Hippocampal mechanisms of cocaine-memory reconsolidation

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PROJECT SUMMARY/ABSTRACT Pathologically strong or intrusive cocaine memories elicit uncontrollable drug craving and can trigger drug relapse in cocaine-predictive environments even after protracted abstinence, yet the contributions of long-term memory maintenance mechanisms to substance use disorders have been understudied. Cocaine memories are not necessarily retained over time; they become destabilized upon retrieval (memory reactivation) and need to be reconsolidated into long-term memory stores to be maintained, updated, and potentially strengthened. Thus, interference with memory reconsolidation weakens cocaine memories in animal models of drug relapse and reduces craving in individuals suffering from substance use disorders. The long-term goal of this proposal is to advance our understanding of the neural basis of cocaine-memory reconsolidation so that cellular/molecular processes and neural circuits suitable for effective therapeutic targeting can be identified in the future. We have discovered that the CA3 region of the dorsal hippocampus (dCA3) plays a critical role in the reconsolidation of cocaine memories. Building on this finding and strong preliminary data, Specific Aim 1 will be to identify cellular and synaptic-plasticity mechanisms of cocaine-memory reconsolidation within the dCA3. We will test the hypothesis that reconsolidation requires glutamatergic pyramidal neuronal activity in the dCA3 stratum pyramidale (SP) cell layer and GABAergic interneuronal activity in the dCA3 SP and stratum lucidum (SL) cell layers. We will identify and phenotype engram cells in the SP and SL and, also, evaluate the hypothesis that the maintenance of cocaine-memory strength via reconsolidation is associated with lasting plasticity in dentate gyrus mossy fiber (MF)dCA3 engram cell synapses, but not in dCA3 non-engram cell synapses. Specific Aim 2 will be to map dCA3 efferent circuits that regulate cocaine-memory strength during reconsolidation and determine related synaptic plasticity mechanisms. Based on extant literature and strong preliminary data, we will test the hypothesis that direct dCA3dCA1 intra-hippocampal and dCA3dorsolateral septum (dlS) extra-hippocampal circuits regulate cocaine-memory strength in an opposite manner during reconsolidation. Further, we will examine the hypothesis that cocaine-memory maintenance after reconsolidation is associated with increased polysynaptic transmission (MFdCA3dCA1/dlS) and excitatory synaptic plasticity in dCA3dCA1/dlS engram cell synapses. The proposed studies will utilize an instrumental model of drug-memory reconsolidation and relapse, engram cell tagging using Targeted Recombination in Active Population protocols, cell type- and pathway-specific in vivo and ex vivo optogenetics, pharmacology, multi-label immunohistochemistry, and whole cell patch-clamp electrophysiology to increase our understanding of how hippocampal-memory reconsolidation processes regulate cocaine memory strength and drug relapse. The findings are expected to provide an essential conceptual framework for future research and insights for the development of effective treatments for substance- use disorders and other psychiatric disorders characterized by intrusive maladaptive memories.