Hypothalamic prodynorphin neurocircuits integrating defensive behaviors

Project Summary Anxiety disorders, such as posttraumatic stress disorder (PTSD), pose a major public health challenge and currently affect millions of people in the United States. Studies have shown that these diseases are linked to the persistence of excessive defensive responses, often resulting from impairments in the ability of the brain's pre-programmed defensive networks to flexibly switch between proper defensive modes (i.e., active fight-or- flight versus passive freezing). Although significant progress has been made in elucidating the brain structures that regulate defensive behaviors, the causes of this inflexibility remain poorly understood. Emerging evidence suggests that neurons in the paraventricular nucleus of the hypothalamus (PVH) are critically implicated in regulating defensive responses. Approximately half of the PVH neurons express the specific marker prodynorphin (Pdyn, denoted as PVHPdyn neurons), the precursor of the neuropeptide dynorphin, an endogenous ligand of kappa-opioid receptors (KORs). In line with the known importance of the dynorphin/KORs system in regulating diverse physiological processes including stress, anxiety, and feeding, our preliminary studies have shown that PVHPdyn neurons send abundant parallel projections to the dorsomedial division of the ventromedial nucleus of the hypothalamus (VMHdm) and the dorsal portion of the periaqueductal gray (dPAG), the two pivotal brain regions for innate defensive control. We have further observed that specific activation of the PVHPdyn→VMHdm pathway induces strong flight behaviors in mice, whereas excitation of the PVHPdyn→dPAG circuit triggers exclusively freezing reactions. In particular, activation of both pathways suppresses feeding motivation driven by hunger, which is a known survival-promoting adjustment during defensive states. These findings collectively suggest that PVHPdyn neurons serve as the key target to regulate flexible defensive responses by integrating both VMHdm and dPAG actions. The proposed research will test this central hypothesis with three specific aims. Employing an ethologically relevant test model and a combination of multiple innovative techniques, we will: 1) examine how defensive flight behaviors are flexibly controlled by the PVHPdyn→VMHdm activity (Aim 1); 2) investigate how defensive freezing behaviors are dynamically encoded by the PVHPdyn→dPAG activity (Aim 1); and 3) explore how the coordinated activity dynamics between these two pathways directly orchestrate flexible switches between defensive modes and contribute to anxiogenic pathophysiology. This research will provide novel insights into the neural underpinnings governing appropriate defensive responses, opening new avenues for developing therapeutics that target the hypothalamic Pdyn neurocircuits for treating anxiety disorders associated with maladaptive defensive states.