Howard Hugues Medical Institute, University of Washington, Seattle, WA, USA.
Department of Biochemistry, University of Washington, Seattle, WA, USA.
Nat Commun. 2024 Nov 9;15(1):9721. doi: 10.1038/s41467-024-53977-w.
Learning to associate cues, both directly and indirectly, with biologically significant events is essential for survival. Second-order conditioning (SOC) involves forming an association between a previously reinforced conditioned stimulus (CS1) and a new conditioned stimulus (CS2) without the presence of an unconditioned stimulus (US). The neural substrates mediating SOC, however, remain unclear. Parabrachial Calca neurons, which react to the noxious US, also respond to a CS after pairing with a US, suggesting that Calca neurons mediate SOC. We established an aversive SOC behavioral paradigm in mice and monitored Calca neuron activity via single-cell calcium imaging during conditioning and subsequent recall phases. These neurons were activated by both CS1 and CS2 after SOC. Chemogenetically inhibiting Calca neurons during CS1-CS2 pairing attenuated SOC. Thus, reactivation of the US pathway by a learned CS plays an important role in forming the association between the old and a new CS, promoting the formation of second-order memories.
学习将线索直接或间接地与具有生物学意义的事件联系起来对于生存至关重要。二级条件作用（SOC）涉及在没有非条件刺激（US）的情况下，在先前强化的条件刺激（CS1）和新的条件刺激（CS2）之间形成关联。然而，介导 SOC 的神经基质仍不清楚。臂旁核 Calca 神经元对有害的 US 作出反应，在与 US 配对后也对 CS 作出反应，这表明 Calca 神经元介导 SOC。我们在小鼠中建立了一种厌恶 SOC 行为范式，并通过单细胞钙成像在条件作用和随后的回忆阶段监测 Calca 神经元的活动。这些神经元在 SOC 后被 CS1 和 CS2 激活。在 CS1-CS2 配对期间化学抑制 Calca 神经元会减弱 SOC。因此，通过学习的 CS 重新激活 US 通路在形成旧 CS 和新 CS 之间的关联中起着重要作用，促进了二级记忆的形成。
