DA-GABA modulation of cortical ACh release

描述(申请人提供)：伏隔核(NAC)是分布式神经系统中的一个关键区域，它整合了目标导向行为的基本信息。注意功能，包括对刺激的检测和选择，以及对所选刺激的适当处理，都是目标导向行为的工具。在这一新的应用中，我们认为动机和注意过程之间的整合是由NAC的谷氨酸和多巴胺能输入之间的相互作用以及随后NAC神经元集合的招募及其向基底前脑皮质胆碱能系统(BFCS)的投射所介导的。BFCS支配所有的大脑皮层区域，通常控制大脑皮层的信息处理。在行为学上，BFCS已被证明调节注意功能的基本方面。拟议的研究将结合体内微透析、脑内注射和操作行为来揭示同一动物的前额叶皮质(RFC)、NAC和基底前脑(BF)内的协调神经化学活动。我们将确定NAC中谷氨酸(Glu)和多巴胺(DA)相互作用对RFC中乙酰胆碱(ACh)释放和注意表现的功能影响。我们认为，与动物休息时的注意表现不同，特别是对注意表现的挑战，触发了注意能力的动机增强，将选择性地招募这一PFC-NAC-BF回路。最后，我们将确定在遭受腹侧海马区损伤的动物中，NAC Glu和DA以及皮质ACh之间的这些功能相互作用是如何改变的。早期发育中的腹侧海马区损伤是一种广泛使用的精神分裂症动物模型，NAC区Glu/DA和RFC区ACh的异常调节以及注意加工的障碍的记录将进一步验证这一重要模型。总体而言，这些研究与重要的公共卫生影响有关。一些神经精神障碍被认为反映了这种分布式神经回路的失调，这些失调表现为注意力和相关执行功能的损害。这些疾病包括毒瘾、多动症和精神分裂症。拟议的研究应进一步开发和验证动物模型，为这些健康相关领域的转化性研究奠定基础。

DESCRIPTION (provided by applicant): The nucleus accumbens (NAC) is a key region in a distributed neural system that integrates essential information underlying goal-directed behavior. Attentional functions, including the detection and selection of stimuli, and the appropriate processing of selected stimuli are instrumental for goal-directed behavior. In this renewal application, we propose that the integration between motivational and attentional processes is mediated by interactions between glutamatergic and dopaminergic inputs to NAC and the subsequent recruitment of NAC neuronal ensembles and their projections to the basal forebrain cortical cholinergic system (BFCS). The BFCS innervates all cortical areas and generally gates cortical information processing. Behaviorally, the BFCS has been demonstrated to mediate essential aspects of attentional functions. The proposed studies will utilize a combination of in vivo microdialysis, intracerebral injections, and operant behavior to reveal the coordinated neurochemical activity within the prefrontal cortex (RFC), NAC, and basal forebrain (BF) of the same animal. We will determine the functional consequences of interactions between glutamate (Glu) and dopamine (DA) in NAC for the release of acetylcholine (ACh) in RFC and attentional performance. We propose that attentional performance, as opposed to when the animal is at rest, specifically challenges on attentional performance which trigger the motivated enhancement of attentional capacities, will selectively recruit this PFC-NAC-BF circuit. Finally, we will determine how these functional interactions between NAC Glu and DA and cortical ACh are altered in animals sustaining lesions of the ventral hippocampus as neonates or as adults. Lesions of the ventral hippocampus during early development are a widely used animal model of schizophrenia and the documentation of dysregulations in Glu/DA in NAC and ACh in RFC, as well as impairments in attentional processing, will further validate this important model. Collectively, these studies have relevance to important public health implications. Several neuropsychiatric disorders are believed to reflect dysregulations in this distributed neural circuit that manifest themselves cognitively in impairments in attentional and related executive functions. These disorders include drug addiction, ADHD, and schizophrenia. The proposed research should further the development and validation of animal models that form the foundation of translational research in these health-related areas.