Functional and molecular organization of threat processing in lateral septum cells and circuits

Abstract

Survival depends on an animal’s ability to rapidly detect, evaluate, and respond to threats while balancing exploration essential for resources against potential risks. The lateral septum (LS), an inhibitory nucleus within the limbic forebrain, is uniquely positioned to integrate external sensory information with internal states and prior experiences to regulate adaptive behavioral outcomes. Despite extensive evidence implicating the LS in threat processing, the specific neuronal subpopulations, circuits, and computational mechanisms that guide defensive behaviors and exploratory actions remain poorly understood. In this dissertation, I investigate how LS neurons expressing the type 2 corticotropin-releasing hormone receptor (LSCrhr2) orchestrate critical computations that shape behavioral responses to threats and novel environments. First, using single-cell calcium imaging, molecular sequencing, and circuit tracing, I identify distinct LSCrhr2 neuronal subclasses characterized by unique molecular profiles, spatial organization, and selective afferent connectivity. I find that the activity dynamics of each subclass collectively encodes diverse features of threat stimuli to drive cue-evoked defensive behaviors. Next, by monitoring the activity of precise LSCrhr2 afferents, I find that the LSCrhr2 population integrates cognitive signals from the hippocampus related to sensory context and cue-outcome associations, together with motivational signals from the hypothalamus linked to physiological arousal and stimulus salience. Together, these findings establish a multifeatured organizational principle that underlies how LS mediates motivated behaviors in response to learned discrete threats. Next, I identify a critical hypothalamic-septal circuit originating from the supramamillary nucleus (SuM) critical for responses to uncertain threats. First, I show that LSCrhr2 population dynamics are intricately tied to the exploratory behavior of the animal and the salience of the environment or stimulus they are exposed to. As the most abundant hypothalamic input to the LSCrhr2 population, we find that the SuM is a primary source of salience and arousal signals to LS. Activation of SuM-LS projections is aversive and imposes a bottom-up brake on exploration through recruitment of LSCrhr2 neurons, promoting arousal and avoidance in environments where threats are uncertain. I show that SuM axons in LS encode the aversive salience of an environment and relays these signals to LSCrhr2 neurons to constrain exploration. The activity of this circuit predicts the vigor of avoidance and thus provides a substrate by which a dynamic internal state can guide exploratory behavior in diverse environments. Together, these findings define the LSCrhr2 neuronal population and its hypothalamic and hippocampal inputs as essential conduits by which the delicate balance between defensive responses and exploratory behavior is achieved. This dissertation thus reveals general principles for how limbic circuits dynamically integrate internal and external signals to adaptively shape complex motivated behaviors in uncertain or explicitly dangerous environments.