Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
Transl Psychiatry. 2020 May 18;10(1):154. doi: 10.1038/s41398-020-0837-3.
Stress increases the risk of neuropsychiatric disorders, such as major depression. Exposure to stress has been reported to induce various neuronal changes, such as alterations in synaptic transmission and structure. However, a causal link between stress-induced neural circuit alterations and changes in emotional behaviours is not well understood. In the present study, we focused on a projection pathway from the orbitofrontal cortex (OFC) to the basolateral nucleus of the amygdala (BLA) as a crucial circuit for negative emotions and examined the effect of stress on OFC-BLA excitatory synaptic transmission using optogenetic and whole-cell patch-clamp methods in mice. As a stress-inducing procedure, we used repeated tail-shock, which increased stress-related behaviours. We found greater α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-D-aspartate current ratios and insertion of calcium-permeable AMPA receptors (AMPARs) in the OFC-BLA synapse after stress. These stress-induced synaptic and behavioural changes were reduced by a blockade of protein kinase A, which plays a principal role in stress-induced targeting of AMPARs into the synaptic membrane. To examine a possible causal relationship between alterations in synaptic transmission in the OFC-BLA pathway and stress-related behaviour, we performed optogenetic activation or chemogenetic inactivation of OFC-BLA transmission in mice. We found that optogenetic activation and chemogenetic inactivation of OFC-BLA transmission increased and decreased stress-related behaviour, respectively. In conclusion, we have demonstrated that stress altered the postsynaptic properties of the OFC-BLA pathway. These synaptic changes might be one of the underlying mechanisms of stress-induced behavioural alterations.
压力会增加患神经精神疾病的风险，例如重度抑郁症。据报道，暴露于压力下会引起各种神经元变化，例如突触传递和结构的改变。然而，压力引起的神经回路改变与情绪行为变化之间的因果关系尚不清楚。在本研究中，我们专注于眶额叶皮层 (OFC) 到杏仁基底外侧核 (BLA) 的投射通路作为负性情绪的关键回路，并使用光遗传学和全细胞膜片钳方法在小鼠中研究了应激对 OFC-BLA 兴奋性突触传递的影响。作为一种诱导应激的程序，我们使用重复尾部电击，这会增加与应激相关的行为。我们发现应激后 OFC-BLA 突触中 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA)/N-甲基-D-天冬氨酸电流比值和钙通透性 AMPA 受体 (AMPAR) 的插入增加。应激诱导的突触和行为变化可通过阻断蛋白激酶 A 来减少，蛋白激酶 A 在应激诱导 AMPAR 靶向突触膜中起主要作用。为了研究 OFC-BLA 通路中突触传递改变与应激相关行为之间的可能因果关系，我们在小鼠中进行了 OFC-BLA 传递的光遗传学激活或化学遗传学失活。我们发现，OFC-BLA 传递的光遗传学激活和化学遗传学失活分别增加和减少了与应激相关的行为。总之，我们已经证明应激改变了 OFC-BLA 通路的突触后特性。这些突触变化可能是应激引起行为改变的潜在机制之一。
