Learning in Vertebrates

Learning in Vertebrates

Introduction

• Researchers have been investigating brain circuits in vertebrates to find mechanisms of learning similar to those found in invertebrate models.
• Long-Term Potentiation (LTP) in mammals is considered a potential mechanism.

What is LTP?

• LTP is defined as a stable and enduring increase in the magnitude of response following high-frequency stimulation of pre-synaptic neurons.

Experimental Setup and Phases

The following describes a typical LTP experiment involving three phases:

Phase 1: Baseline Recording

• A shock is applied once every 20 seconds for 10 minutes (30 stimuli in total).
• The resulting Excitatory Postsynaptic Potentials (EPSPs) are recorded.
• Example amplitude: 2mV

Phase 2: High-Frequency Stimulation (HFS)

• High-frequency stimulation (HFS) is applied.
• HFS consists of 100 stimuli within 10 seconds.

Phase 3: Post-HFS Recording

• Return to stimulating once every 20 seconds.
• Measure the response.
• The response increases by approximately 50% (e.g., to 3.5mV).

Potentiation and LTP

• The increase in response is called potentiation.
• The response can remain potentiated for hours to weeks, which is LTP.
• LTP demonstrates that synapses can vary in strength as a result of some intervention.
• This is similar to what has been observed in invertebrates.

LTP and Memory

• LTP was first discovered by Bliss and Lomo in 1973 in the hippocampus, an area critical for learning and memory.
• LTP shows that synapses are plastic.

Molecular Mechanism Underlying LTP

During Normal Stimulation (Phase 1)

• There are two receptor types involved:
  • NMDA (N-Methyl-D-aspartate) receptors:
    • Glutamate-gated.
    • Voltage-gated.
    • Allow Ca^{++} ions to pass.
  • AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors:
    • Glutamate-gated.
    • Allow Na^+ ions to pass.
• During Phase 1 (stimulating once every 20 seconds):
  • Mg^{2+} block is on the NMDA receptor.
  • AMPA receptors are unblocked.
  • Na^+ ions are free to enter through AMPA receptors.
  • The influx of ions generates an EPSP (e.g., 2.5mV).

During High-Frequency Stimulation (Phase 2)

• More glutamate is released.
• Greater amounts of Na^+ enter.
• Greater depolarization occurs.
• The Mg^{2+} block is removed from the NMDA receptor.

Return to Stimulation (Phase 3)

• Ca^{++} flows through the open NMDA receptor.

Maintaining LTP

• Memories last for days to weeks, even years.
• How is this possible, given that eventually the block will return to the NMDA receptor?
• Three possibilities:
  1. Calcium acts through a second messenger to improve current through the ordinary AMPA receptor.
  2. Calcium acts through second messengers to increase the number of AMPA receptors.
  3. Calcium triggers a retrograde messenger, which diffuses back to the presynaptic terminal and increases the amount of glutamate released.

LTP and Memory (Experimental Evidence)

• Triggering LTP involves the NMDA receptor.

• Morris (1986) showed that blocking the NMDA receptor blocks LTP and learning.

• Age produces a decline in LTP and also in learning (Barnes & McNaughton, 1985).

• Stress can block LTP and also impair learning.

• Genetic deletion of NMDA receptor genes also produces deficits in LTP and learning.

  • Joe Tsien created the first genetically modified mice in which the NMDA receptor was knocked out in the CA1 region of the hippocampus (Tsien et al. 1996b Cell).
  • Experiments suggest that the NMDA receptor in the CA1 is essential for the formation of spatial and non-spatial memories.

• Same group then generated a mouse known as Doogie, in which enhanced NMDA receptor function leads to enhanced learning and memory (Tang et al. 1999 Nature).

Conclusions

• LTP demonstrates that brains are plastic and modifiable.
• It is believed that LTP is a realistic model of how vertebrates learn and remember.

References

• Pinel (2011) Biopsychology, Chapter 11, p 290.
• Kolb and Whishaw (2001) An introduction to brain and behaviour, Chapter 5, 180-184.
• Carlson (2010) Physiology of behaviour. Chapter 13, p. 444.
• Joe Tsien’s webpage http://www.bumc.bu.edu/www/busm/pharmacology/tsien/index.htm
• Own Chapter 7
• Bliss & Collingridge (1993) A synaptic model of learning: LTP in the hippocampus. Nature 361: 31-39
• Kandel & Hawkins (1992). The biological basis of learning and individuality. Scientific American, Sept. 53-60.
• Morris et al., (1986) Selective impairment of learning and blockade of LTP by NMDA receptor antagonist AP5. Nature 319: 774-776.