星型胶质细胞在脑功能成像负信号产生中的作用及机制研究

In functional brain imaging studies, the positive response signal usually indicates increases in oxygen consumption and cerebral blood flow while the negative signal usually indicates decreases in oxygen consumption and cerebral blood flow. Imaging information from the negative hemodynamic signal could provide important insights regarding the brain cognitive function, functional and anatomical organization of inhibitory circuits throughout the cerebral cortex. The study of mechanisms underlying the negative signal has received much attention recently. The existing research mainly interprets the negative signal as the neuronal inhibition. Study shows that astrocytic activity plays an important role in regulating regional cerebral blood flow. Selecting cats as the experimental objects, this project aims to explore the the role and mechanism of astrocytic activity in negative hemodynamic signal generation detected by intrinsic signal optical imaging..Research contents: ①Two different stimulus modes including electrical and optical stimulation will be used to evoke the positive and negative hemodynamic responses in cat visual cortex. By using two-photon imaging, we will study the difference in astrocyte calcium activity between positive and negative response regions. The difference in vascular activity between these two regions will also be revealed. ②We will analyze the relationship between the actrocyte calcium activity and vascular diameter changes at different cortical depths within the negative response region. ③By selectively blocking astrocytic responses, we will explore the vascular changes and cerebral blood volume and blood oxygenation changes in negative response region. ④We will investigate the different roles of astrocytic activity in negative signal generation by different stimulus modes. .Significance: Studies of this project are expected to provide references for the mechanisms underlying the negative functional brain imaging signals, thereby providing more information about what functional brain imaging can tell us.

在脑功能成像中，正、负信号指脑区氧耗和血流量的增加和减少。挖掘负信号中的成像信息在研究大脑认知功能、抑制性回路的功能和解剖组织等领域有重要意义，因此负信号的产生机制受到极大关注，已有的研究主要从神经元活动抑制角度来理解负信号产生机制。鉴于星型胶质细胞的活动在脑区血流量调控中起了重要作用，所以本项目以猫为实验动物，以内源性脑光学成像为研究对象，研究大脑皮层星型胶质细胞在负信号产生中的作用及机制。.研究内容：①分别采用电、光刺激模式诱发猫视觉皮层正、负响应，应用双光子成像技术，研究正、负响应区域的星型胶质细胞钙活动、血管活动差异。②研究皮层负响应区不同深度细胞钙活动和血管直径变化关系。③研究星型胶质细胞活动的抑制对皮层负响应区血管活动和血氧、血量信号的影响。④不同刺激模式下星型胶质细胞活动在负信号产生中作用的异同。.研究意义：为脑功能成像负信号产生机制提供理论依据，为脑功能成像提供更多的信息。

在脑功能成像中，正、负信号指脑区血流量的增加和减少。在电刺激或缺血造成的大脑皮层负响应中，神经元及星型胶质细胞钙信号如何变化，细胞活动与血流量减少的相互作用及机制还不是很清楚，星胶在电刺激引发皮层可塑性及神经调控中起多大作用也不清楚。.本项目研究了电、光刺激下的动物皮层正、负响应；基于缺血负响应模型研究了细胞、树突、树突棘及受体的形态和功能变化，神经网络功能变化，药物干预及血流增加发生正响应后皮层的恢复等问题；低频电刺激下星胶在皮层可塑性中的作用；高频电刺激下细胞的参数相关性及钙信号机制；从光学仿真角度改善双光子荧光内窥成像在深层组织的成像性能。.研究发现通过调整电刺激参数可以实现皮层正/负响应人工调控，有利于研究大脑正/负响应。利用双光子成像检测了缺血负响应中皮层血管分布和血流速度，负响应中神经细胞超兴奋，树突串珠样变化，树突棘缺失和扭曲，AMPA受体消失然后反射性增强，短时间内血流增加发生正响应后细胞树突、树突棘及受体恢复正常状态，避免脑损伤。低频小电流刺激引发不同深度星胶长时程非同步的钙上升，电生理记录发现诱发了皮层可塑性，而大电流刺激导致可塑性受损。电刺激引发的皮层可塑性与星胶的肾上腺素受体有关，其中电流强度大小至关重要。高频电刺激诱发星胶同步的钙活动，这一现象可能在大脑电刺激中广泛存在，星胶最优激活频率接近于深脑刺激普遍使用的130Hz，激活星胶需要较大电流和较长脉宽。与神经元不同胶质细胞钙信号无法跟随长时间电刺激。神经元钙信号反映直接的去极化和突触后效果，星胶钙活动与肾上腺素受体和代新型谷氨酸受体激活有关。基于双波长偏振不敏感超透镜的双光子内窥成像系统可以实现对小鼠皮质高分辨率超深成像，直接基于生物组织环境设计双波长共焦超透镜比在基于空气环境中设计的超透镜性能显着提高。.本研究帮助探索大脑皮层可塑性机制，揭示深脑电刺激中星胶的重要作用，为临床缺血等相关疾病的救治提供理论基础，有利于理解脑功能成像负响应中细胞活动变化及细胞-血管耦合机制，促进电刺激神经调控的应用。

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