Forebrain circuits and control of feeding behavior by learned cues

描述（由申请人提供）：食欲和进食不仅受能量需求的驱动，还受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，可以覆盖稳态信号，以刺激饱足状态下的进食，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。我们使用啮齿动物模型的线索诱导进食，其中一个环境线索先前配对的食物时，动物是饥饿的可以启动进食饱大鼠。增强的进食是通过联想学习由其他中性信号获得的动机特性的结果。该模型提供了一个框架来研究环境线索如何与功能性前脑网络内的稳态信号相结合，以及这些网络如何被经验调制。拟议的研究建立在证据的基础上，即网络组件包括前脑，杏仁核和前额叶皮层中对联想学习和决策至关重要的区域，以及外侧下丘脑，这是喂养，奖励和动机的集成器。有两个独立的，相互关联的具体目标，共同研究神经系统，通过这些系统，来自环境的信号控制摄食行为。第一个目的是确定杏仁核和前额叶皮质子系统在学习线索诱导的进食中的作用，并确定下丘脑底物，使学习线索与稳态系统整合。第二个目标是映射网络可塑性，支持学习下属的线索食物配对。提出的目标将通过行为和神经系统分析的组合来实现，包括选择性神经毒性病变，解剖通路追踪和立即早期基因（IEG）成像。IEG方法将包括对单个事件（c-fos蛋白诱导）的神经元响应的映射，以及对由时间上排列的两个事件（Arc/Arg3.1 mRNA诱导）引起的神经元同时激活的映射。这项应用研究计划下的工作将扩展我们对大脑回路的理解，使学习能够调节进食行为。这些结果也将为人类控制食欲提供信息，包括可能导致暴饮暴食和肥胖的适应不良的环境影响。

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.