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Nature Aug 2023In addition to its canonical function of protection from pathogens, the immune system can also alter behaviour. The scope and mechanisms of behavioural modifications by...
In addition to its canonical function of protection from pathogens, the immune system can also alter behaviour. The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Here, using mouse models of food allergy, we show that allergic sensitization drives antigen-specific avoidance behaviour. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus and central amygdala. Allergen avoidance requires immunoglobulin E (IgE) antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote avoidance requires cysteinyl leukotrienes and growth and differentiation factor 15. Finally, a comparison of C57BL/6 and BALB/c mouse strains revealed a strong effect of the genetic background on the avoidance behaviour. These findings thus point to antigen-specific behavioural modifications that probably evolved to promote niche selection to avoid unfavourable environments.
Topics: Animals; Mice; Allergens; Avoidance Learning; Central Amygdaloid Nucleus; Disease Models, Animal; Food Hypersensitivity; Immunoglobulin E; Intestines; Mast Cells; Mice, Inbred BALB C; Mice, Inbred C57BL; Parabrachial Nucleus; Solitary Nucleus
PubMed: 37437602
DOI: 10.1038/s41586-023-06362-4 -
Nature Nov 2023Visceral sensory pathways mediate homeostatic reflexes, the dysfunction of which leads to many neurological disorders. The Bezold-Jarisch reflex (BJR), first described...
Visceral sensory pathways mediate homeostatic reflexes, the dysfunction of which leads to many neurological disorders. The Bezold-Jarisch reflex (BJR), first described in 1867, is a cardioinhibitory reflex that is speculated to be mediated by vagal sensory neurons (VSNs) that also triggers syncope. However, the molecular identity, anatomical organization, physiological characteristics and behavioural influence of cardiac VSNs remain mostly unknown. Here we leveraged single-cell RNA-sequencing data and HYBRiD tissue clearing to show that VSNs that express neuropeptide Y receptor Y2 (NPY2R) predominately connect the heart ventricular wall to the area postrema. Optogenetic activation of NPY2R VSNs elicits the classic triad of BJR responses-hypotension, bradycardia and suppressed respiration-and causes an animal to faint. Photostimulation during high-resolution echocardiography and laser Doppler flowmetry with behavioural observation revealed a range of phenotypes reflected in clinical syncope, including reduced cardiac output, cerebral hypoperfusion, pupil dilation and eye-roll. Large-scale Neuropixels brain recordings and machine-learning-based modelling showed that this manipulation causes the suppression of activity across a large distributed neuronal population that is not explained by changes in spontaneous behavioural movements. Additionally, bidirectional manipulation of the periventricular zone had a push-pull effect, with inhibition leading to longer syncope periods and activation inducing arousal. Finally, ablating NPY2R VSNs specifically abolished the BJR. Combined, these results demonstrate a genetically defined cardiac reflex that recapitulates characteristics of human syncope at physiological, behavioural and neural network levels.
Topics: Humans; Area Postrema; Bradycardia; Cardiac Output, Low; Echocardiography; Heart; Heart Rate; Hypotension; Laser-Doppler Flowmetry; Nerve Net; Reflex; Sensory Receptor Cells; Single-Cell Gene Expression Analysis; Syncope; Vagus Nerve
PubMed: 37914931
DOI: 10.1038/s41586-023-06680-7