25.1

Chapter 25: Molecular Mechanisms of Learning and Memory

Forging Long-Term Memories: Permanent Synaptic Modification is a Necessity

  • Memory Acquisition:

    • Sensory experiences are encoded by synaptic modifications that alter neuronal firing patterns.

    • Synaptic modifications are temporary and are responsible for short-term memory.

  • Memory Consolidation:

    • Temporary synaptic modifications are made permanent, necessary for long-term memory.

    • This process requires new gene expression and protein synthesis.

Reminder from Chapter 10: Ventral Stream

  • Ventral Stream Overview:

    • Pathway: V1 → V2 → V3 → V4 → IT (Inferotemporal cortex) → Other ventral areas.

  • Fusiform Face Area (FFA):

    • Part of area IT and responsive to faces.

    • Prosopagnosia:

    • A condition characterized by difficulty identifying faces despite having normal vision.

Memory of Faces and Area IT

  • Location of Area IT:

    • Located in the Inferotemporal cortex.

  • Neuronal Response to Faces:

    • Neurons in Area IT demonstrate selective responses to faces from first exposure.

    • The firing pattern of these neurons becomes increasingly selective with repeated exposures to the same face.

    • Each face elicits a unique firing pattern, representing what can be termed a 'memory trace.'

Distributed Memory Storage in Area IT

  • Distributed Activity Pattern:

    • Neurons in Area IT exhibit a distributed pattern of activity representing various faces.

  • Neuron Responses:

    • In the learning phase, neurons A, B, and C initially respond equally to the faces of individuals—Mark, Barry, and Mike.

    • After learning, neurons A, B, and C still respond to all three faces but show specific face preferences.

    • Significance: Memory is encoded in a pattern of activity distributed across multiple neurons, which follows a neural network model.

    • Example: If neuron A were to die, neurons B and C would still maintain a memory pattern for Mark, demonstrating memory degradation but not loss.

Molecular Mechanisms of Learning: Invertebrate Models

  • Advantages of Invertebrate Studies:

    • Invertebrates possess small, rudimentary nervous systems with large, identifiable neurons and simple neural circuits and genetics.

  • Example:

    • Gill-withdrawal reflex studied in Aplysia californica, showcasing simple learning mechanisms.

Molecular Mechanisms of Simple Learning in Aplysia: Sensitization

  • Basic Circuitry: Gill-Withdrawal Reflex:

    • Noxious stimulus (e.g., shock) to the tail activates the serotonergic (5HT) modulatory neuron, making a synapse on the terminal of the siphon sensory neuron.

    • Activation of 5HT receptors stimulates cyclic AMP (cAMPcAMP) production and subsequently activates Protein Kinase A (PKA) at the sensory neuron’s axon terminal.

    • This results in an increased release of glutamate onto the motor neuron following subsequent siphon stimulation.

    • This is noted as short-term sensitization, which is not sustainable over the long term.

  • Long-Term Sensitization:

    • Repeated shocks to the tail lead to new gene expression and protein synthesis due to PKA activation, resulting in long-term changes to synaptic glutamate responses.

Summary of Molecular Mechanisms of Invertebrate Learning

  • Neural Basis of Memory:

    • Studies reveal that short-term memory can arise from altered patterns in synaptic transmission.

    • Synaptic modifications derive from neural activity converting into intracellular second messenger activation—these are foundational for short-term memory.

    • Long-term memory is correlated with changes in synaptic protein expression.

  • Question Addressed:

    • Are similar molecular changes associated with learning in vertebrate models?

Microcircuits in the Hippocampus of the Rodent

  • Main Inputs:

    • The entorhinal cortex serves as the major input to the hippocampus, linking grid cells to place cells.

  • Pathway Overview:

    • Entorhinal Cortex → Dentate Gyrus

    • Perforant Path synapses → Dentate Gyrus → CA3

    • Mossy Fiber synapses → CA3 → CA1

    • Schaffer Collateral synapses → CA1

Molecular Mechanisms of Synaptic Plasticity in the Vertebrate Hippocampus

  • LTP and LTD:

    • Both Long-Term Potentiation (LTP) and Long-Term Depression (LTD) observed in the hippocampus are crucial for forming declarative memories.

    • Landmark studies by Bliss and Lomo (1973) showed that high-frequency electrical stimulation of the excitatory pathway (Perforant Path) induced LTP in awake rats.

    • Advanced methods include hippocampal brain slice preparations that demonstrate LTP and LTD following stimulation of the Schaffer Collateral.

Long-Term Potentiation (LTP) is Long Lasting

  • Stimulation Results:

    • Hippocampal stimulation via the perforant path shows that excitatory postsynaptic potentials (EPSPs) remain enhanced long after the initial high-frequency stimulation, evidencing LTP after one instance of stimulation.

Long-Term Potentiation (LTP) in CA1

  • Tetanization Process:

    • A tetanus is defined as a brief burst of high-frequency stimulation; 50-100 stimuli at a frequency of 100/sec are applied to Input 1 (Schaffer Collateral) in slice preparations.

  • LTP Characteristics:

    • This tetanus produces a sustained enhancement in CA1 responses to subsequent Input 1 stimulation while showing no change in responses to Input 2 (Schaffer Collateral, CA3 to CA1).

    • Notably, LTP is input-specific; stimulation of Input 2 does not alter CA1 response.

Activation of NMDA Receptors is Key to LTP

  • Glutamate's Role:

    • Release of glutamate (GLU) from Input 1 binds to NMDA receptors on the CA1 postsynaptic neuron, which is subject to magnesium (Mg2+) blockade.

Molecular Mechanisms of LTP in CA1

  • Calcium Dynamics:

    • Presynaptic glutamate release activates postsynaptic NMDA and AMPA receptors.

    • Under lower postsynaptic membrane potentials, only minimal calcium (Ca2+) entry occurs due to Mg2+ blockade.

    • Upon substantial presynaptic glutamate release concurrent with significant postsynaptic depolarization, Mg2+ is dislodged, facilitating increased Ca2+ entry into the postsynaptic neuron.

    • This is known as Spike Timing-Dependent Plasticity (STDP). However, the pathway to achieving long-term changes remains to be elucidated.

Role of Protein Kinases in LTP

  • Calcium-Dependent Kinases Activation:

    • Ca2+ entry via NMDA receptors activates specific protein kinases:

    • Protein Kinase C (PKC)

    • Calcium-Calmodulin-Dependent Protein Kinase II (CaMKII)

    • Phosphorylation of AMPA receptors by either PKC or CaMKII enhances ionic conductance.

    • Additionally, synaptic proteins undergo phosphorylation (likely through CaMKII), which increases the cell surface expression of AMPA receptors.

Structural Changes Associated with LTP

  • Dendritic Spine Dynamics:

    • Postsynaptic dendritic spines exhibit budding and formation of new synaptic contacts with presynaptic neurons, achieved by upregulation of AMPA receptors present at the synapse.

    • An experiment using glutamate application (LTP-inducing) at time zero visualizes these new spines over time, corroborating the concept of Hebbian synapses—"cells that fire together, wire together!"

Long-Term Depression (LTD)

  • Synaptic Effectiveness:

    • Information can be retained not only as enhancements but also as reductions in synaptic effectiveness.

    • Long-term depression (LTD) must occur at specific synapses, characterized as an anti-Hebbian mechanism.

    • Inquiry posed: What mechanisms dictate the bidirectional capacity for synaptic plasticity?

Long-Term Depression (LTD) in CA1

  • LTD Mechanism:

    • A low-frequency tetanus (1 Hz) applied to Input 1 (Schaffer Collateral) produces a long-lasting depressed response of CA1 to this input's subsequent stimulation.

    • Similar to LTP, LTD is input-specific; no alteration occurs in responses to Input 2.

Molecular Mechanisms of LTD in CA1

  • Calcium Dynamics:

    • Dependent on Ca2+ influx through NMDA receptors, a low-frequency tetanus enables only a modest calcium entry during subsequent stimulation.

  • Action of Protein Phosphatases:

    • Low Ca2+ concentrations activate protein phosphatases instead of kinases, resulting in dephosphorylation of AMPA receptors and other postsynaptic proteins.

NMDA Receptor Activation and Bidirectional Synaptic Plasticity

  • Synaptic Response:

    • When postsynaptic cells exhibit weak depolarization from other inputs:

    • Active synapses are predisposed to undergo LTD.

    • Conversely, when strongly depolarized:

    • Active synapses are more inclined towards LTP.

    • The activation of NMDA receptors is pivotal for calcium influx, determining the modification threshold for synaptic plasticity.

LTP and LTD: Importance of Calcium Dynamics

  • Stimulation Types:

    • High Frequency Stimulation (HFS) paired with Low Frequency Stimulation (LFS) marks the spectrum of synaptic modifications.

    • Between these two frequencies lies the modification threshold at which no LTP or LTD occurs.

AMPA Receptor Trafficking

  • Egg Carton Model Explaining Receptor Dynamics:

    • An illustrative analogy shows AMPA receptor trafficking at the synapse, where approximately half of AMPA receptors turnover every 15 minutes.

    • The model depicts the membrane's capacity for AMPA receptor insertion, reliant upon the expression of postsynaptic density proteins (e.g., PSD-95, known as a slot protein).

    • Each 'egg' represents an AMPA receptor. The blue eggs signify receptors containing the GluR1 subunit (slot protein).

Conditions Under Different States:

  • Steady State Conditions:

    • Each AMPA receptor's removal is offset by the installation of a new AMPA receptor.

  • Following LTP:

    • There’s an increase in PSD-95 leading to enhanced capacity for new GluR1-containing AMPA receptors to fit into the newly available slots, establishing a new steady state.

  • Following LTD:

    • Some PSD-95 proteins are deconstructed, reducing the available capacity for AMPA receptors. The newly established steady state is characterized by a uniform turnover of non-GluR1 AMPA receptors.

    • Observational studies of GluR1 knockout mice reveal impairments in hippocampal LTP and cerebellar long-term depression.

LTD Observed in the Cerebellum

  • Cerebellar Learning Mechanisms:

    • Investigates synaptic plasticity within the cerebellar cortex, which comprises climbing fibers (excitatory input from the medulla) and parallel fibers (input from cerebellar granule cells).

    • The concurrent input from both fibers aids in coordinating movements while also highlighting disruptions needing correction (movement error signals).

LTD in Cerebellar Learning

  • Conditioning Mechanisms:

    • Pairing of climbing fiber stimulation with parallel fiber stimulation simulates an error signal. This results in LTD at the Purkinje cells upon further parallel fiber stimulation.

    • The process underlying LTD demands a significant postsynaptic calcium influx, paralleling LTP mechanisms observed in the hippocampus.

Conclusion of Today's Lecture

  • Topics Covered:

    • Memory acquisition, the strengthening and weakening of synapses, with a detailed examination of LTP and LTD but excluding long-term memory discussions except for the Aplysia model.

  • Final Remark:

    • The next lecture encapsulates concepts surrounding LTP, LTD, and memory consolidation.