Selective impairment of circuits between prefrontal cortex glutamatergic neurons and basal forebrain cholinergic neurons in a tauopathy mouse model.
Selective impairment of circuits between prefrontal cortex glutamatergic neurons and basal forebrain cholinergic neurons in a tauopathy mouse model.
复制标题
tau蛋白病小鼠模型中前额叶皮层谷氨酸能神经元和基底前脑胆碱能神经元之间回路的选择性损伤。
DOI：
10.1093/cercor/bhac036
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Yan,Zhen
中科院分区：
文献类型：
--
作者：
Zhong,Ping;Cao,Qing;Yan,Zhen
阿尔茨海默病（AD）是一种普遍的神经退行性疾病，与认知能力下降有关。为了了解AD中特定神经元回路是如何受损的，我们利用光遗传学和电生理学方法揭示了脑损伤小鼠模型中前额叶皮质（PFC）和基底前脑（BF）这两个控制认知过程的关键区域之间的功能变化。我们发现P301S Tau小鼠（6-8月龄）BF胆碱能神经元的谷氨酸能突触反应明显减弱。在AD模型中，PFC到BF的远程通路减弱，显著增加了PFC谷氨酸末端光遗传刺激引发BF胆碱能神经元动作电位发射的失败率，而PFC到杏仁核和纹状体等其他区域的投射基本不变。另一方面，BF对胆碱能末端的光遗传刺激引起Tau小鼠PFC锥体神经元兴奋性的持续降低，而不是野生型小鼠的短暂性降低。综上所述，这些数据揭示了脑损伤小鼠模型中PFC锥体神经元和BF胆碱能神经元之间通路的选择性畸变。这种电路缺陷可能是AD患者注意力和执行功能丧失的基础。
Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder linked to cognitive decline. To understand how specific neuronal circuits are impaired in AD, we have used optogenetic and electrophysiological approaches to reveal the functional changes between prefrontal cortex (PFC) and basal forebrain (BF), 2 key regions controlling cognitive processes, in a tauopathy mouse model. We found that the glutamatergic synaptic responses in BF cholinergic neurons from P301S Tau mice (6–8 months old) were markedly diminished. The attenuated long-range PFC to BF pathway in the AD model significantly increased the failure rate of action potential firing of BF cholinergic neurons triggered by optogenetic stimulations of glutamatergic terminals from PFC. In contrast, the projection from PFC to other regions, such as amygdala and striatum, was largely unaltered. On the other hand, optogenetic stimulation of cholinergic terminals from BF induced a persistent reduction of the excitability of PFC pyramidal neurons from Tau mice, instead of the transient reduction exhibited in wild-type mice. Taken together, these data have revealed a selective aberration of the pathway between PFC pyramidal neurons and BF cholinergic neurons in a tauopathy mouse model. This circuit deficit may underlie the loss of attention and executive function in AD.