Novel brain networks influenced by ageing; effects on gene expression and synapses of diet-induced obesity.

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Obesity is currently a contributing factor to many diseases and deaths in developed nations. The burden on health care systems will expand with large predicted increases in the number of obese individuals worldwide, especially in developed nations (Ng et al., 2014).In addition to a host of health problems such as cardiac complications, cancer and diabetes (Haslam & James, 2005); obesity is also linked to cognitive decline, synaptic dysfunction and brain volume loss ((Alzoubi, Abdulaziz, & Alkadhi, 2005; Massa et al., 2010; Pistell et al., 2010; Raji et al., 2010). As the average age of the world population increases, long term effects of obesity in relation to age will be become more apparent and investigation into the cognitive dysfunction caused will be helpful to understand the ageing process in the brain. Certain research suggests that brain ageing may reflect a continuum between obesity and restriction of calorie intake. Calorie restriction can lead to increased lifespan and improved cognition (Fontana & Partridge, 2015; Praag, Fleshner, Schwartz, & Mattson, 2014), while obesity can lead to decreased lifespan and impaired cognition (Muller, Dietrich, Assis, Souza, & Portela, 2013; Nguyen, Killcross, & Jenkins, 2014). Obesity is also a risk factor for developing age-related cognitive disorders such as Alzheimer's in middle but not old age (Hsu et al., 2016; Pedditizi, Peters, & Beckett, 2016). This suggests a complex interaction between ageing and obesity that requires further study. However, to date no study has followed the effects of obesity over the lifespan while measuring concurrent changes in synaptic activity and brain gene expression. The current study aims investigate these aspects of obesity in C57BL/6 mice fed a high-fat diet at 6, 12, 18 and 24 months of age. At these ages, RNAseq will be conducted on one hemisphere and synaptic analysis using field recording of synaptic plasticity will be conducted on the other. Where interesting electrophysiological results emerge this analysis will be refined with patch clamp. Additionally, interesting targets identified from gene analysis may be followed up at the protein level using immunohistochemistry in some animals.