Role of the medial septum in perseverative behaviors

描述（由申请人提供）：毅力是面对导致生产力下降的变化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。海马接收来自内侧隔膜的有影响力的输入，主要来自胆碱能和gaba能神经元。海马体和内侧隔膜共同构成了一个系统，该系统促进了行为和认知的灵活性，从而控制了持久性行为。然而，中隔参与这一重要功能的机制和神经元尚不清楚。基于我们之前的结果，我们假设gaba能内侧间隔神经元对行为灵活性至关重要。gaba能内侧间隔神经元的损伤被认为会增强主动干扰，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，并专注于逆转学习。目的1和2将利用免疫细胞化学和体内微透析来描述这种新的gaba能毒素对内侧隔膜的影响。目的3将研究gaba能损伤在几种任务转换形式中增强主动干扰的程度。目的4将利用即时早期基因、c-fos和电生理学的激活来研究反转学习和规则转移中各种MSDB神经元的激活。目的5将测试两种可能的机制来解释gaba能MSDB损伤后持久性增加的原因。这些研究的结果将有助于更好地理解海马隔区系统对行为灵活性、持久性和主动干预的作用机制。由于内隔和海马体与许多具有持续性行为的疾病有关，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方面的进展。公共卫生相关性：持久性行为可以在衰老、药物滥用、阿尔茨海默病、精神分裂症、强迫症和自闭症中发现。了解与毅力有关的大脑机制将提高我们治疗或预防这些疾病中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.