Biology subjects

Flom, L. T.

Publications and source records attributed to Flom, L. T..

3 recordsLinked to original sources

bioRxiv2025

Functional and Structural Plasticity in Cocaine-Seeking Ensembles of the Nucleus Accumbens Core

Relapse vulnerability in substance use disorder (SUD) is primarily driven by cue-induced activation of neurons within the nucleus accumbens core (NAcore), among other contributing factors. Neuronal ensembles within the NAcore, defined here as selectively co-activated neurons during specific behavioral experiences, are essential during cocaine sensitization and recall. While transient synaptic plasticity (t-SP) has been widely observed in general neuronal populations within the NAcore during reinstatement, its ensemble-specific dynamics remain unclear. Here, we used c-Fos-TRAP2-based tagging to identify cocaine-seeking ensembles in mice following cocaine intravenous self-administration, extinction, and cue-induced reinstatement. Structural spine plasticity was assessed via confocal microscopy, and functional changes were measured using whole-cell electrophysiology across multiple reinstatement time points. Ensemble neurons exhibited enhanced dendritic spine head diameter (dh) and AMPA/NMDA (A/N) ratios following cue exposure, consistent with t-SP. Notably, spine classification revealed a reduction in mature spines during reinstatement, suggesting morphological remodeling rather than new spine formation in both ensemble and non-ensemble cells. Non-ensemble neurons exhibited classical functional transient synaptic plasticity, characterized by increased A/N ratios but no significant changes in dh. To begin assessing if presynaptic vesicle release impacts t-SP, paired-pulse ratio analysis indicated no differences in population or time point. Importantly, ensemble neurons displayed elevated A/N ratio following cocaine exposure, suggesting prior silent synapse maturation. These findings demonstrate that t-SP is not uniformly distributed across NAcore neurons but differs significantly between ensemble and non-ensemble neurons. By linking ensemble identity to both structural and functional plasticity, this study refines our understanding of cue-induced relapse mechanisms. Significance StatementRelapse in substance use disorder is strongly driven by cue-induced reactivation of neuronal ensembles in the nucleus accumbens core. While transient synaptic potentiation has been widely described in bulk neuronal populations within the nucleus accumbens core, its ensemble-specific expression has remained unclear. Here, we combined c-Fos-TRAP2 tagging, confocal imaging, and slice electrophysiology to show that transient synaptic potentiation is selectively expressed in behaviorally relevant ensembles. By linking ensemble identity with structural and functional plasticity during cue-induced cocaine seeking, these findings refine current models of relapse and identify ensemble-specific plasticity as a potential target for therapeutic intervention.

neuroscience↗

bioRxiv2025

Characterization of neuronal ensembles in a model of dual reward conditioned place preference

Substance use disorder (SUD) is associated with maladaptive alterations in behavior. Drug-seeking behavior has been associated with neuronal ensembles, defined here as a small group of neurons exhibiting coordinated activity patterns, in the prelimbic prefrontal cortex (PL) and nucleus accumbens core (NAcore). Most SUD preclinical research focuses on the effects of single-reward exposure on the general population of neurons within the reward pathway, rather than on poly-reward exposure. Here, we seek to characterize and compare the ensembles linked to cocaine and chocolate using a within-subject approach. We used Ai14xFos2A-iCreER (c-Fos-TRAP2) transgenic mice to tag neuronal ensembles in a novel dual cocaine and chocolate conditioned place preference (CPP) model, where each chamber was associated with a different reward, either cocaine or chocolate. We found that, after successful dual conditioning and in the absence of the rewards, mice preferred cocaine over chocolate. Additionally, in mice exposed to both cocaine and chocolate, cortical and accumbal ensembles linked to each reward were comparable in size to reward ensembles in mice exposed only to one reward. However, reward-seeking ensembles were larger than ensembles tagged in homecage control mice across groups. We also found that ensemble size does not correlate with the level of reward seeking across single and dual CPP models. These results offer a new paradigm for studying drug-related neuronal ensembles in comparison to natural rewards in non-contingent behavioral models.

neuroscience↗

bioRxiv2023

Sex-Dependent Genetic Expression Signatures within Cocaine- and Sucrose-Seeking Ensembles in Mice

Maladaptive reward seeking is a hallmark of cocaine use disorder. To develop therapeutic targets, it is critical to understand the neurobiological changes specific to cocaine-seeking without altering the seeking of natural rewards, e.g., sucrose. The prefrontal cortex (PFC) and the nucleus accumbens core (NAcore) are known regions associated with cocaine- and sucrose-seeking ensembles, i.e., a sparse population of co-activated neurons. Within ensembles, transcriptomic alterations in the PFC and NAcore underlie the learning and persistence of cocaine- and sucrose-seeking behavior. However, transcriptomes exclusively driving cocaine seeking independent from sucrose seeking have not yet been defined using a within-subject approach. Using Ai14:cFos-TRAP2 transgenic mice in a dual cocaine and sucrose self-administration model, we fluorescently sorted (FACS) and characterized (RNAseq) the transcriptomes defining cocaine- and sucrose-seeking ensembles. We found reward- and region-specific transcriptomic changes that will help develop clinically relevant genetic approaches to decrease cocaine-seeking behavior without altering non-drug reward-based positive reinforcement.

neuroscience↗