Restoration of Estradiol Effects on Learning by Cholinergic Enhancement

通过胆碱能增强恢复雌二醇对学习的影响

• 批准号: 7583364
• 负责人: ROBERT B GIBBS
• 金额: $ 18.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7583364
• 关键词: Acetylcholine; Acetylcholinesterase; Ache; Age; Age-Months; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animals; Behavioral; Brain; Brain Injuries; Characteristics; Choline O-Acetyltransferase; Cholinergic Agents; Cholinesterase Inhibitors; Cognition; Cognitive; Data; Denervation; Diagonal Band of Broca; Dose; Effectiveness; Estradiol; Estrogens; Galantamine; Goals; Hippocampus (Brain); Human; Immunotoxins; Impaired cognition; Laboratories; Learning; Lesion; Measures; Medial; Mediating; Menopause; Methods; Microdialysis; Motivation; Neurodegenerative Disorders; Operant Conditioning; Ovarian; Ovariectomy; Performance; Pilot Projects; Positioning Attribute; Postmenopause; Public Health; Rattus; Relative (related person); System; Testing; Therapeutic; Time; Training; Woman; aged; aging brain; animal data; basal forebrain; base; cholinergic; cholinergic neuron; cognitive function; critical developmental period; donepezil; experience; frontal lobe; hormone therapy; improved; in vivo; indexing; juvenile animal; prevent; research study; response; restoration; treatment effect

DESCRIPTION (provided by applicant): The goal of this project is to provide proof of principle that estradiol-mediated enhancement of cognitive function can be restored (a) in young rats with cholinergic lesions, and (b) in aged rats that have undergone long-term loss of ovarian function, by treating with a cholinesterase inhibitor and thereby enhancing cholinergic activity in the brain. We hypothesize that the critical period for eliciting positive effects of estradiol on cognitive performance post menopause is defined by the functionality of basal forebrain cholinergic projections (i.e., responsiveness is lost when the cholinergic system becomes significantly impaired). Based on this, we predict that enhancing the cholinergic system pharmacologically (e.g., via the use of cholinesterase inhibitors) will re-open the window of opportunity and restore responsiveness, even after prolonged loss of ovarian function. Selective lesions of cholinergic neurons in the medial septum and diagonal band of Broca will be produced in young ovariectomized rats using the selective immunotoxin 192IgG-saporin (SAP) and methods established in our laboratory. These rats will be treated with specific doses of donepezil or galantamine (cholinesterase inhibitors commonly used in the treatment of Alzheimer's disease), with and without estradiol, and then studied using in vivo microdialysis and behavioral training. Aged rats that are ovariectomized at 3 month of age, and then treated at 12 months of age with donepezil or galantamine with and without estradiol, will also be evaluated. All rats will be trained on two cognitive tasks, a delayed matching-to-position (DMP) T-maze task, and a configural association (CA) operant conditioning task. In vivo microdialysis will be used to measure effects on acetylcholine release in the hippocampus. Levels of choline acetyltransferase and acetylcholinesterase activities in the hippocampus and frontal cortex also will be measured as indices of the degree of cholinergic denervation. Our prediction is that in rats with cholinergic lesions, and in aged rats, effects of estradiol will be restored by treatment with the cholinesterase inhibitors, and that these effects will correlate with AChE inhibition and with acetylcholine release in the hippocampus. This would provide proof of principle that enhancing cholinergic activity in the brain can reinstate the ability of estradiol to enhance cognitive performance both in young rats with impaired basal forebrain cholinergic function, and in aged rats that have undergone long-term loss of ovarian function. PUBLIC HEALTH RELEVANCE Both human and animal data suggest that the timing of hormone therapy relative to menopause is critical for determining whether therapy will have a beneficial effect on brain aging and cognition. We hypothesize that the critical period for eliciting positive effects of estradiol on cognitive performance post menopause is defined by the functionality of basal forebrain cholinergic projections (i.e., responsiveness is lost when the cholinergic system becomes significantly impaired). Based on this hypothesis, we predict that enhancing the cholinergic system pharmacologically (e.g., via the use of a cholinesterase inhibitor) will re-open the window of opportunity and restore beneficial effects of hormone therapy on cognitive performance (a) in young rats with cholinergic lesions, and (b) in aged rats that have undergone long-term loss of ovarian function. This pilot project will provide proof of principal for this hypothesis. Positive results would identify a mechanism to explain why the timing of hormone therapy post menopause is critical, and would provide a viable strategy for restoring the effectiveness of hormone therapy in postmenopausal women who have not used hormone therapy for many years.

描述（由申请人提供）：该项目的目的是提供原理证明，表明雌激素病变的年轻大鼠可以恢复雌二醇介导的认知功能的增强（a），以及（b）在具有长期长期卵巢功能的老年大鼠中，通过使用胆碱酯酶抑制蛋白抑制作用来治疗卵巢功能的长期丧失。我们假设，引起雌二醇对更年期后认知绩效的积极影响的关键时期是由基底前脑胆碱能投影的功能定义的（即，当胆碱能系统显着受损时，响应性丧失）。基于此，我们预测，即使在卵巢功能长期丧失之后，即使在胆碱酯酶抑制剂的使用中，增强胆碱能系统的药理（例如，通过使用胆碱酯酶抑制剂）也将重新打开机会窗口并恢复反应性。使用选择性免疫毒素192igg-saporin（SAP）和我们的实验室中建立的方法，将在幼年切除大鼠的内侧隔膜和对角线带中的胆碱能神经元的选择性病变。这些大鼠将用特定剂量的多奈哌兹尔或甘氨酸（通常用于治疗阿尔茨海默氏病的胆碱酯酶抑制剂），有或没有雌二醇，然后使用体内微透析和行为训练进行研究。还将评估在3个月大时进行卵巢切除术的老年大鼠，然后在有和没有雌二醇的情况下用多奈哌齐或甘氨酸在12个月大时进行治疗。所有大鼠将接受两个认知任务，延迟匹配对位（DMP）T-Maze任务以及配置关联（CA）操作调理任务的训练。体内微透析将用于测量海马中乙酰胆碱释放的影响。海马和额叶皮层中胆碱乙酰转移酶和乙酰胆碱酯酶活性的水平也将作为胆碱能神经疗法程度的指标进行测量。我们的预测是，在患有胆碱能病变的大鼠中，在老年大鼠中，雌二醇的作用将通过用胆碱酯酶抑制剂进行治疗来恢复，并且这些作用将与ACHE抑制作用，并与Hippocampus中的乙酰胆碱释放相关。这将提供原理证明，即增强大脑中的胆碱能活性可以恢复雌二醇在基础前脑胆碱能功能受损的年轻大鼠中增强认知性能的能力，以及在经历长期卵巢功能的长期损失的老年大鼠中。人类和动物的数据都表明，相对于更年期的激素治疗的时间对于确定治疗是否对脑衰老和认知产生有益影响至关重要。我们假设，引起雌二醇对更年期后认知绩效的积极影响的关键时期是由基底前脑胆碱能投影的功能定义的（即，当胆碱能系统显着受损时，响应性丧失）。基于这一假设，我们预测，通过使用胆碱酯酶抑制剂来增强胆碱能系统（例如，通过使用胆碱酯酶抑制剂）将重新开放机会窗口并恢复激素治疗对年轻鼠的认知性能（a）对年轻鼠对胆碱疗法的幼鼠的有益作用（a），而胆碱能病变的长期损失了。该试点项目将为这一假设提供本金证明。积极的结果将确定一种机制来解释为什么更年期激素治疗的时间至关重要，并将为恢复激素治疗在多年未使用激素治疗的绝经后妇女中的有效性提供可行的策略。