Abstract
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.
Highlights
Major depressive disorder (MDD) is a prevalent mental illness linked to diminished quality of life and increased mortality
Genetic and chemical manipulation of dopaminergic neurons confirmed that ketamine needed intact dopamine signals to work, and revealed that it acted indirectly on dopamine dynamics via another brain region called the medial prefrontal cortex
To define the function of midbrain DA neurons during aversive learning, we used a variant of learned helplessness (LH) (Chourbaji et al, 2005)
Summary
Major depressive disorder (MDD) is a prevalent mental illness linked to diminished quality of life and increased mortality. Genetic and chemical manipulation of dopaminergic neurons confirmed that ketamine needed intact dopamine signals to work, and revealed that it acted indirectly on dopamine dynamics via another brain region called the medial prefrontal cortex. These results shed new light on how a promising new anti-d epressant works. Ketamine ameliorates depressive-like behaviors in animal models of acute and prolonged stress (Duman et al, 2016; Duman and Aghajanian, 2012; Fuchikami et al, 2015; Harmer et al, 2017; Krishnan and Nestler, 2011), and rescues escape actions in response to aversive stimuli after LH induction (Belujon and Grace, 2014). Combining fiber photometry, anatomical tracing, and chemogenetics, we find that mPFC serves as an action site of ketamine to restore DA dynamics and escape actions
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