Control of cortico-limbic feeding behavior using optogenetics

描述（由申请人提供）：全球肥胖人数持续增加，每年导致数百万人死亡。研究营养过剩的神经基础的研究传统上集中在下丘脑，那里被认为是调节新陈代谢的地方。然而，现在假设大脑中参与决策的部分（前额叶皮层）和奖励处理（核）在强迫性或习惯性进食中起着重要作用。这项计划的目的是研究前额叶皮层和脑桥核是如何共同控制食物摄入的。我们将使用一种新颖的“光遗传学”技术，该技术使用两种特殊类型的离子通道，盐视紫红质和通道视紫红质，它们被光激活。通过采用病毒注射技术，我们将在前额叶皮质神经元及其投射中选择性地表达这些光激活通道，这些通道终止于延髓核。然后，我们可以使用特定波长的激光，只激发（用通道视紫红质）或抑制（用盐视紫红质）那些来自前额皮质的突触前末梢，从而实现前所未有的空间选择性。我们预测，黄光，激活盐视紫红质，将抑制发射谷氨酸释放皮层神经元，从而促进正常，饱足动物的食物摄入。我们相信这与肥胖、习惯性进食的个体发生的情况类似--前额叶皮层神经元放电减少。提案的后半部分试图扭转这种反常行为。我们将首先证明，营养过剩，作为一个高脂肪饮食的结果，诱导习惯样反应的食物摄入。然后，我们将通过使用蓝光来扭转这种习惯行为，这将通过视紫红质通道激活前额叶皮层神经元，并恢复谷氨酸盐的兴奋。通过解决这些大脑区域之间的重要联系，我们希望为肥胖和相关疾病的治疗提供新的见解。 公共卫生相关性：这项研究试图更好地了解肥胖如何改变决策，以加强有害的饮食习惯。通过确定这在大脑中是如何发生的，我们将能够更好地提供治疗干预措施，可能有助于控制体重增加和与肥胖相关的疾病。

DESCRIPTION (provided by applicant): The number of obese individuals continues to increase worldwide, contributing to millions of deaths each year. Research investigating the neural underpinnings of overnutrition has traditionally focused on the hypothalamus, where metabolism is thought to be regulated. However, parts of the brain involved in decision making (prefrontal cortex) and reward processing (nucleus accumbens) are now hypothesized to play an important role in compulsive, or habitual, feeding. The goal of this proposal is to investigate how the prefrontal cortex and the nucleus accumbens may be working together to control food intake. We will use a novel, "optogenetic" technique that uses two special types of ion channels, halorhodopsin and channelrhodopsin, that are activated by light. By employing viral injection techniques, we will express these light-activated channels selectively in prefrontal cortical neurons and their projections, which terminate in the nucleus accumbens. We can then use laser light with specific wavelengths to either excite (with channelrhodopsin) or inhibit (with halorhodopsin) only those presynaptic terminals arriving from the prefrontal cortex in accumbens, allowing unprecedented spatial selectivity. We predict that yellow light, which activates halorhodopsin, will inhibit the firing of glutamate-releasing cortical neurons and thus promote food intake in normal, sated animals. We believe that this is similar to what is occurring in obese, habitually eating individuals- a reduction in firing of the prefrontal cortical neurons. The second half of the proposal seeks to reverse this aberrant behavior. We will first demonstrate that overnutrition, as a result of a high-fat diet, induces habit-like responses to food intake. We will then reverse this habit behavior by using blue light, which will activate the prefrontal cortical neurons via the channelrhodopsin and restore glutamate to the accumbens. By resolving this important connection between these brain areas, we hope to provide new insights into the treatment of obesity and related disorders. PUBLIC HEALTH RELEVANCE: This research attempts to better understand how obesity may alter decision making to reinforce detrimental eating habits. By determining how this occurs in the brain, we will be better able to provide therapeutic interventions that may help control weight gain and diseases associated with obesity.