Exploring the physical and social environment is essential for understanding the surrounding world. We do not know how novelty-seeking motivation initiates the complex sequence of actions that make up investigatory behavior. We found in mice that inhibitory neurons in the medial zona incerta (ZIm), a subthalamic brain region, are essential for the decision to investigate an object or a conspecific. These neurons receive excitatory input from the prelimbic cortex to signal the initiation of exploration. This signal is modulated in the ZIm by the level of investigatory motivation. Increased activity in the ZIm instigates deep investigative action by inhibiting the periaqueductal gray region. A subpopulation of inhibitory ZIm neurons expressing tachykinin 1 (TAC1) modulates the investigatory behavior.

Selecting the right response to emotional stressors is vital for survival. From the psycho-spatial point of view, the perceived stressors can fall into two conditions: the stressors outside the confined safe zone or inside. Although this novel approach of categorizing the stressors distinguishes two anxiety-associated pathological conditions, agoraphobia, and claustrophobia, the difference between the behavioral responses in these two conditions and the underlying brain circuits are not well understood. Here, using novel behavioral paradigms in mice, we found that outside- and inside-stressors elicit two distinct behaviors, push-bedding and escape-jumping, respectively. Next, in an attempt to identify the brain regions activated in both outside- and inside-stressor conditions, the whole-brain c-Fos staining led us to an unexpected brain region, dorsomedial hypothalamus (DMH). Using optogenetics, chemogenetics, and photometry recording, we discovered that glutamatergic projections from DMH to the periaqueductal gray drive the escape to the inside-stressor, while GABAergic projections, in particular from neurons expressing tachykinin 1, are essential for coping with the outside-stressor. We conclude that distinct populations within the DMH region control the response to psycho-spatially distinct stressors. This discovery shows how the stressors and the spatial information of the stressors integrate in the brain and it is the first to shed light on understanding the narrow border between the two space-associated stress disorders/phobias, i.e. agoraphobia and claustrophobia and the underlying brain mechanisms.