Neuroanatomical adaptation at synaptic level to chronic*

突触水平对慢性的神经解剖学适应*

• 批准号: 6533693
• 负责人: FENG C. ZHOU
• 金额: $ 14.8万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533693
• 关键词: NMDA receptors; alcoholism /alcohol abuse; amygdala; autoradiography; behavioral /social science research tag; brain regulatory center; cooperative study; dopamine receptor; drug /alcohol abstinence; drug addiction; fluorescence microscopy; gamma aminobutyrate; glutamate receptor; immunocytochemistry; laboratory rat; neural plasticity; neurons; nucleus accumbens; receptor binding; receptor expression; reinforcer; relapse /recurrence; synapses; thalamus

Evidence indicates that a similar key brain reward pathway is involved in both alcohol and drug abuse. In this pathway, alcohol affects the akey entry signals, mesolimbic dopamine (DA) and cortical limbic glutamate (GLU) into the extended amygdala (EA), an area integrating the stimulation for appropriate response. We hypothesized that chronic alcohol exposure and its follow-up with episodic alcohol deprivation alter the brain's wiring at the synaptic level in the EA. The key circuits between cortical limbic GLU as well as mesolimbic DA neurons and the EA medium spiny projecting GABA neurons will be studied in the alcohol preferring (P) line of rats. The key reward circuitry will be examined in three treatment groups---(a) AlcoholNaive, water over entire period of the experiment; (b) Chronic Alcohol Treatment, concurrent free access to 10, 20, and 30% alcohol for 20 weeks, (c) or Repeated Deprivation, similar access to alcohol for 6 weeks before deprivation for two weeks and followed by 3 additional cycles of repeated 2- wk water and 2-wk free choice access drinking. The brain wiring of these rats will be monitored at the synaptic level in EA using three quantitatively determined checkpoints -- the number of GLU and DA synaptic boutons using stereologic counting; autoradiography to assess the density of responsive receptors NMDA, D1, and D2; and the number and length of dendrites, density of spines, and morphometric plasticity of spines of principal medium neurons employing two-photon fluorescence microscopy and Neurolucida analysis. In the key reward circuitry of stereotypic alcohol drinking behaviors, the amplitude of the alcohol signal may alter the number of GLU and or DA synaptic boutons in EA; numbers of dendrites and spines, the sites of reception to alcohol signal; and/or changes in the density of receptors, which determines the degree of reception of the alcohol signal. As a result, the brain may set a new threshold upon the over- stimulation of alcohol. The setting of this threshold might be derailed when alcohol is cyclically deprived. Current and future study along this line will provide information enabling us to better understanding excess drinking behavior.

有证据表明，酒精和药物滥用都涉及类似的关键大脑奖励通路。 在此通路中，酒精影响关键的进入信号、中脑边缘多巴胺 (DA) 和皮质边缘谷氨酸 (GLU) 进入扩展杏仁核 (EA)，这是一个整合刺激以做出适当反应的区域。我们假设，长期饮酒及其后续的间歇性戒酒会改变大脑在 EA 突触水平的线路。将在嗜酒 (P) 系大鼠中研究皮质边缘 GLU 以及中脑边缘 DA 神经元和 EA 中型多刺突出 GABA 神经元之间的关键回路。将在三个处理组中检查关键的奖励回路——（a）在整个实验期间不使用酒精、水； (b) 慢性酒精治疗，同时免费饮用 10%、20% 和 30% 的酒精，持续 20 周，(c) 或重复戒酒，在戒酒两周前 6 周内以类似方式戒酒，然后再进行 3 个额外的重复周期2 周水和 2 周自由选择饮用。这些大鼠的大脑线路将在 EA 的突触水平上使用三个定量确定的检查点进行监测——使用体视计数的 GLU 和 DA 突触纽扣的数量；放射自显影评估反应性受体 NMDA、D1 和 D2 的密度；以及使用双光子荧光显微镜和 Neurolucida 分析的主要中等神经元的树突数量和长度、棘密度和棘的形态可塑性。在刻板饮酒行为的关键奖励回路中，酒精信号的幅度可能会改变 EA 中 GLU 和/或 DA 突触按钮的数量；树突和刺的数量，接收酒精信号的部位；和/或受体密度的变化，这决定了酒精信号的接收程度。因此，大脑可能会在酒精过度刺激时设定一个新的阈值。当周期性戒酒时，该阈值的设置可能会脱轨。目前和未来的研究将为我们提供信息，使我们能够更好地了解过度饮酒行为。