Control of cortico-limbic feeding behavior using optogenetics

描述(申请人提供)：全球范围内肥胖人数持续增加，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，那里的新陈代谢被认为是受调节的。然而，大脑中参与决策的部分(前额叶皮质)和奖赏处理(伏隔核)现在被认为在强迫性或习惯性进食方面发挥着重要作用。这项提议的目的是研究前额叶皮质和伏隔核如何协同工作来控制食物摄入量。我们将使用一种新的“光遗传”技术，它使用两种特殊类型的离子通道，卤视紫质和通道视紫红质，它们可以被光激活。通过病毒注射技术，我们将有选择地在前额叶皮质神经元及其投射中表达这些光激活通道，这些神经元和投射终止于伏隔核。然后，我们可以使用特定波长的激光来刺激(使用通道视紫红质)或抑制(使用卤视紫质)仅从伏隔核前额叶皮质到达的突触前终末，从而实现前所未有的空间选择性。我们预测，激活卤视紫质的黄光将抑制释放谷氨酸的皮质神经元的放电，从而促进正常、饱足的动物的食物摄入量。我们认为，这与肥胖、习惯进食的人所发生的情况类似--前额叶皮质神经元的放电减少。提案的后半部分试图扭转这种反常行为。我们将首先证明，高脂肪饮食导致的营养过剩会导致对食物摄取的类似习惯的反应。然后，我们将通过使用蓝光来逆转这种习惯行为，蓝光将通过视紫红质通道激活前额叶皮质神经元，并将谷氨酸恢复到伏隔。通过解决这些大脑区域之间的这种重要联系，我们希望为肥胖症和相关疾病的治疗提供新的见解。

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.