Department of Psychiatry, Yale University School of Medicine, 34 Park Street, 3rd Floor Research, New Haven, CT, 06508, USA.
Interdepartmental Neuroscience Program, Yale University School of Medicine, 34 Park Street, 3rd Floor Research, New Haven, CT, 06508, USA.
Mol Psychiatry. 2022 Dec;27(12):4918-4927. doi: 10.1038/s41380-022-01749-7. Epub 2022 Sep 1.
The balance between excitatory and inhibitory (E/I) signaling is important for maintaining homeostatic function in the brain. Indeed, dysregulation of inhibitory GABA interneurons in the amygdala has been implicated in human mood disorders. We hypothesized that acetylcholine (ACh) signaling in the basolateral amygdala (BLA) might alter E/I balance resulting in changes in stress-sensitive behaviors. We therefore measured ACh release as well as activity of calmodulin-dependent protein kinase II (CAMKII)-, parvalbumin (PV)-, somatostatin (SOM)- and vasoactive intestinal protein (VIP)-expressing neurons in the BLA of awake, behaving male mice. ACh levels and activity of both excitatory and inhibitory BLA neurons increased when animals were actively coping, and decreased during passive coping, in the light-dark box, tail suspension and social defeat. Changes in neuronal activity preceded behavioral state transitions, suggesting that BLA activity may drive the shift in coping strategy. In contrast to exposure to escapable stressors, prolonging ACh signaling with a cholinesterase antagonist changed the balance of activity among BLA cell types, significantly increasing activity of VIP neurons and decreasing activity of SOM cells, with little effect on CaMKII or PV neurons. Knockdown of α7 or β2-containing nAChR subtypes in PV and SOM, but not CaMKII or VIP, BLA neurons altered behavioral responses to stressors, suggesting that ACh signaling through nAChRs on GABA neuron subtypes contributes to stress-induced changes in behavior. These studies show that ACh modulates the GABAergic signaling network in the BLA, shifting the balance between SOM, PV, VIP and CaMKII neurons, which are normally activated coordinately during active coping in response to stress. Thus, prolonging ACh signaling, as occurs in response to chronic stress, may contribute to maladaptive behaviors by shifting the balance of inhibitory signaling in the BLA.
兴奋和抑制（E/I）信号之间的平衡对于维持大脑的内稳态功能很重要。事实上，杏仁核中抑制性 GABA 中间神经元的失调与人类情绪障碍有关。我们假设基底外侧杏仁核（BLA）中的乙酰胆碱（ACh）信号可能会改变 E/I 平衡，导致应激敏感行为的变化。因此，我们在清醒、行为的雄性小鼠的 BLA 中测量了 ACh 释放以及钙调蛋白依赖性蛋白激酶 II（CAMKII）、parvalbumin（PV）、somatostatin（SOM）和血管活性肠肽（VIP）表达神经元的活性。当动物在明暗箱、悬尾和社交挫败中积极应对时，ACh 水平和兴奋性和抑制性 BLA 神经元的活性均增加，而在被动应对时则降低。神经元活性的变化先于行为状态的转变，这表明 BLA 活性可能驱动应对策略的转变。与暴露于可逃避的应激源不同，用胆碱酯酶抑制剂延长 ACh 信号会改变 BLA 细胞类型之间的活性平衡，显著增加 VIP 神经元的活性，降低 SOM 细胞的活性，对 CaMKII 或 PV 神经元的影响很小。在 PV 和 SOM 中的α7 或β2 包含型 nAChR 亚型中敲低，而不是在 CaMKII 或 VIP 中，BLA 神经元改变了对应激源的行为反应，这表明 ACh 通过 GABA 神经元亚型上的 nAChR 信号传递有助于应激诱导的行为变化。这些研究表明，ACh 调节 BLA 中的 GABA 能信号网络，改变 SOM、PV、VIP 和 CaMKII 神经元之间的平衡，这些神经元通常在积极应对应激时协同激活。因此，像在慢性应激中那样延长 ACh 信号可能会通过改变 BLA 中抑制性信号的平衡导致适应不良的行为。
