1. 1 Activity-dependent Development (2) Hebb’s hypothesis Hebbian plasticity in visual system Cellular mechanism of Hebbian plasticity

2. 2 Donald Hebb (1949) When an axon of cell 1 is near enough to excite a cell 2 and repeatedly and persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that 1's efficacy, as one of the cells firing 2, is increased. Common interpretation: “Cells that fire together wire together” Other people also made the following extension: “neurons out of synch lose the link” Hebb’s rule has been a central hypothesis guiding the studies of learning, memory, and their cellular basis in the past several decades

3. 3 A property of Hebbian synapse

4. 4 Hebb’s rule and OD development left right cortical cell in layer 4 A. Normal OD development Small differences in either the activity level or the initial strength causes the postsynaptic cell activity to be more similar (correlated) to the activity of the more active/strong input. This input will be strengthened and will win the competition.

5. 5 B. Monocular deprivation Deprived eye input is uncorrelated with cortical cell activity, and will lose the competition cortical cell in layer 4 left right (MD) C. Binocular deprivation Similar to normal development. The outcome of competition is determined by small differences in initial input strengths or spontaneous activity levels of the two inputs.

6. 6 D. TTX, block all action potentials Both eye inputs correlated with cortical cell, both stay cortical cell in layer 4 left right

7. 7 But, each layer 4 cortical neuron receives inputs from many LGN axons representing the same eye, why don’t these axons compete with each other? If two presynaptic cells are correlated with each other, they do not compete! Neighboring inputs representing the same eye are believed to be highly correlated. left right cortical cell in layer 4

8. 8 Further tests of Hebb’s rule in OD development  If you force inputs from the two eyes to be correlated (synchronous stimulation), you can prevent competition and OD segregation  If you make the inputs from the two eyes even less correlated (asynchronous stimulation or strabismus), you enhance competition and OD segregation (there will be very few binocular cells in V1)

9. 9 Problem: OD exists to some extent before eye opening Normal visual input may not be necessary for the initial formation, but required for fine tuning and maintenance of visual circuit Initial OD development may depend on spontaneous activity (e.g., retinal waves, correlated between neighboring RGC, but uncorrelated between the two eyes)

10. 10 OD in 3-eyed frog A. normal frog (Constantine-Paton and Law)

11. 11 B. three-eyed frog

12. 12 Molecular mechanism of Hebbian plasticity 1. NMDA receptor - coincidence detector - ligand dependent (requires binding of Glu) - voltage dependent (requires depolarization of the postsynaptic cell to remove Mg 2+ from the channel pore) Pre and post fires asynchronously presynaptic postsynaptic resting membrane potential depolarization Glu Na + Ca 2+ Mg 2+ NMDAR Pre and post fires synchronously trigger LTP, strengthen synapse

13. 13 Molecular mechanism of OD plasticity 1. NMDA receptor -- Block NMDA receptor, prevent the segregation of OD columns in three-eyed frog A. Normal development B. NMDA receptor blockade

14. 14 2. Neurotrophins Criteria for neurotrophins to function as molecular signals in synaptic plasticity: 1) expressed in the right places and at the right times 2) expression and secretion are activity-dependent 3) regulate aspects of neuronal function 4) For competitive plasticity, the amount of neurotrophins should be limited Molecular mechanism of OD plasticity

15. 15 from L eyefrom R eye pre- post- Axons from R eye - relatively stronger - cause larger depolarization in postsynaptic neuron - larger amounts of neurotrophin release by postsynaptic neuron - stabilize the input 2. Neurotrophins Development of OD - target neuron depolarized, releases neurotrophin - neurotrophin is taken up by the presynaptic axon - promotes long-term growth and stabilization of the input. Molecular mechanism of cortical plasticity

16. 16 2. Neurotrophins Development of OD - infusion of BDNF or NT-4/5, disrupt OD columns Molecular mechanism of cortical plasticity BDNF NT-4/5 Disrupt formation of OD column NT-3 no effect NGF A Normal Layer 4 C NT-4/5 or BDNF administration Layer 4 B NGF or NT-3 administration Layer 4

17. 17 Source of activity during OD development 1. Before eye-opening (before birth) - spontaneous retinal wave 2. After eye-opening - visually driven activity