High-Resolution Structural and Functional Brain Imaging of Medial Temporal Lobe i

描述（由申请人提供）：我们的记忆随着年龄的增长而变化。与年龄相关的记忆力衰退本身就对公众健康产生了重大影响，但认知能力下降——尤其是记忆力下降——已被证明是阿尔茨海默病（AD）的一个重要风险因素。检查神经认知老化将帮助我们更好地描述整个生命周期中大脑的病理和非病理变化，并确定认知衰退的临床前标志物。这个项目将我们之前的工作扩展到与年龄相关的记忆衰退的确切性质及其神经基础。就像我们之前的项目一样，这个建议大量利用衰老的动物模型和记忆的计算模型来测试与年龄相关的记忆衰退的特定假设。在我们之前的资助时期，我们几乎只关注海马体，证明了与年龄相关的海马体回路的破坏与啮齿动物的相似，并证明了这些变化是如何影响特定类型的记忆的。特别是，我们展示了人类海马体齿状回是如何通过其执行模式分离的特殊能力，或将彼此相似的记忆分离出来的能力，来关键地参与情景记忆的。我们还展示了这个回路是如何随着年龄的增长而逐渐被破坏的，以及它是如何与年龄相关的记忆细节或情景成分的丧失联系在一起的。该项目的一个目标是在我们已经开创并在该领域被广泛采用的行为任务的基础上进行广泛的构建，这样我们就可以开发并从神经生物学上验证一整套对海马体功能和与年龄相关的认知衰退最敏感的行为任务。由于这种损失并不局限于海马体，还包括邻近的内侧颞叶皮层和前额叶皮层的变化，我们建议详细检查这些区域的变化及其与海马体的相互作用。在这里，我们再次大量引用了啮齿动物的神经生物学发现，以测试有关周围皮层等区域的年龄相关变化的特定假设，并评估海马和前额叶年龄相关的记忆变化的功能贡献和相互关系。像我们之前的工作一样，我们建议从大量成年人样本中收集一套全面的行为和神经成像数据。通过收集关于每个参与者的一系列广泛的措施，我们可以检查相互关系，否则这是不可能的。除了我们自己的具体问题和假设之外，广泛的测量方法（包括对我们之前工作中的参与者的纵向评估）对其他研究人员也很有价值。和以前一样，我们将向其他人广泛提供数据的所有组成部分。

DESCRIPTION (provided by applicant): Our memory changes as we age. Age-related memory decline in and of itself represents a significant public health impact, but cognitive decline - and in particular memory decline - has been shown to be an important risk factor for Alzheimer's Disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. This project extends our prior work into the exact nature of age-related memory decline and into its neural bases. Like our prior project, this proposal draws heavily on animal models of aging and computational models of memory to test specific hypotheses about age-related memory decline. In our prior funding period, we focused almost exclusively on the hippocampus, demonstrating age- related disruptions in the hippocampal circuit that parallel those found in the rodent and demonstrating how these changes affect specific kinds of memory. In particular, we showed how the human hippocampal dentate gyrus is critically involved in episodic memory by virtue of its exceptional capacity for performing pattern separation, or the ability to isolate similar memories from each other. We also showed how this circuit is disrupted gradually over the course of aging and how this is linked to age-related loss of the detail or episodic components of a memory. One goal of the project is to build extensively on the behavioral tasks that we have pioneered and that are being widely adopted in the field so that we can develop and neurobiologically validate an entire suite of behavioral tasks that are maximally sensitive to hippocampal function and to age- related cognitive decline. As this loss is not confined to the hippocampus, but includes changes in the adjacent medial temporal lobe cortices and in the prefrontal cortex, we propose to examine in detail changes in these regions and in their interactions with the hippocampus. Here again we draw heavily on neurobiological findings from the rodent to test specific hypotheses about age-related changes in regions like the perirhinal cortex and to assess changes in the functional contributions of and interrelationship between hippocampal and prefrontal age-related changes in memory. Like our prior work, we propose to collect a comprehensive suite of behavioral and neuroimaging data from a large sample of adults. By collecting an extensive set of measures on each participant, we can examine interrelationships that would otherwise be impossible. In addition to our own specific questions and hypotheses, the extensive set of measures (which includes longitudinal assessment of participants from our prior work) will be valuable to other researchers. As before, we will make all components of the data widely available to others.