D-galactose-injected rodent models recapitulate many features of brain aging. The alterations in the septo-hippocampal network associated with memory decline in rat model of aging induced by D-galactose (D-gal) administration are not defined. The present study was designed to determine changes in the number of cholinergic (choline acetyltransferase immunoreactive – ChAT-ir) and GABAergic (parvalbumine immunoreactive – PV-ir) medial septum (MS) projection neurons and the hippocampal cholinergic activity and how these changes are associated with mnemonic dysfunction in a rat model of aging induced by subcutaneous administration of D-gal, and then to compare the effect of D-gal against natural aging. The male rats - young-adult (3 months-old) and old (O; 22 months-old) served as subjects. Young-adult rats were randomly assigned to two experimental groups: Control - with injection of 0.9% saline and D-gal - with administration of D-gal - 150 mg/kg once a day for 8 weeks. Immunohistochemical studies showed a significant decrease in the number of ChAT-ir cells and an increase in the number of PV-ir cells in MS, also a significant decrease in the number of cholinergic (acetylcholinesterase immunoreactive) neurons in hippocampal CA1 field in groups D-gal and O compared to controls. Rats of D-gal and O groups showed impaired spatial memory in the Morris Water Maze task. The results demonstrate for the first time that changes in the septo-hippocampal network revealed in naturally aging memory-impaired rats are also observed in a D-gal-induced animal model of aging.Supported by the funding from the SRNSFG: Grant # - YS-22-3254.