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

描述(申请人提供)：我们的记忆力随着年龄的增长而变化。与年龄相关的记忆力下降本身就代表着对公共健康的重大影响，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。研究神经认知老化将有助于我们更好地描述大脑一生中的病理性和非病理性变化，并识别认知衰退的临床前标志。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，以及它的神经基础。像我们之前的项目一样，这个建议主要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具体假设。在我们之前的资助期间，我们几乎只关注海马体，展示了与年龄相关的海马体电路中断，这与在啮齿动物中发现的一样，并展示了这些变化如何影响特定类型的记忆。特别是，我们展示了人类海马齿状回如何凭借其执行模式分离的非凡能力，即相互隔离相似记忆的能力，关键地参与情景记忆。我们还展示了这种回路是如何在衰老过程中逐渐被破坏的，以及这如何与与年龄相关的记忆细节或情节成分的丧失有关。该项目的一个目标是广泛地建立在我们开创并在该领域被广泛采用的行为任务的基础上，以便我们能够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下降最敏感的行为任务。由于这种丢失不仅限于海马体，还包括邻近内侧颞叶皮质和前额叶皮质的变化，我们建议详细研究这些区域及其与海马体相互作用的变化。在这里，我们再次大量借鉴啮齿类动物的神经生物学发现，以测试关于大脑周围皮质等区域年龄相关变化的具体假设，并评估海马体和前额叶年龄相关记忆变化的功能贡献和相互关系的变化。像我们之前的工作一样，我们计划从一大批成年人中收集一套全面的行为和神经成像数据。通过收集每个参与者的一套广泛的衡量标准，我们可以检查原本不可能的相互关系。除了我们自己的具体问题和假设外，广泛的一套测量(包括对我们以前工作中的参与者的纵向评估)对其他研究人员将是有价值的。像以前一样，我们将使数据的所有组成部分广泛提供给其他人。

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.