Cahill Michael E, Bagot Rosemary C, Gancarz Amy M, Walker Deena M, Sun HaoSheng, Wang Zi-Jun, Heller Elizabeth A, Feng Jian, Kennedy Pamela J, Koo Ja Wook, Cates Hannah M, Neve Rachael L, Shen Li, Dietz David M, Nestler Eric J
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Pharmacology and Toxicology, Research Institute on Addictions, Program in Neuroscience, State University of New York at Buffalo, Buffalo, NY 14214, USA.
Neuron. 2016 Feb 3;89(3):566-82. doi: 10.1016/j.neuron.2016.01.031.
Dendritic spines are the sites of most excitatory synapses in the CNS, and opposing alterations in the synaptic structure of medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a primary brain reward region, are seen at early versus late time points after cocaine administration. Here we investigate the time-dependent molecular and biochemical processes that regulate this bidirectional synaptic structural plasticity of NAc MSNs and associated changes in cocaine reward in response to chronic cocaine exposure. Our findings reveal key roles for the bidirectional synaptic expression of the Rap1b small GTPase and an associated local synaptic protein translation network in this process. The transcriptional mechanisms and pathway-specific inputs to NAc that regulate Rap1b expression are also characterized. Collectively, these findings provide a precise mechanism by which nuclear to synaptic interactions induce "metaplasticity" in NAc MSNs, and we reveal the specific effects of this plasticity on reward behavior in a brain circuit-specific manner.
树突棘是中枢神经系统中大多数兴奋性突触的所在部位，在给予可卡因后的早期和晚期，作为主要脑奖赏区域的伏隔核（NAc）中型多棘神经元（MSN）的突触结构会出现相反的变化。在此，我们研究了调节NAc MSN这种双向突触结构可塑性以及慢性可卡因暴露后可卡因奖赏相关变化的时间依赖性分子和生化过程。我们的研究结果揭示了Rap1b小GTP酶的双向突触表达以及相关的局部突触蛋白翻译网络在此过程中的关键作用。还对调节Rap1b表达的转录机制和NAc的通路特异性输入进行了表征。总体而言，这些发现提供了一种精确的机制，通过该机制核与突触的相互作用在NAc MSN中诱导“元可塑性”，并且我们以脑回路特异性方式揭示了这种可塑性对奖赏行为的特定影响。
