UC Irvine

Chronic pain and addiction are two prevalent and interconnected health challenges that significantly impact individuals' quality of life. This dissertation investigates the neurobiological underpinnings of these complex behaviors through two parallel research projects.The first part of the dissertation (Chapter 1) focuses on elucidating the neural circuits underlying chronic pain. Utilizing a combination of whole-brain screening techniques, classic pain assays, in vivo calcium imaging, and slice electrophysiology, key neural circuits implicated in chronic pain and comorbid mood disorders are identified. In particular, we identified a critical circuit projecting from the agranular insula (AI) to the basolateral amygdala (BLA) that emerges as a central hub orchestrating maladaptive nociceptive processing and emotional regulation in chronic pain states. This circuit not only contributes to sensory aspects of chronic pain but also mediates behaviors resembling emotional distress and anxiety commonly observed in chronic pain patients. In contrast, we identified a second projection from the paraventricular thalamus (PVT) to the lateral amygdala (LA) that contributes primarily to the sensation of pain, without altering anxiety-like behaviors. In the second half of the dissertation, we explored the relationship between early life adversity and nicotine addiction-related behaviors, such as addiction susceptibility and withdrawal symptoms. We found that both nicotine withdrawal and early life adversity induce increases in pain sensitivity (Chapter 2). However, animals with early life adversity that had undergone nicotine withdrawal display reduced pain sensitivity relative to control-reared counterparts (Chapter 3). Leveraging unbiased whole-brain screening methodologies, we identified the anterior cingulate area as a key brain region implicated in mediating the effects of early life adversity on these nicotine addiction-related behaviors (Chapter 4). Together, these projects offer complementary perspectives on the neural underpinnings of complex behaviors, highlighting common themes of circuit dysregulation and behavioral maladaptation across chronic pain and substance use disorders. By advancing our understanding of the brain's response to various challenges, this research contributes to a more holistic understanding of brain function and behavior and lays the groundwork for innovative approaches to treat neurological disease.