The Effect of Alcohol and Opioid Withdrawal on Single-Cell Glia and Neuronal Gene Expression in the Visceral Emotional Neuraxis
Alcohol and opioid abuse pose major social, economic, and health-related consequences to society. These depressants have distinct yet overlapping effects on mammalian systems. Both substances induce dependence in habitual users and have extremely unpleasant withdrawal syndromes. These withdrawal syndromes differ in some of their specific physiological sequelae, yet both involve marked visceral symptoms and autonomic dysregulation. Moreover, both withdrawal syndromes are characterized by the experience of severe negative emotion—fear and anxiety. I hypothesized that these two observations may be related; that visceral and autonomic feedback influences emotional circuits in the withdrawal syndromes from these different substances of abuse in similar ways. The negative-reinforcement model of addiction postulates that avoidance of negative physical and emotional symptoms during substance withdrawal drives substance dependence. I suggest that visceral and autonomic feedback to emotional circuits contributes to negative emotion and thus substance dependence via negative feedback. The amygdala plays a central role in this phenomenon as it is a limbic structure responsible for negative emotion—fear and anxiety. The amygdala also processes autonomic inputs, generates autonomic outputs, and has consistently demonstrated involvement in addiction and motivated behaviors. Additionally, the solitary nucleus (NTS), which has prominent bidirectional connections to the amygdala, receives interoceptive inputs via vagal afferents that reflect visceral states and strongly influences autonomic efferents as well as endocrine stress systems and higher brain centers. Thus, amygdala and NTS are hubs in a visceral-emotional neuraxis that reflect and drive the peripheral, central, and emotional effects of alcohol and opioid withdrawal syndromes. My dissertation compares and contrasts the withdrawal syndromes these two substances of abuse and suggests inflammation in the amygdala as a common mechanism of negative emotion in withdrawal. I support this suggestion by investigating how these substances alter gene expression in these brain regions in two separate chapters. A subset of the transcriptome of single neuronal and glial cells was assayed in the central nucleus of the amygdala of morphine-dependent and withdrawn rats. Similarly, a subset of the transcriptome of single neuronal and glial cells was assayed in the NTS of alcohol dependent and withdrawn rats. Both experiments were accomplished using high-throughput microfluidic RT-qPCR. We observed cell type-specific transcriptional shifts in neuroimmune, oxidative, and signaling genes suggesting pathologic signaling networks emerge in these processes. Strikingly, both withdrawal syndromes demonstrated alterations consistent with neuroinflammatory processes. Broader multivariate gene network analyses identified cellular subphenotypes and gene networks therein that point to altered glial-neuronal signaling in these withdrawal states.
O'Sullivan, Sean, "The Effect of Alcohol and Opioid Withdrawal on Single-Cell Glia and Neuronal Gene Expression in the Visceral Emotional Neuraxis" (2021). ETD Collection for Thomas Jefferson University. AAI27999489.