Balancing the pursuit of rewards (approach) and the avoidance of threats is essential for survival and well-being. However, this delicate balance is often disrupted in individuals suffering from ...neuropsychiatric disorders, such as major depression or drug abuse, where patients display maladaptive approach-avoidance decision-making. The neurobiology underlying this maladaptation remains largely unexplored, in part due to the lack of appropriate behavioral models in combination with complementing standard and cutting-edge neuroscience tools. This dissertation work provides a translational pipeline to assess behavioral, cellular, and molecular mechanisms of approach-avoidance decision-making upon maladaptive conditions. We first adapted a platform-mediated avoidance (PMA) task from rats, to measure approach-avoidance conflict decision-making in naïve mice or after chronic social defeat exposure. We then performed brain-wide neuronal activity mapping via iDISCO+, in vivo calcium imaging via fiber photometry, and chemogenetics, to reveal key mechanistic insights. Our main findings highlight the nucleus accumbens (NAc) as a key brain region contributing to approach-avoidance decisions. Specifically, the NAc’s main resident cell types, D1- and D2-receptor-expressing dopamine neurons, increase calcium activity upon both approach and avoidance decisions during PMA conditioning and extinction trials. Capitalizing on the PMA as a readout of conflict decision-making, we further show that approach-avoidance biases are sensitive to the detrimental effects of stress and drug exposure at the behavioral and cellular levels. In ongoing and future studies, we further examine the cellular and molecular changes associated with maladaptive approach-avoidance biases upon stress or drug insults, by employing RNA-sequencing targeting the NAc and other key reward circuitry brain regions. Overall, our findings shed light on the neurobiology underlying approach-avoidance conflict, clarifying the fundamental role of dopaminergic signaling in the NAc, and revealing potential therapeutic targets to combat maladaptive decision-making.
The ability of neurons to respond to external stimuli involves adaptations of gene expression. Induction of the transcription factor ΔFOSB in the nucleus accumbens, a key brain reward region, is ...important for the development of drug addiction. However, a comprehensive map of ΔFOSB’s gene targets has not yet been generated.
We used CUT&RUN (cleavage under targets and release using nuclease) to map the genome-wide changes in ΔFOSB binding in the 2 main types of nucleus accumbens neurons—D1 or D2 medium spiny neurons—after chronic cocaine exposure. To annotate genomic regions of ΔFOSB binding sites, we also examined the distributions of several histone modifications. Resulting datasets were leveraged for multiple bioinformatic analyses.
The majority of ΔFOSB peaks occur outside promoter regions, including intergenic regions, and are surrounded by epigenetic marks indicative of active enhancers. BRG1, the core subunit of the SWI/SNF chromatin remodeling complex, overlaps with ΔFOSB peaks, a finding consistent with earlier studies of ΔFOSB’s interacting proteins. Chronic cocaine use induces broad changes in ΔFOSB binding in both D1 and D2 nucleus accumbens medium spiny neurons of male and female mice. In addition, in silico analyses predict that ΔFOSB cooperatively regulates gene expression with homeobox and T-box transcription factors.
These novel findings uncover key elements of ΔFOSB’s molecular mechanisms in transcriptional regulation at baseline and in response to chronic cocaine exposure. Further characterization of ΔFOSB’s collaborative transcriptional and chromatin partners specifically in D1 and D2 medium spiny neurons will reveal a broader picture of the function of ΔFOSB and the molecular basis of drug addiction.
High relapse rate is a key feature of opioid addiction. In humans, abstinence is often voluntary due to negative consequences of opioid seeking. To mimic this human condition, we recently introduced ...a rat model of incubation of oxycodone craving after electric barrier-induced voluntary abstinence. Incubation of drug craving refers to time-dependent increases in drug seeking after cessation of drug self-administration. Here, we used the activity marker Fos, muscimol-baclofen (GABAa + GABAb receptor agonists) global inactivation, Daun02-selective inactivation of putative relapse-associated neuronal ensembles, and fluorescence-activated cell sorting of Fos-positive cells and quantitative polymerase chain reaction to demonstrate a key role of vSub neuronal ensembles in incubation of oxycodone craving after voluntary abstinence, but not homecage forced abstinence. We also used a longitudinal functional magnetic resonance imaging method and showed that functional connectivity changes in vSub-related circuits predict opioid relapse after abstinence induced by adverse consequences of opioid seeking.
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