1.Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD

DOI: 10.1016/j.cell.2024.02.031

https://www.cell.com/cell/abstract/S0092-8674(24)00234-4

This study compares the transcriptional changes in ALS and FTLD across specific cortical cell types using a single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices. It reveals similarities in vulnerable populations within cortical layer 5 between the two diseases and identifies potential disease mechanisms affecting these cell types. The research suggests that neuron loss in cortical layer 5 correlates more closely with transcriptional identity than cellular morphology, extending beyond previously identified vulnerable cell types. This comprehensive analysis sheds light on shared molecular features between ALS and FTLD and implicates both neuronal and non-neuronal factors in disease pathogenesis.

2.Biofilm exopolysaccharides alter sensory-neuron-mediated sickness during lung infection

DOI: 10.1016/j.cell.2024.03.001

https://www.cell.com/cell/article/S0092-8674(24)00249-6/fulltext

In lung infections, sickness symptoms arise from inflammation, alerting others to avoid contagion. Gram-negative bacteria, like Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli), produce exopolysaccharide (EPS) for protection, but its effect on sickness is unclear. Comparing EPS-producing and non-producing P. aeruginosa strains, and virulent E. coli in mice, researchers found EPS-negative P. aeruginosa and E. coli caused severe sickness, inflammation, and hypothermia by activating lung TRPV1+ sensory neurons via TLR4 detection of lipopolysaccharide (LPS). However, sickness wasn't solely due to inflammation. Lung nociceptor stimulation triggered acute stress responses in the brain, inducing sickness behavior and hypothermia. EPS-producing pathogens evade this response, suppressing sickness symptoms. This study uncovers mechanisms behind sickness in lung infections, revealing how certain pathogens mitigate immune responses.

3.Cellular architecture of evolving neuroinflammatory lesions and multiple sclerosis pathology

DOI: 10.1016/j.cell.2024.02.030

https://www.cell.com/cell/fulltext/S0092-8674(24)00233-2

This study delves into the cellular dynamics of multiple sclerosis (MS) using mouse models and human tissue analysis. Through single-cell spatial expression profiling, researchers mapped disease progression in experimental autoimmune encephalomyelitis (EAE) mice, uncovering centrifugal evolution of active lesions and dynamic induction and resolution of disease-associated glia (DA-glia). Human MS spinal cord analysis confirmed differential glial distribution and identified new lesion areas. By establishing a single-cell resolution spatial resource for MS neuropathology, the study sheds light on the intricate cellular processes driving MS progression.

4.CGRP sensory neurons promote tissue healing via neutrophils and macrophages

DOI: 10.1038/s41586-024-07237-y

https://www.nature.com/articles/s41586-024-07237-y

This study reveals the critical role of nociceptive sensory neurons in tissue repair and regeneration following acute injury. Ablation of NaV1.8 nociceptors impairs skin wound repair and muscle regeneration, with nociceptor endings signaling to immune cells through calcitonin gene-related peptide (CGRP). CGRP, acting via receptor activity-modifying protein 1 (RAMP1), enhances immune cell functions crucial for tissue healing, including recruitment inhibition, accelerated death, enhanced efferocytosis, and polarization towards a pro-repair phenotype. In mice lacking nociceptors and diabetic mice with peripheral neuropathies, engineered CGRP delivery accelerates wound healing and muscle regeneration. Understanding neuro-immune interactions offers potential for treating non-healing tissues, particularly where dysregulated interactions impair healing, as in diabetes or advanced age.

5.Formation of memory assemblies through the DNA-sensing TLR9 pathway

DOI: 10.1038/s41586-024-07220-7

https://www.nature.com/articles/s41586-024-07220-7

This study uncovers a novel process in hippocampal neurons where learning induces persistent double-stranded DNA breaks, nuclear envelope ruptures, and histone release. Neurons with these features activate TLR9 signaling, leading to an inflammatory phenotype and DNA repair complex accumulation. Neuron-specific TLR9 knockdown impairs memory and blunts gene expression changes in CA1 neurons associated with fear conditioning. TLR9 also plays a crucial role in centrosome function and perineuronal net formation. Dysfunctional TLR9 leads to genomic instability and cognitive impairments implicated in aging, psychiatric, and neurodegenerative disorders. Maintaining TLR9 signaling integrity emerges as a promising strategy for preventing neurocognitive deficits.