Disrupting the Reconsolidation of Maladaptive Memories Underlying Compulsive Behaviour

In addiction, drug-associated environmental cues are pivotal factors for relapse to compulsive drug-seeking behaviour during abstinence. Evidence suggests that re-exposure to these drug-associated cues can lead to engagement of memory reconsolidation, providing a window of opportunity in which the maladaptive memory becomes malleable and vulnerable to disruption with pharmacological or behavioural treatments[1]. The host lab have shown that the impact of drug-associated cues on relapse can be reduced by disrupting reconsolidation[2], but it is not yet known whether the memory underlying the compulsive drug-seeking behaviour itself can be disrupted.

The goals of the research are to know:
1. Which brain structures support the compulsive habitual memories.
2. Whether targeting key plasticity molecules in these brain regions, in conjunction with memory reactivation, can disrupt the reconsolidation of compulsive habitual memories.
3. Whether compulsive habitual memory reconsolidation can be disrupted with systemic treatments upstream of key plasticity molecules.
This project will address these questions in rats that have developed compulsive, habitual memories in rodent models of alcohol-seeking[3] using a combination of correlative cellular imaging techniques and causal tests involving central and systemic administration of amnestic drugs to disrupt memory reconsolidation.
This project aims to:
1. Use immunohistochemistry (IHC) to identify brain regions undergoing plasticity changes during the reactivation of compulsive, habitual memories, using the immediate early gene Zif268 as a marker.
2. Use the IHC findings as a guide to selectively knock down the plasticity-related immediate early gene zif268 in specific brain regions engaged by the reactivation of compulsive, habitual memories.
3. Use novel in situ tissue-clearing and light-sheet microscopy (LSM) techniques to supplement the IHC approaches, and to gain a broader understanding to how brain regions are communicating during the reactivation of the drug-seeking memory.
4. Disrupt the reconsolidation of compulsive, habitual memories with the systemic administration of the NMDA receptor antagonist MK-801, which has been previously observed to control downstream Zif268 expression during memory reactivation.
References
1. AL Milton & BJ Everitt (2010) The psychological and neurochemical mechanisms of drug memory reconsolidation: implications for the treatment of addiction. E J Neurosci 31(12): 2308-2319.
2. MJ Schramm, BJ Everitt & AL Milton (2016) Bidirectional modulation of alcohol-associated memory reconsolidation through manipulation of adrenergic signaling. Neuropsychopharmacology 41(4): 1103-1111.
3. C Giuliano, D Belin & BJ Everitt (2019) Compulsive alcohol seeking results from a failure to disengage dorsolateral striatal control over behavior. J Neurosci 39(9): 1744-1754.