An essential question in evolutionary biology is whether shifts in a set of polygenic behaviors share a genetic basis across species. Such a behavioral shift is seen in the cave-dwelling Mexican tetra, Astyanax mexicanus. Relative to surface-dwelling conspecifics, cavefish do not school (asocial), are hyperactive and sleepless, adhere to a particular vibration stimulus (imbalanced attention), behave repetitively, and show elevated stress hormone levels. Interestingly, these traits largely overlap with the core symptoms of human autism spectrum disorder (ASD), raising the possibility that these behavioral traits are underpinned by a similar set of genes (i.e. a repeatedly used suite of genes). Here, we explored whether modification of ASD-risk genes underlies cavefish evolution. Transcriptomic analyses revealed that > 58.5% of 3152 cavefish orthologs to ASD-risk genes are significantly up- or down-regulated in the same direction as genes in postmortem brains from ASD patients. Enrichment tests suggest that ASD-risk gene orthologs in A. mexicanus have experienced more positive selection than other genes across the genome. Notably, these positively selected cavefish ASD-risk genes are enriched for pathways involved in gut function, inflammatory diseases, and lipid/energy metabolism, similar to symptoms that frequently coexist in ASD patients. Lastly, ASD drugs mitigated cavefish’s ASD-like behaviors, implying shared aspects of neural processing. Overall, our study indicates that ASD-risk genes and associated pathways (especially digestive, immune and metabolic pathways) may be repeatedly used for shifts in polygenic behaviors across evolutionary time.

Transient receptor potential melastatin 2 (TRPM2) channel is a Ca²⁺-permeable, redox-activated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. Here, we investigated whether TRPM2 contributes to the atrial natriuretic peptide (ANP) response during β-adrenergic stimulation. We compared how male C57BL/6J wild-type (WT) and TRPM2 knockout (TRPM2^−/−) mice (8–12 weeks old) respond to β-adrenergic stress induced by isoproterenol (ISO) using echocardiography, histology, RT-PCR, electrophysiology, Ca²⁺ imaging, ELISA, and atrial RNA-seq. We detected abundant Trpm2 transcripts in WT atria and measured ADP-ribose (ADPr)-evoked currents and hydrogen peroxide (H₂O₂)-induced Ca²⁺ influx characteristic of TRPM2; these were absent in TRPM2^−/− cells. Under the ISO-induced hypertrophic model, TRPM2^−/− mice developed greater cardiac hypertrophy, fibrosis, and systolic dysfunction compared with WT mice. Atrial bulk RNA-seq showed significant induction of Nppa (ANP precursor gene) in WT + ISO, accompanied by higher circulating ANP; TRPM2^−/− + ISO showed blunted Nppa and ANP responses. ISO-treated TRPM2^−/− mice exhibited more blunt responses, in both Nppa transcripts and circulating ANP levels. Exogenous ANP attenuated ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2^−/− mice, suggesting that TRPM2 is needed for the cardioprotective endocrine response via ANP to control stress-induced β-adrenergic remodeling.

Transient receptor potential melastatin 2 (TRPM2) channel is a Ca²⁺-permeable, redox-activated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. We compared how wild-type (WT) and TRPM2 knockout (TRPM2^−/−) mice respond to β-adrenergic stress induced by isoproterenol (ISO) using echocardiography, histology, RT-PCR, electrophysiology, Ca²⁺ imaging, ELISA, and atrial RNA-seq. We detected abundant Trpm2 transcripts in the atria of WT mice, and measured ADP-ribose (ADPr)–evoked currents as well as hydrogen peroxide (H₂O₂)–induced Ca²⁺ influx characteristic for TRPM2 of WT atrial myocytes; these were absent in TRPM2^−/− cells. Under the ISO-induced hypertrophic model, TRPM2^−/− mice developed greater cardiac hypertrophy, fibrosis, and systolic dysfunction compared with WT mice. Atrial bulk RNA-seq showed significant induction of Nppa (ANP precursor gene) in WT + ISO, accompanied by higher circulating ANP; TRPM2^−/− + ISO showed blunted Nppa and ANP responses. ISO-treated TRPM2^−/− mice exhibited more blunt responses, in both Nppa transcripts and circulating ANP levels. Exogenous ANP attenuated ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2^−/− mice, suggesting that TRPM2 is needed for the cardioprotective endocrine response via ANP to control stress-induced β-adrenergic remodeling.