Survival in a hostile environment requires the ability to assess potential threats and take the most appropriate defensive action. Accumulating evidence suggests that the amygdala is well positioned to integrate information about threats and to guide or shift responses along a spectrum of potential defensive behaviors. In both humans and mice, the amygdala plays an essential role in defensive responses to the threat of suffocation, signaled by rising systemic carbon dioxide (CO2) levels in the body. Lesioning the amygdala, or manipulating it more precisely in other ways, reduces some defensive behaviors evoked by CO2 inhalation (e.g. freezing) while simultaneously increasing others (e.g. fight-or-flight). Because CO2 inhalation evokes a variety of defensive responses in a robust, reproducible, and concentration-dependent manner, CO2 provides a straightforward and translatable approach to studying the amygdala's role in defensive behavior regulation. In this application, we propose to study defensive behaviors evoked by CO2 using state-of-the-art, neuron- specific manipulations and electrophysiological recording to deconstruct roles of select neuron populations in the basolateral amygdala (BLA). We hypothesize that distinct defensive behaviors are differentially regulated by the BLA and that principal neurons and interneurons in the BLA each play unique roles. To test this hypothesis we will use genetic, optogenetic, and electrophysiological approaches to specifically activate and silence specific BLA neuron populations and quantify the effects on neural activity and defensive behaviors. Together these experiments will allow us to discern how these neurons regulate different defensive behaviors. Understanding basic mechanisms that guide or shift defensive behaviors along their spectrum will be essential for identifying abnormalities in these processes and for finding ways to correct them. This knowledge will ultimately impact mental illnesses where defensive behaviors are inappropriately extreme such as panic disorder and post-traumatic stress disorder.
Defensive behaviors are encompassed within the negative valence systems construct of the NIMH Research Domain Criteria (RDoC) project, which was conceived to provide a translational research framework for mental illnesses. Experiments in this proposal will help deconstruct how defensive behaviors are regulated and will thus suggest new ways to identify and correct processes underlying abnormal defensive behaviors. This work will be particularly relevant to mental illnesses where defensive behaviors are dysregulated and often inappropriately extreme, such as post-traumatic stress disorder, panic disorder, depression, and psychotic disorders.