Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis
M Wu, S Minkowicz, V Dumrongprechachan, P Hamilton, L Xiao, Y Kozorovitskiy
bioRxiv Preprint Server March 11, 2020 preprint DOI: 10.1101/2020.03.11.987818 via bioRxiv
Summary
AI-generated from the abstractProlonged stress can lead to maladaptive learning, but the antidepressant ketamine can restore escape behavior in a learned helplessness paradigm. Dopamine neuron activity in the ventral tegmental area changes systematically during aversive learning and predicts future sensitivity to ketamine treatment. Ketamine's effects depend on dopamine signaling, as chemogenetic inhibition blocks them and optogenetic activation mimics them. In the medial prefrontal cortex, ketamine recovers dendritic spine formation on pyramidal neurons in a dopamine-dependent manner, reversing stress-induced reductions. These findings reveal circuits linking dopamine dynamics, aversive learning, and plasticity enhancements driven by ketamine.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Intervention | Ketamine |
| Topics | Neuroplasticity |
| Keywords | Psychological stress Chronic stress Maladaptive learning Brain health Psychiatric conditions |
| Citations | 3 |
| Key finding | Ketamine restores escape behavior after aversive learning by acting through dopamine-dependent mechanisms that recover dendritic spine plasticity in the medial prefrontal cortex. |
Abstract
Escaping aversive stimuli is essential for complex organisms, but prolonged exposure to stress leads to maladaptive learning. Stress alters plasticity, neuromodulatory signaling, and neuronal activity in distributed networks, yet the field lacks a unifying framework for its varied consequences. Here we describe neuromodulatory and plasticity changes following aversive learning by using a learned helplessness paradigm, where ketamine restores escape behavior. Dopaminergic neuron activity in the ventral tegmental area systematically varies across learning, correlating with future sensitivity to ketamine treatment. Ketamine’s effects are blocked by chemogenetic inhibition of dopamine signaling and mimicked by optogenetic activation. We use 2-photon glutamate uncaging/imaging to interrogate structural plasticity in medial prefrontal cortex, revealing that dendritic spinogenesis on pyramidal neurons is both regulated by aversive experience and recovered by ketamine in a dopamine-dependent manner. Together, these data describe recurrent circuits that causally link neuromodulatory dynamics, aversive learning, and plasticity enhancements driven by a therapeutically promising antidepressant.