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.