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

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Presentation on theme: "Dopamine regulates working memory and its cellular correlates in the PFC."— Presentation transcript:

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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 I NAP activation

9 D1 receptor activation sustains evoked firing by Slowing I NAP inactivation by 42%

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

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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%

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

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

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

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21 Effects of dopamine on inhibitory transmission

22 Dopamine has bi-directional effects on IPSCs D2D1

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)

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28 Summary of the Physiological Effects of Dopamine

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

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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

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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 I NAP, I KS, I NMDA, & glutamate release.

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37 Supervisors 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)

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