Hypothalamic deep brain stimulation as a novel experimental and therapeutic approach in the treatment of adiposity

荷尔蒙和营养物质以下丘脑和脑干为靶点，调节食物摄入量和能量消耗，从而促进能量储备的维持。在弓状核内，食欲性NPY和厌食性POMC神经元对这些刺激作出反应，并与下丘脑外侧核(LH)和室旁核(PVN)神经元进行通讯，以调节能量平衡。食物奖赏感觉的改变也是通过中枢神经结构来调节的。减肥后瘦素信号的减少会增加食物的奖赏特性，这一过程可能包括伏隔核(NAC)。黄体生成素和NAC之间的双向神经元投射支持那些能量平衡的信号，可能调节食物奖赏感觉，反之亦然。这提供了通过局部干预来瞄准这些神经元群体的机会。消融性电凝实验的立体定向方法已经令人信服地证明了下丘脑解剖区域的完整性对于维持能量平衡的关键重要性。模拟这些损害效应的脑深部刺激(DBS)是治疗特发性震颤、帕金森S病和肌张力障碍的安全、有效和(值得注意的)可逆疗法。我们现在的目标是将这项技术应用于肥胖症的治疗。在这个项目中，重点是下丘脑的促黄体生成素和神经元的DBS，将在两个不同的肥胖小鼠模型中检查这些结构的间歇性双侧DBS的影响，一个是由于MC4R功能突变而导致的单基因肥胖症，另一个是饮食诱导的肥胖症模型。将考虑安全因素(体温、水平衡、昼夜节律或大脑完整性)对动物进行关于能量平衡、身体成分和新陈代谢的表型鉴定。由于外部刺激被限制在每天2-8小时的总刺激时间内，因此将开发用于小鼠双侧DBS的新型植入性微刺激系统，并用于后续使用相同动物模型的研究。这将为分析慢性或间歇性刺激对能量稳态和安全性方面的长期影响提供机会。鉴于DBS的广泛应用，它可能是一种可行的、可逆的、病理生理学上合理的治疗方法，用于治疗因中枢信号分子如MC4R或瘦素受体功能突变而导致的病态或单基因肥胖症，这些内分泌途径可能会失败。除了预期的科学意义外，该项目还代表了一种真正的转化性研究方法，提供了在适当的时间框架内将结果转化为临床方案的机会。

Hormones and nutrients target hypothalamus and brainstem to regulate food intake and energy expenditure, thereby promoting the maintenance of energy reserves. Within the arcuate nucleus, orexigenic NPY and anorexigenic POMC neurons respond to these stimuli and communicate with lateral hypothalamus (LH) and paraventricular nucleus (PVN) neurons modifying energy homeostasis. Modification of food reward sensations is also mediated via central-nervous structures. Reduced leptin signaling after weight loss increases rewarding properties of food, a process likely to include the Nucleus accumbens (NAc). Bidirectional neuronal projections between LH and NAc, supporting those signals of energy homeostasis, may modulate food reward sensations and vice versa. This offers the opportunity to target those neuronal populations by local interventions. Stereotactic approaches with ablative electrocoagulation experiments have convincingly demonstrated the crucial importance of the integrity of hypothalamic anatomical regions for maintenance of energy balance. Deep brain stimulation (DBS), mimicking these lesion effects, is a safe, effective and (notably) reversible therapy for essential tremor, Parkinson´s disease and dystonia. We now aim to apply this technology to the treatment of adiposity. Focusing on hypothalamic DBS (hDBS) of the LH and NAc within this project, effects of an intermittent overnight external bilateral DBS of those structures will be examined in two different mouse models of adiposity, one with monogenic obesity resulting from a loss of function mutation of the MC4R and a model of diet-induced adiposity. Phenotyping of the animals regarding energy homeostasis, body composition and metabolism will be performed considering safety aspects (body temperature, water homeostasis, circadian rhythms or brain integrity). Since external stimulation is limited to a total stimulation time of 2-8 hours per day, novel implantable microstimulation systems for bilateral DBS in mice will be developed and used for subsequent studies using the same animal models. This will offer the opportunity to analyze long-term effects of a chronic or intermittent stimulation on energy homeostasis and safety aspects. Given the existing wide applications of DBS, it might be a feasible, reversible and pathophysiologically reasonable therapeutic approach to treat morbid or monogenic obesity resulting from loss of function mutations of central signaling molecules such as MC4R or leptin receptor, where endocrine approaches might fail. Apart from the expected scientific significance, this project represents a true translational research approach offering the opportunity to transfer the results within an appropriate time frame to the clinical scenario.