![]() In order to fully reveal the neural circuits that underly pathological fear, it is first important to understand the distinct neural circuits that underly various defensive modes and how they are gated or modulated by context 29. The SCS conditioning procedure thus presents a unique opportunity to investigate mechanisms by which context interacts with threat signals to select and scale defensive behavior. This contrasts with freezing behavior, which is readily evoked by a conditioned stimulus in any context in which it is encountered. Interestingly, SCS-evoked flight is context-dependent and only expressed in the conditioning context. Moreover, they show that the switch between freezing and flight behavior is gated by microcircuitry within the central nucleus of the amygdala (CeA), a structure critical to the expression of Pavlovian CRs 27, 28. The SCS is comprised of a pure tone stimulus immediately followed by a white noise stimulus that elicits two conditioned responses (CRs): freezing and flight behavior, respectively. Recently, Fadok and colleagues developed a modified auditory Pavlovian fear conditioning procedure that uses a serial-compound stimulus (SCS) to elicit both freezing and flight defensive modes in mice 26. This has been demonstrated in both humans and rodents using naturalistic predator threats 23, 24, 25, but it remains unclear whether conditioned threats, such as an auditory conditioned stimuli commonly used in Pavlovian fear conditioning, can drive circa-strike behavior such as flight. ![]() An influential theory of defensive behavior, predatory imminence theory, posits that defensive behavior scales with threat proximity on a spatiotemporal scale such that freezing behavior is observed in post-encounter modes (once threat has been realized), whereas flight behavior is part of the circa-strike defensive mode (when threat is proximal) 22. This raises an important question about the factors governing the selection and topography of defensive behavior under threat. Although conditioned fear can manifest as a wide range of behaviors, it is typically expressed as defensive freezing behavior in rodents. Previous work has revealed that contexts can both directly elicit conditioned defensive responses via contextual fear and also modulate the efficacy of another stimulus to control fear behavior without fear to the context itself, a process known as occasion setting 1, 20, 21. Pavlovian fear conditioning has been used for decades to model aversive learning and memory in rodents, and many have investigated the role of contextual cues on multiple measures of fear 1, 18, 19. This suggests that a complete understanding of how contexts regulate conditioned defensive behavior is essential to identifying neural circuits relevant to fear and anxiety disorders. For example, context processing deficits in patients with PTSD can lead to the overgeneralization fear 4, 5, 6, 7, 8, 9, 10, deficits in the extinction of fear 9, 11, 12, 13, 14, 15, 16, and the renewal of extinguished fear in safe contexts 17. Traumatic events can lead to pathological fear and the dysregulation of contextual processing appears to be central to various psychopathologies, such as post-traumatic stress disorder (PTSD) 1, 2, 3. Associative learning allows animals and humans to adapt their behavior to avoid predicted danger, and environmental contexts are critical for discriminating between fear and safety. The selection of appropriate defensive behavior is vital to survival in the face of threat. This work demonstrates that contextual fear can summate with cued and innate fear to drive a high fear state and transition from post-encounter to circa-strike defensive modes. All of these effects were similar in male and female rats. Finally, we show that pharmacological inactivation of two brain regions critical to the expression of contextual fear, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), attenuates both contextual fear and flight responses. Nonetheless, rats that received unpaired SCS trials did not show flight-like behavior to the SCS, indicating it is associative. Flight behavior was only expressed to white noise regardless of temporal order within the compound. Flight behavior was dependent on contextual fear insofar as it was only evoked in a shock-associated context and was reduced in the conditioning context after context extinction. Similar to previous work in mice, we show that male and female rats display context-dependent flight-like behavior in the SCS paradigm. Here we investigated context-dependent flight responses with a Pavlovian serial-compound stimulus (SCS) paradigm that evokes freeze-to-flight transitions. Environmental contexts can inform animals of potential threats, though it is currently unknown how context biases the selection of defensive behavior.
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