Comprehensive Study Notes on Cortical Plasticity and Synaptic Mechanisms

Overview of Cortical Plasticity

Cortical plasticity refers to the brain's inherent ability to reorganize itself by forming new neural connections. This process is fundamental to the brain's structure and function throughout the human lifespan, even into old age. Plasticity serves as the primary mechanism behind the modification of behavior, the acquisition of new motor skills, and the recovery process following neurological injuries.

Evidence for this capacity is detailed in scientific literature and popular texts, such as the book by Norman Deutsch, which explores how scientific discoveries exploiting plasticity transform human lives. Academic foundations for these concepts are found in texts by Bayer and Perfs regarding cellular aspects of synaptic plasticity and a review by Donohue concerning the mechanisms of cortical reorganization.

Cortical Map Representation and Somatotopy

The human body is represented in an organized map within both the primary sensory and motor cortex. This organizational structure is consistent across species, showing specific mapped regions for body parts.

Structure of the Hand Area

• Primary Cortical Areas: Recordings from areas $3B$ and $1$ reflect the primary sensory and motor cortex.

• Mirroring: Mapping of the hand area reveals that the sensory and motor cortex maps are mirror images of one another.

• Specific Regions:

  • The shaded regions in these maps represent the dorsal (back) of the hands.

  • The unshaded regions represent the ventral (front) of the hands.

• Resolution: These somatotopic maps are highly detailed, capable of detecting and representing individual fingers (digits) rather than just general body regions.

Evidence from Amputation and Sensory Deprivation

Cortical maps are dynamic and adjust based on the presence or absence of sensory experience. When a sensory input is removed, such as through the amputation of a finger, the brain undergoes significant reorganization.

Animal Studies

• Micro-electrode Mapping: Studies in monkeys mapped primary sensory cortex sensitive to hand stimulation.

• Post-Amputation Changes: Several months after a finger was removed, the cortical region originally devoted to that amputated finger began responding to the stimulation of adjacent fingers.

• Syndactyly Simulation: When two fingers are surgically fused together so they are always used simultaneously, the sharp boundaries between their cortical representations are abolished. This suggests that the development of cortical boundaries is guided by experience and synchronized input, not just genetics.

Human Amputees and Phantom Limb Sensations

• Cortical Encroachment: In a human subject whose right arm was amputated below the elbow at age $11$, functional brain imaging showed that the face and upper arm regions in the left hemisphere (contralateral to the amputation) extended into the territory previously reserved for the hand.

• Phantom Limb Phenomenon: Amputees often perceive sensations in a missing limb when other body parts are touched. This occurs because the stimulation of skin regions bordering the missing limb's map (like the face) activates the now-vacant cortical territory.

• Topographic Arrangement on the Face: Stimulation of the face can reveal a large representation for the thumb (mapped as area $1$ on the face) and a topographic arrangement of other missing fingers on the facial skin.

Evidence from Training and Increased Use

Just as the loss of input causes map shrinkage or invasion, increased sensory experience leads to the expansion of cortical representations.

Training in Animals

Monkeys trained to use a specific finger to receive a food reward showed an increased cortical representation for those specific stimulated fingers after several weeks of training.

Human Motor Skill Acquisition

• Sequence Training: Human subjects trained in rapid finger movements showed improved accuracy and speed after $3$ weeks of daily practice.

• Functional MRI (fMRI) Data: Post-training scans revealed a significantly larger area of yellow-coded activation in the cortex. This expansion persisted for several months after the training period ended.

• Musicianship: Highly trained string players provide a unique case study.

  • The Left Hand: Used for individualized string manipulation.

  • The Right Hand: Used for bowing, acting more like a fist.

  • Magnetoencephalography (MEG) Findings: Neural activity in the right cortex (controlling the left hand) is significantly greater in string players than in non-musicians.

  • Age Factor: Plasticity is more pronounced in players who began training before the age of $13$, indicating a sensitive period for training-induced cortical expansion.

The Hebbian Synapse and Spike Timing

In $1949$, psychologist Hebb theorized that the coordinated activity of a presynaptic input and a postsynaptic neuron strengthens the connection between them. This is often summarized as: "Cells that fire together, wire together."

Hebb’s Rule

• Strengthening: Synapses are strengthened by correlated activity.

• Weakening: Synapses are weakened by uncorrelated activity.

• Visual System Example: In the development of the visual cortex (layer $4$), if inputs from the left eye are more correlated with the firing of the postsynaptic cell than inputs from the right eye, the left-eye synapses will strengthen and increase in number. The right-eye synapses, being uncorrelated, will gradually weaken and undergo elimination.

Mechanisms of Motor Cortical Reorganization

There are three primary mechanisms through which the brain reorganizes, ranging from rapid physiological shifts to slow structural changes.

1. Axonal Sprouting

• Process: Pyramidal neurons ($P$) grow new connections via horizontal collaterals to reach new sets of neurons.

• Timescale: This is a slow process occurring over several weeks.

• Key Features: Observation of growth cones on axon collaterals and the formation of new synaptic connections from sprouting horizontal collaterals.

2. Altering the Balance of Excitation and Inhibition

• Process: Many existing connections are "silent" or suppressed by inhibitory interneurons.

• Mechanism: Reduction in $GABAergic$ transmission (inhibition) can "unmask" these pre-existing connections.

• Triggers: This can be caused by deafferentation (loss of input) or intense sensory stimulation.

3. Long-Term Potentiation (LTP) and Long-Term Depression (LTD)

This mechanism involves long-term modifications in synaptic effectiveness based on input timing.

Long-Term Potentiation ($LTP$)

• Induction: Traditionally studied in the hippocampus (specifically $CA1$ neurons) by delivering a high-frequency train of action potentials called a tetanus.

• Result: A much larger Excitatory Postsynaptic Potential ($EPSP$) amplitude after the tetanus, increasing synaptic effectiveness.

• Specificity: $LTP$ is restricted to the stimulated synapse; unstimulated neighboring synapses do not show potentiation.

• Duration: In animals, this can last up to a year, though it is shorter in humans.

Long-Term Depression ($LTD$)

• Induction: Produced by low-frequency activation of fibers.

• Mechanism: Triggered by specific (lower) concentrations of calcium ($Ca$).

Cellular and Molecular Basis of $LTP$ and $LTD$

The interaction between glutamate and its receptors—$AMPA$ and $NMDA$—is central to synaptic plasticity.

The Role of the $NMDA$ Receptor

• Resting State: At normal resting membrane potential, the $NMDA$ receptor channel is blocked by magnesium ($Mg$).

• Activation Requirement: The postsynaptic neuron must be depolarized to expel the $Mg$ ion from the channel.

• Ion Flow: Once unblocked, glutamate binding allows calcium ($Ca$) to enter the postsynaptic cell.

Intracellular Signaling and Modification

• $LTP$ Pathway: High levels of $Ca$ entry activate protein kinases. These kinases trigger the insertion of new $AMPA$ receptors into the postsynaptic membrane, increasing sensitivity to glutamate.

• $LTD$ Pathway: Weak depolarization leads to partial blocking of $NMDA$ receptors, resulting in small elevations of $Ca$. This activates protein phosphatases, which dephosphorylate $AMPA$ receptors, leading to their removal or decreased sensitivity.

• Presynaptic Potentiation: In some cases, a retrograde signal (likely Nitric Oxide, $NO$) spreads from the postsynaptic neuron back to the presynaptic terminal to increase glutamate release.

Spike Timing Dependent Plasticity (STDP)

• Order Matters:

  • If the presynaptic $EPSP$ occurs before the postsynaptic action potential, $LTP$ results.

  • If the presynaptic $EPSP$ occurs after the postsynaptic action potential, $LTD$ results.

• Temporal Window: The strongest effects occur within a few milliseconds. If the gap between events exceeds $100\,milliseconds$, no plastic effect is observed.

Metaplasticity and the Modification Threshold

Plasticity is not static; the internal rules for when a synapse strengthens or weakens can change based on the history of cellular activity. This is known as Metaplasticity.

Synaptic Modification Threshold

• Definition: The specific level of $NMDA$ receptor activation that marks the transition between inducing $LTD$ and $LTP$.

• Sliding Threshold:

  • If activity is too high (excessive $LTP$), the threshold slides up, making it harder to produce more $LTP$.

  • If activity is too low (excessive $LTD$), the threshold slides down, making $LTP$ easier to achieve.   

Molecular Adjustment of Threshold

• Subunit Composition: $NMDA$ receptors consist of four subunits: two $NR1$ and two $NR2$ subunits.

• $NR2$ Types:

  • $NR2A$

  • $NR2B$

• Plasticity Ratio: A higher ratio of $NR2B$ subunits results in greater expression of $LTP$ because these subunits allow more calcium ($Ca$) to pass through the receptor channel.