The broad, long-term objective of the proposed research is to identify the underlying mechanisms for the increased susceptibility to age-related cognitive decline and dementia in obesity and diabetes. This objective will be addressed through a series of experiments in two mouse models of obesity arising from diet or genetic manipulation. The central hypothesis is that fat is a source of inflammatory cytokines that impair cognition by inducing local inflammation in the hippocampus, a brain region involved in learning and memory. While the brain is normally protected from systemic inflammation, the protective barrier between blood and brain is compromised in obesity, and the goal of these studies is to determine what blood-borne signal contributes to cognitive impairment in obesity and diabetes. These experiments are relevant to the goals of the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) because of the focus on inflammation in obesity and diabetes, and the implications of increased inflammation for cognition in individuals suffering from these debilitating conditions. The proposed studies will take place in the Physiology Department at the Medical College of Georgia, which has an institutional track record of excellence in diabetes and obesity research. The environment is extraordinarily supportive and conducive to the research career development plan described in the current application, which includes didactic and experimental approaches to further the candidate's goal of establishing an independent research program in neuroimmunology. The rationale for additional training under this award is twofold: first, the candidate has demonstrated excellence in neuroendocrinology, but has no experience with the methods and theories of immunology, therefore in order to pursue the studies in this proposal, additional training is required;and second, although the candidate currently holds an Assistant Professorship, the short duration of the candidate's postdoctoral training (2 years) means that additional time and training will be required in order to establish a productive research program in neuroimmunology. The candidate's immediate career goal is to establish an externally funded research program and demonstrate independence in publications. Over the long term, the candidate hopes to conduct research that identifies molecular mediators linking metabolism and immune function with cognition. By building a bridge between diabetes and obesity and the field of learning and memory research, it may be possible to develop personalized interventions to prevent increased rates of cognitive impairment and dementia in individuals with metabolic syndrome features.
Individuals with obesity and diabetes have a higher risk of age-related cognitive decline and dementia, but the underlying mechanisms for this vulnerability remain poorly understood. Experiments in this application utilize two models of obesity arising from diet or genetics to determine what factor(s) promote cognitive impairment in obesity and diabetes. The central hypothesis is that fat is a source of inflammatory cytokines that impair cognition by inducing local inflammation in the hippocampus, a brain region involved in learning and memory.
|Hao, Shuai; Dey, Aditi; Yu, Xiaolin et al. (2016) Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Brain Behav Immun 51:230-9|
|Stranahan, A M (2015) Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience 309:125-39|
|Dey, Aditi; Hao, Shuai; Erion, Joanna R et al. (2014) Glucocorticoid sensitization of microglia in a genetic mouse model of obesity and diabetes. J Neuroimmunol 269:20-7|
|Erion, Joanna R; Wosiski-Kuhn, Marlena; Dey, Aditi et al. (2014) Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J Neurosci 34:2618-31|
|Stranahan, Alexis M; Mattson, Mark P (2012) Metabolic reserve as a determinant of cognitive aging. J Alzheimers Dis 30 Suppl 2:S5-13|
|Stranahan, Alexis M; Martin, Bronwen; Maudsley, Stuart (2012) Anti-inflammatory effects of physical activity in relationship to improved cognitive status in humans and mouse models of Alzheimer's disease. Curr Alzheimer Res 9:86-92|