Histamine H2 receptor in substantia nigra pars reticulata parvalbumin positive neurons mediates risk-taking behavior.

Risk-taking is frequently observed in psychiatric conditions such as attention-deficit hyperactivity disorder, yet the neuronal mechanisms underlying this behavior remain unclear. Here, we show that histamine H2 receptor (H2R) in parvalbumin-positive neurons (PV+) of the substantia nigra pars reticulata (SNr) bidirectionally regulates risk-taking behaviors. Dysfunction of superior colliculus-projecting SNr PV+ neurons contributes to the increased risk-taking caused by H2R deficiency. Moreover, H2R deficiency promotes risk-taking behavior by altering PV+ neuronal dynamics during risk assessment in an H2R-dependent manner. Pharmacological activation of H2R in the SNr rescues excessive risky exploration in dopamine transporter heterozygous mutant mice (DAT+/-), a well-established mouse model of attention deficit hyperactivity disorder (ADHD)-like phenotypes with increased risk-taking behavior. Collectively, these findings demonstrate that H2R deficiency in SNr PV+ neurons drives risk-taking execution by disrupting the function of PV+ neurons and their downstream projections in mice. It may enhance the understanding of the neural mechanism underlying threat-related risk-taking and highlight H2R as a potential therapeutic target for pathological risk-taking behavior.