Endogenous Kynurenic Acid Modulates Prefrontal ACh Levels and Cognitive Behavior

描述（由申请人提供）：精神分裂症（SZ）是一种使人衰弱的精神障碍，在前额皮质（PFC）中具有显着且复杂的病理生理学。这种皮质病理学的几个方面与执行功能的缺陷有关，例如工作记忆、注意力和认知灵活性。更彻底地了解导致这些认知障碍的神经化学机制至关重要，因为传统的抗精神病药物在减轻这些障碍方面并不是特别有效，而且这些缺陷的严重程度可以预测患者融入社会的能力。 PFC 中 17 种烟碱受体 (17nAChR) 的活性与许多测量执行认知功能的行为任务的表现呈正相关。相反，皮质 17nAChR 的失调与 SZ 的病因有关。犬尿酸 (KYNA) 是一种星形胶质细胞衍生的神经调节剂，在内源浓度下可抑制包括 PFC 在内的多个大脑区域的 17nAChR 活性。精神分裂症患者 PFC 中的 KYNA 水平升高，并且这种升高并非继发于抗精神病药物。该项目旨在定义 KYNA 在调节 PFC 中基础谷氨酸和乙酰胆碱 (ACh) 水平以及调节前额介导的认知行为（知觉定势转换）中的作用。我们在大鼠中的初步数据表明，KYNA 内源性水平的波动调节 PFC 中谷氨酸和乙酰胆碱的水平。拟议的实验将使用互补的生化、药理学和行为方法，以及两位经验丰富的 PI 的协同专业知识，来评估大鼠 PFC 中 KYNA、ACh 和谷氨酸之间这种联系的关键化学事件和功能影响。目标#1 将利用体内微透析来测试以下假设：在 17nAChR 活性基础水平的条件下，PFC 内内源 KYNA 水平的波动会影响谷氨酸和 ACh 水平。我们还将确定这些效应是否如假设的那样可以追溯到 KYNA 拮抗 17nAChR 的能力，以及 KYNA 相关的 ACh 水平调节是否是由局部谷氨酸介导的。作为执行任务的大鼠中后续目标的前奏，目标 #2 将确定 KYNA 在激活 17nAChR（一种集中给药的药物和行为调节范例）的两种条件下保留调节前额谷氨酸和乙酰胆碱释放的能力的程度。目标 #3 将这些神经化学研究扩展到认知行为领域，并将检验这样的假设：皮质 KYNA 水平的升高选择性地损害大鼠执行感知设定转换任务的能力，该任务取决于前额皮层中神经传递的完整性。我们还将确定胆碱能和谷氨酸能功能减弱在这种 KYNA 诱导的行为缺陷中的相对作用。这与 SZ 的病理生理学尤其相关，SZ 与 PFC 中 KYNA 水平过高、皮质谷氨酸能和烟碱能传递异常以及设定转换任务中的明显损伤有关。最后，由于在 SZ 中观察到皮质 KYNA 水平长期升高，我们将在目标 #4 中研究大脑 KYNA 水平持续升高的生化和功能后果。这些慢性影响将在对照动物和接受典型（氟哌啶醇）或非典型（氯氮平）精神安定药物联合针对 17nAChR 的辅助治疗和临床使用的认知增强药物（加兰他敏）治疗的大鼠中进行评估。总的来说，拟议的实验将检验新的假设，即星形胶质细胞衍生的 KYNA 水平的波动有效调节皮质神经传递和前额介导的认知行为。我们将利用这些发现构建一个实验平台，用于测试基于 KYNA 的治疗方法在缓解 SZ 认知缺陷方面的疗效。 公共卫生相关性：精神分裂症 (SZ) 是一种使人衰弱的精神疾病，其前额皮质 (PFC) 表现出复杂的损伤。这些皮质异常是大多数患者执行功能缺陷的原因，并且可能与神经递质谷氨酸和乙酰胆碱 (ACh) 的特定受体功能障碍有关。值得注意的是，已知增强相同受体的活性可以改善认知功能的表现。犬尿酸 (KYNA) 是一种神经胶质细胞衍生的神经调节剂，存在于哺乳动物大脑中，具有调节皮质谷氨酸能和胆碱能神经传递的能力。有趣的是，SZ 患者大脑中 KYNA 水平升高，因此可能损害谷氨酸和乙酰胆碱功能，从而损害前额介导的认知行为。该假设将在拟议的项目中进行实验测试。总的来说，这些实验将 a) 为 KYNA 的神经化学效应提供新的见解； b) 探索神经胶质细胞在注意力和认知灵活性调节中的作用； c) 评估大脑中 KYNA 慢性升高对于 SZ 研究的结构有效性； d) 开始检查治疗引起的大脑 KYNA 水平降低是否构成治疗 SZ 认知缺陷的有效策略。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a debilitating mental disorder with significant and complex pathophysiology in the prefrontal cortex (PFC). Several aspects of this cortical pathology have been linked to deficits in executive functions such as working memory, attention, and cognitive flexibility. A more thorough understanding of the neurochemical mechanisms contributing to these cognitive disorders is critical, as conventional antipsychotics are not particularly effective in alleviating these impairments, and since the severity of these deficits is predictive of the patient's ability to integrate into society. The activity of 17 nicotinic receptors (17nAChR) in the PFC has been positively linked to performance in a number of behavioral tasks that measure executive cognitive functions. Conversely, dysregulation of cortical 17nAChRs has been implicated in the etiology of SZ. Kynurenic acid (KYNA) is an astrocyte-derived neuromodulator that, at endogenous concentrations, inhibits 17nAChR activity in several brain regions, including the PFC. KYNA levels are elevated in the PFC of individuals with schizophrenia, and this increase is not secondary to antipsychotic medication. This project is designed to define the role of KYNA in the modulation of basal and stimulated glutamate and acetylcholine (ACh) levels in the PFC and in the mediation of a prefrontally- mediated cognitive behavior (perceptual set-shifting). Our preliminary data in rats demonstrate that fluctuations in the endogenous levels of KYNA modulate levels of glutamate and ACh in the PFC. The proposed experiments will use complementary biochemical, pharmacological and behavioral methods, and the synergistic expertise of two experienced PIs, to evaluate key chemical events and functional implications of this link between KYNA, ACh and glutamate in the rat PFC. Aim #1 will utilize in vivo microdialysis to test the hypothesis that fluctuations in endogenous KYNA levels within the PFC influence glutamate and ACh levels under conditions of basal levels of 17nAChR activity. We will also determine whether these effects, as hypothesized, can be traced to KYNA's ability to antagonize the 17nAChR and whether the KYNA-related modulation of ACh levels is mediated by local glutamate. Aim #2 will determine, as a prelude to subsequent aims in task-performing rats, the extent to which KYNA retains the ability to modulate prefrontal glutamate and ACh release under two conditions that activate the 17nAChR (a centrally-administered drug and a behavioral conditioning paradigm). Aim #3 extends these neurochemical studies to the realm of cognitive behavior and will test the hypothesis that elevations in cortical KYNA levels selectively impair the ability of rats to perform in a perceptual set-shifting task, which is dependent upon the integrity of neurotransmission in the PFC. We will also determine the relative roles of diminished cholinergic and glutamatergic function in this KYNA-induced behavioral deficit. This is especially relevant to the pathophysiology of SZ which is associated with excessive KYNA levels in the PFC, abnormal cortical glutamatergic and nicotinergic transmission, and pronounced impairments in set- shifting tasks. Finally, since prolonged elevations of cortical KYNA levels are seen in SZ, we will, in Aim #4, study the biochemical and functional consequences of persistent increases in brain KYNA levels. These chronic effects will be evaluated both in control animals and in rats treated with typical (haloperidol) or atypical (clozapine) neuroleptic drugs in combination with an adjunctive therapy targeting the 17nAChR with a clinically used cognition-enhancing drug (galantamine). Collectively, the proposed experiments will test the new hypothesis that fluctuations in astrocyte-derived KYNA levels potently modulate cortical neurotransmission and prefrontally-mediated cognitive behavior. We will use these findings to generate an experimental platform for testing the therapeutic efficacy of KYNA-based treatments in alleviating the cognitive deficits seen in SZ. PUBLIC HEALTH RELEVANCE: Individuals with schizophrenia (SZ), a debilitating psychiatric disorder, show complex impairments of the prefrontal cortex (PFC). These cortical abnormalities are responsible for the deficits in executive functions seen in most patients and are likely related to a dysfunction of specific receptors for the neurotransmitters glutamate and acetylcholine (ACh). Notably, enhanced activity of the same receptors is known to improve performance in cognitive functions. Kynurenic acid (KYNA) is a glial cell-derived neuromodulator that is present in the mammalian brain and has the capacity to modulate cortical glutamatergic and cholinergic neurotransmission. Interestingly, KYNA levels are elevated in the brain of SZ patients and may thereby impair glutamate and ACh function and, as a result, prefrontally-mediated cognitive behaviors. This hypothesis will be tested experimentally in the proposed project. Collectively, the experiments will a) provide new insights into the neurochemical effects of KYNA; b) explore the role of glial cells in the regulation of attention and cognitive flexibility; c) evaluate the construct validity of chronic elevations of KYNA in the brain for the study of SZ; and d) begin to examine whether treatment- induced reductions of KYNA levels in the brain constitute an efficacious strategy for the treatment of cognitive deficits in SZ.