The detailed crosstalk between the neuroendocrine and immune systems in Oreochromis niloticus, an economically important fish, in response to pathogenic infections, remains unclear. This study revealed the head kidney transcriptional profiles of O. niloticus upon infections with Streptococcus agalactiae, a prevalent pathogen known to cause severe meningitis. Twelve cDNA libraries of O. niloticus head kidney, representing four treatment time points (0, 6, 24, and 48 h), were constructed and a total of 2,528 differentially expressed genes were identified based on pairwise comparisons. KEGG pathway analysis revealed a significant enrichment of the 'neuroactive ligand-receptor interaction' pathway (ko04080), with 13 genes exhibiting differential expression during S. agalactiae infection. Among these, six neuroactive receptor genes (lepr, nr3c1, ptger4, thrb, tspo, and β2-ar) were selected, cloned, and characterized. Although these genes are ubiquitously expressed, and in head kidney leukocytes, their expression was mainly observed in T cells, Mo/Mφ, and NCCs, which are characterized by antimicrobial responses. Furthermore, we examined the response patterns of these six neuroactive receptor genes to gram-positive (S. agalactiae) and gram-negative (Aeromonas hydrophila) bacteria in four different tissues. Notably, lepr, ptger4, tspo, and β2-ar were upregulated in all selected tissues in response to S. agalactiae and A. hydrophila infections. However, nr3c1 and thrb were downregulated in response to S. agalactiae infection in the head kidney and spleen, whereas nr3c1 was upregulated, and thrb was unresponsive to A. hydrophila infection. Our findings provide a theoretical foundation for understanding new links between the neuroendocrine and immune systems during bacterial infection in teleost fish.

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