Rates of depression and anxiety are greater among individuals with type 2 (insulin resistant) diabetes. Diabetes is associated with an increased prevalence of clinical depression. Changes in brain structure in diabetes occur within temporal lobe circuits that are also sensitive to stress-related mood disorders. Diabetics exhibit hippocampal atrophy, particularly in the dentate gyrus subfield, and hippocampal atrophy is associated with changes in memory and mood regulation in this population. Given the established role of hippocampal activity in appropriate termination of the hypothalamic-pituitary-adrenal axis (HPA axis) response to stress, it is likely that there is some mechanistic relationship between impairment of hippocampal function and HPA axis dysregulation in insulin resistant individuals. The studies in this proposal are designed to determine whether hippocampal atrophy disinhibits the HPA axis, initiating a cycle of glucocorticoid- mediated synaptic impairment in a genetic mouse model of obesity and insulin resistance. We will test this model using leptin receptor mutant mice (db/db mice), which are obese and diabetic and exhibit elevated levels of corticosterone, the primary glucocorticoid in rodents. Hippocampal brain-derived neurotrophic factor (BDNF) expression is significantly reduced and we have preliminary data demonstrating that negative feedback on the adrenocortical response to stress is impaired in db/db mice. We plan to manipulate BDNF expression using a lentivirus to determine the network consequences of alterations in hippocampal neurotrophic factor expression for HPA axis negative feedback. We will measure markers of neural activation in chemically identified neuronal populations to evaluate recruitment along the circuitry mediating HPA axis shutoff after restraint stress. These studies in leptin receptor deficient mice could elucidate mechanisms related to the comorbidity between diabetes and depression in human populations.
Type 2 diabetes is frequently accompanied by depressed mood and elevated levels of the stress- responsive hormone cortisol, but the extent to which these characteristics are mechanistically related has yet to be addressed. Reduced neurotrophic factor expression in diabetes may increase vulnerability to depressive disorders by suppressing the recruitment of brain regions that terminate stress responses. The hippocampus is critically involved in turning off the stress response, and molecular mediators associated with hippocampal activity are compromised in type 2 diabetes, so we plan to manipulate the expression of proteins that support neuronal activity in the hippocampus of diabetic mice in order to elucidate mechanisms for increased vulnerability to depression and anxiety among diabetic individuals.
|Wosiski-Kuhn, Marlena; Erion, Joanna R; Gomez-Sanchez, Elise P et al. (2014) Glucocorticoid receptor activation impairs hippocampal plasticity by suppressing BDNF expression in obese mice. Psychoneuroendocrinology 42:165-77|
|Wosiski-Kuhn, Marlena; Stranahan, Alexis M (2012) Transient increases in dendritic spine density contribute to dentate gyrus long-term potentiation. Synapse 66:661-4|