Normal aging can result in cognitive decline even in the absence of neurodegenerative disease. Successful identification of neurobiological changes that occur in association with age-related cognitive decline is needed to develop strategies to restore or preserve cognitive function in elderly individuals and to understand the neurobiology of aging. The present studies were designed to assess the effects of aging on cognitive abilities dependent on hippocampal/mediotemporal lobe and frontostriatal function, brain regions involved in memory and behavioral flexibility, respectively, and to investigate potential factors associated with cognitive decline.

In the first study, the effect of peri-pubertal growth hormone deficiency in spatial learning ability was investigated. This study demonstrates that deficits in growth hormone around the time of puberty affects hippocampal/mediotemporal lobe function by mid life and led to the conclusion that manipulation of growth hormone for a relatively brief period during the transitional period between puberty and young adulthood is sufficient to alter age-related pathology later in life.

The second study investigated the effects of aging on the memory and executive cognitive domains across the lifespan and its relationship with striatal cholinergic function. In this study, young, middle-age and aged Fisher344 x BN rats were cognitively characterized in spatial leaning, reversal learning and set-shifting abilities. By old age, cognitive deficits were pronounced across cognitive domains, suggesting deterioration of both hippocampal and frontostriatal-dependent damage. Middle-age rats were impaired in spatial learning ability, but unaffected in reversal learning and set shifting abilities when compared to young. Studies have shown that acetylcholine function, an important neuromodulator, is involved in cognitive function. Assessment of muscarinic receptor function in the striatum showed a significant decrease in muscarinic GTP-coupling limited to the dorsomedial striatum of aged rats while no difference in muscarinic GTP-coupling was observed in the dorsolateral striatum, cingulate and motor cortices. Our results demonstrate that muscarinic receptor function in the dorsomedial striatum is significantly reduced due to aging, and suggests its involvement in age-related decline behavioral flexibility.

Together, the studies presented in these studies suggest that GH/IGF-1 levels early in life are fundamental for later-in-life cognitive function and emphasize the importance of early diagnosis of growth hormone deficiency and supplementation in children. In addition, these studies suggest an association between age-related changes in striatal function and behavioral flexibility impairment. Therapies to help prevent or restore striatal cholinergic neurotransmission may help in the prevention or amelioration of age-related impairment in behavioral flexibility.