Ketamine restores escape behavior by re-engaging dopamine systems to drive cortical spinogenesis
bioRxiv Preprint Server – March 11, 2020
Source: bioRxiv
Summary
Prolonged stress can impair the brain's ability to adapt and escape difficult situations. Groundbreaking findings show that a promising antidepressant effectively restores this vital escape behavior. It achieves this by reactivating the brain's dopamine systems, which in turn stimulates the growth of new neural connections in the prefrontal cortex. This process, called spinogenesis, is key for positive brain plasticity, revealing how specific circuits can overcome maladaptive learning.
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.