Forebrain circuits and control of feeding behavior by learned cues

描述（申请人提供）：食欲和进食不仅受到能量需求的驱动，还受到与能量平衡无关的外在（环境）因素的影响。环境信号，包括习得的线索，可以超越稳态信号来刺激饱腹状态下的进食，或抑制饥饿状态下的进食。这项研究的长期目标是确定潜在神经回路的功能组织。我们使用了一个啮齿动物模型来进行提示诱导进食，在这个模型中，当动物饥饿时，先前的环境提示与食物配对，可以在饱腹的老鼠中引发进食。增强的进食是通过联想学习获得的动机特性的结果，否则中性信号。该模型提供了一个框架来研究环境线索如何与功能前脑网络中的稳态信号相结合，以及这些网络如何被经验调节。提出的研究建立在证据的基础上，这些网络组成部分包括对联想学习和决策至关重要的前脑、杏仁核和前额叶皮层，以及负责喂养、奖励和动机整合的外侧下丘脑。有两个独立的、相互关联的特定目标，共同研究来自环境的信号控制摄食行为的神经系统。第一个目标是确定杏仁核和前额叶皮层子系统在习得性线索诱导进食中的作用，并确定下丘脑底物，使习得性线索与稳态系统整合。第二个目标是绘制支持线索-食物配对下学习的网络可塑性。提出的目标将通过行为和神经系统分析的结合来完成，包括选择性神经毒性病变，解剖途径追踪和即时早期基因成像（eeg）。eeg方法将包括绘制神经元对单一事件（c-fos蛋白诱导）的反应图，以及绘制由两个暂时安排的事件（Arc/Arg3.1 mRNA诱导）同时激活的神经元图。在这个应用程序的研究计划下的工作将扩展我们对大脑回路的理解，使我们能够学习调节进食行为。研究结果还将为控制人类的食欲提供信息，包括可能导致暴饮暴食和肥胖的不适应环境影响。

DESCRIPTION (provided by applicant): Appetite and eating are not only driven by energy needs, but also by extrinsic (environmental) factors unrelated to energy balance. Environmental signals, including learned cues, can override homeostatic signals to stimulate eating in sated states, or inhibit eating in states of hunger. The long-term goal of the proposed research is to define the functional organization of the underlying neural circuits. We use a rodent model for cue-induced eating, in which an environmental cue previously paired with food when an animal was hungry can initiate eating in sated rats. The enhanced eating is a consequence of motivational properties acquired by an otherwise neutral signal through associative learning. The model provides a framework to study how environmental cues are integrated with homeostatic signals within functional forebrain networks, and how these networks are modulated by experience. The proposed research builds on evidence that the network components include areas in the forebrain, amygdala and prefrontal cortex critical for associative learning and decision-making, and the lateral hypothalamus, which is an integrator for feeding, reward and motivation. There are two independent, interrelated specific aims that collectively investigate the neural systems through which signals from the environment control feeding behavior. The first aim is to define the role of the amygdala, and prefrontal cortex subsystems in learned cue-induced feeding, and to identify the hypothalamic substrates that allow learned cue integration with the homeostatic system. The second aim is to map network plasticity that supports learning underling cue-food pairing. The proposed goals will be accomplished with a combination of behavioral and neural systems analysis that include selective neurotoxic lesions, anatomical pathway tracing, and imaging with immediate early genes (IEGs). The IEGs methods will include mapping of neuronal responses to a single event (c-fos protein induction), and mapping of neuronal coincident activation by two events that are temporally arranged (Arc/Arg3.1 mRNA induction). The work under the research plan in this application will extend our understanding of the brain circuitry that allows learning to modulate feeding behavior. The results will be also informative for control of appetite in humans including maladaptive environmental influences that could contribute to overeating and obesity.