Enhanced hippocampal long-term potentiation and spatial learning in aged 11ß-hydroxysteroid dehydrogenase type 1 knock-out mice

Glucocorticoids are pivotal in the maintenance of memory and cognitive functions as well as other essential physiological processes including energy metabolism, stress responses, and cell proliferation. Normal aging in both rodents and humans is often characterized by elevated glucocorticoid levels that correlate with hippocampus-dependent memory impairments. 11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies local intracellular ("intracrine") glucocorticoid action; in the brain it is highly expressed in the hippocampus. We investigated whether the impact of 11ß-HSD1 deficiency in knock-out mice (congenic on C57BL/6J strain) on cognitive function with aging reflects direct CNS or indirect effects of altered peripheral insulin-glucose metabolism. Spatial learning and memory was enhanced in 12 month "middle-aged" and 24 month "aged" 11ß-HSD1<sup>–/–</sup> mice compared with age-matched congenic controls. These effects were not caused by alterations in other cognitive (working memory in a spontaneous alternation task) or affective domains (anxiety-related behaviors), to changes in plasma corticosterone or glucose levels, or to altered age-related pathologies in 11ß-HSD1<sup>–/–</sup> mice. Young 11ß-HSD1<sup>–/–</sup> mice showed significantly increased newborn cell proliferation in the dentate gyrus, but this was not maintained into aging. Long-term potentiation was significantly enhanced in subfield CA1 of hippocampal slices from aged 11ß-HSD1<sup>–/–</sup> mice. These data suggest that 11ß-HSD1 deficiency enhances synaptic potentiation in the aged hippocampus and this may underlie the better maintenance of learning and memory with aging, which occurs in the absence of increased neurogenesis

Glucocorticoid metabolism and the Metabolic Syndrome: associations in an elderly cohort

Objective: The phenotype of the Metabolic Syndrome (hypertension, insulin resistance and hyperlipidaemia) bears similarities to Cushing's Syndrome, in which the cause of these features is elevated cortisol production. We have investigated relationships between glucocorticoid production and features of the Metabolic Syndrome in a cohort of elderly subjects.Design: A cross-sectional analysis was carried out of a subset of a birthweight cohort from Sheffield.Methods: 92 men and 40 women (aged 69-75 y) representative of the original cohort were investigated. Features of the Metabolic Syndrome (blood pressure, BMI, waist hip ratio, fasting glucose, insulin and triglycerides) were recorded and urinary glucocorticoid metabolites were measured by gas chromatography mass spectrometry.Results: Total glucocorticoid metabolites were correlated with the overall phenotype of the Metabolic Syndrome (P = 0.002), whereas specific pathways of metabolism (activity of 11?-hydroxysteroid dehydrogenases and A-ring reductases) did not show significant associations. Specifically total glucocorticoid production increased with increasing systolic blood pressure (r = 0.21, P = 0.013), fasting glucose (r = 0.19, P = 0.02) and insulin (r = 0.23, P = 0.025). Glucocorticoid production was greater with increasing abdominal girth (r = 0.19, P = 0.033), but there was no association with enhanced metabolism via a specific pathway. Within this cohort, birthweight was not associated with total glucocorticoid metabolites. However, decreasing birthweight (P = 0.022), increasing obesity (P = 0.026) and increasing total glucocorticoid production (P = 0.009) were all independent predictors of fasting glucose.Conclusions: These data support the concept that cortisol production is enhanced in the Metabolic Syndrome, although they did not confirm the recent evidence that increased cortisol secretion is predicted by low birthweight.<br/

Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour

Diabetes mellitus: pathophysiological changes and therap

Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats

NoGestational stress (GS) produces profound behavioural impairments in the offspring and may permanently programme hypothalamic¿pituitary¿adrenal (HPA) axis function. We investigated whether or not GS produced changes in the maternal behaviour of rat dams, and measured depression-like behaviour in the dam, which might contribute to effects in the progeny. We used the Porsolt test, which measures immobility in a forced-swim task, and models depression in rodents, while monitoring maternal care (arched-back nursing, licking/grooming, nesting/grouping pups). Pregnant rats underwent daily restraint stress (1 h/day, days 10¿20 of gestation), or were left undisturbed (control). On post-parturition days 3 and 4, dams were placed into a swim tank, and time spent immobile was measured. GS significantly elevated immobility scores by approximately 25% above control values on the second test day. Maternal behaviours, in particular arched-back nursing and nesting/grouping pups, were reduced in GS dams over post-natal days 1¿10. Adult offspring showed increased immobility in the Porsolt test, and also hypersecreted ACTH and CORT in response to an acute stress challenge. These data show that GS can alter maternal behaviour in mothers, and this might contribute to alterations in the offspring. GS may be an important factor in maternal post-natal depression, which may in turn detrimentally effect the offspring because depressed mothers do not sufficiently care for their offspring

Serum leptin and cognitive function in people with Type 2 diabetes

People with obesity and type 2 diabetes are at increased risk of cognitive impairment. We aimed to investigate the association of leptin with cognitive abilities in an elderly population with type 2 diabetes. We performed a cross-sectional study of 1057 men and women aged 60–75 years with type 2 diabetes living in Lothian (Scotland). A cognitive battery was administered. Prior intelligence was estimated from vocabulary testing and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning leptin levels and cognitive ability and estimated cognitive change were tested. Higher leptin levels were associated with significantly poorer estimated overall cognitive decline, and poorer performance in 2 cognitive domains assessing mental flexibility and executive function, only amongst men (p &#60; 0.05). High morning leptin levels in elderly men with type 2 diabetes are associated with estimated age-related cognitive change