Functional Organization of the Hippocampal Formation

描述（由申请人提供）：海马结构是大脑内侧颞叶记忆系统的重要组成部分，允许个体对有关其生活片段的信息进行编码。关于成熟大脑中调节这一功能的连接网络，我们已经知道得很多。齿状回、海马和下托通过穿通通路接受来自内嗅皮层的主要信息，这可能是情景记忆形成的“原材料”。内嗅皮质，反过来，有显着的双向连接与几个多感觉皮质区显着包括嗅周，海马旁和压后皮质。这种神经解剖学表明，海马体主要使用高度加工的多感觉信息来产生记忆，并可能将编码信息存储在这些多感觉皮层中。关于海马结构在任何物种中的发育的研究都非常少，在人类和非人类灵长类动物中的研究就更少了。如果这些信息是可用的，它可能会提供一些见解，为什么人类通常无法记住他们三岁之前的生活片段。在妊娠19-22周时观察到向人类海马区和下托的内嗅投射（Hevner和Kinney，1996），尽管没有关于纤维投射的成熟模式何时发育的可用证据。在前一个资助期间，我们证明了一个基本上成年模式的穿孔路径连接建立在新生恒河猴。我们现在建议将这些研究扩展到胎儿脑，以确定何时首次在恒河猴中建立穿孔通路，以及何时以及如何成熟为成年模式。我们现在也准备开始对发育中的人类海马结构进行分析，这方面的信息非常有限。我们建议将我们的非人灵长类动物的研究扩展到人类大脑进行定量，体视学分析的细胞数量和体积增加的海马结构在整个生命周期。最后，我们建议启动一个新的程序的结构/功能分析的出生后发展中的恒河猴海马结构进行纵向磁共振成像（MRI）分析的大脑发育中的恒河猴其次是行为评估他们的记忆能力。我们之前发现，发育正常的儿童海马体的总体积在4.5立方厘米到6.5立方厘米之间，这些儿童海马体的大小与他们的智商密切相关。这表明海马体越大，记忆功能越好。但是，一个人天生就有一个更大的海马体，还是海马体从丰富的成长中受益？另外，如果单个海马体更大，这是因为有更多的神经元，还是神经元有更复杂的连接？我们将使用恒河猴模型来探讨这些先天/后天问题。 公共卫生相关性： 海马体是大脑记忆系统的一部分，它使人们能够记住他们生活中的片段。关于海马体如何发育的信息很少。但是，很明显，它容易受到胎儿生命期间，出生期间和出生后不久发生的各种创伤的影响。这些研究将为人类和恒河猴的海马体如何发育提供新的信息。新的信息将对整个生命周期的正常认知功能以及癫痫、学习障碍和易患阿尔茨海默病等疾病产生影响。

DESCRIPTION (provided by applicant): The hippocampal formation is an important component of the brain's medial temporal lobe memory system that allows individuals to encode information about episodes of their lives. Much is known about the network of connections that mediates this function in the mature brain. The dentate gyrus, hippocampus and subiculum receive major inputs from the entorhinal cortex via the perforant path. This is likely the "raw material" from which episodic memories are made. The entorhinal cortex, in turn, has prominent bidirectional connections with several polysensory cortical regions prominently including the perirhinal, parahippocampal and retrosplenial cortices. This neuroanatomy suggests that the hippocampus makes memories mainly using highly processed, multisensory information and likely stores the encoded information in these very same polysensory cortices. There are remarkably few studies of the development of the hippocampal formation in any species, and even fewer in man and in the nonhuman primate. If this information were available, it might provide some insights into why humans are typically unable to remember episodes of their lives prior to three years of age. Entorhinal projections to the human hippocampal fields and subiculum are observed by 19-22 weeks of gestation (Hevner and Kinney, 1996) though there is no available evidence concerning when the mature pattern of fiber projections is developed. During the previous funding period, we demonstrated that an essentially adult pattern of perforant path connections is established in the newborn rhesus monkey. We now propose to extend these studies to the fetal brain to determine when the perforant path is first established in the rhesus monkey and when and how it matures to an adult pattern. We are also now prepared to start an analysis of the developing human hippocampal formation for which there is only very limited information. We propose to extend our nonhuman primate studies to the human brain by carrying out quantitative, stereological analyses of cell number and volume increases of the hippocampal formation throughout the lifespan. Finally, we propose to initiate a new program of structure/function analyses of the postnatally developing hippocampal formation in the rhesus monkey by carrying out a longitudinal magnetic resonance imaging (MRI) analysis of the brains of developing rhesus monkeys followed by behavioral assessments of their memory capacity. We had previously found that the total volume of the hippocampus in typically developing children ranges in size from 4.5 cm3 to 6.5 cm3 and that the size of the hippocampus in these children was strongly correlated with their IQ. This would suggest that a larger hippocampus predicts better memory function. But, is one born with a larger hippocampus or does the hippocampus benefit from an enriched upbringing? Also, if an individual hippocampus is larger, is this because there are more neurons, or neurons that have more elaborate connections? We will explore these nature/nurture questions using the rhesus monkey model. PUBLIC HEALTH RELEVANCE: The hippocampus is part of the brain's memory system that allows individuals to remember episodes of their lives. There is very little information about how the hippocampus develops. But, it is clear that it is vulnerable to a variety of traumas that occur during fetal life, during birth and shortly after birth. These studies will provide new information on how the hippocampus develops in humans and in rhesus monkeys. The new information will have implications for normal cognitive function through the lifespan and for disorders such as epilepsy, learning disabilities and the vulnerability to Alzheimer's disease.