Sleep benefits different stages of memory in Drosophila.

Understanding the physiological mechanisms that modulate memory acquisition and consolidation remains among the most ambitious questions in neuroscience. Massive efforts have been dedicated to deciphering how experience affects behavior, and how different physiological and sensory phenomena modulate memory. Our ability to encode, consolidate and retrieve memories depends on internal drives, and sleep stands out among the physiological processes that affect memory: one of the most relatable benefits of sleep is the aiding of memory that occurs in order to both prepare the brain to learn new information, and after a learning task, to consolidate those new memories. Drosophila lends itself to the study of the interactions between memory and sleep. The fruit fly provides incomparable genetic resources, a mapped connectome, and an existing framework of knowledge on the molecular, cellular, and circuit mechanisms of memory and sleep, making the fruit fly a remarkable model to decipher the sophisticated regulation of learning and memory by the quantity and quality of sleep. Research in Drosophila has stablished not only that sleep facilitates learning in wild-type and memory-impaired animals, but that sleep deprivation interferes with the acquisition of new memories. In addition, it is well-accepted that sleep is paramount in memory consolidation processes. Finally, studies in Drosophila have shown that that learning itself can promote sleep drive. Nevertheless, the molecular and network mechanisms underlying this intertwined relationship are still evasive. Recent remarkable work has shed light on the neural substrates that mediate sleep-dependent memory consolidation. In a similar way, the mechanistic insights of the neural switch control between sleep-dependent and sleep-independent consolidation strategies were recently described. This review will discuss the regulation of memory by sleep in Drosophila, focusing on the most recent advances in the field and pointing out questions awaiting to be investigated.

The Making of Long-Lasting Memories: A Fruit Fly Perspective.

Understanding the nature of the molecular mechanisms underlying memory formation, consolidation, and forgetting are some of the fascinating questions in modern neuroscience. The encoding, stabilization and elimination of memories, rely on the structural reorganization of synapses. These changes will enable the facilitation or depression of neural activity in response to the acquisition of new information. In other words, these changes affect the weight of specific nodes within a neural network. We know that these plastic reorganizations require de novo protein synthesis in the context of Long-term memory (LTM). This process depends on neural activity triggered by the learned experience. The use of model organisms like Drosophila melanogaster has been proven essential for advancing our knowledge in the field of neuroscience. Flies offer an optimal combination of a more straightforward nervous system, composed of a limited number of cells, and while still displaying complex behaviors. Studies in Drosophila neuroscience, which expanded over several decades, have been critical for understanding the cellular and molecular mechanisms leading to the synaptic and behavioral plasticity occurring in the context of learning and memory. This is possible thanks to sophisticated technical approaches that enable precise control of gene expression in the fruit fly as well as neural manipulation, like chemogenetics, thermogenetics, or optogenetics. The search for the identity of genes expressed as a result of memory acquisition has been an active interest since the origins of behavioral genetics. From screenings of more or less specific candidates to broader studies based on transcriptome analysis, our understanding of the genetic control behind LTM has expanded exponentially in the past years. Here we review recent literature regarding how the formation of memories induces a rapid, extensive and, in many cases, transient wave of transcriptional activity. After a consolidation period, transcriptome changes seem more stable and likely represent the synthesis of new proteins. The complexity of the circuitry involved in memory formation and consolidation is such that there are localized changes in neural activity, both regarding temporal dynamics and the nature of neurons and subcellular locations affected, hence inducing specific temporal and localized changes in protein expression. Different types of neurons are recruited at different times into memory traces. In LTM, the synthesis of new proteins is required in specific subsets of cells. This de novo translation can take place in the somatic cytoplasm and/or locally in distinct zones of compartmentalized synaptic activity, depending on the nature of the proteins and the plasticity-inducing processes that occur. We will also review recent advances in understanding how localized changes are confined to the relevant synapse. These recent studies have led to exciting discoveries regarding proteins that were not previously involved in learning and memory processes. This invaluable information will lead to future functional studies on the roles that hundreds of new molecular actors play in modulating neural activity.

Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models.

DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein ß-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.