Lateral septum modulates cortical state to tune responsivity to threat stimuli.

Sudden unexpected environmental changes capture attention and, when perceived as potentially dangerous, evoke defensive behavioral states. Perturbations of the lateral septum (LS) can produce extreme hyperdefensiveness even to innocuous stimuli, but how this structure influences stimulus-evoked defensive responses and threat perception remains unclear. Here, we show that Crhr2-expressing neurons in mouse LS exhibit phasic activation upon detection of threatening but not rewarding stimuli. Threat-stimulus-driven activity predicts the probability but not vigor or type of defensive behavior evoked. Although necessary for and sufficient to potentiate stimulus-triggered defensive responses, LSCrhr2 neurons do not promote specific behaviors. Rather, their stimulation elicits negative valence and physiological arousal. Moreover, LSCrhr2 activity tracks brain state fluctuations and drives cortical activation and rapid awakening in the absence of threat. Together, our findings suggest that LS directs bottom-up modulation of cortical function to evoke preparatory defensive internal states and selectively enhance responsivity to threat-related stimuli.

Stimulus salience determines defensive behaviors elicited by aversively conditioned serial compound auditory stimuli.

Assessing the imminence of threatening events using environmental cues enables proactive engagement of appropriate avoidance responses. The neural processes employed to anticipate event occurrence depend upon which cue properties are used to formulate predictions. In serial compound stimulus (SCS) conditioning in mice, repeated presentations of sequential tone (CS1) and white noise (CS2) auditory stimuli immediately prior to an aversive event (US) produces freezing and flight responses to CS1 and CS2, respectively (Fadok et al., 2017). Recent work reported that these responses reflect learned temporal relationships of CS1 and CS2 to the US (Dong et al., 2019). However, we find that frequency and sound pressure levels, not temporal proximity to the US, are the key factors underlying SCS-driven conditioned responses. Moreover, white noise elicits greater physiological and behavioral responses than tones even prior to conditioning. Thus, stimulus salience is the primary determinant of behavior in the SCS paradigm, and represents a potential confound in experiments utilizing multiple sensory stimuli.

If you notice the skies above you becoming darker, your first thought might be to seek shelter. Experience will have taught you that darkening skies are often a sign of an approaching storm. Learning to recognise changes that occur prior to an unpleasant event can help us avoid danger. But this is not the only strategy people can use to predict when something bad is about to happen. Another option is to use the intensity, or salience, of sensory information. Soldiers fighting on the front line, for example, might rely on the loudness of enemy voices or vehicles to judge how close an advancing enemy is. This information will help them decide when to retreat. Different brain processes are active when individuals use each of these two strategies to predict when an upcoming event will occur. One approach to study these processes is to use a technique called "SCS conditioning". This involves exposing mice to two sounds, followed by a mild electric shock administered to the feet. The first sound is a pure tone; the second is a burst of white noise. After repeated trials, mice begin to show distinct responses to the two sounds. They freeze in response to the tone but run away upon hearing the white noise. These responses parallel behaviors seen in the wild. When mice detect a distant predator, they freeze to avoid detection. But if the predator comes too close for the mice to avoid being spotted, they instead try to flee. Some have argued that in the SCS task, mice learn that the white noise predicts an imminent shock. The mice therefore flee as soon as they hear it. By contrast, they learn that the tone predicts a delayed shock and therefore choose to freeze instead. However, by tweaking the SCS procedure, Hersman et al. now show that even if the white noise occurs before the tone, it is still more likely than the tone to trigger an escape response. In fact, mice are more reactive to white noise than tones even if the sounds are never paired with shocks. This suggests that mice find white noise naturally more noticeable than tones. Moreover, Hersman et al. show that tones can also trigger escape responses if they are sufficiently intense. Together these results suggest that mice use the intensity of the stimuli ­ rather than the length of time between each stimulus and the shock ­ to decide whether to freeze or flee. People with anxiety disorders often show exaggerated responses to things that do not pose a genuine threat. At present the pathways in the brain that are responsible for these excessive reactions are unclear. The results of Hersman et al. will aid research into the brain circuits that detect, assess and respond to threats. Understanding these circuits could in the future lead to better treatments for anxiety disorders.