Wu Qi, Boyle Maureen P, Palmiter Richard D
Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Cell. 2009 Jun 26;137(7):1225-34. doi: 10.1016/j.cell.2009.04.022.
Neurons in the arcuate nucleus that produce AgRP, NPY, and GABA (AgRP neurons) promote feeding. Ablation of AgRP neurons in adult mice results in Fos activation in postsynaptic neurons and starvation. Loss of GABA is implicated in starvation because chronic subcutaneous delivery of bretazenil (a GABA(A) receptor partial agonist) suppresses Fos activation and maintains feeding during ablation of AgRP neurons. Moreover, under these conditions, direct delivery of bretazenil into the parabrachial nucleus (PBN), a direct target of AgRP neurons that also relays gustatory and visceral sensory information, is sufficient to maintain feeding. Conversely, inactivation of GABA biosynthesis in the ARC or blockade of GABA(A) receptors in the PBN of mice promote anorexia. We suggest that activation of the PBN by AgRP neuron ablation or gastrointestinal malaise inhibits feeding. Chronic delivery of bretazenil during loss of AgRP neurons provides time to establish compensatory mechanisms that eventually allow mice to eat.
弓状核中产生刺鼠相关蛋白（AgRP）、神经肽Y（NPY）和γ-氨基丁酸（GABA）的神经元（AgRP神经元）促进进食。成年小鼠中AgRP神经元的消融会导致突触后神经元中的Fos激活以及饥饿。GABA的缺失与饥饿有关，因为慢性皮下注射布雷替奈（一种GABA(A)受体部分激动剂）可抑制Fos激活，并在AgRP神经元消融期间维持进食。此外，在这些条件下，将布雷替奈直接注入臂旁核（PBN），AgRP神经元的直接靶点，它也传递味觉和内脏感觉信息，足以维持进食。相反，小鼠ARC中GABA生物合成的失活或PBN中GABA(A)受体的阻断会促进厌食。我们认为，AgRP神经元消融或胃肠道不适对PBN的激活会抑制进食。在AgRP神经元缺失期间慢性注射布雷替奈为建立最终使小鼠能够进食的补偿机制提供了时间。
