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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Intervention | Ketamine |
| Topics | Neuroplasticity Esketamine Ketamine |
| Keywords | Psychological stress Chronic stress Maladaptive learning Brain health Psychiatric conditions Mental well-being Spinogenesis Neural connections Brain adaptation Cognitive function Prefrontal cortex Antidepressant therapy Psychiatric medication Psychopharmacology Drug treatment Mental health treatment Therapeutic intervention Dopamine system Dopaminergic pathways Neurotransmitters Brain chemistry |
| Citations | 3 |
| Key findings | 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.