Hilar mossy cells and dentate gyrus function

肺门苔藓细胞和齿状回功能

• 批准号: 9321241
• 负责人: Helen E Scharfman
• 金额: $ 38.52万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321241
• 关键词: Address; Adult; Affect; Alpha Cell; Anatomy; Area; Axon; Behavior; Behavioral; Brain Injuries; Cells; Data; Detection; Disease; Distal; Dorsal; Electrophysiology (science); Elements; Enterobacteria phage P1 Cre recombinase; Epilepsy; FOS gene; Functional disorder; Glutamates; Hilar; Image; Impairment; In Vitro; Injury; Interneurons; Light; Location; Memory; Mental disorders; Microelectrodes; Mus; Neurologic; Neurons; Parahippocampal Gyrus; Pathologic; Pathway interactions; Pattern; Plasticizers; Play; Preparation; Publishing; Research Personnel; Role; Slice; Source; Synapses; Testing; Traumatic Brain Injury; activity marker; aging brain; behavioral impairment; cell injury; cell type; cognitive function; dentate gyrus; entorhinal cortex; experimental study; granule cell; immunoreactivity; in vivo; injured; nervous system disorder; neurogenesis; novel; optogenetics; patch clamp; relating to nervous system; response; tool; voltage; young adult

ABSTRACT Mossy cells (MCs) of the dentate gyrus (DG) are glutamatergic neurons that are considered to be important to normal function and their injury has been suggested to contribute to neurological and psychiatric disorders, as well as deficits after traumatic brain injury. Anatomical and slice electrophysiology studies have described MCs in detail, but there is a gap between these studies and understanding how MCs contribute to DG-dependent behavior in vivo. To address this issue, we began with a simple approach: mice were engaged in behaviors related to DG function, and MCs were examined afterwards using the neural activity marker c-fos. We quickly found that simply exploring novel objects led to a large increase in MC c-fos immunoreactivity (ir). Interestingly, most c- fos-ir did not increase in most of the other DG neurons, suggesting preferential activation of MCs by novelty. However, there was one area of the DG where c-fos-ir was consistent: a subset of GCs in dorsal DG. In contrast, the majority of MCs with c-fos-ir were ventral. Because the main projection of ventral MCs is to dorsal GCs, these data suggest that ventral MCs excite dorsal GCs. This circuitry helps explain how normally quiescent GCs become activated in dorsal DG, which is considered essential for cognitive functions of the DG. In Aim 1 we will use optogenetics to test this hypothesis, taking advantage of new mouse lines that have targeted Cre recombinase to MCs. We will also ask if dorsal MCs have effects analogous to ventral MCs, i.e., dorsal MCs contribute to ventral DG functions. In Aim 2 the underlying circuitry will be addressed. We suggest that optogenetic excitation of MCs in a normal adult mouse will recapitulate the results with c-fos: MCs excite proximal GCs weakly but distal GCs in a more robust manner. This idea has been supported by data from slices that were cut at an angle to preserve MC axons, and will be tested further in Aim 2 using voltage imaging and microelectrodes. In Aim 3 we will address the hypothesis that a large number of the distal GCs that are activated by MCs are immature. That hypothesis supports a previously published study showing that MCs are a primary source of afferent input to young GCs that are born in adulthood. This is potentially important because immature GCs are considered central to DG functions. Therefore, we will address the additional hypothesis that MCs activate adult-born GCs primarily in distal locations, leading to stronger excitation of distal GCs than proximal GCs. By providing afferent input to immature GCs, MCs could play a critical role in behaviors associated with adult DG neurogenesis. Together these experiments will significantly advance our understanding of DG circuitry and its contribution to behavior. Because MC injury is associated with several disorders, these experiments will also shed light on impairments in DG functions in those pathological conditions.

摘要 齿状回（DG）的苔藓细胞（MC）是海马能神经元，被认为是 重要的正常功能和他们的损伤已被认为有助于神经和 精神疾病以及创伤性脑损伤后的缺陷。解剖和切片 电生理学研究已经详细描述了MC，但这些研究之间存在差距， 了解MC如何促进体内DG依赖性行为。为了解决这个问题，我们 从一个简单的方法开始：小鼠参与与DG功能相关的行为， 随后使用神经活性标记物c-fos进行检查。我们很快发现， 探索新的物体导致MC c-fos免疫反应性（IR）的大幅增加。有趣的是，大多数C- 在大多数其他DG神经元中，fos-ir没有增加，这表明MCs的优先激活是由 新奇然而，DG中有一个区域的c-fos-ir是一致的： 背侧DG相反，大多数具有c-fos-ir的MC位于腹侧。因为主投影 腹侧MCs对背侧GCs的兴奋程度最高，提示腹侧MCs对背侧GCs的兴奋程度最高。该电路 有助于解释正常静止的GC如何在背侧DG中被激活， 对DG的认知功能至关重要。在目标1中，我们将使用光遗传学来验证这一假设， 利用将Cre重组酶靶向MC的新小鼠品系。我们也会问，如果 背侧MC具有与腹侧MC类似的作用，即，背侧MC参与腹侧DG 功能协调发展的在目标2中，将讨论潜在的电路。我们认为光遗传学激发 在正常成年小鼠中的MCs将概括c-fos的结果：MCs激发近端GC 弱但远端GC以更稳健的方式。这一想法得到了切片数据的支持 以一定角度切割以保留MC轴突，并将在目标2中使用电压进行进一步测试 成像和微电极。在目标3中，我们将讨论一个假设，即大量的 被MC激活的远端GC是不成熟的。这一假设支持了先前发表的一项研究。 一项研究表明，MC是出生于下丘脑的年轻GC的传入输入的主要来源。 成年这是潜在的重要性，因为不成熟的GC被认为是DG的核心 功能协调发展的因此，我们将解决额外的假设，即MC激活成人出生的GC 主要在远端位置，导致远端GC比近端GC更强的激发。通过 作为向未成熟GC提供传入输入的一种方式，MC在与以下行为相关的行为中发挥着关键作用： 成年DG神经发生。这些实验将大大促进我们对 DG电路及其对行为的贡献。由于MC损伤与几种疾病有关， 这些实验也将揭示在DG功能的损害，在那些病理性 条件