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

对杂交的Long Evans大鼠的研究有助于确定认知的神经生物学基础 在其他方面健康的实验动物的老年大脑的损伤。在内侧颞叶记忆中 穿孔路径连接的选择性丢失以及它所处的网络状况的改变 齿状回(DG)和CA3区是记忆受损大鼠的特征。相比之下， 这种网络在认知功能保留的老年大鼠中相对保持，包括解剖学上的 穿孔剂路径的完整性以及用于图案分离和图案的计算特性的平衡 在DG/CA3中完成，类似于年轻人。该网络的一个独特功能是集成了新的 成人大脑中的DG神经元。目前还没有研究在大脑老化的背景下检验这种整合。 项目2的拟议研究将补充其他项目的研究，方法是检查 新产生的DG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，与年轻成年大鼠一致，可能显示出外侧内嗅觉的主要作用 整合网络中的皮层(LEC)。因为新的DG神经元的电路集成涉及其他 强烈区分认知结果的元素，如肺门中间神经元、CA3神经元和基底神经元 前脑胆碱能投射，我们将确定是否在新的回路整合中存在广泛的差异 DG神经元存在于受损和未受损的老年大鼠中。除了更好地理解 与年龄相关的损害，这一发现将有助于了解老年人大脑的状况， 高水平的认知能力，例如测试这类动物(但不损害老年群体)的假设 以类似于年轻的方式整合一组新的DG神经元。该项目中的其他研究将 进一步测试是否可以通过一种治疗方法改善受损老年大鼠的贫困整合 治疗已被证明提高了内嗅中关键的单突触传入的分子标记 皮质和DG/门。这些发现，连同项目1和3中的研究，将解决一个新兴的 这项研究计划中的假设是，通过LEC流的信息处理失败 不成比例地导致老年大脑中的记忆障碍。同时更好地维护这些 在老年未受损大鼠的特性中，该模型的研究表明，衰老大脑的调节，这 有别于年轻人，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觉/DG/CA3网络进行更大的抑制控制 我们的研究结果表明。受损老年大鼠大脑中的神经过度活动及其平行状态 功能成像在人类衰老/MCI研究中的检测表明，抑制控制在 未受损的老年大鼠在神经认知老化中可能起到适应性有益的作用。

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.