A corticostriatal circuit mediates the switching of defensive responses to an approaching threat

Defensive responses are evolutionarily conserved adaptive behaviors that species exhibit in response to threats to protect themselves from harm or death. The selection of context-appropriate defensive strategies, particularly the transition between freezing and flight behaviors, constitutes a critical determinant of species survival. We first established a two pure tone serial-compound stimulus (TTSCS) paradigm to evaluate the dynamic transition of defensive behaviors evoked by conditioned stimuli. This paradigm minimizes potential confounding effects on defensive behavior caused by differences in tone. Using this approach, we found that as the threat stimulus approached more closely, mice exhibited increased escape behaviors characterized by shorter latencies and larger magnitudes of response. These behavioral changes were associated with the dynamic responses of dopamine receptor 1 expressing MSNs (D1 MSNs) and dopamine receptor 2 expressing MSNs (D2 MSNs) in the dorsomedial striatum (DMS). Following functional validation through manipulation of the PFC (prefrontal cortex)-DMS circuit, we found that activating the PFC-DMS^D1 pathway significantly shortened the response latency of mice to heightened threat stimuli, enabling faster defensive reactions. However, activation of D2 MSNs subtypes of PFC-DMS pathway resulted in no significant alterations in the defensive behaviors. In conclusion, D1and D2 MSNs in the DMS likely act in an antagonistic manner to regulate defensive behaviors, and furthermore, the PFC projection specifically to the direct pathway within the DMS mediates the shift in defensive responses to an approaching threat.