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，每年造成数百万人死亡。调查营养过剩的神经基础的研究传统上集中在下丘脑，新陈代谢被认为是受调节的。然而，大脑中参与决策（前额叶皮质）和奖励处理（伏隔核）的部分现在被假设在强迫性或习惯性进食中起着重要作用。这项研究的目的是研究前额叶皮层和伏隔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”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。通过病毒注射技术，我们将在前额皮质神经元及其投影中选择性地表达这些光激活通道，这些通道终止于伏隔核。然后，我们可以使用特定波长的激光来激发（通道视紫红质）或抑制（盐视紫红质）来自伏隔脑前额叶皮层的突触前终端，从而实现前所未有的空间选择性。我们预测，激活盐视紫红质的黄光将抑制释放谷氨酸的皮质神经元的放电，从而促进正常饱食动物的食物摄入。我们认为，这与肥胖、习惯性进食的人发生的情况类似——前额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的行为。我们将首先证明，高脂肪饮食导致的营养过剩，会诱发对食物摄入的习惯性反应。然后，我们将用蓝光来扭转这种习惯行为，蓝光将通过视紫红质通道激活前额皮质神经元，并将谷氨酸恢复到伏隔核。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。

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.