2. Dopamine regulates working memory and its cellular correlates in the PFC

3. Adapted from: Sawaguchi et al. (1986; 1988; 1990a,b)

4. How does dopamine regulate working memory at the cellular level in the PFC?
Study effects of dopamine on intrinsic properties of PFC neurons.
Study effects of dopamine on synaptic inputs to PFC neurons.
Make a model incorporating these data and see if you can answer the above question.

5. Experimental Set-up

6. Overview

7. Effects of D1 receptor activation on pyramidal cell firing

8. D1 receptor activation enhances evoked firing by shifting INAP activation

9. D1 receptor activation sustains evoked firing by Slowing INAP inactivation by 42%

10. D1 receptor activation also sustains evoked firing by reducing a slowly-inactivating K+ current

12. Effects of dopamine on excitatory transmission

13. D1 agonists have no effect on low frequency inputs but enhance high frequency inputs.

14. D1 receptor activation increases NMDA EPSCs selectively

15. D1 receptor stimulation reduces release probability very slightly.
Minimal Stimulation
MK-801 Blocking Function
12.2 ± 7%

17. D1 receptor activation increases post-synaptic NMDA conductance
Voltage-Clamp(Cs, TTX, Cd)
Control
D1 Agonist
2.5pA
100ms
Control
D1 Agonist
GNMDA=
1+e (v-(-35))
GNMDA
GNMDA=
1+e (v-(-25)) Vm

18. D1 agonists do not enhance response to trains when NMDA receptors are blocked

19. GNMDA shift + depression shift
Models indicate that the selective increase in depolarization is due to both reduced Pr and enhanced NMDA conductance
Simulated D1
Data
Simulation
D1 condition
control
GNMDA shift + depression shift
GNMDA shift alone
Data

21. Effects of dopamine on inhibitory transmission

22. Dopamine has bi-directional effects on IPSCs

23. Dopamine can switch IPSCs from a reduced state (D2-mediated) to an enhanced state (D1-mediated)

24. D1 agonists increase action-potential evoked
Spontaneous IPSCs but not Mini IPSCs.

25. Dopamine via D1 but not D2 receptors directly excites interneurons

26. D2-mediated reduction of IPSCs is blocked by a muscarinic acetylcholine antagonist (Atropine)

28. Summary of the Physiological Effects of Dopamine

29. Linking cellular mechanisms to the functions of dopamine in the PFC
Computational Modeling
(Daniel Durstewitz)

31. Simulation of D1 effects leads to reduction in spontaneous but large enhancement in evoked “delay-period” activity

32. The model reproduces qualitative aspects of dopamine’s actions in vivo

34. How does dopamine regulate working memory at the cellular level in the PFC?
It gates the flow of synaptic input into the PFC and regulates network activity via its effects on inhibition.
It aids in establishing and stabilizing up-states (delay-period activity) via its actions on INAP, IKS, INMDA, & glutamate release.

37. Supervisors Collaborators Anthony Phillips (UBC)
Charles Yang (UBC, Lilly Research Labs. )
Natalia Gorelova (UBC)
Terry Sejnowski (Salk Institute)
Charles Stevens (Salk Institute)
Collaborators
Stan Floresco (UBC)
Daniel Durstewitz (Salk Institute)