Neurobiology: the role of metabolic stress on hypothalamic neuronal identity

大脑负责维持生物体的体重稳定。中枢神经系统，特别是下丘脑，通过调节能量平衡来确保体重平衡。这是通过微调食物摄入和能量消耗来实现的。下丘脑内稳态网络的一个重要组成部分是黑素皮质素系统，它包括两个以阴阳方式作用的神经元群：一侧的“Agrp”神经元促进食欲和能量节约，而另一侧的“Pomc”神经元促进饱腹感和能量消耗。尤其是Pomc神经元，在长时间暴露于高浓度的营养物质、激素和细胞因子中，会变得功能失调，这会损害它们触发饱腹感和增加能量消耗的能力，最终损害生物体的稳态调节。虽然传统上认为神经元的神经递质分布是固定的，但在实验室啮齿动物和人类中，越来越多的证据挑战了这一教条。最近的研究，包括我的博士后工作，已经表明需要几个转录因子来维持神经元的神经递质概况，或者可以被称为神经元的“身份”。这些转录因子的遗传缺失会损害神经元分泌特定神经递质的能力，如转录因子Tbx3和Pomc的分泌。这种现象，即神经元神经递质分泌能力的增加、减少或排列，是一个保守的生物学过程，被定义为神经递质再规范，它被描述为神经元可塑性的另一层（除了突触强度和缩放的变化之外）。虽然在负责运动技能学习、哺乳、神经和精神疾病的神经元中观察到这一新的未充分研究的过程，但尚不清楚神经递质重新规范是否有助于负责体重稳态的下丘脑网络的可塑性。因此，我提出的研究计划的目标是研究Pomc神经元在长期暴露于代谢应激（如营养素，激素和细胞因子）后的命运和作用，并了解发生变化的分子基础。总之，该项目旨在揭示和表征下丘脑稳态网络中神经元可塑性的重要新层。完成拟议的研究项目将使人们更好地了解神经元（正常）适应代谢压力背后的生物学。

The brain is responsible for maintaining an organism's body weight stable. Several mechanisms work in parallel in the central nervous system, in particular within the hypothalamus, to ensure body weight homeostasis by adjusting energy balance. This is achieved via the fine tuning of food intake and energy expenditure. One important component of this hypothalamic homeostatic network is the melanocortin system, which includes two neuronal populations acting in a yin-yang fashion: the "Agrp" neurons on one side promote appetite and energy sparing, while "Pomc" neurons on the other side promote satiety and energy expenditure. Pomc neurons, in particular, become dysfunctional upon prolonged exposure to high concentrations of nutrients, hormones and cytokines, which impairs their ability to trigger satiety and increase energy expenditure, ultimately harming the organism's homeostatic regulation. While the neurotransmitter profile of a neuron has traditionally been considered fixed in time, evidence has been accumulating that challenges this dogma, in both laboratory rodents and humans. Recent research, including my postdoctoral work, has shown that several transcription factors are required to maintain a neuron's profile of neurotransmitters, or what could be termed as a neuron's "identity". Genetic loss of these transcription factors can impair the ability of a neuron to secrete specific neurotransmitters, as in the case with the transcription factor Tbx3 and the secretion of Pomc. This phenomenon, the gain, loss or permutation of neurotransmitter secretion capacity by a neuron, is a conserved biological process defined as neurotransmitter respecification, which has been described as an additional layer of neuronal plasticity (in addition to changes in synaptic strength and scaling). While this novel and understudied process has been observed in neurons responsible for motor skill learning, lactation, neurological and psychiatric disorders, it is not known whether neurotransmitter respecification contributes to the plasticity of hypothalamic networks in charge of body weight homeostasis. Thus, the goal of the research program I propose is to investigate the fate and role of Pomc neurons in mice after prolonged exposure to metabolic stresses such as nutrients, hormones and cytokines, and understand the molecular underpinnings of the changes occurring. In conclusion, the proposed project aims to uncover and characterize a significant new layer of neuronal plasticity within the homeostatic networks of the hypothalamus. The completion of the proposed research project would allow a better understanding of the biology behind neuronal (mal)adaptation to metabolic stresses.