DA-GABA modulation of cortical ACh release

超出提供的空间。这是一项竞争性续订申请。这项研究的总体目标是了解整个分布式神经系统中功能递质的相互作用，该神经系统被认为是调节注意加工的。该系统包括伏核的壳区(NAC)、基底前脑(BF，皮质顶叶胆碱能神经元的所在地)和内侧前额叶皮质(RnPFC)。这个系统内各种神经递质之间的功能相互作用还不是很清楚。大鼠的注意加工需要一个完整的基底前脑-皮质胆碱能系统(BFCS)。此外，皮质乙酰胆碱(ACh)在持续注意力任务的执行过程中会增加。该研究利用一种强大的微透析程序，将3个探针同时放置到觉醒区(进入NAC、BF和mPFC)，以直接比较基线条件下和明显影响注意加工的条件下的动态递质相互作用。我们假设NAC内的谷氨酸传递调节BFCs的兴奋性[通过在BF内释放GABA和谷氨酸(Glu)]，并且这一调节受NAC DA受体活性的调节。我们还提出，这些递质相互作用的性质受到动物在测量时是否参与注意加工的深刻影响。我们将检验以下具体假设：1)阻断NAC中的离子型Glu受体或刺激代谢型Glu受体会减少BF中GABA的释放并刺激BF中的Glu释放，从而刺激mPFC中ACh的释放；2)Nac1和D2受体双向调节Glu配体影响BF中GABA/Glu释放和mPFC中ACh释放的能力；3)在持续注意任务中的表现伴随着BF和皮质中递质释放的不同于在没有明确对注意加工征税的控制任务中的表现。4)基底内对GABA或Glu受体活性的操纵将影响持续注意任务而不是控制操作任务的动物的表现和皮层ACh释放。了解调节基底前脑皮质胆碱能系统兴奋性的机制，对于我们理解以注意加工功能障碍为特征的神经精神障碍的病因和潜在的治疗方法是至关重要的。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. This is a competitive renewal application. The overall goal of this research is to understand functional transmitter interactions throughout a distributed neural system postulated to mediate attentional processing. This system includes the shell region of the nucleus accumbens (NAC), the basal forebrain (BF, the site of the corticopetal cholinergic neurons) and the medialprefrontal cortex (rnPFC). The functional interactions amongthe various neurotransmitters within this system are not well understood. Attentional processing in rats requires an intact basal forebrain-cortical cholinergic system (BFCS). Moreover, cortical acetylcholine (ACh) is increased during performancein a sustained attention task. The proposed research utilizes a powerful microdialysis procedure in which 3 probes are simultaneouslyplaced into awakerats (into NAC, BF, and mPFC) to directly compare dynamic transmitter interactions under baseline conditionsand under conditions that explicitly tax attentional processing. We hypothesize that glutamatergictransmission within the NAC regulates theexcitability of the BFCS [via the release of GABA and glutamate (Glu) withinthe BF] and that this regulation is modulatedby NAC DA receptor activity. We also propose that the nature of these transmitter interactions isprofoundly influenced by whether or not the animal is engaged in attentionalprocessing at the time of measurement. We will test the following specific hypotheses: 1)that blockade of ionotropic Glu receptors or stimulation of metabotropic Glu receptors in NAC decreases GABA release and stimulates Glu release in BF, and, as a result stimulates ACh release in mPFC, 2) that NAC Dl and D2 receptors bidirectionallymodulate the ability of Glu ligands to affect GABA/Glu release in BF and ACh release in mPFC, 3) that performance in a sustained attention task is accompanied by a different profile of transmitter release in BF and cortex than performance in a control task that does not explicitly tax attentional processing, and 4) that intrabasalis manipulations of GABA or Glu receptor activity will affect performance and cortical ACh release in animals engaged in a task of sustained attention but not in control operant tasks. An understanding of the mechanisms regulating the excitability of the basal forebrain cortical cholinergic system is central to our understanding of the etiology and potential therapeutics of neuropsychiatric disorders characterized by dysfunctionsin attentional processing. PERFORMANCE SITE ========================================Section End===========================================