OXYTOCIN NEURON ACTIVATION AMELIORATES SOCIAL ISOLATION-INDUCED COGNITIVE IMPAIRMENT AND AMYLOID-Β PATHOLOGY IN MICE MODEL OF ALZHEIMER'S DISEASE

Loneliness has been reported to increase the risk of Alzheimer’s disease (AD), but its underlying mechanisms remain unclear. We previously demonstrated that activation of oxytocin (OXT) neurons improves cognitive function in mice. Additionally, OXT neuronal activity has been suggested to be reduced under social isolation. Based on these observations, we hypothesized that decreased OXT signaling contributes to the isolation-induced progression of AD. To test this hypothesis, we modeled a loneliness-like condition by housing AD model mice in social isolation and examined its effects on amyloid-β (Aβ) accumulation and cognitive function, as well as the therapeutic potential of OXT neuron activation.APP^{NL-G-F/NL-G-F} (APPKI) mice were socially isolated for 12 weeks after weaning. APPKI mice were crossed with OXT-iCre mice to generate APPKI OXT-iCre mice, in which OXT neurons were selectively activated by injecting AAV8-hSyn-DIO-hM3Dq-mCherry into the paraventricular nucleus followed by clozapine-N-oxide (CNO; 1.0 mg/kg, i.p.) administration. Cognitive function was assessed using the Y-maze and novel object recognition test (NORT), and Aβ accumulation was evaluated by immunohistochemistry.
Social isolation significantly impaired performance in the Y-maze and NORT and increased Aβ accumulation in the hippocampus of APPKI mice. CNO-induced activation of OXT neurons during social isolation ameliorated these cognitive deficits and significantly reduced Aβ accumulation in socially isolated APPKI mice. These findings demonstrate that social isolation exacerbates cognitive impairment and Aβ pathology in AD model mice, whereas activation of the OXT system counteracts these effects. These findings further suggest that OXT signaling represents a therapeutic target linking loneliness to increased AD risk.