Forebrain Circuits and Control of Feeding Behavior by Learned Cues

肥胖已经达到流行病的程度，相关的健康后果令人担忧，但成功的 治疗仍然是一个重大挑战，因为根本原因很复杂。除了有 生理能量和营养需求，外部，环境影响可以驱动食欲和进食 通过认知和享乐的过程，独立于饥饿。取得实质性进展 我们对食物摄入和体重的稳态调节以及 下丘脑和脑干回路内的生理和中枢机制。知之甚少 关于神经机制介导的环境影响，但他们是重要的健康和 疾病通过联想学习，来自环境的线索可以成为食物的信号， 后天获得的能力可以控制进食行为。这些认知过程增强了生存， 与内环境稳定控制一致的功能及其刺激作用在过去可能是适应性的 当时能源资源匮乏。发达国家拥有丰富的容易获得的美味食品， 无处不在的食物线索的刺激作用是适应不良的，因为它们会导致暴饮暴食和体重增加。因此，在本发明中， 确定这种认知的、非稳态的进食动机背后的神经机制， 潜在的治疗干预。线索诱导的前脑网络的核心组成部分 进食区包括杏仁核的基底外侧区（BLA）、外侧下丘脑 和食欲素/下丘脑泌素（ORX）神经元以及腹内侧前额叶皮质（vmPFC）。仍有许多工作 未知的时间功能连接在这个网络，这是至关重要的，以确定 特定的神经回路和神经递质系统是测试时食物动机的控制者。拟议的研究 将利用尖端的化学遗传学方法，DREADDs和Daun 02灭活， 神经解剖学和神经化学技术建立一个新的vmPFC电路与前 丘脑室旁核（PVTa）和ORX受体1信号传导是关键的决定因素-开/关 在网络中切换-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神经元整体可塑性通过动态通信介导的 与BLA和PVTa（目标3）。这些机制将在行为准备中进行询问，以获得线索- 诱导消费（目标1）和持续的食物寻求（上下文介导的熄灭更新） 对食物线索的反应;目的2）在雄性和雌性大鼠中。食物寻求情境更新的性别差异 是最近建立的，这里的实验将测试vmPFC和PVTa是否是性的位点- 通过与腹侧海马结构的连接进行特异性调节。这些研究的结果将 建立调节认知食物动机和潜力关键神经递质和电路机制 性别差异和治疗食欲不振和暴饮暴食的新目标的网站。

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.