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Motor circuits in the vertebrate hindbrain need to become functional early in development. What are the fundamental mechanisms that establish early synaptic inputs to motor neurons? Previous evidence is consistent with the hypothesis that motor neuron dendrite positioning serves a causal role in early spinal motor circuit development, with initial connectivity determined by the overlap between premotor axons and motor neuron dendrites (perhaps without the need for molecular recognition). Does motor neuron dendrite topography serve a similar role in the hindbrain? In the current study, we provide the first quantitative analysis of the dendrites of facial branchiomotor neurons (FBMNs) in larval zebrafish. We previously demonstrated that FBMNs exhibit functional topography along the dorsoventral axis, with the most ventral cell bodies most likely to exhibit early rhythmic activity-suggesting that FBMNs with ventral cell bodies are most likely to receive inputs from premotor neurons carrying rhythmic respiratory signals. We hypothesized that this functional topography can be explained by differences in dendrite positioning, giving ventral FBMNs preferential access to premotor axons carrying rhythmic signals. If this hypothesis is true, we predicted that FBMN cell body position would be correlated with dendrite position along the dorsoventral axis. To test this prediction, we used single-cell labeling to trace the dendritic arbors of FBMNs in larval zebrafish at 5-days post-fertilization (dpf). FBMN dendrites varied in complexity, and this variation could not be attributed to differences in the relative age of neurons. Most dendrites grew caudally, laterally, and ventrally from the cell body-though FBMN dendrites could extend their dendrites dorsally. Across our sample, FBMN cell body position correlated with dendrite position along the dorsoventral axis, consistent with our hypothesis that differences in dendrite positioning serve as the substrate for differences in activity patterns across neurons. Future studies will build on this foundational data, testing additional predictions of the central hypothesis-to further investigate the mechanisms of early motor circuit development., (© 2024 The Author(s). The Journal of Comparative Neurology published by Wiley Periodicals LLC.)

Proneural transcription factors establish molecular cascades to orchestrate neuronal diversity. One such transcription factor, Atonal homolog 1 (Atoh1), gives rise to cerebellar excitatory neurons and over 30 distinct nuclei in the brainstem critical for hearing, breathing, and balance. Although Atoh1 lineage neurons have been qualitatively described, the transcriptional programs that drive their fate decisions and the full extent of their diversity remain unknown. Here, we analyzed single-cell RNA sequencing and ATOH1 DNA binding in Atoh1 lineage neurons of the developing mouse hindbrain. This high-resolution dataset identified markers for specific brainstem nuclei and demonstrated that transcriptionally heterogeneous progenitors require ATOH1 for proper migration. Moreover, we identified a sizable population of proliferating unipolar brush cell progenitors in the mouse Atoh1 lineage, previously described in humans as the origin of one medulloblastoma subtype. Collectively, our data provide insights into the developing mouse hindbrain and markers for functional assessment of understudied neuronal populations., Competing Interests: Declaration of interests R.S.D. is a paid consultant for AstraZeneca. H.Y.Z. is a member of the Board of Regeneron, co-founder of Cajal Neuroscience, and on the science advisory board of the Column group. This is work in the Zoghbi Lab and has not been licensed anywhere. The work in this paper has no connection to any of the consulting or companies named here., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting 1,2 , effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTS GLP1R neurons triggers satiety in the absence of aversion, whereas activation of AP GLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTS GLP1R and AP GLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTS GLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Cerebellar granule neuron progenitors (GNPs) originate from the upper rhombic lip (URL), a germinative niche in which developmental defects produce human diseases. T-cell factor (TCF) responsiveness and Notch dependence are hallmarks of self-renewal in neural stem cells. TCF activity, together with transcripts encoding proneural gene repressors hairy and enhancer of split (Hes/Hey), are detected in the URL; however, their functions and regulatory modes are undeciphered. Here, we established amphibian as a pertinent model for studying vertebrate URL development. The amphibian long-lived URL is TCF active, whereas the external granular layer (EGL) is non-proliferative and expresses hes4 and hes5 genes. Using functional and transcriptomic approaches, we show that TCF activity is necessary for URL emergence and maintenance. We establish that the transcription factor Barhl1 controls GNP exit from the URL, acting partly through direct TCF inhibition. Identification of Barhl1 target genes suggests that, besides TCF, Barhl1 inhibits transcription of hes5 genes independently of Notch signaling. Observations in amniotes suggest a conserved role for Barhl in maintenance of the URL and/or EGL via co-regulation of TCF, Hes and Hey genes., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)