Prefrontal Neuronal Excitability Maintains Cocaine-Associated Memory During Retrieval

Abstract

Presentation of drug-associated cues provokes craving and drug seeking, and elimination of these associative memories would facilitate recovery from addiction. Emotionally salient memories are maintained during retrieval, as particular pharmacologic or optogenetic perturbations of memory circuits during retrieval, but not after, can induce long-lasting memory impairments. For example, in rats, inhibition of noradrenergic beta-receptors, which control intrinsic neuronal excitability, in the prelimbic medial prefrontal cortex (PL-mPFC) can cause long-term memory impairments that prevent subsequent cocaine-induced reinstatement. The physiologic mechanisms that allow noradrenergic signaling to maintain drug-associated memories during retrieval, however, are unclear. Here we combine patch-clamp electrophysiology ex vivo and behavioral neuropharmacology in vivo to evaluate the mechanisms that maintain drug-associated memory during retrieval in rats. Consistent with previous studies, we find that cocaine experience increases the intrinsic excitability of pyramidal neurons in PL-mPFC. In addition, we now find that this intrinsic plasticity positively predicts the retrieval of a cocaine-induced conditioned place preference (CPP) memory, suggesting that such plasticity may contribute to drug-associated memory retrieval. In further support of this, we find that pharmacological blockade of a cAMP-dependent signaling cascade, which allows noradrenergic signaling to elevate neuronal excitability, is required for memory maintenance during retrieval. Thus, inhibition of PL-mPFC neuronal excitability during memory retrieval not only leads to long-term deficits in the memory, but this memory deficit provides protection against subsequent cocaine-induced reinstatement. These data reveal that PL-mPFC intrinsic neuronal excitability maintains a cocaine-associated memory during retrieval and suggest a unique mechanism whereby drug-associated memories could be targeted for elimination.

Infralimbic Cortex Biases Preference Decision Making for Offspring over Competing Cocaine-Associated Stimuli in New Mother Rats

“…In distinct contrast to their specific role in the choice, inactivation of the PrL or IL had no effect on CPP in the absence of conflict, indicating that neither of these cortical regions are necessary for context-induced cocaine seeking or infant seeking, respectively. Our finding regarding the lack of a role for PrL in the expression of a cocaine-CPP is consistent with some previous work (Hemby et al, 1992; although see Otis et al, 2018). Results also reveal that inactivation of the Cg1 did not alter decisions on any of the CPP tasks.…”

Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer’s Disease

“…Formation of a memory trace not only requires longterm changes in the strength of the synapses connecting the neurons that constitute the engram, but also stable changes in their intrinsic excitability [200][201][202] . Because Arc controls the expression of a large number of ion channels and pumps/transporters, it appears that Arc is capable of supporting this functional aspect of memory consolidation as well.…”

Divergent behavioral consequences of manipulations enhancing pyramidal neuron excitability in the prelimbic cortex

“…Prolonged exposure to cocaine persistently elevates PL pyramidal neuron excitability (35,(40)(41)(42)80) and reduces GABAergic neurotransmission in these neurons (40,43,44). In an attempt to mimic these adaptations in drug-naïve mice, we used three distinct approaches: viral Cre ablation of GIRK channels, For our projection-specific manipulations, we targeted brain regions that receive glutamatergic input from the PL and regulate fear learning and/or motor activity.…”

“…Pyramidal neurons, particularly those from layers 5 and 6, are the primary projection neurons, while GABA neurons regulate pyramidal neuron excitability (3,4). Repeated cocaine exposure triggers an array of adaptations that increase PL pyramidal neuron excitability (35)(36)(37)(38)(39)(40)(41)(42). Repeated cocaine also reduces GABAergic neurotransmission in PL pyramidal neurons via suppression of presynaptic GABA release (43), and blunting of postsynaptic GABAAR-and GABABR-mediated signaling (40,43,44).…”