Diabetes impairs hippocampal function via glucocorticoid– mediated effects on new and mature neurons

Multiple organ systems are adversely affected by diabetes, including the brain, which undergoes changes that may increase the risk of cognitive decline. Although diabetes influences the hypothalamic–pituitary–adrenal axis, the role of this neuroendocrine system in diabetes–induced cognitive dysfunction remains unexplored. Here we demonstrate that, in both insulin–deficient rats and insulin–resistant mice, diabetes impairs hippocampus–dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Rats treated with streptozocin have reduced levels of insulin, and exhibit hyperglycemia, increased levels of corticosterone, and impairments in hippocampal neurogenesis, synaptic plasticity and learning. Similar deficits are observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone levels and obesity. Changes in hippocampal plasticity and function in both models are reversed when normal physiological levels of corticosterone are maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoid– mediated deficits in neurogenesis and synaptic plasticity.