TMT predator odor activated neural circuit in C57BL/6J mice indicates TMT-stress as a suitable model for uncontrollable intense stress

• TMT predator odor exposure activates a distinct brain circuit including the BNST, the LS, the PVN, the PAG and the LC in mice.
• pronounced Fos expression indicates an important role of the BNST, as a relay station in TMT-stress.
• results indicate the TMT-tool as model of maladaptive stress responses for mice.

Intense stressful events can result in chronic disorders such as posttraumatic stress disorder (PTSD). In vulnerable individuals, a single aversive experience can be sufficient to cause long-lasting behavioral changes. Candidate brain regions implicated in stress-related psychopathology are the amygdala, the bed nucleus of the stria terminalis (BNST), and the hypothalamic pituitary adrenal (HPA) axis. In rodents exposure to 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), an ethologically relevant stressor, has been shown to induce intense stress and innate anxiety responses. To study dispositions for the development of maladaptive stress responses, mice models are required. Therefore C57BL/6J mice were exposed to TMT and Fos expression was studied in key brain regions implicated in stress responses and anxiety-like behavior. Our results show TMT-induced activation of a distinct neural circuit involving the BNST, the lateral septum (LS), the paraventricular nucleus of the hypothalamus (PVN), the periaqueductal gray (PAG) and the locus coeruleus (LC). Anatomical interconnection of the BNST with all these regions could point to an important modulatory role of this nucleus. Since, the BNST gets direct input from the olfactory bulbs and projects to the PVN and PAG and is therefore well positioned to modulate behavioral and endocrine stress responses to TMT. Hence, we suggest that TMT exposure is suitable to investigate uncontrollable stress responses in mice which exhibit similarities to maladaptive stress responses underlying PTSD in humans.