DA-GABA modulation of cortical ACh release

描述（由申请人提供）：伏隔核（NAC）是分布式神经系统的关键区域，它集成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，以及对选择的刺激的适当处理，是目标导向行为的工具。在这一更新应用中，我们提出动机和注意过程之间的整合是由谷氨酸能和多巴胺能输入NAC和NAC神经元群随后的募集及其向基底前脑皮质胆碱能系统（BFCS）的投射之间的相互作用介导的。BFCS支配所有皮质区域，通常控制皮质信息处理。在行为上，BFCS已被证明可以调节注意功能的基本方面。该研究将利用体内微透析、脑内注射和操作行为的结合来揭示同一动物前额皮质（RFC）、NAC和基底前脑（BF）内协调的神经化学活动。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）释放和注意力表现的功能后果。我们认为，与动物休息时的注意力表现相反，对注意力表现的挑战会选择性地激活PFC-NAC-BF回路，而这种挑战会触发注意力能力的主动增强。最后，我们将确定NAC - Glu、DA和皮质乙酰胆碱之间的功能相互作用如何在新生儿或成年海马腹侧受损的动物中发生改变。早期发育的腹侧海马损伤是一种广泛使用的精神分裂症动物模型，NAC中Glu/DA和RFC中ACh的失调以及注意加工的损伤将进一步验证这一重要模型。总的来说，这些研究具有重要的公共卫生意义。一些神经精神疾病被认为反映了这种分布式神经回路的失调，这种失调在注意力和相关执行功能的认知障碍中表现出来。这些疾病包括药物成瘾、注意力缺陷多动症和精神分裂症。拟议的研究应进一步发展和验证动物模型，为这些健康相关领域的转化研究奠定基础。

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.