mWAKE in the Central Amygdala Regulates Fear Learning and Memory

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 mWAKE 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. Significance statement 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.