Dopamine regulates working memory and its cellular correlates in the PFC.
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Transcript of Dopamine regulates working memory and its cellular correlates in the PFC.
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Dopamine regulates working memory and its cellularcorrelates in the PFC
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Adapted from: Sawaguchi et al. (1986; 1988; 1990a,b)
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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.
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Experimental Set-up
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Overview
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Effects of D1 receptor activation on pyramidal cell firing
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D1 receptor activation enhances evoked firing by shifting INAP activation
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D1 receptor activation sustains evoked firing by Slowing INAP inactivation by 42%
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D1 receptor activation also sustains evoked firing by reducing a slowly-inactivating K+ current
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Effects of dopamine on excitatory transmission
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D1 agonists have no effect on low frequency inputs but enhance high frequency inputs.
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D1 receptor activation increases NMDA EPSCs selectively
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D1 receptor stimulation reduces release probability very slightly.
Minimal Stimulation
MK-801 Blocking Function
12.2 ± 7%
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D1 receptor activation increases post-synaptic NMDA conductance
GNMDA= 5.9 1+e-0.0038(v-(-35))
GNMDA= 5.07 1+e-0.0038(v-(-25))
GNMDA
Vm
2.5pA
100ms
ControlD1 Agonist
Control
D1 Agonist
Voltage-Clamp(Cs, TTX, Cd)
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D1 agonists do not enhance response to trains when NMDA receptors are blocked
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Models indicate that the selective increase in depolarization is due to both reduced Pr and
enhanced NMDA conductance
DataSimulation
GNMDA shift + depression shift
GNMDA shift alone
Data
Simulated D1
controlD1 condition
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Effects of dopamine on inhibitory transmission
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Dopamine has bi-directional effects on IPSCs
D2 D1
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Dopamine can switch IPSCs from a reduced state (D2-mediated) to an enhanced state (D1-mediated)
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D1 agonists increase action-potential evoked Spontaneous IPSCs but not Mini IPSCs.
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Dopamine via D1 but not D2 receptors directly excites interneurons
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D2-mediated reduction of IPSCs is blocked by a muscarinic acetylcholine antagonist (Atropine)
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Summary of the Physiological Effects of Dopamine
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Linking cellular mechanisms to the functions of dopamine in the PFC
Computational Modeling
(Daniel Durstewitz)
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Simulation of D1 effects leads to reduction in spontaneous but large enhancement in evoked “delay-period” activity
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The model reproduces qualitative aspects of dopamine’s actions in vivo
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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.
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SupervisorsAnthony Phillips (UBC)
Charles Yang (UBC, Lilly Research Labs. )
Natalia Gorelova (UBC)
Terry Sejnowski (Salk Institute)
Charles Stevens (Salk Institute)
CollaboratorsStan Floresco (UBC)
Daniel Durstewitz (Salk Institute)
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