Forebrain Circuits and Control of Feeding Behavior by Learned Cues

肥胖症已经达到流行的程度，相关的健康后果令人担忧，但却是成功的 治疗仍然是一个重大挑战，因为根本原因很复杂。除 生理能量和营养需求，外部的，环境的影响可以推动食欲和饮食 通过认知和享乐过程，独立于饥饿。在以下方面取得了实质性进展 我们对食物摄入量和体重的动态平衡调节以及两者之间的整合的理解 下丘脑和脑干回路中的生理和中枢机制。我们知道的要少得多 关于调节环境影响的神经机制，但它们在健康和 疾病。来自环境的线索可以通过联想学习成为食物的信号，并基于 这种后天获得的能力可以控制进食行为。这些认知过程可以提高存活率 与体内平衡控制相协调的功能及其刺激作用在过去可能是适应性的 在能源资源稀缺的时候。发达国家有丰富的易得可口的食物和 无处不在的食物暗示的刺激作用是不适应的，因为它们会导致暴饮暴食和体重增加。因此， 确定这种认知的、非内环境平衡的进食动机背后的神经机制对 潜在的治疗干预措施。线索诱导下的前脑网络的核心成分 已经确定了摄食，包括杏仁核的基底外侧区(BLA)，即下丘脑的外侧 以及食欲素/下丘脑(ORX)神经元和腹内侧额叶皮质(VmPFC)。剩下的很多 此网络中的临时功能连通性未知，因此确定 特定的回路和神经递质系统是测试时食物动机的控制器。建议进行的研究 将利用尖端的化学遗传方法、DREADDS和Daun02灭活，并精确 神经解剖学和神经化学技术建立新的vmPFC前路 丘脑室旁核(PVTa)和ORX受体1信号是关键的控制器-开/关 在网络中转换--用于认知食物动机(目标1和2)。另一个目标是确定这是否 整合功能是由vmPFC神经元系综的可塑性通过动态交流所介导的 与BLA和PVTa(目标3)。这些机制将在线索的行为准备中被询问- 诱导性消费(目标1)和持久的食物寻找(上下文中介的灭绝的更新 对食物提示的反应；目的2)雄性和雌性大鼠。寻食情境更新中的性别差异 是最近建立的，这里的实验将测试vmPFC和PVTa是否是性爱的场所- 通过与腹侧海马结构的连接进行特定的调节。这些研究的发现将 建立关键的神经递质和回路机制，调节认知食物的动机和潜力 性别差异的部位和治疗贪婪食欲和暴饮暴食的新靶点。

Obesity has reached epidemic proportions and associated health consequences are alarming, but successful treatment remains a significant challenge, because the underlying causes are complex. In addition to the physiological energy and nutrient needs, external, environmental influences can drive appetite and eating through cognitive and hedonic processes, independently from hunger. Substantial progress has been made in our understanding the homeostatic regulation of food intake and body weight and the integration between physiological and central mechanisms within the hypothalamic and brainstem circuitries. Much less is known about the neural mechanisms mediating environmental influences, yet they are important in health and disease. Cues from the environment can become signals for food through associative learning, and based on that acquired ability can control feeding behavior. These cognitive processes enhance survival when they function in concert with homeostatic control and their stimulatory effects may have been adaptive in the past when energy resources were scarce. The developed world is rich in easily accessible palatable foods and stimulatory effects of omnipresent food cues are maladaptive, as they drive overeating and weight gain. Thus, determining the neural mechanisms underlying this cognitive, non-homeostatic motivation to eat is crucial for potential therapeutic interventions. The core components of the forebrain network underlying cue-induced feeding have been identified and include the basolateral area of the amygdala (BLA), the lateral hypothalamus and orexin/hypocretin (ORX) neurons, and the ventromedial prefrontal cortex (vmPFC). Much remains unknown about the temporal functional connectivity within this network and it is critical to determine which specific circuit and neurotransmitter system is the controller of food motivation at test. The proposed studies will utilize cutting-edge chemogenetic methods, DREADDs and Daun02 inactivation, and precise neuroanatomical and neurochemical techniques to establish a novel vmPFC circuitry with the anterior paraventricular nucleus of the thalamus (PVTa) and ORX receptor 1 signaling is the key controller—an on/off switch within the network—for cognitive food motivation (Aim 1 & 2). Another goal is to determine if this integrative function is mediated by the vmPFC neuronal ensemble plasticity, through dynamic communications with the BLA and PVTa (Aim 3). These mechanisms will be interrogated in behavioral preparations for cue- induced consumption (Aim 1) and persistent food seeking (context-mediated renewal of extinguished responding to food cues; Aim 2) in male and female rats. Sex differences in context renewal of food seeking were recently established and experiments here will test whether the vmPFC and PVTa are sites of sex- specific regulation via connections with the ventral hippocampal formation. The findings from these studies will establish key neurotransmitter and circuitry mechanisms mediating cognitive food motivation and potential sites of sex differences and novel targets for treatment of insatiable appetite and overeating.