Threat processing via the septohippocampal system

Abstract

In the face of danger, animals must quickly detect and process environmental stimuli to produce appropriate behavioral responses. Moreover, internal states both tune animal behavior and change in response to external stimuli. These behavioral states are dynamic and permit animals to efficiently transition between behaviors that are appropriate to any given situation. For example, when an animal is presented with an unexpected threat, the animal may quickly switch from an offline, quiescent state to an aroused, hypervigilant state – this transition is necessary for the survival of the animal. However, excessive hypervigilance can be maladaptive and is a common diagnostic marker of various human mental illnesses. The septohippocampal system, composed of the septum and the hippocampus, has previously been implicated in regulating behavioral responses to external sensory stimuli and in modulating affective components of behavior. Yet little is understood on how the septohippocampal system integrates threat-related sensory information to guide appropriate defensive behaviors. In this work, we leverage a subpopulation of Lateral Septum (LS) neurons labeled by the type 2 corticotropin-releasing hormone receptor (LSCrhr2) as a genetic entry point into the septohippocampal system. Here, we demonstrate that 1) LSCrhr2 neurons bidirectionally modulate stimulus-evoked defensive behaviors, 2) LSCrhr2 neurons promote physiological changes in arousal and 3) LSCrhr2 neurons are polysynaptically connected with higher-order cortical brain regions. Additionally, we find evidence that upstream hippocampal projection neurons correlate with physiological arousal and partially respond to threat-related sensory stimuli. These data place the septohippocampal system as a node that controls stimulus-evoked defensive behaviors potentially through its indirect connectivity with the cortex.