Attenuated dopamine signaling after aversive learning is restored by ketamine to rescue escape actions

eLife

Vasin Dumrongprechachan¹  Lei Xiao¹  Samuel Minkowicz¹  Pauline Hamilton¹  Mingzheng Wu¹  Yevgenia Kozorovitskiy¹ 

[1] Department of Neurobiology, Northwestern University, Evanston, United States;

关键词: dopamine;    aversive learning;    ketamine;    mPFC;    VTA;    Mouse;   

DOI  :  10.7554/eLife.64041

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY