Verma D, Wood J, Lach G, Mietzsch M, Weger S, Heilbronn R, Herzog H, Bonaventure P, Sperk G, Tasan R O
Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria.
Department of Pharmacology, Medical University Innsbruck, 6020 Innsbruck, Austria; Capes Foundation, Ministry of Education of Brazil, 70040-020 Brasília, DF, Brazil.
Neuropharmacology. 2015 Dec;99:665-74. doi: 10.1016/j.neuropharm.2015.08.038. Epub 2015 Aug 24.
The amygdala is fundamental for associative fear and extinction learning. Recently, also the central nucleus of the amygdala (CEA) has emerged as a site of plasticity actively controlling efferent connections to downstream effector brain areas. Although synaptic transmission is primarily mediated by glutamate and GABA, neuropeptides critically influence the overall response. While neuropeptide Y (NPY) acting via postsynaptic Y1 receptors exerts an important anxiolytic and fear-reducing action, the role of the predominantly presynaptic Y2 receptors is less defined. To investigate the role of Y2 receptors in the CEA we employed viral-vector mediated over-expression of the Y2 selective agonist NPY3-36 in fear conditioning and extinction experiments. NPY3-36 over-expression in the CEA resulted in reduced fear expression during fear acquisition and recall. Interestingly, this effect was blocked by intraperitoneal injection of a brain-penetrant Y2 receptor antagonist. Furthermore, over-expression of NPY3-36 in the CEA also reduced fear expression during fear extinction of CS-induced but not context-related fear. Again, fear extinction appeared delayed by peripheral injection of a Y2 receptor antagonist JNJ-31020028. Importantly, mice with over-expression of NPY3-36 in the CEA also displayed reduced spontaneous recovery and reinstatement, suggesting that Y2 receptor activation supports a permanent suppression of fear. Local deletion of Y2 receptors in the CEA, on the other hand, increased the expression of CS-induced freezing during fear recall and fear extinction. Thus, NPY inhibits fear learning and promotes cued extinction by reducing fear expression also via activation of presynaptic Y2 receptors on CEA neurons.
杏仁核对于联想性恐惧和消退学习至关重要。最近，杏仁核中央核（CEA）也已成为一个可塑性位点，积极控制与下游效应脑区的传出连接。虽然突触传递主要由谷氨酸和GABA介导，但神经肽对整体反应有至关重要的影响。虽然通过突触后Y1受体起作用的神经肽Y（NPY）发挥重要的抗焦虑和减轻恐惧作用，但主要位于突触前的Y2受体的作用尚不太明确。为了研究Y2受体在CEA中的作用，我们在恐惧条件反射和消退实验中采用病毒载体介导Y2选择性激动剂NPY3-36的过表达。CEA中NPY3-36的过表达导致在恐惧获得和回忆期间恐惧表达减少。有趣的是，腹腔注射一种可穿透脑的Y2受体拮抗剂可阻断这种效应。此外，CEA中NPY3-36的过表达在CS诱导的恐惧消退期间也减少了恐惧表达，但与情境相关的恐惧则未减少。同样，外周注射Y2受体拮抗剂JNJ-31020028似乎延迟了恐惧消退。重要的是，CEA中NPY3-36过表达的小鼠也表现出自发性恢复和重新出现减少，这表明Y2受体激活支持对恐惧的永久性抑制。另一方面，CEA中Y2受体的局部缺失增加了恐惧回忆和恐惧消退期间CS诱导的僵住行为的表达。因此，NPY通过激活CEA神经元上的突触前Y2受体来减少恐惧表达，从而抑制恐惧学习并促进线索性消退。
