Department of Anatomy and Neurobiology, University of Maryland School of Medicine Baltimore, MD, USA.
Front Mol Neurosci. 2013 May 24;6:13. doi: 10.3389/fnmol.2013.00013. eCollection 2013.
Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin-cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant-mediated behavior and function.
暴露于精神兴奋剂会导致纹状体中型多棘神经元（MSNs）的结构和突触可塑性。这些细胞适应性源自参与肌动蛋白细胞骨架重排的基因的改变，例如 T 淋巴细胞瘤入侵和转移 1（Tiam1）。先前的研究表明，多巴胺受体 1（D1）包含的纹状体 MSNs 在介导精神兴奋剂诱导的可塑性变化中起着至关重要的作用。这些伏隔核（NAc）中的 D1-MSNs 积极调节药物寻求、奖励和运动行为效应以及精神兴奋剂药物的形态适应。在这里，我们证明主动自我给予可卡因的大鼠在 NAc 中显示出 Tiam1 水平降低。为了进一步研究这些 Tiam1 变化的细胞类型特异性贡献，我们使用光遗传学选择性地操纵 NAc D1-MSN 或多巴胺受体 2（D2）表达的 MSNs。我们发现，重复通道视紫红质-2 激活 D1-MSNs 但不是 D2-MSNs 导致 Tiam1 水平下调类似于可卡因的作用。此外，激活 D2-MSNs 导致可卡因介导的运动行为反应延迟减弱，但不会改变 Tiam1 水平。然后，我们研究了 D1-MSNs 对可卡因介导的 Tiam1 减少的贡献。使用光激活氯离子泵，eNpHR3.0（增强的纳氏盐单胞菌盐藻视紫红质 3.0），我们在可卡因暴露期间选择性地抑制 D1-MSNs，这导致可卡因诱导的运动敏感化的行为阻断。此外，在可卡因暴露期间抑制这些 NAc D1-MSNs 逆转了 Tiam1 基因表达和蛋白水平的下调。这些数据表明，用光遗传学改变特定神经回路的活动可以影响精神兴奋剂介导的行为和功能的潜在分子底物。
