COBRE: TU: PROJ 2: MECHANISMS OF ACETYLCHOLINE PLASTICITY IN HYPOTHALAMUS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。谷氨酸和γ -氨基丁酸（GABA）是两种主要的快速神经递质（分别为兴奋性和抑制性），存在于中枢神经系统（CNS）的大多数区域，包括下丘脑。它们共同在控制神经元的活动和兴奋性中发挥关键作用，并决定许多神经元回路中的突触兴奋/抑制平衡。在癫痫、阿尔茨海默病、缺血和心肺骤停期间，人类海马和大脑皮层中含有谷氨酸的突出神经元发生选择性变性。我们之前的实验表明，长期阻断嗜离子性谷氨酸受体可显著增加大鼠下丘脑神经元培养中乙酰胆碱（ACh）神经传递的表达。谷氨酸兴奋减弱后乙酰胆碱活性的增加与乙酰胆碱受体的上调有关。这证明了NMDA谷氨酸受体阻断（但不是非NMDA受体阻断或活性依赖机制）在诱导胆碱能活性中的重要作用。此外，数据表明，在下丘脑培养缺乏谷氨酸兴奋的情况下，乙酰胆碱，另一种兴奋性神经递质，支持兴奋/抑制平衡。因此，我们假设在下丘脑神经元培养中谷氨酸兴奋的长期下降过程中，通常在下丘脑中表现出弱活性的乙酰胆碱开始发挥主要兴奋性神经递质的作用，并支持兴奋/抑制平衡。我们还假设，在没有谷氨酸兴奋的情况下，兴奋性乙酰胆碱传递的增加是一种神经元可塑性的形式，在谷氨酸/GABA失衡期间调节神经元的活动和兴奋性。在我们未来的研究中，我们将研究谷氨酸依赖调节乙酰胆碱传递的Ca2+机制，在没有谷氨酸兴奋的情况下，谷氨酸依赖调节乙酰胆碱传递是一种神经元可塑性的形式，在谷氨酸/GABA失衡期间调节神经元的活性和兴奋性。在我们未来的研究中，我们将在体外研究谷氨酸依赖性调节下丘脑乙酰胆碱传递的Ca2+机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glutamate and gamma-aminobutyric acid (GABA) are two major fast neurotransmitters (excitatory and inhibitory, respectively) in most regions of the central nervous system (CNS), including the hypothalamus. Together, they play a key role in the control of the activity and excitability of neurons and determine the synaptic excitation/inhibition balance in many neuronal circuits. Selective degeneration of glutamate-containing projecting neurons occurs in the human hippocampus and cerebral cortex during epilepsy, Alzheimer's disease, ischemia, and cardiorespiratory arrest. Our previous experiments revealed that a chronic blockade of ionotropic glutamate receptors dramatically increased the expression of acetylcholine (ACh) neurotransmission in rat hypothalamic neuronal cultures. The increase in ACh activity following the decrease in glutamate excitation was associated with the up-regulation of ACh receptors. This demonstrates the important role of NMDA glutamate receptor blockade (but not non-NMDA receptor blockade or activity-dependent mechanisms) for the induction of cholinergic activity. Additionally, the data suggest that in the absence of glutamate excitation in hypothalamic cultures, Ach, another excitatory neurotransmitter, supports the excitation/inhibition balance. We therefore postulate that during a long-term decrease in the glutamate excitation in hypothalamic neuronal cultures, Ach, which normally exhibits a weak activity in the hypothalamus, begins to play the role of the major excitatory neurotransmitter and to support the excitation/inhibition balance. We also hypothesize that the increase in excitatory ACh transmission in the absence of glutamate excitation is a form of neuronal plasticity that regulates the activity and excitability of neurons during the glutamate/GABA imbalance. In our future research, we will address Ca2+ mechanisms of glutamate-dependent regulation of ACh transmission in the absence of glutamate excitation is a form of neuronal plasticity that regulates the activity and excitability of neurons during the glutamate/GABA imbalance. In our future research, we will address Ca2+ mechanisms of glutamate-dependent regulation of ACh transmission in the hypothalamus in vitro.