Identifying Prefrontal Cortex Neural Ensembles in Cocaine-associated Memories - ABSTRACT
Recent studies have demonstrated that memories are formed and expressed from small groups of neurons, neural
ensembles, within brain areas pertinent to the memory. Repeated drug use establishes drug-related memories
thought to drive relapse. When these memories are recalled by re-exposure to drug-associated cues, context, or the
drug itself, they become labile for several hours and are then reconsolidated to maintain or strengthen them. However,
they can also be disrupted with certain amnestic agents or behavioral manipulations given shortly after recall.
We have shown that reconsolidation of cocaine memories can be disrupted by manipulating the prelimbic portion of
the rat medial prefrontal cortex (PL PFC). PL PFC neurons projecting to the nucleus accumbens (NAc) critically
control reinstatement, the rodent model for relapse in humans. In our Preliminary Studies, this memory disruption may
depend on updating the memory during a memory reactivation session so that it becomes labile for disruption.
Updating a well-trained (habit) memory, such as that learned during cocaine self-administration in rats, appears to
depend on creating prediction error; that is, a difference in what the rat expects to receive by pressing a lever and
what it actually receives after pressing the lever to receive cocaine. Our Preliminary Studies show if we use the same
reinforcement schedule as given during the many self-administration training days, a fixed ratio 1 (FR1), the memory
may not become labile for disruption, but that a different reinforcement schedule, a variable ratio 5 (VR5) that is
unpredictable, may allow for the memory to be disrupted. However, we do not know which ensembles of neurons
in the PL PFC allow these memories to become labile for disruption. Here we propose to use in rats a new,
highly sensitive robust activity marking (RAM) system to identify neural ensembles in the PL PFC activated by
two types of memory reactivation sessions, one that involves memory updating and the other that does not.
Specifically, we will 1) identify which neural ensembles are activated within the PL PFC during cocaine memory
reactivation in cocaine self-administering rats, 2) identify the phenotype of these ensembles, and 3) begin to define the
neural circuitry involved in memory updating. We will use dual viral injections, behavioral, and immunohistochemical
approaches. This proposal is significant because it will allow us to decipher the underlying neural ensembles
that render difficult-to-disrupt cocaine memories labile for disruption, with the long-term goal of reducing
relapse to cocaine.
