We describe neuronal density, neuroplasticity and vascular remodelling and their association with spatial memory in young (4-6 months), middle-aged (9-11 months) and aged (18-20 months) rats of both genders. The neuronal density was reduced in the hippocampus of middle-aged and aged rats, particularly in male rats. However the loss of spatial memory investigated using the Morris water maze, T-maze and 8-radial arm maze tests was found only in the aged groups. The data suggested a pre-symptomatic period of pathological brain aging. Surprisingly, the middle-aged groups showed an elevation of glutamate-decarboxylase immunoreactive neurons in the hippocampus and the striatum, an increase of dopamine output in the striatum and enhanced vascular remodelling in the hippocampus when compared with the young and, in some cases, aged groups. Together, the data suggest that the loss of neurons during midlife may stimulate and enhance neuronal plasticity and vascular remodelling. These compensatory responses to initial neuronal degeneration may play a role in delaying impending memory loss during the pre-symptomatic period of pathological brain aging.