Role of the medial septum in perseverative behaviors

描述（由申请人提供）：固执是面对导致生产力下降的变化时的持续反应或持续思考。它是衰老、阿尔茨海默病、药物滥用和各种精神健康障碍的显著特征。海马从内侧隔接受有影响的输入，主要来自胆碱能和GABA能神经元。海马体和内侧隔共同构成了一个系统，这个系统促进行为和认知的灵活性，从而控制了持续性行为。然而，内侧隔参与这一重要功能的机制和神经元尚不清楚。基于我们以前的研究结果，我们推测内侧隔GABA能神经元对行为灵活性起着关键作用。GABA能内侧隔神经元的损伤被假定为增强前摄干扰，导致持续性。拟议的研究将利用一种新的GABA能毒素来验证这一假设，并重点关注逆转学习。目的1和2将使用免疫细胞化学和体内微透析来表征这种新的GABA能毒素在内侧隔中的作用。目标3将研究GABA能损伤在多大程度上增强了几种形式的任务转换中的主动干扰。目的4将研究激活的各种MSDB神经元在逆转学习和规则转换使用立即早期基因，c-fos，和电生理学的激活。目标5将测试两种可能的机制，以解释GABA能MSDB损伤后持续性增加。这些研究的结果将提供一个更好的理解的机制，隔海马系统有助于行为的灵活性，坚持和积极的干预。由于内侧隔和海马参与了许多具有持续行为的疾病，因此从拟议的研究中获得的信息可能会导致其治疗和预防的进展。公共卫生相关性：在衰老、药物滥用、阿尔茨海默病、精神分裂症、强迫症和自闭症中可以发现顽固行为。了解与持续性行为有关的大脑机制将提高我们治疗或预防这些疾病中一个非常衰弱的组成部分的能力。

DESCRIPTION (provided by applicant): Perseveration is the continued response or persistent thought in the face of change that leads to diminished productivity. It is a notable feature of aging, Alzheimer's disease, drug abuse and various mental health disorders. The hippocampus receives influential input from the medial septum, predominantly from cholinergic and GABAergic neurons. Together, the hippocampus and medial septum are part of a system that fosters behavioral and cognitive flexibility, and as a result controls perseverative behaviors. However, the mechanism and neurons of the medial septum that are involved in this important function are unclear. Based on our previous results, it is hypothesized that the GABAergic medial septal neurons are critical for behavioral flexibility. Damage of the GABAergtic medial septal neurons is postulated to enhance proactive interference, resulting in perseveration. The proposed studies will test this hypothesis utilizing a novel GABAergic toxin and focusing on reversal learning. Aims 1 and 2 will characterize the effects of this new GABAergic toxin in the medial septum using immunocytochemistry and in vivo microdialysis. Aim 3 will examine the extent to which GABAergic damage enhances proactive interference in several forms of task switching. Aim 4 will investigate the activation of the various MSDB neurons in reversal learning and rule shifting using activation of the immediate early gene, c-fos, and electrophysiology. Aim 5 will test two possible mechanisms to account for the increased perseveration following GABAergic MSDB damage. The results of these studies will provide a better understanding of the mechanisms by which the septohippocampal system contributes to behavioral flexibility, perseveration and proactive interference. Because the medial septum and hippocampus are involved in a number of disorders with perseverative behaviors, the information gained from the proposed studies may lead to advances in their treatment and prevention. PUBLIC HEALTH RELEVANCE: Perseverative behaviors can be found in aging, drug abuse, Alzheimer's disease, schizophrenia, obsessive compulsive disorders and autism. Understanding the brain mechanisms involved in perseveration will advance our ability to treat or prevent a very debilitating component of these disorders.