Ventromedial prefrontal cortex pyramidal cells have a temporal dynamic role in recall and extinction of cocaine-associated memory.
In addicts, associative memories related to the rewarding effects of drugs of abuse can evoke powerful craving and drug seeking urges, but effective treatment to suppress these memories is not available. Detailed insight into the neural circuitry that mediates expression of drug-associated memory is therefore of crucial importance. Substantial evidence from rodent models of addictive behavior points to the involvement of the ventromedial prefrontal cortex (vmPFC) in conditioned drug seeking, but specific knowledge of the temporal role of vmPFC pyramidal cells is lacking. To this end, we used an optogenetics approach to probe the involvement of vmPFC pyramidal cells in expression of a recent and remote conditioned cocaine memory. In mice, we expressed Channelrhodopsin-2 (ChR2) or Halorhodopsin (eNpHR3.0) in pyramidal cells of the vmPFC and studied the effect of activation or inhibition of these cells during expression of a cocaine-contextual memory on days 1-2 (recent) and ∼3 weeks (remote) after conditioning. Whereas optical activation of pyramidal cells facilitated extinction of remote memory, without affecting recent memory, inhibition of pyramidal cells acutely impaired recall of recent cocaine memory, without affecting recall of remote memory. In addition, we found that silencing pyramidal cells blocked extinction learning at the remote memory time-point. We provide causal evidence of a critical time-dependent switch in the contribution of vmPFC pyramidal cells to recall and extinction of cocaine-associated memory, indicating that the circuitry that controls expression of cocaine memories reorganizes over time.
Departments of Molecular and Cellular Neurobiology and Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University Amsterdam, 1081 HV, The Netherlands, Department Bioengineering, Stanford University School of Medicine, Stanford, California 94305, Departments of Psychiatry and Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
Michel C
MC
Van den Oever
Diana C
DC
Rotaru
Jasper A
JA
Heinsbroek
Yvonne
Y
Gouwenberg
Karl
K
Deisseroth
Garret D
GD
Stuber
Huibert D
HD
Mansvelder
August B
AB
Smit
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D011939:Mental Recall / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D011897:Random Allocation; D013997:Time Factors
D003042:Cocaine