Department of Psychological Sciences, and.
Brain Health Research Institute, Kent State University, Kent, OH 44242.
J Neurosci. 2019 Aug 14;39(33):6526-6539. doi: 10.1523/JNEUROSCI.0810-19.2019. Epub 2019 Jun 17.
A common symptom of anxiety disorders is the overgeneralization of fear across a broad range of contextual cues. We previously found that the ACC and ventral hippocampus (vHPC) regulate generalized fear. Here, we investigate the functional projections from the ACC and vHPC to the amygdala and their role in governing generalized fear in a preclinical rodent model. A chemogenetic approach (designer receptor exclusively activated by designer drugs) was used to inhibit glutamatergic projections from the ACC or vHPC that terminate within the BLA at recent (1 d) or remote (28 d) time points after contextually fear conditioning male mice. Inactivating ACC or vHPC projections to the BLA significantly reduced generalized fear to a novel, nonthreatening context but had no effect on fear to the training context. Further, our data indicate that the ACC-BLA circuit supports generalization in a time-independent manner. We also identified, for the first time, a strictly time-dependent role of the vHPC-BLA circuit in supporting remote generalized contextual fear. Dysfunctional signaling to the amygdala from the ACC or the HPC could underlie overgeneralized fear responses that are associated with anxiety disorders. Our findings demonstrate that the ACC and vHPC regulate fear expressed in novel, nonthreatening environments via projections to the BLA but do so as a result of training intensity or time, respectively. Anxiety disorders are characterized by a common symptom that promotes overgeneralization of fear in nonthreatening environments. Dysregulation of the amygdala, ACC, or hippocampus (HPC) has been hypothesized to contribute to increased fear associated with anxiety disorders. Our findings show that the ACC and HPC projections to the BLA regulate generalized fear in nonthreatening, environments. However, descending ACC projections control fear generalization independent of time, whereas HPC projections play a strictly time-dependent role in regulating generalized fear. Thus, dysfunctional ACC/HPC signaling to the BLA may be a predominant underlying mechanism of nonspecific fear associated with anxiety disorders. Our data have important implications for predictions made by theories about aging memories and interactions between the HPC and cortical regions.
焦虑障碍的一个常见症状是将恐惧泛化到广泛的情境线索上。我们之前发现，ACC 和腹侧海马体（vHPC）调节泛化恐惧。在这里，我们研究了从 ACC 和 vHPC 到杏仁核的功能投射及其在控制临床前啮齿动物模型中泛化恐惧中的作用。使用化学遗传方法（专门被设计药物激活的受体）来抑制谷氨酸能投射，这些投射来自于最近（1 天）或远程（28 天）在情境恐惧条件下的雄性小鼠的 ACC 或 vHPC，投射终止于 BLA 内。抑制 ACC 或 vHPC 投射到 BLA 可显著减少对新的、无威胁的情境的泛化恐惧，但对训练情境的恐惧没有影响。此外，我们的数据表明，ACC-BLA 回路以独立于时间的方式支持泛化。我们还首次发现，vHPC-BLA 回路在支持远程泛化的上下文恐惧方面具有严格的时间依赖性作用。来自 ACC 或 HPC 的信号传递到杏仁核的功能障碍可能是与焦虑障碍相关的过度泛化恐惧反应的基础。我们的研究结果表明，ACC 和 vHPC 通过投射到 BLA 来调节在新的、无威胁的环境中表达的恐惧，但这是由于训练强度或时间的不同。焦虑障碍的一个共同特征是促进在无威胁环境中过度泛化恐惧。杏仁核、ACC 或海马体（HPC）的失调被假设为与焦虑障碍相关的恐惧增加的原因。我们的研究结果表明，ACC 和 HPC 投射到 BLA 调节了无威胁环境中的泛化恐惧。然而，ACC 的下行投射独立于时间控制恐惧泛化，而 HPC 的投射在调节泛化恐惧方面具有严格的时间依赖性作用。因此，ACC/HPC 到 BLA 的信号传递功能障碍可能是与焦虑障碍相关的非特异性恐惧的主要潜在机制。我们的数据对关于记忆老化的理论和 HPC 与皮质区域之间相互作用的预测具有重要意义。
