Dec 14, 2015
Dopamine regulates working memory and its cellularcorrelates in the PFC
Adapted from: Sawaguchi et al. (1986; 1988; 1990a,b)
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.
Experimental Set-up
Overview
Effects of D1 receptor activation on pyramidal cell firing
D1 receptor activation enhances evoked firing by shifting INAP activation
D1 receptor activation sustains evoked firing by Slowing INAP inactivation by 42%
D1 receptor activation also sustains evoked firing by reducing a slowly-inactivating K+ current
Effects of dopamine on excitatory transmission
D1 agonists have no effect on low frequency inputs but enhance high frequency inputs.
D1 receptor activation increases NMDA EPSCs selectively
D1 receptor stimulation reduces release probability very slightly.
Minimal Stimulation
MK-801 Blocking Function
12.2 ± 7%
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)
D1 agonists do not enhance response to trains when NMDA receptors are blocked
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
Effects of dopamine on inhibitory transmission
Dopamine has bi-directional effects on IPSCs
D2 D1
Dopamine can switch IPSCs from a reduced state (D2-mediated) to an enhanced state (D1-mediated)
D1 agonists increase action-potential evoked Spontaneous IPSCs but not Mini IPSCs.
Dopamine via D1 but not D2 receptors directly excites interneurons
D2-mediated reduction of IPSCs is blocked by a muscarinic acetylcholine antagonist (Atropine)
Summary of the Physiological Effects of Dopamine
Linking cellular mechanisms to the functions of dopamine in the PFC
Computational Modeling
(Daniel Durstewitz)
Simulation of D1 effects leads to reduction in spontaneous but large enhancement in evoked “delay-period” activity
The model reproduces qualitative aspects of dopamine’s actions in vivo
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.
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)