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The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regenerative rate 1 . Regenerative ability is influenced by both injury-dependent and injury-independent mechanisms 2 . Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signalling pathways that promote axonal regeneration 3 . Several of these pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism and the release of neurotrophins, can be activated by intermittent fasting (IF) 4 , 5 . However, whether IF influences the axonal regenerative ability remains to be investigated. Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the gut bacteria-derived metabolite indole-3-propionic acid (IPA) in the serum. IPA production by Clostridium sporogenes is required for efficient axonal regeneration, and delivery of IPA after sciatic injury significantly enhances axonal regeneration, accelerating the recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis. Our results demonstrate the ability of a microbiome-derived metabolite, such as IPA, to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, prompting extensive efforts to pinpoint novel therapeutic targets for effective intervention. Among the hallmark features of AD is the development of neurofibrillary tangles comprised of hyperphosphorylated tau protein, whose progressive spread throughout the brain is associated with neuronal death. Trans-synaptic propagation of tau has been observed in mouse models and indirect evidence for tau spread via synapses has been observed in human AD. Halting tau propagation is a promising therapeutic target for AD, thus a scalable model system to screen for modifiers of tau spread would be very useful for the field. To this end, we sought to emulate the trans-synaptic spread of human tau (hTau) in Drosophila melanogaster. Employing the trans-Tango circuit mapping technique, we investigated whether tau spreads between synaptically connected neurons. Immunohistochemistry and confocal imaging were used to look for tau propagation. Examination of hundreds of flies expressing 4 different human tau constructs in two distinct neuronal populations reveal a robust resistance in Drosophila to the trans-synaptic spread of hTau. This resistance persisted in lines with concurrent expression of amyloid-β, in lines with global hTau knock-in to provide a template for human tau in downstream neurons, and with manipulations of temperature. These negative data are important for the field as we establish that Drosophila expressing human tau in subsets of neurons are unlikely to be useful to perform screens to find mechanisms to reduce the trans-synaptic spread of tau. The inherent resistance observed in Drosophila may serve as a valuable clue, offering insights into strategies for impeding tau spread in future studies.

Children's Books Editor Anne Johnstone reveals the results of My Favourite Children's Book Ever - The Herald's competition, held in conjunction with Ottakar's Bookshop, which celebrates the timeless pleasure of curling up with a much-loved story With the disarming simplicity of an eight-year-old, Caroline Dunlop summed up the essence of the assignment in just nine words: \"When I read it, I felt excited and happy.\" The Herald had asked readers of all ages to name for us their favourite children's book and justify their choice in 150 words or less. The object of the exercise was to get beyond the publisher's blurb and the necessary contrivance of a professional review to arrive at that private and passionate relationship between author and reader. Some readers chose treasured books that are little known to the general public or long out of print. Laura Hansen-Just, aged 12, painted a delightful word picture of herself snuggling up with her gran and the book they always called The Yammy of Yawn. \"It was like a dream you could step inside and explore,\" she said. Gran has passed away now, but Laura still treasures the book (actually called Wide Awake Jake) and the memories it conjures. Given her vast following from children round the world, it comes as little surprise that Edinburgh-based J K Rowling easily tops our authors poll. Her Harry Potter books also occupy all top three slots in the top books section. Scores of children wrote about one or other of them, including 10-year-old Leila Wilkinson who told us: \"I couldn't put it down. When I read this book, I felt like I was in the story. Even my Mum has read it!!!\"