Dorsomedial Striatal Medium Spiny Neurons Orchestrate Temporally approaching threat Driven Defensive Switching in Fear Conditioning

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. By employing the serial-compound stimulus (SCS) Pavlovian fear conditioning, we found that the decision-making process of mice, specifically their inclination to exhibit freezing versus flight in the presence of threats, is primarily determined by learned temporal relationships of conditioned stimulus (CS) and unconditioned stimulus (US). As the threat stimulus approached more closely, mice exhibited enhanced escape behaviors characterized by reduced response latencies and increased response magnitudes. Furthermore, medium spiny neurons (MSNs) within the dorsal medial striatum (DMS) exhibited differential engagement based on threat proximity, as assessed through fiber photometry to record the population response of these neurons during the SCS. Dopamine receptor 2 expressing MSNs (D2 MSNs) predominantly modulated responses to temporally distant threats, while dopamine receptor 1 expressing MSNs (D1 MSNs) primarily regulated responses to imminent threats. Both types of MSNs contribute to the magnitude of the defensive response. These findings suggest that the switching of defensive responses during SCS Pavlovian fear conditioning is primarily determined by the temporal proximity of the CS to the US. This process is regulated through the collaborative interaction between D1 MSNs and D2 MSNs within the DMS region, underscoring the DMS as a critical neural hub for threat assessment and defensive strategy selection.