Protective role of hemokinin-1 against age-dependent spatial memory and attention decline in mice

Age-related cognitive decline is a major social and medical challenge, but its mechanisms remain poorly understood; prevention and therapy are unsatisfactory. The tachykinin hemokinin-1 (HK-1), encoded by the Tac4 gene, is expressed in brain regions involved in learning and memory and has been implicated in neuroimmune regulation, but its contribution to age-dependent cognitive impairment remains unclear. Here, we investigated whether endogenous HK-1 modulates cognitive performance during aging. Young (3-5 months), middle-aged (12-15 months), and old (18-20 months) male and female C57BL/6 J wildtype (WT) and HK-1-deficient mice were examined in complementary longitudinal and cross-sectional paradigms. Spatial learning and memory were assessed with the Barnes maze, radial arm maze, Y-maze spontaneous alternation, and place recognition tests. Attention and operant learning were examined using 5-choice serial-reaction time task, object recognition memory with the novel object recognition test, and aversive associative memory with fear conditioning. Young mice of both sexes and genotypes generally acquired spatial tasks, but HK-1-dependent deficits emerged with age and task complexity. HK-1-deficient mice showed impaired long-term spatial memory in the Barnes maze and poorer 5-choice serial-reaction time task performance, indicating deficits in spatial memory retention, attention, and reinforcement-based learning. In the radial arm maze, middle-aged female and old male knockouts displayed increased memory errors and reduced reward retrieval. Knockout males also showed reduced freezing in fear conditioning, suggesting weaker aversive memory. In contrast, Y-maze spontaneous alternation and novel object recognition revealed no robust genotype-dependent impairments. These findings indicate that HK-1 contributes to maintaining cognitive performance during aging.