多巴胺能奖赏通路在nesfatin-1摄食调控中的作用

Nesfatin-1 is an anorexigenic brain-gut peptide discovered in 2006. The previous studies about nesfatin-1 focused on hypothalamus and brainstem circuits which implicated in feeding regulation. Recently，nesfatin-1 was reported to be also expressed in the nucleus accumbens (NAc), lateral parabrachial nucleus and amygdaloid nucleus of mice, which were related to the control of rewarding behavior. Therefore, it is postulated that nesfatin-1 might also inhibit food intake via central reward circuit. Using electrophysiological, electrochemical recordings and behaviour tests, the present study is carried to observe the effect of nesfatin-1 on food intake after injection into the ventral tegmental area (VTA) and NAc and to investigate whether nesfatin-1 influences the excitability of dopaminergic neurons in VTA as well as the content and releae of dopamine in NAc. We aim to determine whether the VTA-NAc dopaminergic reward pathway is involved in the regulation of nesfatin-1's effect on food intake and to clarify the central mechanism, which provides reliable evidence for treatment of obesity.

Nesfatin-1是2006年发现的能够抑制摄食的脑肠肽，以往有关nesfatin-1抑制摄食的研究均集中在下丘脑、脑干的调节通路。最新的研究表明nesfatin-1在小鼠的伏隔核（NAc）、外侧臂旁核、杏仁核等部位中也有表达。因此我们推测中枢神经系统的奖赏通路可能也参与nesfatin-1抑制摄食的调节。本项目采用电生理、电化学、行为学等技术手段，观察腹侧背盖区（VTA）、NAc中微量注射nesfatin-1对摄食的影响，并探讨其机制是否通过调制VTA中多巴胺能神经元的兴奋性，以及改变NAc中多巴胺含量、释放量来实现。通过上述实验阐明VTA-NAc多巴胺能奖赏通路是否参与nesfatin-1对摄食的调控。该项目有助于明确nesfatin-1的中枢作用机制，为其作为治疗肥胖的药物提供可靠的实验依据。

Nesfatin-1是由82个氨基酸组成的抑制摄食的脑肠肽，以往有关nesfatin-1抑制摄食的研究均集中在下丘脑、脑干的调节通路。而已有研究表明nesfatin-1在小鼠的伏隔核（NAc）、外侧臂旁核、杏仁核等部位中也有表达。因此本项目旨在研究中枢腹侧背盖区投射至NAc的奖赏通路是否也参与nesfatin-1抑制摄食的调节。主要实验结果显示：（1）VTA中微量注射nesfatin-1可抑制摄食。（2）体电生理结果显示，nesfatin-1可抑制VTA中多巴胺能神经元的自发放电。（3）离体脑片结果同样证实nesfatin-1可抑制VTA中多巴胺能神经元的电活动。（4）电化学结果显示nesfatin-1可减少NAc中多巴胺的释放量。我们推测nesfatin-1可作用于VTA中多巴胺能神经元，并且可能为其抑制摄食的机制之一。