Department of Neurobiology, Northwestern University, Evanston, United States.
Elife. 2021 Apr 27;10:e64041. doi: 10.7554/eLife.64041.
Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters neuronal activity and neuromodulatory signaling in distributed networks, modifying behavior. Here, we describe changes in dopaminergic neuron activity and signaling following aversive learning in a learned helplessness paradigm in mice. A single dose of ketamine suffices to restore escape behavior after aversive learning. Dopaminergic neuron activity in the ventral tegmental area (VTA) systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine's effects are blocked by chemogenetic inhibition of dopamine signaling. Rather than directly altering the activity of dopaminergic neurons, ketamine appears to rescue dopamine dynamics through actions in the medial prefrontal cortex (mPFC). Chemogenetic activation of Drd1 receptor positive mPFC neurons mimics ketamine's effects on behavior. Together, our data link neuromodulatory dynamics in mPFC-VTA circuits, aversive learning, and the effects of ketamine.
逃避厌恶刺激对复杂生物至关重要，但长期暴露于应激下会导致适应不良的学习。应激会改变分布式网络中的神经元活动和神经调质信号，从而改变行为。在这里，我们描述了在小鼠习得性无助范式中，厌恶学习后多巴胺能神经元活动和信号的变化。单次给予氯胺酮足以恢复厌恶学习后的逃避行为。腹侧被盖区（VTA）中的多巴胺能神经元活动在学习过程中系统地变化，与未来对氯胺酮治疗的敏感性相关。多巴胺信号的化学遗传抑制阻断了氯胺酮的作用。氯胺酮似乎不是通过直接改变多巴胺能神经元的活动，而是通过中前额叶皮层（mPFC）的作用来挽救多巴胺动力学。Drd1 受体阳性 mPFC 神经元的化学遗传激活模拟了氯胺酮对行为的影响。总之，我们的数据将 mPFC-VTA 回路中的神经调质动力学、厌恶学习和氯胺酮的作用联系起来。
