Fernandes-Henriques Carolina, Guetta Yuval, Sclar Mia G, Zhang Rebecca, Miura Yuka, Surrence Katherine R, Friedman Allyson K, Likhtik Ekaterina
Biology Program, The Graduate Center, CUNY, New York 10016.
Departments of Biological Sciences, Hunter College, CUNY, New York 10065.
J Neurosci. 2025 May 28;45(22):e1001242025. doi: 10.1523/JNEUROSCI.1001-24.2025.
Fear extinction is critical for decreasing fear responses to a stimulus that is no longer threatening. While it is known that the infralimbic (IL) region of the medial prefrontal cortex mediates retrieval of an extinction memory through projections to the basolateral amygdala (BLA), IL pathways contributing to extinction learning are not well understood. Given the dense projection from the IL to the substantia innominata-ventral pallidum (SI/VP), an area that processes aversive and appetitive cues, we compared how the IL→SI/VP functions in extinction compared with the IL→BLA pathway in male mice. Using retrograde tracing, we demonstrate that IL projections to the SI/VP originate from superficial [Layer (L)2/3] and deep cortical layers (L5) and that they are denser than IL projections to the BLA. Next, combining retrograde tracing with labeling for the immediate early gene cFos, we show increased activity of L5 IL→SI/VP output during extinction learning and increased activity of L2/3 IL→BLA output during extinction retrieval. Then, using in vitro recordings, we demonstrate that neurons in the IL→SI/VP pathway are more excitable during extinction learning than retrieval. Finally, using optogenetics, we inactivate the IL→SI/VP pathway and show that this increases defensive freezing during extinction learning and re-extinction, without affecting memory. Taken together, we demonstrate that the IL→SI/VP pathway is active during extinction learning, when it constrains the defensive freezing response. We propose that the IL acts as a switchboard operator, increasing IL L5 communication with the SI/VP during extinction learning and IL L2/3 communication with the BLA during extinction retrieval.
恐惧消退对于减少对不再构成威胁的刺激的恐惧反应至关重要。虽然已知内侧前额叶皮质的腹内侧前额叶（IL）区域通过投射到基底外侧杏仁核（BLA）介导消退记忆的提取，但对IL中有助于消退学习的通路尚不清楚。鉴于从IL到无名质-腹侧苍白球（SI/VP）有密集投射，而SI/VP是一个处理厌恶和奖赏线索的区域，我们比较了雄性小鼠中IL→SI/VP通路与IL→BLA通路在消退过程中的作用。通过逆行追踪，我们证明IL到SI/VP的投射起源于浅层[第（L）2/3层]和深层皮质层（L5），并且它们比IL到BLA的投射更密集。接下来，将逆行追踪与即时早期基因cFos标记相结合，我们发现在消退学习期间L5 IL→SI/VP输出的活性增加，在消退提取期间L2/3 IL→BLA输出的活性增加。然后，通过体外记录，我们证明在消退学习期间IL→SI/VP通路中的神经元比提取期间更易兴奋。最后，使用光遗传学，我们使IL→SI/VP通路失活，并表明这会增加消退学习和重新消退期间的防御性僵住，而不影响记忆。综上所述，我们证明IL→SI/VP通路在消退学习期间是活跃的，此时它会抑制防御性僵住反应。我们提出，IL起到了一个总机接线员的作用，在消退学习期间增加IL L5与SI/VP的通信，在消退提取期间增加IL L2/3与BLA的通信。
