Functional Organization of the Hippocampal Formation

描述(申请人提供)：海马体结构是大脑内侧颞叶记忆系统的重要组成部分，允许个人编码关于他们生活事件的信息。关于在成熟大脑中调节这一功能的连接网络，我们知道得很多。齿状回、海马体和下丘脑经穿支通路接受内嗅皮层的主要输入。这很可能是构成情节记忆的“原材料”。反过来，内嗅觉皮质与几个多感觉皮质区域有显著的双向联系，这些区域主要包括大脑周围皮质、海马旁皮质和脾后皮质。这种神经解剖学表明，海马体主要使用经过高度处理的多感觉信息来产生记忆，并可能将编码信息存储在这些完全相同的多感觉皮质中。在任何物种中，关于海马体结构发育的研究都非常少，在人类和非人类灵长类动物中就更少了。如果这些信息是可用的，它可能会提供一些洞察力，解释为什么人类通常无法记住三岁之前的生活片段。内嗅觉投射到人的海马区和下丘脑区是在妊娠19-22周时观察到的(Hevner和Kinney，1996)，尽管没有可用的证据来说明纤维投射的成熟模式是什么时候发展起来的。在之前的资助期间，我们证明了在新生恒河猴中建立了一种基本上是成人的穿通径连接模式。我们现在建议将这些研究扩展到胎儿大脑，以确定穿孔路径何时在恒河猴身上首次建立，以及它何时和如何成熟到成年模式。我们现在也准备开始对发育中的人类海马体结构进行分析，关于它的信息非常有限。我们建议将我们的非人类灵长类动物的研究扩展到人脑，方法是对海马体结构在整个生命周期中的细胞数量和体积增加进行定量的体视学分析。最后，我们建议启动一个新的程序，通过对发育中的恒河猴的大脑进行纵向磁共振成像(MRI)分析，然后对其记忆能力进行行为评估，对出生后发育的恒河猴的海马体结构进行结构/功能分析。我们之前发现，在典型发育儿童中，海马体的总体积大小在4.5厘米~6.5厘米之间，而且这些儿童的海马体大小与他们的智商密切相关。这表明较大的海马体预示着更好的记忆功能。但是，海马体是与生俱来的，还是海马体受益于丰富的成长？另外，如果一个单独的海马体更大，是因为有更多的神经元，还是因为神经元有更复杂的连接？我们将使用恒河猴模型来探索这些先天/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，允许个人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，它很容易受到发生在胎儿时期、出生期间和出生后不久的各种创伤的影响。这些研究将为人类和恒河猴的海马体发育提供新的信息。这些新信息将对人的一生中的正常认知功能以及癫痫、学习障碍和阿尔茨海默病的易感性等疾病产生影响。

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.