Bowles Center for Alcohol Studies, Curriculum in Neurobiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Bowles Center for Alcohol Studies, Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Transl Psychiatry. 2018 Mar 6;8(1):60. doi: 10.1038/s41398-018-0106-x.
Fear extinction involves the formation of a new memory trace that attenuates fear responses to a conditioned aversive memory, and extinction impairments are implicated in trauma- and stress-related disorders. Previous studies in rodents have found that the infralimbic prefrontal cortex (IL) and its glutamatergic projections to the basolateral amygdala (BLA) and basomedial amygdala (BMA) instruct the formation of fear extinction memories. However, it is unclear whether these pathways are exclusively involved in extinction, or whether other major targets of the IL, such as the nucleus accumbens (NAc) also play a role. To address this outstanding issue, the current study employed a combination of electrophysiological and chemogenetic approaches in mice to interrogate the role of IL-BLA and IL-NAc pathways in extinction. Specifically, we used patch-clamp electrophysiology coupled with retrograde tracing to examine changes in neuronal activity of the IL and prelimbic cortex (PL) projections to both the BLA and NAc following fear extinction. We found that extinction produced a significant increase in the intrinsic excitability of IL-BLA projection neurons, while extinction appeared to reverse fear-induced changes in IL-NAc projection neurons. To establish a causal counterpart to these observations, we then used a pathway-specific Designer Receptors Exclusively Activated by Designer Drugs (DREADD) strategy to selectively inhibit PFC-BLA projection neurons during extinction acquisition. Using this approach, we found that DREADD-mediated inhibition of PFC-BLA neurons during extinction acquisition impaired subsequent extinction retrieval. Taken together, our findings provide further evidence for a critical contribution of the IL-BLA neural circuit to fear extinction.
恐惧消退涉及形成新的记忆痕迹,从而减弱对条件性厌恶记忆的恐惧反应,而消退障碍与创伤和应激相关障碍有关。以前在啮齿动物中的研究发现,额下回皮层(IL)及其谷氨酸能投射到外侧杏仁核(BLA)和基底内侧杏仁核(BMA)指导恐惧消退记忆的形成。然而,尚不清楚这些途径是否专门参与消退,或者 IL 的其他主要靶点,如伏隔核(NAc)是否也发挥作用。为了解决这个悬而未决的问题,本研究在小鼠中结合使用了电生理学和化学遗传学方法,以探究 IL-BLA 和 IL-NAc 途径在消退中的作用。具体来说,我们使用膜片钳电生理学结合逆行追踪,检查恐惧消退后 IL 和额前皮质(PL)投射到 BLA 和 NAc 的神经元活动的变化。我们发现,消退显著增加了 IL-BLA 投射神经元的固有兴奋性,而消退似乎逆转了 IL-NAc 投射神经元的恐惧诱导变化。为了与这些观察结果建立因果关系,我们随后使用特定通路的 Designer Receptors Exclusively Activated by Designer Drugs(DREADD)策略,在消退获得期间选择性地抑制 PFC-BLA 投射神经元。使用这种方法,我们发现,在消退获得期间,DREADD 介导的 PFC-BLA 神经元抑制会损害随后的消退检索。总之,我们的研究结果进一步证明了 IL-BLA 神经回路对恐惧消退的关键贡献。
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