Synaptic Plasticity and Regeneration

Synaptic Plasticity and Regeneration

Types of Memory

• Explicit (Declarative Memory):

  • Medial temporal lobe; diencephalon

  • Facts

  • Events

• Implicit (Nondeclarative Memory):

  • Classical conditioning

    • Emotional responses (Amygdala)

    • Skeletal musculature (Cerebellum)

  • Procedural memory: skills and habits (Striatum)

Learning

• Learning is the response of the brain to environmental events.

• It involves adaptive changes in synaptic connectivity, which in turn alter behaviour.

Cell Assembly

• Reciprocal connections between neurons.
  *Neurons.

• Activation of the cell assembly by a stimulus.

• Reverberating activity continues activation after the stimulus is removed.

• Hebbian modification strengthens the reciprocal connections between neurons that are active at the same time.

• The strengthened connections of the cell assembly contain the engram for the stimulus.

• After learning, partial activation of the assembly leads to activation of the entire representation of the stimulus.

Hebb's Rule

• "Let us assume that the persistence or repetition of a reverberatory activity (or "trace") tends to induce lasting cellular changes that add to its stability.… When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased."

• Donald Hebb, The Organization of Behavior, 1949

Rules of Synaptic Modification

1. Neurons that fire together wire together.

2. Neurons that fire out of sync lose their link.

3. Strengthening and weakening synaptic connections in the brain provide a means by which learning occurs and memories can be formed.

Long-Term Potentiation (LTP)

• High-frequency electrical stimulation (HFS) of the perforant pathway (input).

• Record from cells within the dentate gyrus:
  *Subsequent perforant pathway stimulation results in increase in EPSP amplitude (size).

• Long-term potentiation (LTP): mechanism underlying synaptic strengthening.

• Hippocampus: shape and anatomy means pathways can be easily distinguished and recorded from electrophysiologically.

• LTP has now been studied in most other brain areas too.

• One HFS: LTP lasts hours.

• Multiple HFS: LTP lasts days/months.

Synaptic Mechanisms of LTP

• Glutamate release onto an active cell (membrane depolarized):

  • AMPA receptor activated.

  • $Mg^{2+}$ block on NMDA receptor relieved.

  • $Na^+$ through AMPA and NMDA channels.

  • $Ca^{2+}$ through NMDA channel.

• Glutamate release onto inactive cell (membrane at resting potential):

  • AMPA receptor activated to create EPSP.

  • NMDA receptor blocked by $Mg^{2+}$ ion.

  • Depolarization from AMPA activation not sufficient to expel $Mg^{2+}$.

Continued Synaptic Mechanisms of LTP

• $Ca^{2+}$ entry through the NMDA receptor leads to activation of:

  • Protein kinase C.

  • Calcium calmodulin-dependent protein kinase II (CaMKII).

    1. Phosphorylates existing AMPA receptors, increasing their effectiveness.

    2. Stimulates the insertion of new AMPA receptors into the membrane.

• Before: Few AMPA receptors, small EPSPs.

• After: More AMPA receptors working more effectively, Larger EPSPs.

CaMKII - Molecular Switch

• Sustained activity after repolarization.

• $Ca^{2+}$ entry through the NMDA receptor leads to activation of Calcium calmodulin-dependent protein kinase II (CaMKII).

• CaMKII has autocatalytic activity: becomes phosphorylated.

• When phosphorylated, it is constitutively active: no longer requires $Ca^{2+}$.

• Maintains phosphorylation, insertion of AMPA receptors, etc., after the depolarizing stimulus has receded.

• Molecular switch which maintains increased excitability of neuron for minutes to hours.

Late Phase LTP

• Protein synthesis required for long-lasting LTP (days, months).

• Protein synthesis inhibitors prevent the consolidation of long term memories and LTP.

• Stages of memory formation:

  1. Acquisition (training).

  2. Consolidation.

  3. Recall (testing).

• Protein synthesis inhibitor injected just post-acquisition (training) inhibits recall: necessary for consolidation.

• CREB (cAMP Response Element Binding protein) activated by phosphorylation by a number of kinases (PKA, CaMKII etc).

Long Term Depression (LTD)

• Long Term Potentiation is created in slice preparations by High frequency stimulation (HFS: 100x 100Hz).

• Low frequency stimulation (LFS: 100x 1 Hz) actually causes the opposite, and rather than getting an increase in EPSP amplitude on further stimulation you get a decrease.

• Same players involved:

  • NMDA dependent process.

  • AMPA receptors are de-phosphorylated and removed from the membrane.

  • Prolonged low level rises in $Ca^{2+}$ activate phosphatases rather than kinases.

Bidirectional Regulation

LTP and LTD reflect bidirectional regulation of:

1. phosphorylation and

2. number of postsynaptic AMPA receptors

Experimental Evidence: NMDA Receptors and Learning

• NMDA receptor activity in the hippocampus is essential for both LTP and spatial learning.

• AP5: NMDA receptor antagonist.

  • Blocks hippocampal LTP.

  • Blocks learning in the Morris Water Maze.

Human Studies

• Human inferotemporal cortex removed during surgery maintained in vitro.

• HFS: produced LTP.

• LFS: produced LTD.

Drug Effects on Learning and Memory

I. Alcohol

• NMDA receptor antagonist (as well as other sites).

• Blackouts and amnesia caused by drinking directly blocking normal LTP processes?

• Alcohol disrupts hippocampal theta rhythms and disrupts short term memory.

• Chronic alcoholism and associated nutritional deficiency can result to Korsakoff syndrome or psychosis: loss of recent memory, and tendency to fabricate accounts of recent events (confabulation).

II. Benzodiazepines

• Indirect agonist of GABAA receptors:

  • Binding increases the receptor affinity for GABA.

  • Increase frequency of channel opening.

  • Anxiolytic and hypnotic drugs.

• Side effect to anxiolytic and sedative properties: anterograde amnesia.

III. Cholinergics / Anticholinergics

• Acetylcholine projections:

  • Basal forebrain bundle: Medial septum to hippocampus, Basal nucleus to cortex

  • Septum to hippocampus projection regulates theta waves

• Scopolamine (muscarinic receptor antagonist) suppresses theta waves and impairs spatial learning.

IV. Alzheimer’s Disease

• Acetylcholinesterase inhibitors (e.g., physostigmine)

• Boost cholinergic function

• Improves memory impairments

• In a healthy brain?

  • Controversial as to whether they improve memory

  • May increase attention

• Most cognitive enhancing effects of both acetylcholinesterases and other cholinergic drugs, e.g. nicotine, seen in impaired subjects, i.e. Alzheimer’s patients, or in restoring performance of animals with lesions.

Other Learning Processes using LTP

• Activity dependent synaptogenesis (development).

• Motor learning (e.g., riding a bike): cerebellar.

Connectome

• Map of neural connections.

Summary

• Cells that fire together wire together.

• Long Term Potentiation: molecular mechanism for memory?

  • early and late phases

• Cells that fire out of sync, lose their link: LTD

• Drugs that modulate memory

• Connectome

Review Questions

• CREB, cAMP Response Element Binding protein, is involved in which aspect of memory and LTP formation?

  • B. consolidation

• LTD involves

  • E. Prolonged low level rises in $Ca^{2+}$ concentration

Neurogenesis

• Neurogenesis: the process by which neurons are generated

• 5th week – 5th month of gestation

• Peak rate of 250,000 new neurons / minute.

Neuroblast

• Postmitotic, immature nerve cell that will differentiate into a neuron

• The fate of the migrating neuron will be determined by a combination of factors, e.g.

  • Age of precursor cell

  • Position in ventricular zone

  • Environment at time of division

Inside-Out Development of the Cortex

• The cortex develops from the inside out, with later-born neurons migrating past earlier-born neurons to form the outer layers.

Critical Periods

• Modification of brain circuits as a result of experience.

• First steps in constructing brain circuitry rely largely on intrinsic cellular and molecular mechanisms (establishment of distinct brain regions, neurogenesis, major axon tracts, guidance of growing axons to appropriate targets, initiation of synaptogenesis).

• Activity-mediated influence on the developing brain is most consequential in early life, during temporal windows called critical periods.

The Critical Period Concept

• Variable time window for different skills/behaviours e.g. sensorimotor skills, language acquisition, visual perception, emotional functions

• Two important factors for successful completion of the critical period:

  1. Availability of appropriate influences (e.g. exposure to language, or species-specific songs for songbirds)

  2. Neural capacity to respond to them

Visual Deprivation and Ocular Dominance

• Effects of visual deprivation on ocular dominance (layer 4 of the primary visual cortex, V1).

• Normal visual input in both eyes.

• Monocular deprivation during critical period BUT not after.

• Visual deprivation in adult animal.

• Development of visual perception requires sensory experience.

Competitive Imbalance

• First evidence of how experience during a critical period changes the way the brain is wired, and how individual neurons respond to stimuli.

Imprinting

• Neural development and learning.

• Imprinting in birds.

• Early social interaction with other humans is essential for normal social development.

Plasticity in the Adult Cerebral Cortex

• The adult cerebral cortex retains some plasticity, allowing it to reorganize in response to experience or injury.

Peripheral vs. Central Nerve Regeneration

• Peripheral Nerve Regeneration:

  • Schwann cells rapidly remove myelin debris.

  • Expression of growth-related genes.

  • Axon growth-promoting signals, neurotrophins, and ECM adhesion molecules.

  • Proliferating Schwann cells promote axon regeneration.

• Central Nerve Regeneration:

  • Oligodendrocytes, Microglia, Astrocytes.

  • Glial scar forms.

Adult Neurogenesis

1. Sub Ventricular Zone (SVZ) to olfactory bulb

2. Hippocampus

   • primarily interneurons

   • some integrate in functional networks, but most die (www.bioedonline.org)

Neurogenesis in the Hippocampus and Memory

• Computational theories of neurogenesis (Deng, Aimone & Cage, Nat Rev Neurosci, 2010)

• The most prevalent proposed function of adult neurogenesis is to help in pattern separation, the separation of overlapping or conflicting information.