Homeostatic control of hippocampal synaptic transmission

在海马体中，一个涉及学习、记忆和空间导航的大脑区域，神经元之间的突触连接经历强度变化的能力显示了昼夜节律。海马突触可塑性的这一特性表明，形成新记忆的能力也是在一天中动态调节的。海马功能的每日变化与激素的循环水平相关，如褪黑激素和皮质类固醇。 该项目研究这些激素如何有助于神经元，星形胶质细胞的昼夜节律功能，构成大脑中重要的非神经元细胞类型，以及海马突触不同集合的兴奋性传递。了解这些细胞和分子机制对于理解为什么以及如何在一天中调节记忆形成至关重要。 除了推进海马功能的基本方面的知识，该项目提供了跨学科的研究机会，为本科生，特别是来自代表性不足的少数民族学生。该项目还将公众参与作为一项核心活动，使受训者的家人和朋友能够了解研究环境，从而对许多第一代大学生的生活产生切实影响。许多研究已经确定了不同形式的神经元可塑性的分子基础，但对与神经元密切相互作用的不同类型的胶质细胞（星形胶质细胞）的可塑性知之甚少。哺乳期下丘脑的星形胶质细胞发生了深刻的形态学变化，越来越多的证据表明星形胶质细胞的重塑比以前认为的要普遍得多。星形胶质细胞与突触的紧密联系和神经递质转运蛋白的丰富表达使其能够有力地控制突触传递和可塑性。 然而，目前对这些细胞如何调节海马体中的兴奋性突触传递以及它们的调节如何在一天中变化的知识有限。该项目的总体目标是：（i）确定神经元和星形胶质细胞重塑的分子触发器;以及（ii）确定这些重塑形式如何在不同的突触组中塑造突触传递。中心假设是星形胶质细胞重塑改变了CA 1锥体细胞近端与远端兴奋性输入的重量。确定海马中突触传递和可塑性的昼夜节律调节的分子机制，特别是星形细胞在其中发挥的作用，将促进对大脑活动受非神经递质调节的复杂机制的理解。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准。

In the hippocampus, a brain region involved in learning, memory, and spatial navigation, the ability of synaptic connections between neurons to undergo changes in strength shows circadian rhythmicity. This property of hippocampal synaptic plasticity suggests that the ability to form new memories similarly is regulated dynamically over the course of the day. The daily changes in hippocampal function correlate with cycling levels of hormones, such as melatonin and corticosteroids. This project examines how these hormones contribute to the circadian functionality of neurons, astrocytes, which constitute an important non-neuronal cell type in brain, and excitatory transmission at different sets of hippocampal synapses. Understanding these cellular and molecular mechanisms is crucial for understanding why and how memory formation is modulated across the course of the day. In addition to advancing knowledge of fundamental aspect of hippocampal function, this project provides inter-disciplinary research opportunities for undergraduate students, especially students from under-represented minorities. The project also includes public engagement as a core activity and allows for the trainees’ families and friends to learn about the research environment, thereby making a tangible impact on the lives of many first-generation college students. Numerous studies have identified the molecular underpinnings of different forms of neuronal plasticity, but much less is known about the plasticity of distinct types of glial cells that closely interact with neurons: astrocytes. Astrocytes undergo profound morphological changes in the hypothalamus during lactation, and a growing body of evidence indicates that astrocyte remodeling is much more common than previously thought. Their close proximity to synapses and abundant expression of neurotransmitter transporters allow astrocytes to powerfully control synaptic transmission and plasticity. Yet, there currently is limited knowledge of how these cells modulate excitatory synaptic transmission in the hippocampus, and how their modulation varies across the course of the day. The overall objectives of this project are to: (i) identify the molecular trigger(s) of neuron and astrocyte remodeling; and (ii) determine how these forms of remodeling shape synaptic transmission at different sets of synapses. The central hypothesis is that astrocyte remodeling changes the weight of proximal versus distal excitatory inputs in CA1 pyramidal cells. Identification of the molecular mechanisms that underlie circadian regulation of synaptic transmission and plasticity in the hippocampus and, in particular, the role that astrocytic cells play therein, will advance understanding of the complex mechanisms through which brain activity is modulated by non-neuronal cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.