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Developmental molecular signatures define de novo cortico-brainstem circuit for skilled forelimb movement

ABSTRACT: Skilled motor control requires precise connections between subcerebral projection neurons (SCPN) in the cerebral cortex and their appropriate subcerebral targets in the brainstem or spinal cord. The brainstem has been widely recognized as a key integration and processing hub between “upper” motor centers and spinal circuits involved in execution of movements. Cortical input into the brainstem may fine-tune movement execution and support motor planning and is established by two SCPN supopulations: 1) cortico-brainstem neurons (CBN) that limit their axon extension to supraspinal levels, directly innervating brainstem nuclei, and 2) corticospinal neurons (CSN) that extend their axons into the spinal cord but additionally collateralize within the brainstem. Classical anatomical tracing approaches are not able to distinguish CBN from CSN, since these distinct subpopulations reside interdigitated in cortex, thus precluding the investigation of the function of CBN in skilled motor movement execution and planning until now. We used a combination of transcriptomics, tracing, and imaging techniques to identify the molecular program that CBN vs. CSN at the time point of initial axon extension. We found that Neuropeptide Y (Npy) is specifically enriched in CBN in lateral cortex, while CART prepropeptide (Cartpt) delineates cervical-projecting CSN, which now provides, for the first time in the field, molecular access to specifically investigate direct cortical input into the brainstem. By using established Cre mouse lines for CBN / CSN specific markers, we now aim to investigate the function and connectivity of these CBN vs. CSN within the brainstem. Our preliminary results suggest a topographic organization of these subpopulations within the brainstem. Selectively silencing of Npy+ CBN within the lateral cortex will allow us to investigate the contribution of CBN to skilled motor movements in the single pellet reaching task and other selected motor tasks. Our results provide a foundation for future studies aiming to unravel the complexity of cortico-brainstem and cortico-spinal circuits, and their contribution to movement control in health and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE270265 | GEO | 2026/04/03

REPOSITORIES: GEO

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Project description:ALS is a uniformly fatal neurodegenerative disease in which motor neurons in the spinal cord and brain stem are selectively lost. Individual motor - groups of motor neurons innervating single muscles - show widely varying degrees of disease resistance: in the final stages of ALS, nearly all voluntary movement is lost but eye movement and eliminative and sexual functions remain relatively unimpaired. These functions are controlled by motor neurons of the oculomotor (III), trochlear (IV) and abducens (VI) nuclei in the midbrain and brainstem, and by Onuf's nucleus in the lumbosacral spinal cord, respectively. Correspondingly, in ALS autopsies the oculomotor and Onuf's nuclei are almost completely preserved. We used microarray profiling of isolated wildtype mouse motor neurons to identify genes whose expression was characteristic of both oculomotor and Onuf's nuclei but not of vulnerable lumbar spinal neurons, or vice versa. Three wild-type C57BL/6J P7 male animals were perfused with 30% sucrose, lumbosacral spinal cord and midbrain regions were rapidly recovered, embedded in OCT compound, and frozen in liquid nitrogen. 12 um-thick cryosections were mounted on RNAse-free, PEN-foil covered glass slides (Zeiss), fixed for 2 min in 100% EtOH, rinsed in 50% EtOH, stained with 1% cresyl violet for 2 min, rinsed with 50% EtOH, dehydrated in graded solutions of ethanol and air dried prior to LCM using PALM Microbeam system (Zeiss). From each animal, ~200 DL, L5, and oculomotor motor neurons were collected directly in lysis buffer. RNA was purified using Absolutely RNA, NanoPrep kit (Stratagene, La Jolla, CA). RNA integrity was assessed on the Bioanalyzer 2100 (Agilent Technologies, Santa Clara, CA). At least 1.5 ng of purified RNA was the starting material used in the WT-Ovation Pico RNA Amplification System (Nugen, San Carlos,CA) with the FL-Ovation cDNA Biotin Module V2 (Nugen) to generate labeled probe. 10 ug of biotinylated cRNA from three independent samples for each motor neuron group isolated by LCM was hybridized to on Affymetrix (Santa Clara, CA) Mouse Genome 430 2.0 Arrays. Gene ontology and pathway analysis was performed using DAVID Bioinformatics Resources 6.7 (National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD).

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Developmental molecular signatures define de novo cortico-brainstem circuit for skilled forelimb movement

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