypothesis II: Learning processes modify the strengths of these synaptic connections.

    • This suggests a causal relationship between learning experiences and alterations in synaptic weights.

Experimental Evidence of Learning-Induced LTP

  • Studies question whether learning induces hippocampal LTP.

    • Utilizing multielectrode recordings at CA1 to measure neural activity before and after training provides insights.

    • Findings indicate that a small fraction of electrodes from trained rats exhibited detectable potentiation post-training, supporting the hypothesis of induced synaptic changes.

  • Saturation of LTP:

    • Examined how residual LTP affects further learning; findings suggested that minimal residual LTP may indicate saturation and limit the capacity for further synaptic strengthening during learning.

Cellular Mechanisms of Memory Recall

  • Investigating whether specific neuron populations active during learning can be reactivated to trigger memory recall.

    • Tagging Neurons: Techniques such as using Fos-tTA mice, where immediate early gene c-Fos under controlled conditions marks active neurons during learning, allows tracking and retrieval experiments.

    • Expression under specific conditions (absence of doxycycline, dox) confirms the successful tagging and activation of targeted neurons.

  • Contextual Fear Conditioning:

    • Activation of neuron populations engaged during fear conditioning can evoke fear responses, demonstrating the functional role of these previously active circuits in memory recall.