INSIGHT of Medicine(phase 19, 2024)


1.Anterior cingulate cross-hemispheric inhibition via the claustrum resolves painful sensory conflict

DOI: 10.1038/s42003-024-06008-9

The study explores the role of anterior cingulate cortex (ACC) projections to the contralateral claustrum (ACC→contraCLA) in sensory processing. These neurons show heightened responses to contralateral mechanical stimuli, especially during attentive behavior. Optogenetic activation of ACC→contraCLA neurons inhibits contralateral ACC pyramidal neurons, suppressing withdrawal responses to ipsilateral stimuli. This effect is mediated by local circuit interneurons in the claustrum. Chemogenetic silencing confirms the importance of this cross-hemispheric circuit in prioritizing attention between competing sensory inputs. Overall, the findings reveal a cortical-subcortical-cortical pathway that regulates attentional allocation to both innocuous and noxious stimuli.

2.Complexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles

DOI: 10.1038/s41467-024-46438-x

The study examines the structure of microtubule (MT) bundles in the axon-initial-segment (AIS), crucial for retaining tau protein and preventing neurodegeneration. Using varying concentrations of divalent cations, they observe different phases of MT bundles through synchrotron SAXS and TEM. A phase diagram reveals wide-spacing bundles (Bws), intermediate bundles (Bint), and a tubulin ring phase. They propose a model where tau stabilizes MT bundles by crosslinking tubulin oligomers, challenging the role of microtubule-associated proteins (MAPs) alone. Additionally, they suggest an intervening network (IN) of tubulin-tau complexes within bundles, serving as potential sites for tau modification and fibril formation in tauopathies. This research sheds light on the intricate mechanisms regulating tau distribution within axons and its implications for neurodegenerative diseases.

3.METTL3-dependent m6A modification of PSEN1 mRNA regulates craniofacial development through the Wnt/β-catenin signaling pathway

DOI: 10.1038/s41419-024-06606-9

The study investigates the role of METTL3, an m6A methyltransferase, in craniofacial development using zebrafish models and cell cultures. Mettl3 knockdown in zebrafish embryos results in craniofacial malformations and behavioral abnormalities. Similarly, reduced METTL3 expression inhibits cell proliferation and migration in bone marrow stromal cells and dental pulp stem cells. Loss of METTL3 reduces mRNA m6A methylation and PSEN1 expression, impacting craniofacial phenotypes. Co-injection of mettl3 or psen1 mRNA rescues these phenotypes. Mechanistically, YTHDF1 enhances mRNA stability of m6A-modified PSEN1, while decreased METTL3-mediated m6A methylation hinders β-catenin binding to PSEN1, suppressing Wnt/β-catenin signaling. Pharmacological activation of Wnt/β-catenin pathway partially alleviates mettl3 morphant phenotypes. This study elucidates the role of METTL3 in craniofacial development through the METTL3/YTHDF1/PSEN1/β-catenin signaling axis.

4.Gephyrin phosphorylation facilitates sexually dimorphic development and function of parvalbumin interneurons in the mouse hippocampus

DOI: 10.1038/s41380-024-02517-5

The study investigates the role of kinase signaling in the development and function of parvalbumin-type (PV) neurons, crucial for synaptic inhibition in brain circuits. They find that phosphorylation of the inhibitory post-synaptic scaffolding protein gephyrin at specific sites varies during development in both sexes. Blocking phosphorylation alters PV neuron density and inhibitory input onto principal cells, leading to sex-specific deficits in hippocampus-dependent memory tasks in mice. Fate mapping experiments reveal that phosphorylation at these sites drives early sex differences in PV neuron density. Additionally, patch-sequencing shows that phosphorylation influences the transcriptomic profile of developing interneurons. These findings highlight kinase signaling as a crucial regulator of PV neuron development, connectivity, and function in a sex-dependent manner, suggesting a new mechanism for sex-biased brain disorders.

5.The AMPK-related kinase NUAK1 controls cortical axons branching by locally modulating mitochondrial metabolic functions

DOI: 10.1038/s41467-024-46146-6

The study delves into the cellular mechanisms of axonal morphogenesis, crucial for forming functional neuronal networks. They previously identified NUAK1 kinase as a key regulator of axon branching by controlling mitochondria trafficking. They now find that mitochondria localization at synaptic boutons stabilizes collateral branches rather than initiating them. NUAK1 deficiency impairs mitochondrial metabolism and axonal ATP concentration, disrupting branching. Boosting mitochondrial function rescues branching in NUAK1-deficient neurons. Additionally, they discover that NUAK1 acts through the mitochondria-targeted microprotein BRAWNIN to regulate branching. These findings unveil NUAK1's dual role in axon branching by modulating mitochondrial distribution and metabolic activity, shedding light on mechanisms underlying neurodevelopmental disorders like autism.