Intrusive thinking: Circuit and synaptic mechanisms of a transdiagnostic psychiatric symptom

Spontaneous thought is an adaptive cognitive process that can produce novel and insightful thought sequences useful in guiding future behavior. In many psychiatric disorders, spontaneous thinking becomes intrusive and uncontrolled, and can trigger symptoms such as craving, repetitive negative thinking and trauma-related memories. We link studies using clinical imaging and rodent modeling towards understanding the neurocircuitry and neuroplasticity of intrusive thinking. We propose a framework in which drugs or stress change the homeostatic set point of brain reward circuitry, which then impacts subsequent plasticity induced by drug/stress conditioned cues (metaplastic allostasis). We further argue for the importance of examining not only the canonical pre- and postsynapse, but also the adjacent astroglial protrusions and extracellular matrix that together form the tetrapartite synapse and that plasticity throughout the tetrapartite synapse is necessary for cue-induced drug or stress behaviors. This analysis reveals that drug use or trauma cause long-lasting allostatic brain plasticity that sets the stage for subsequent drug/trauma-associated cues to induce transient plasticity that can lead to intrusive thinking.