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Hunger makes Drosophila larvae move faster in search of food. Koon and colleagues show that starvation increases the branching of octopaminergic motoneurons' axonal terminal arbors, driven by octopamine released from these same motoneurons. The increased locomotor activity of starved larvae requires octopaminergic signaling. Adrenergic signaling has important roles in synaptic plasticity and metaplasticity. However, the underlying mechanisms of these functions remain poorly understood. We investigated the role of octopamine, the invertebrate counterpart of adrenaline and noradrenaline, in synaptic and behavioral plasticity in Drosophila . We found that an increase in locomotor speed induced by food deprivation was accompanied by an activity- and octopamine-dependent extension of octopaminergic arbors and that the formation and maintenance of these arbors required electrical activity. Growth of octopaminergic arbors was controlled by a cAMP- and CREB-dependent positive-feedback mechanism that required Octβ2R octopamine autoreceptors. Notably, this autoregulation was necessary for the locomotor response. In addition, octopamine neurons regulated the expansion of excitatory glutamatergic neuromuscular arbors through Octβ2Rs on glutamatergic motor neurons. Our results provide a mechanism for global regulation of excitatory synapses, presumably to maintain synaptic and behavioral plasticity in a dynamic range.

For nearly a century, the fruit fly, , has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD). Discoveries regarding the possible mechanisms of RNA toxicity will be focused here. These studies demonstrate as an excellent model system that can reveal novel mechanistic insights into human disorders, providing the foundation for translational research and therapeutic development.

Neuronal activity regulates the development and maturation of excitatory and inhibitory synapses in the mammalian brain. Several recent studies have identified signalling networks within neurons that control excitatory synapse development. However, less is known about the molecular mechanisms that regulate the activity-dependent development of GABA (γ-aminobutyric acid)-releasing inhibitory synapses. Here we report the identification of a transcription factor, Npas4, that plays a role in the development of inhibitory synapses by regulating the expression of activity-dependent genes, which in turn control the number of GABA-releasing synapses that form on excitatory neurons. These findings demonstrate that the activity-dependent gene program regulates inhibitory synapse development, and suggest a new role for this program in controlling the homeostatic balance between synaptic excitation and inhibition. Balance of mind A fine balance between the numbers of excitatory and inhibitory synapses must be maintained for neuronal circuits to function. The intracellular molecular signalling pathways involved in activity-dependent formation of synapses, particularly inhibitory ones, are largely unknown. A new study has identified the transcription factor Npas4 as a 'master switch' acting in brain cells to maintain the homeostatic balance between synaptic excitation and inhibition, a balance that is thought to be disrupted in neurologic disorders such as autism, epilepsy and schizophrenia. Npas4 acts by regulating the expression of more than 200 activity-dependent genes, which in turn control the number of GABA-mediated synapses that form excitatory neurons.

Arthropods comprise the majority of all described animal species, and understanding their evolution is a central question in biology. Their developmental processes are under the precise control of distinct hormonal regulators, including the sesquiterpenoids juvenile hormone (JH) and methyl farnesoate. The control of the synthesis and mode of action of these hormones played important roles in the evolution of arthropods and their adaptation to diverse habitats. However, the precise roles of non-coding RNAs, such as microRNAs (miRNAs), controlling arthropod hormonal pathways are unknown. Here, we investigated the miRNA regulation of the expression of the juvenile hormone acid methyltransferase gene (JHAMT), which encodes a rate-determining sesquiterpenoid biosynthetic enzyme. Loss of function of the miRNA bantam in the fly Drosophila melanogaster increased JHAMT expression, while overexpression of the bantam repressed JHAMT expression and resulted in pupal lethality. The male genital organs of the pupae were malformed, and exogenous sesquiterpenoid application partially rescued the genital deformities. The role of the bantam in the regulation of sesquiterpenoid biosynthesis was validated by transcriptomic, qPCR and hormone titre (JHB3 and JH III) analyses. In addition, we found a conserved set of miRNAs that interacted with JHAMT, and the sesquiterpenoid receptor methoprene-tolerant (Met) in different arthropod lineages, including insects (fly, mosquito and beetle), crustaceans (water flea and shrimp), myriapod (centipede) and chelicerate (horseshoe crab). This suggests that these miRNAs might have conserved roles in the post-transcriptional regulation of genes in sesquiterpenoid pathways across the Panarthropoda. Some of the identified lineage-specific miRNAs are potential targets for the development of new strategies in aquaculture and agricultural pest control.

Arthropods comprise the majority of all described animal species, and understanding their evolution is a central question in biology. Their developmental processes are under the precise control of distinct hormonal regulators, including the sesquiterpenoids juvenile hormone (JH) and methyl farnesoate. The control of the synthesis and mode of action of these hormones played important roles in the evolution of arthropods and their adaptation to diverse habitats. However, the precise roles of non-coding RNAs, such as microRNAs (miRNAs), controlling arthropod hormonal pathways are unknown. Here, we investigated the miRNA regulation of the expression of the juvenile hormone acid methyltransferase gene (JHAMT), which encodes a rate-determining sesquiterpenoid biosynthetic enzyme. Loss of function of the miRNA bantam in the fly Drosophila melanogaster increased JHAMT expression, while overexpression of the bantam repressed JHAMT expression and resulted in pupal lethality. The male genital organs of the pupae were malformed, and exogenous sesquiterpenoid application partially rescued the genital deformities. The role of the bantam in the regulation of sesquiterpenoid biosynthesis was validated by transcriptomic, qPCR and hormone titre (JHB3 and JH III) analyses. In addition, we found a conserved set of miRNAs that interacted with JHAMT, and the sesquiterpenoid receptor methoprene-tolerant (Met) in different arthropod lineages, including insects (fly, mosquito and beetle), crustaceans (water flea and shrimp), myriapod (centipede) and chelicerate (horseshoe crab). This suggests that these miRNAs might have conserved roles in the post-transcriptional regulation of genes in sesquiterpenoid pathways across the Panarthropoda. Some of the identified lineage-specific miRNAs are potential targets for the development of new strategies in aquaculture and agricultural pest control.

Myotonic dystrophy type 1 is a multisystemic disorder that has been extensively studied for decades, yet our understanding of its neuropathological aspect remains rudimentary. Building on an established Drosophila model, we study the neuropathological features of the disease by expressing untranslated expanded CUG repeats at the Drosophila larval neuromuscular junction. In this model, we show that both pre- and postsynaptic expressions of CUG repeats participate in inducing phenotypes in synaptic boutons, arbors, transmission and larval locomotor activity. Furthermore, expression of CUG repeats in either motorneurons or body wall muscles induces upregulation of the cell adhesion molecule FasII (NCAM1 in mammals), and the knockdown of fasII is sufficient to rescue the phenotypes. Overexpression of FasII-C, a FasII isoform with no cytoplasmic domain, mimics the phenotypes of expanded CUG expression at the neuromuscular junction. In contrary, overexpression of FasII-A-PEST+ rescues the synaptic and behavioral defects. Our study provides insights into the fundamental mechanisms underlying synapse dysregulation in myotonic dystrophy type 1. Myotonic dystrophy type 1 affects both muscle and neuronal function, but its synaptic pathology is poorly understood. Here, the authors show that upregulation of FasII (NCAM1) in both pre- and postsynaptic cells synergistically drives neuropathological and behavioral DM1 phenotypes, which can be rescued by FasII knockdown or specific isoform modulation.

[This corrects the article DOI: 10.3389/fmed.2024.1500216.].

Primary care providers or clinicians (PCPs) have the potential to assist dermatologists in screening patients at risk for skin cancer, but require training to appropriately identify higher-risk patients, perform skin checks, recognize and biopsy concerning lesions, interpret pathology results, document the exam, and bill for the service. Very few validated dermatology training programs exist for PCPs and those that are available focus primarily on one emphasis area, which results in variable efficacy and single-topic limited scope. We have created a free, online, continuing education program (Melanoma Toolkit for Early Detection, MTED) that allows learners to choose from a variety of multimedia tools (image recognition, videos, written material, in-person seminars, self-tests, etc.) that suits their learning style and time availability. Here we present the toolkit, the development and validation of the curriculum, and report on 1-year outcomes of a nested survey study. Because the goal of the program is to maximize participation by allowing PCPs to tailor their experience to their own needs and interests, the majority of participants did not complete every element of the program. A total of 8,683 PCPs have accessed at least one element of the toolkit from 2019-2024. Participants completed a pre-survey, online training module, and post-survey that included self-reported screening behaviors, changes in confidence, and malignant and benign lesion categorization based on clinical images. A total of 139 pre-surveys and 92 post-surveys were completed, including 55 matched participants that completed both the pre- and post-training surveys. There were significant improvements in PCP confidence ( < 0.001) and malignant ( < 0.001) and benign image ( = 0.029) identification respectively. PCPs may serve as a valuable aid in skin cancer screening efforts, but additional studies are needed to evaluate the impact of these curricula in clinical practice.

[This corrects the article DOI: 10.3389/fmed.2025.1427136.].

Melanoma is one of the deadliest forms of skin cancer but is typically cured with surgical excision when detected early. As an access point to medical care, primary care providers (PCP) play an integral role in early skin cancer detection. However, limited time for examinations and dermatologic training may present barriers to effective skin examination in the primary care setting. As a facet of Oregon Health & Science University’s War on Melanoma™ (WoM), our multi-pronged outreach initiative aims to provide PCPs across Oregon with free, convenient, and effective melanoma education. The WoM PCP education campaign was disseminated starting in May 2019 through primary care networks throughout the state of Oregon to 12,792 PCPs, and education was delivered across several platforms: online multimedia tools, large group didactics, individualized practice-based sessions, and in-person distribution of materials to clinics. To date, 829 PCPs have participated in the online Melanoma Toolkit for Early Detection curriculum, 1,874 providers have attended CME didactics, and 9 clinics have received facilitated meetings by Oregon Rural Practice-based Research Network. Eighty-three clinics (comprising 770 providers) were visited on-site and provided educational materials, and more than 150 PCPs have received a free smartphone dermatoscope to aid in skin examination and e-consultation. OHSU’s WoM has successfully implemented a multifaceted approach to provide accessible melanoma education to PCPs across the state of Oregon. As a result, we hope to encourage appropriate skin examination in the primary care setting and improve PCPs’ diagnostic accuracy and confidence in pigmented lesion evaluation.