Glutamate-Dependent Regulation of Acetylcholine Activity

神经元之间通过化学物质和神经递质进行交流。谷氨酸是中枢神经系统(CNS)中主要的快速兴奋性神经递质，由某些神经元分泌并激活其他神经元。在胚胎发育和某些病理状态下，中枢神经系统谷氨酸活性降低。最近的研究表明，在谷氨酸活性长期下降的过程中，另一种不太占优势的兴奋性神经递质乙酰胆碱(ACh)的活性显著增加。有人推测，在缺乏谷氨酸的情况下，ACh在中枢某些区域起主要的兴奋性神经递质的作用。然而，谷氨酸活性降低时提高ACh活性的机制尚未被研究。它们将在拟议的研究中进行研究。使用从大脑下丘脑区获得的神经元培养，将检验两个假设。第一种假设是，在谷氨酸活性下降期间，分泌谷氨酸的神经元改变了它们的表型，开始分泌ACh。第二种假设认为，表型的改变是由于细胞内钙离子内流减少和某些细胞内钙信号通路失活所致。谷氨酸是中枢神经系统中一种主要的兴奋性神经递质，参与大脑的许多功能，了解谷氨酸活性降低时神经网络功能的调节机制是非常重要的。ACH传输率的增加可能是其中一种机制。本项目致力于研究神经元可塑性的基本机制，以及在谷氨酸兴奋减少时神经元回路中神经元活动的调节。

Neurons communicate with each other through chemical substances, neurotransmitters. Glutamate is the predominant fast excitatory neurotransmitter in the central nervous system (CNS) that is secreted by some neurons and activates other neurons. A decreased level of glutamate activity can be found in the CNS during embryonic development and during some pathological conditions. Recent studies indicate that during a long-term decrease in glutamate activity, the activity of another less predominant excitatory neurotransmitter, acetylcholine (ACh), is dramatically increased. It was hypothesized that in the absence of glutamate, ACh plays the role of the major excitatory neurotransmitter in some regions of the CNS. However, the mechanisms that increase ACh activity when glutamate activity is decreased have not yet been studied. They will be studied in the proposed research. Using neuronal cultures obtained from the hypothalamic region of the brain, two hypotheses will be tested. The first hypothesis is that during a decrease in glutamate activity neurons that secrete glutamate change their phenotype and begin to secrete ACh. The second hypothesis is that the change in phenotype is due to the decrease in Ca2+ influx to the neurons and the inactivation of certain intracellular Ca2+ signaling pathways. Since glutamate is a major excitatory neurotransmitter in the CNS and is involved in many functions of the brain, it is very important to know the mechanisms that regulate the functions of neuronal networks when glutamate activity is decreased. Increased ACh transmission is likely one of such mechanisms. This project addresses the investigation of the fundamental mechanisms of neuronal plasticity and the regulation of neuronal activity that can take place in neuronal circuits during a decrease in glutamate excitation.