Is there a role for GABA-A receptor alpha-5 subunits in cognitive deficits caused by consumption of a high fat diet?

该项目将使用小鼠的饮食操作，并观察行为对记忆的影响，以及突触可塑性的电生理变化和大脑受体表达的变化。它将调查认知增强药物的靶标GABA-A受体α-5亚单位是否被高脂肪饮食上调，以及这是否与炎症细胞因子激活有关。它的目的是定义脂肪消耗和记忆力丧失之间的机械联系。小鼠的认知缺陷出现在开始高脂肪喂养的几天内。这是在II型糖尿病患者中出现的认知衰退的模型，事实上，在高BMI的健康年轻受试者中也是如此。我们先前已经证明，在小鼠中，高脂肪饮食(HFD)迅速而显著地影响复杂的关联性情景式记忆，这种记忆结合了关于特定事件的信息，包括空间位置和发生事件的环境的上下文特征[2]。情节记忆是阿尔茨海默病最初受损的记忆之一，位于海马体。这些认知缺陷可能是由炎性细胞因子的激活引起的，如白介素类，被认为调节GABA-A受体的功能(3)。含有α-5亚单位的GABA-A受体在海马区密度很高，与学习和记忆有关。下调这些受体可能是一种认知增强的方法，这已经在健康的人类志愿者中得到证明，目前正在进行唐氏综合症的临床试验。这些受体是否可能是高脂肪喂养和认知能力下降之间的联系，可能是由于它们被炎性细胞因子激活？

This project will use dietary manipulations in mice and look at behavioural effects on memory alongside electrophysiological changes in synaptic plasticity and changes in receptor expression in the brain. It will investigate the question of whether GABA-A receptor alpha-5 subunits, a target for cognitive enhancing drugs, are upregulated by a high fat diet and whether this is linked to inflammatory cytokine activation. It aims to define a mechanistic link between fat consumption and memory loss. Cognitive deficits in mice appear within days of initiating high fat feeding. This models cognitive decline seen in Type II diabetics and in fact in healthy young subjects with a high BMI (1). We have previously demonstrated that a high-fat diet (HFD), in mice, rapidly and dramatically impacts on complex associative episodic-like memory, which incorporates information about specific events, including spatial locations and the contextual features of the environment in which the event took place (2). Episodic memory is one of the memories initially compromised in Alzheimer's disease and is located in the hippocampus. These cognitive deficits could be caused by the activation of inflammatory cytokines such as the interleukins, which are thought to modulate GABA-A receptor function (3). GABA-A receptors containing the alpha-5 subunit are found in a high density in the hippocampus and are involved in learning and memory. Downregulating these receptors can be a method of cognitive enhancement which has been shown in healthy human volunteers and is currently in clinical trials for Down's syndrome. Could these receptors could be a link between high fat feeding and cognitive decline, potentially due to their activation by inflammatory cytokines?