Xiong Jiali, Mehta Anuradha, Liu Qiang, Luo Anna X, Li Pan P, Janak Patricia H, Wu Mark N
Biochemistry, Cellular and Molecular Biology Graduate Program, Johns Hopkins University, Baltimore, MD 21205, U.S.A.
Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, U.S.A.
J Neurosci. 2025 Aug 20. doi: 10.1523/JNEUROSCI.0225-25.2025.
The central amygdala (CeA) is an important neuronal hub that integrates external sensory inputs and information about internal states to regulate a range of innate and learned behaviors, including fear learning and memory. Prior studies, leveraging robust fear conditioning assays, have delineated detailed circuit mechanisms underlying the acquisition and recall of fear memories. However, the specific molecular mechanisms underlying these processes in the CeA remain poorly understood. Here, we investigate the role of the clock output molecule mWAKE/ANKFN1 within the CeA of male mice in fear learning and memory. mWAKE is expressed in multiple neuronal sub-clusters in the lateral CeA. Surprisingly, mWAKE levels do not exhibit rhythmic expression in the CeA. In line with this observation, expression of the core clock genes PER2 and BMAL also does not cycle in the CeA. Consistent with prior studies, loss of mWAKE function increases intrinsic excitability of CeA neurons. Furthermore, conditional knockout of mWAKE and chemogenetic activation of CeA neurons impair fear learning and memory. Finally, we show that mWAKE levels in a subset of CeA neurons are reduced following fear conditioning. These findings suggest a potential molecular mechanism modulating the activity and function of CeA neurons in fear learning and memory. The central amygdala (CeA) plays a crucial role in the acquisition and recall of fear learning, yet the molecular mechanisms underlying this process remain incompletely understood. This study shows that an evolutionarily conserved molecule (mWAKE) is enriched in a subset of CeA neurons, acts to reduce neuronal excitability, and is required for fear learning and memory. Although mWAKE functions as a clock output molecule in other contexts, its expression, as well as that of core clock genes, does not cycle in the CeA. Instead, mWAKE levels are reduced after fear conditioning. These findings hint at a potential molecular mechanism that may support the generation of fear memory.
中央杏仁核（CeA）是一个重要的神经枢纽，它整合外部感觉输入和有关内部状态的信息，以调节一系列先天和习得行为，包括恐惧学习和记忆。先前的研究利用强大的恐惧条件反射试验，已经阐明了恐惧记忆获取和回忆背后的详细神经回路机制。然而，CeA中这些过程背后的具体分子机制仍知之甚少。在这里，我们研究了时钟输出分子mWAKE/ANKFN1在雄性小鼠CeA中对恐惧学习和记忆的作用。mWAKE在外侧CeA的多个神经元亚群中表达。令人惊讶的是，mWAKE水平在CeA中不表现出节律性表达。与此观察结果一致，核心时钟基因PER2和BMAL的表达在CeA中也不循环。与先前的研究一致，mWAKE功能丧失会增加CeA神经元的内在兴奋性。此外，mWAKE的条件性敲除和CeA神经元的化学遗传学激活会损害恐惧学习和记忆。最后，我们表明恐惧条件反射后，CeA神经元亚群中的mWAKE水平会降低。这些发现提示了一种潜在的分子机制，可调节CeA神经元在恐惧学习和记忆中的活性和功能。中央杏仁核（CeA）在恐惧学习的获取和回忆中起关键作用，然而这一过程背后的分子机制仍未完全了解。这项研究表明，一种进化上保守的分子（mWAKE）在CeA神经元亚群中富集，其作用是降低神经元兴奋性，并且是恐惧学习和记忆所必需的。尽管mWAKE在其他情况下作为时钟输出分子发挥作用，但其表达以及核心时钟基因的表达在CeA中并不循环。相反，恐惧条件反射后mWAKE水平会降低。这些发现暗示了一种可能支持恐惧记忆生成的潜在分子机制。
