Cognitive functions show many alternative outcomes and great individual variation during normal aging. We examined learning over the adult life span in CBA mice, along with morphological and electrophysiological substrates. Our aim was to compare cerebellum-dependent delay eyeblink classical conditioning and hippocampus-dependent contextual fear conditioning in the same animals using the same conditioned and unconditioned stimuli for eyeblink and fear conditioning. In a subset of the behaviorally tested mice, we used unbiased stereology to estimate the total number of Purkinje neurons in cerebellar cortex and pyramidal neurons in the hippocampus. Several forms of synaptic plasticity were assessed at different ages in CBA mice: long-term depression (LTD) in both cerebellum and hippocampus and NMDA-mediated long-term potentiation (LTP) and voltage-dependent calcium channel LTP in hippocampus. Forty-four CBA mice tested at one of five ages (4,8,12,18, or 24 months) demonstrated statistically significant age differences in cerebellum-dependent delay eyeblink conditioning, with 24-month mice showing impairment in comparison with younger mice. These same CBA mice showed no significant differences in contextual or cued fear conditioning. Stereology indicated significant loss of Purkinje neurons in the 18-and 24-month groups, whereas pyramidal neuron numbers were stable across age. Slice electrophysiology recorded from an additional 48 CBA mice indicated significant deficits in LTD appearing in cerebellum between 4 and 8 months, whereas 4-to 12-month mice demonstrated similar hippocampal LTD and LTP values. Our results demonstrate that processes of aging impact brain structures and associated behaviors differentially, with cerebellum showing earlier senescence than hippocampus.aging | cerebellum | hippocampus | behavior | synaptic plasticity P rocesses of normal aging do not affect the CNS uniformly.There is stability in neuron number in most brain regions, including most regions of the hippocampus (reviewed in refs. 1 and 2), whereas significant loss of Purkinje neurons occurs in the cerebellum (3, 4). Stereological assessments of hippocampal pyramidal and granule neurons and cerebellar granule and Purkinje neurons in the same mice aged 12 or 28 months revealed stability in hippocampal neurons and cerebellar granule neurons and significant loss of Purkinje neurons (5). Learning and memory show many alternative outcomes and great individual variation during normal aging. Cerebellum-dependent learning is associated with Purkinje neuron number and is impaired by age-related decrements in morphology and function. Hippocampus-dependent learning is associated with reduced capacity for new learning in pyramidal neurons in the perforant pathway in normal aging (6). Data over the adult life span in human (7) and nonhuman mammals (8) suggest that cerebellum-essential tasks show age-related deficits at earlier ages than do hippocampus-essential tasks.Traditionally, cerebellar and hippocampal substrates of learning, memory, and ag...