Emerging Activity Dynamics and Noradrenergic Modulation of Prefrontal Neuronal Ensembles During Heroin Seeking

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PROJECT SUMMARY Opioid use disorder is a chronically relapsing disease characterized by compulsive drug seeking, but how precise neural circuits orchestrate these motivational states is unknown. This is in part due to a lack of experimental feasibility, as it has been difficult to control and monitor the activity of cell-type specific neurons in vivo. For example, development of functional hypoactivity in the dorsomedial prefrontal cortex (dmPFC) is a hallmark of substance use disorder that reliably predicts future relapse susceptibility, while re-exposure to drug-associated cues evokes robust dmPFC activity. However, how dynamic activity patterns in dmPFC neurons regulate drug seeking is unclear. Thus, the objective of this project is to use contemporary tools to study the precise activity dynamics and neurocircuitry that engages dmPFC for the control of drug seeking. Here I propose to identify the precise activity dynamics and noradrenergic modulation of dmPFC neurons for heroin-seeking behavior. Single-cell resolution of dmPFC neuronal activity dynamics will be identified using longitudinal in vivo two-photon calcium imaging in head-restrained mice undergoing heroin self-administration (Aim 1). Furthermore, as the rapid shifts in neuronal excitability observed during re-exposure to drug-associated cues may be mediated by noradrenaline, which is released in dmPFC by the locus coeruleus (LC), inhibitory chemogenetics will be used to determine the function of LC-dmPFC inputs on activity dynamics during cue- induced heroin seeking (Aim 2). Based on my preliminary data and published work by my sponsors and others, I hypothesize that cue-induced heroin-seeking reinstatement directly corresponds to excitatory activity reemergence in dmPFC ensembles (Aim 1) and that LC-dmPFC activation is necessary for both cue-induced reinstatement and reemergence of excitatory activity in dmPFC ensembles (Aim 2). These data would suggest heroin-seeking behavior is regulated by discrete activity dynamics in dmPFC neurons which are subject to noradrenergic regulation. Regardless of the results, the experiments proposed here will be the first to longitudinally track activity in single neurons from the onset of drug use to relapse. The studies will provide unprecedented insight into the characteristics and noradrenergic mechanisms of prefrontal excitatory neuronal ensemble dynamics during heroin seeking.