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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。谷氨酸和γ-氨基丁酸（GABA）是包括下丘脑在内的中枢神经系统（CNS）大部分区域中的两种主要快神经递质（分别为兴奋性和抑制性）。它们共同在控制神经元的活性和兴奋性方面发挥关键作用，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、局部缺血和心跳呼吸停止期间，人海马和大脑皮层中含有谷氨酸的投射神经元发生选择性变性。我们以前的实验表明，慢性阻断离子型谷氨酸受体显着增加乙酰胆碱（ACh）神经传递在大鼠下丘脑神经元培养的表达。ACh活性的增加，谷氨酸兴奋的减少与ACh受体的上调。这证明了NMDA谷氨酸受体阻断剂（而非非NMDA受体阻断剂或活性依赖性机制）对诱导胆碱能活性的重要作用。此外，数据表明，在下丘脑培养物中没有谷氨酸兴奋时，另一种兴奋性神经递质Ach支持兴奋/抑制平衡。因此，我们假设，在长期减少谷氨酸兴奋在下丘脑神经元的文化，乙酰胆碱，这通常表现出一个弱的活动在下丘脑，开始发挥作用的主要兴奋性神经递质，并支持兴奋/抑制平衡。我们还假设，在谷氨酸兴奋的情况下，兴奋性乙酰胆碱传输的增加是一种形式的神经元可塑性，调节活动和兴奋性的神经元在谷氨酸/GABA的不平衡。在我们未来的研究中，我们将解决谷氨酸依赖性调节ACh传输的Ca 2+机制，在没有谷氨酸兴奋的情况下，是一种形式的神经元可塑性，调节神经元的活动和兴奋性，在谷氨酸/GABA失衡。在我们未来的研究中，我们将解决钙离子的谷氨酸依赖性调节乙酰胆碱在下丘脑在体外传输的机制。

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.