Organisms must continuously navigate complex environments, balancing the drive to seek rewards with the need to avoid potential threats. This tradeoff between approach and avoidance behaviors, known as approach-avoidance conflict, is a critical determinant of survival. The medial prefrontal cortex (mPFC) plays a key role in regulating these behaviors, with the ventromedial (vmPFC) and dorsomedial components thought to suppress and promote, respectively, behavioral responses to threats. Within the vmPFC, neural populations expressing the opioid peptide dynorphin (Dyn) and its receptor, the kappa opioid receptor (KOR), have been implicated in stress responses. However, the specific role of the vmPFC Dyn system in encoding threat-related information and shaping behavioral responses remains largely unexplored.
To address this, we employed a multi-faceted approach, utilizing fiber photometry, calcium imaging, shRNA-mediated knockdown, and DREADD-mediated inhibition to investigate the vmPFC Dyn system in various threat-related paradigms. These included the platform-mediated avoidance (PMA) task, which assesses approach-avoidance conflict; the repeated looming disk test, a pain-free model of innate fear suppression; and standard fear conditioning, a well-established paradigm for studying learned fear responses.
Our findings reveal that while the vmPFC Dyn system is not differentially regulated under non-threatening baseline conditions, it is actively recruited upon threat exposure. Fiber photometry recordings during the PMA task showed that vmPFC Dyn neurons bidirectionally signal features related to approach and avoidance behaviors in the presence of threat.
Furthermore, shRNA-mediated downregulation of Dyn in the vmPFC led to enhanced avoidance in the repeated looming disk test, indicating that Dyn is necessary for suppressing avoidance in this context. Calcium imaging of the pan-neuronal vmPFC population in conjunction with Dyn knockdown revealed that loss of Dyn impairs cortical activity, as evidenced by reduced synchrony and decreased performance of a logistic regression decoder. These findings suggest that Dyn plays a critical role in shaping the activity of vmPFC neurons during threat processing.
Taken together, our results highlight a specific role for the vmPFC Dyn system in toggling threat-driven behavioral responses, particularly in the context of approach-avoidance conflict. By demonstrating how Dyn shapes both behavior and neural activity in the vmPFC during threat exposure, this study provides novel insights into an understudied area of opioidergic circuitry. Moreover, our findings contribute to a deeper understanding of how distinct cell types within the vmPFC encode threat-related features to promote or suppress avoidance behaviors, shedding light on the neural mechanisms underlying adaptive responses to environmental challenges.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/xh5m-qf78 |
| Date | January 2024 |
| Creators | Limoges, Aaron |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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