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）：该项目的目标是提供原理证明，证明雌二醇介导的认知功能增强可以在（a）患有胆碱能损伤的年轻大鼠中，以及（b）在经历长期卵巢功能丧失的老年大鼠中恢复，通过用胆碱酯酶抑制剂治疗，从而增强大脑中的胆碱能活性。我们假设雌二醇对绝经后认知表现产生积极影响的关键时期是由基础前脑胆碱能投射的功能定义的（即，当胆碱能系统显着受损时，反应性丧失）。基于此，我们预测，即使在卵巢功能长期丧失后，通过药理学增强胆碱能系统（例如通过使用胆碱酯酶抑制剂）也将重新打开机会之窗并恢复反应性。使用选择性免疫毒素192IgG-皂草素（SAP）和我们实验室建立的方法，在年轻的卵巢切除大鼠中产生内侧隔膜和布罗卡对角带中胆碱能神经元的选择性损伤。这些大鼠将接受特定剂量的多奈哌齐或加兰他敏（常用于治疗阿尔茨海默氏病的胆碱酯酶抑制剂）、有或没有雌二醇的治疗，然后使用体内微透析和行为训练进行研究。还将评估在 3 个月大时切除卵巢，然后在 12 个月大时用多奈哌齐或加兰他敏（含或不含雌二醇）治疗的老年大鼠。所有大鼠都将接受两项认知任务的训练，即延迟位置匹配（DMP）T 迷宫任务和配置关联（CA）操作条件反射任务。体内微透析将用于测量对海马乙酰胆碱释放的影响。还将测量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，作为胆碱能去神经支配程度的指标。我们的预测是，在患有胆碱能损伤的大鼠和老年大鼠中，雌二醇的作用将通过胆碱酯酶抑制剂治疗而恢复，并且这些作用将与 AChE 抑制和海马中乙酰胆碱的释放相关。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增强认知能力的能力，无论是在基础前脑胆碱能功能受损的年轻大鼠中，还是在卵巢功能长期丧失的老年大鼠中。公共健康相关性人类和动物数据表明，激素治疗相对于更年期的时机对于确定治疗是否会对大脑衰老和认知产生有益影响至关重要。我们假设雌二醇对绝经后认知表现产生积极影响的关键时期是由基础前脑胆碱能投射的功能定义的（即，当胆碱能系统显着受损时，反应性丧失）。基于这一假设，我们预测，通过药理学增强胆碱能系统（例如，通过使用胆碱酯酶抑制剂）将重新打开机会之窗，恢复激素治疗对认知能力的有益影响（a）患有胆碱能损伤的年轻大鼠，以及（b）长期丧失卵巢功能的老年大鼠。该试点项目将为这一假设提供原理证明。积极的结果将确定一种机制来解释为什么绝经后激素治疗的时机至关重要，并且将为多年未使用激素治疗的绝经后妇女恢复激素治疗的有效性提供可行的策略。