PROJECT 2-Network properties of entorhinal/dentate gyrus and CA3 region in behaviorally-characterized aged rats

项目 2-行为特征老年大鼠内嗅/齿状回和 CA3 区的网络特性

• 批准号: 8935171
• 负责人: Michela Gallagher
• 金额: $ 34.02万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8935171
• 关键词: Address; Adult; Aftercare; Age; Aging; Animal Model; Animals; Biological Preservation; Brain; Clinical; Cognition; Cognitive; Complement; Data; Dose; Elements; Equilibrium; Exhibits; Failure; Functional Imaging; Funding; Hilar; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Individual Differences; Interneurons; Label; Laboratory Animals; Lateral; Levetiracetam; Long-Evans Rats; Maintenance; Medial; Mediating; Memory; Memory impairment; Methodology; Methods; Modeling; Molecular; Mus; Neurobiology; Neurocognitive; Neurons; Newborn Infant; Outcome; Patients; Pattern; Perforant Pathway; Performance; Placebo Control; Placebos; Play; Population Study; Procedures; Property; Rabies virus; Rattus; Research; Rodent Model; Role; Shapes; Somatostatin; Steam; System; Temporal Lobe; Testing; Therapeutic; Therapeutic Intervention; Time; Tracer; Transfection; Translations; Work; age related; aged; aging brain; basal forebrain; basal forebrain cholinergic neurons; base; cholinergic; cognitive capacity; cognitive function; cohort; comparison group; dentate gyrus; entorhinal cortex; granule cell; improved; in vivo; information processing; insight; mild cognitive impairment; molecular marker; neurocognitive disorder; neurophysiology; novel; older patient; programs; relating to nervous system; research study; synaptic function; young adult

Studies in outbred Long Evans rats have contributed to the identification of a neurobiological basis for cognitive impairment in the aged brain of otherwise healthy laboratory animals. Within the medial temporal lobe memory system the selective loss of perforant path connections and an altered condition of the network it innervates in the dentate gyrus (DG) and CA3 region are hallmarks of rats that age with memory impairment. In contrast, that network is relatively maintained in aged rats with preserved cognitive function, including anatomical integrity of the perforant path and a balance of computational properties for pattern separation and pattern completion in DG/CA3 that resembles young adults. A unique feature of this network is the integration of new DG neurons in the adult brain. No studies have yet examined that integration in the context of brain aging. The proposed research in Project 2 will complement studies in the other projects by examining whether the integration of newly DG generated neurons aligns with individual differences in cognitive outcomes. Unimpaired aged rats, consistent with young adults may show a predominant role for the lateral entorhinal cortex (LEC) in the integrating network. Because the circuit integration of new DG neurons involves other elements that strongly differentiate cognitive outcomes, such as hilar interneurons, CA3 neurons, and basal forebrain cholinergic projections, we will determine whether a broad difference in the circuit integration of new DG neurons occurs in impaired and unimpaired aged rats. In addition to a better understanding of the basis for age-related impairment, the findings will be informative about the condition of the aged brain that maintains a high-level of cognitive capacity, e.g. testing the hypothesis that such animals (but not impaired aged cohorts) integrate a complement of new DG neurons in a manner similar to young. Additional studies in this project will further test whether an impoverished integration in impaired aged rats can be improved by a therapeutic treatment that has been shown to boost molecular markers in key monosynaptic afferents in the entorhinal cortex and DG/hilus. Those findings, together with studies in Project 1 and 3, will address an emerging hypothesis in this research program that a failure through the LEC steam of information processing disproportionately contributes to memory impairment in the aged brain. Alongside better maintenance of those properties in aged unimpaired rats, research in this model suggests that adjustments in the aging brain, which are distinct from young adults, contribute to preserving cognitive function. Project 2 will further examine whether unimpaired aged rats engage greater inhibitory control over the entorhinal/DG/CA3 network as suggested by our findings. Neural overactivity in the brains of impaired aged rats, and a parallel condition detected by functional imaging in studies of human aging/MCI suggest that recruitment of inhibitory control in unimpaired aged rats could play an adaptive beneficial role in neurocognitive aging.

对远交Long Evans大鼠的研究有助于确定认知功能障碍的神经生物学基础。 在其他健康的实验室动物的老化大脑中的损伤。在内侧颞叶记忆中 系统的穿孔路径连接的选择性损失和它所支配的网络的改变的条件 齿状回（DG）和CA3区域是具有记忆损伤的衰老大鼠的标志。与此相反， 该网络在具有保留的认知功能的老年大鼠中相对维持，包括解剖学功能。 穿孔路径的完整性和图案分离和图案的计算特性的平衡 在DG/CA3完成类似于年轻人。该网络的一个独特之处在于， 成年人大脑中的DG神经元。还没有研究在大脑老化的背景下研究这种整合。 项目2的拟议研究将与其他项目的研究相辅相成， 新DG产生的神经元的整合与认知结果的个体差异一致。 未受损的老年大鼠，与年轻成年人一致，可能显示出外侧内嗅的主导作用。 皮层（LEC）在整合网络中的作用。由于新DG神经元的电路整合涉及其他神经元， 强烈区分认知结果的元素，如门部中间神经元，CA3神经元和基底神经元， 前脑胆碱能投射，我们将确定是否在电路整合的新的广泛差异 DG神经元存在于受损和未受损的老年大鼠中。除了更好地了解基础之外， 与年龄有关的损害，研究结果将提供有关老年大脑状况的信息， 高水平的认知能力，例如，检验这类动物（但非受损老年队列） 以类似于年轻的方式整合新DG神经元的补充。本项目的其他研究将 进一步测试是否可以通过治疗来改善受损老年大鼠中的贫乏整合 治疗已被证明可以提高内嗅神经中关键单突触传入神经的分子标记物， 皮质和DG/门。这些研究结果以及项目1和项目3中的研究将解决一个新出现的 假设在这个研究计划中，一个失败通过LEC流的信息处理 不成比例地导致老年大脑的记忆障碍。除了更好地维护这些 在老年未受损大鼠中，对该模型的研究表明， 与年轻人不同，有助于保持认知功能。项目2将进一步研究 未受损的老年大鼠是否对内嗅/DG/CA3网络进行更大的抑制控制， 根据我们的发现。受损老年大鼠大脑中的神经过度活动，以及一种平行条件 在人类衰老/MCI研究中通过功能成像检测到的结果表明， 未受损老年大鼠在神经认知老化中可能发挥适应性有益作用。