The three main phases of neural development

2. The three main phases of neural development 1. Genesis of neurons (and migration). 2. Outgrowth of axons and dendrites, and synaptogenesis. 3. Refinement of synaptic connections.

3. Ocular dominance and monocular deprivation This led to the competitive interactions hypothesis, which can explain circuit refinement

4. Explanations of OD plasticity Hebbian plasticity: • When the pre-synaptic and the post-synaptic neurons fire together their synapse is strengthened (~LTP). • When the pre-synaptic and the post-synaptic neurons do not fire together their synapse is weakened (~LTD). • Thus, in binocular neurons, the synapses from the closed eye are weakened, while the synapses from the open eye are potentiated. Homeostatic plasticity: • This concept is founded on the observation that neurons can maintain their responsiveness (e.g. firing rate) within a preferred range in spite of chronic alterations of neuronal activity levels. • - Thus, visual responsiveness of deprived neurons could be enhanced directly, without Hebbian plasticity, by increasing synaptic strength, intrinsic excitability, or both.

5. 2-photon calcium imaging (opto-physiology) Green- neuron somata Red- glia - Used for non-invasive measurement of optical activity of dozens of cells, with single-cell resolution. - Compared with multi-electrode recording, optical population recording has the advantage that all of the cells in a field of view can be probed, regardless of whether or not they are firing action potentials. - As their spatial locations are precisely known, the cell types of all recorded cells can be determined. - Calcium signal ~ spiking activity:

7. Mapping Ocular Dominance (OD) in Mouse Binocular Visual Cortex by Two-Photon Calcium Imaging (1)

8. Mapping Ocular Dominance (OD) in Mouse Binocular Visual Cortex by Two-Photon Calcium Imaging (2)

9. So… we can look directly at OD with single-cell resolution, now let’s examine plasticity

10. OD Plasticity - Just like in the classical OD experiments, contra eye monocular deprivation (MD) shifts the distribution to the ipsi eye, and vice versa. • Generally: • The response to the deprived eye is decreased. • The response to the non-deprived eye is increased. • Timescales: • After 1 day of MD there is no change. • After 2-3 days the main effect is the reduction of deprived eye responses. • Depression precedes potentiation during OD plasticity in rodents (as was shown previously).

11. What are the possible mechanisms of OD plasticity? - Deprived-eye response depression can be explained by homosynaptic LTD of excitatory synapses or by LTP of inhibitory synapses (Hebbian plasticity). - The increased visual drive from the non-deprived eye could be mediated equally well by LTP or non-Hebbian, compensatory mechanisms (homeostatic plasticity). - If the increased visual drive from the non-deprived eye is mediated by homeostatic plasticity, what can we predict to test this experimentally?

12. Predictions for testing the contribution of homeostaticplasticity • The proportion of neurons responding preferentially to the deprived eye (~”monocular neurons”) should not change after MD (as the LTD is compensated to retain homeostasis). • The responses of these monocular neurons should be increased after eye reopening, as they should have increased their responsiveness to the reduced visual drive through the closed eyelid. • The duration of MD necessary for an increase in deprived-eye response in these monocular neurons should match that required for delayed strengthening of open-eye responses in binocular neurons (as they presumably arise from the same homeostatic mechanism). • If homeostatic mechanisms act to maintain neuronal firing rates within a certain range, the strength of eye-specific inputs should be adjusted such that the combined visual drive from the two eyes remains roughly constant.

13. Testing the contribution of homeostatic mechanisms to OD plasticity (1) - The proportion of monocular, deprived-eye neurons, in deprived animals was no different to the proportion of these neurons in controls (supporting prediction ‘a’). - The entire deprived-eye response range of neurons responding predominantly or exclusively to the deprived eye (OD score 0–0.25) was shifted to higher response values after contralateral-eye MD (supporting prediction ‘b’). (This observation is best explained by homeostatic mechanisms acting independently of Hebbian learning rules).

14. binocular Testing the contribution of homeostatic mechanisms to OD plasticity (2) - The decrease in the response to the closed eye in binocular neurons was full after 2-3 days of MD. - The increase in the response to the closed eye in monocular neurons was only full after 4-7 days of MD, just like the general increase in binocular neurons (supporting prediction ‘c’). monocular This further validates the existence of separate mechanisms for (fast) Hebbian plasticity and (slow) homeostatic plasticity.

15. How can we verify that these neurons indeed received the majority of their inputs from the deprived eye before MD? - One approach to verify this is to perform chronic recordings from the same animal before and after MD, but this is technically difficult. - Another reasonable possibility is to measure visually evoked responses in the monocular cortex of normal and monocularly deprived mice and see if the same effect is evident. - This effect (and the calcium imaging as a measure of spiking activity) was also verified with electrophysiological recordings.

16. Is this effect also evident with binocular deprivation (BD)? - The increased response was evident, as expected, alsoin BD (5-6 days). This result confirms that response depression in binocular cortex occurs only during MD, when the activity through one eye is higher than in the other. If not then there is a general potentiation.

17. Back to testing the contribution of homeostatic mechanisms to OD plasticity (3) Reminder (prediction ‘d’): If homeostatic mechanisms act to maintain neuronal firing rates within a certain range, the strength of eye-specific inputs should be adjusted such that the combined visual drive from the two eyes remains roughly constant.

18. Summary and conclusions (1) • In neurons with significant open-eye input, deprived-eye responses were reduced while those of the open eye increased. • In contrast, the deprived-eye responses of neurons largely devoid of open-eye input were stronger after MD. • Therefore,the direction of the shift of deprived-eye responses in each cell depended critically on the amount of open-eye input and net visual drive experienced during MD. • Consistent with these findings, responses to both eyes were up-regulated after BD.

19. Summary and conclusions (2) • The proportion of neurons responding preferentially to the deprived eye did not change after MD (as the LTD is compensated to retain homeostasis). • The responses of these monocular neurons were increased after eye reopening, as they have increased their responsiveness to the reduced visual drive through the closed eyelid. • The duration of MD necessary for an increase in deprived-eye response in these monocular neurons did match that required for delayed strengthening of open-eye responses in binocular neurons (as they presumably arise from the same homeostatic mechanism). • Homeostatic mechanisms probably act to maintain neuronal firing rates within a certain range as the strength of eye-specific inputs were adjusted such that the combined visual drive from the two eyes remains roughly constant.

20. The proposed sequence of events in binocular neurons (a combination of Hebbian and homeostatic plasticity): • The decorrelated input though the closed eye initially causes a Hebbian weakening (LTD) of deprived-eye synapses during the first few days of MD. • Subsequently, this triggers a compensatory (“homeostatic”) upscaling of responses to the open eye. • This keeps the total post-synaptic drive constant (in homeostasis).

21. Question?