A molecular architecture of the vagal interoceptive system
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA794066 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17423674.fastq.gz | Fastqsanger.gz | |||
| SRR17423675.fastq.gz | Fastqsanger.gz | |||
| SRR17423676.fastq.gz | Fastqsanger.gz | |||
| SRR17423677.fastq.gz | Fastqsanger.gz | |||
| SRR17423678.fastq.gz | Fastqsanger.gz |
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Project description:Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1-4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.
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Project description:Aging is accompanied by declining memory function, necessitating the development of effective countermeasures1. Brain- extrinsic factors influencing cognitive decline, including the intestinal microbiome, have emerged as attractive targets for peripheral interventions2-6, but the underlying mechanisms remain largely unclear. Here, by charting a high-resolution map of microbiome aging and its functional consequences throughout the lifespan of mice, we identify a mechanism whereby age- associated inhibition of gut-brain signalling results in impaired novelty-induced neuronal activation in the hippocampus and loss of memory encoding. Specifically, gut bacteria producing medium-chain fatty acids, such as Parabacteroides goldsteinii, accumulate over the lifespan and drive intestinal myeloid cell inflammation through GPR84 signalling. As a result, the function of afferent gut-innervating vagal neurons is impaired, the interoceptive signal received by the brain is weakened, and hippocampal function declines. We leverage this pathway to define interventions that restore memory in aged mice, such as phage targeting of Parabacteroides, GPR84 inhibition, and restoration of vagal activity. These findings indicate a key role for interoceptive signalling from the gastrointestinal tract in regulating brain aging and suggest that interoceptomimetics that stimulate gut-brain communication may counteract age-associated cognitive decline.
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