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

Abstract

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.

Keywords: Astroglia; Brain imaging; Circuitry; Extracellular matrix; Intrusive thinking; PTSD; Resting state MRI; Substance use disorder; Tetrapartite synapse.

Figure 1.. Diagram illustrating the differences between adaptive transitions from spontaneous to deliberate thinking versus transitioning from spontaneous to intrusive thinking.

A) Overall organization of key brain areas into the default mode (DMN), salience mode (SN) and executive mode (ECN) networks. Note that the SN has substantial overlap with the DMN and ECN. B) Illustration of how increasing motivation and attention converts unrestrained spontaneous thoughts into constrained deliberate thinking through a hierarchical dominance of ECN connectivity over SN and DMN. C) In some psychiatric disorders, the ECN-dominant hierarchy is disrupted and the transition from spontaneous thinking is dominated by the SN, resulting in intrusive thinking. SN dominance over ECN is indicated by a more bold SN and a smaller, dashed ECN. MTL- medial temporal lobe, PFC- prefrontal cortex, VTA- ventral tegmental area

Figure 2.. Illustration of key brain circuitry at the SN – ECN interface.

This drawing is based on the rat atlas by Paxinos and Watson (Paxinos and Watson, 2007), and shows projections between the PFC (green), basolateral amygdala (BLA; red) and core and shell of the nucleus accumbens (NAcore and NAshell, respectively). Arrows are color coded according to PFC or BLA outputs and double headed arrows indicate reciprocal projections between two regions. ac- anterior commissure, cc- corpus callosum, CnA- central nucleus of the amygdala, ic- internal capsule, Pir- pyriform cortex

Figure 3.. The enduring metaplasticity and transient synaptic plasticity possibly underpinning intrusive thinking.

A) Addictive drug or stress exposure converts homeostatic plasticity into enduring allostatic metaplasticity, characterized after cocaine or stress as long-term potentiation (LTP) and after opioids as long-term depression (LTD). A subsequent drug or stress associated cue produces intrusive thinking (craving/rumination) and additional transient plasticity. The intrusive thinking terminates for example by actual drug use (relapse) and the allostatic condition of metaplasticity-induced vulnerability to intrusive thinking is restored. B) An illustration of a glutamatergic tetrapartite synapse in the NAcore during cue-induced sucrose seeking where astroglial metaplasticity is not induced by sucrose self-administration. Note the intact astroglial morphology and glutamate uptake via GLT-1. C) The state of metaplasticity after drug use or stress is characterized by astroglial down regulation of GLT-1 and withdrawal of the astroglia protrusions from synaptic proximity. D) The transient plasticity induced by a drug or stress cue that is necessary for cues to trigger drug, but not sucrose seeking. Glutamate spillover due to astroglial metaplasticity indirectly activates MMP-9 (see Figure 4), which catalytically liberates β3-integrin ligands from the ECM. Increased signaling through β3-integrin promotes spine head expansion and increased AMPA receptor signaling. In parallel, the astroglial actin binding protein ezrin is phosphorylated, causing a transient return of the astroglial protrusion to the synapse. FAK- focal adhesion kinase, GLT-1- astroglia-selective glutamate transporter, MMP- matrix metalloprotease (blue inactive, red active), RGD- arginine-glycine-aspartate

Figure 4.. Sequence of neurobiological events at NAcore glutamatergic synapses contributing to the cue-induced transient plasticity that underpins cue- or stress-induced drug seeking and possibly intrusive thinking.

The drug use or stress exposure induces metaplasticity in astroglia that makes the animal prone to drug/stress, not sucrose, cue-induced seeking. On this metaplastic background, the cue induces a sequence of signaling events involving presynaptic glutamate release and spillover from the synapse. The extrasynaptic glutamate stimulates mGluR5 receptors on nNOS interneurons to promote nitric oxide (NO) synthesis. Elevated extracellular NO promotes MMP-9 activation which catalyzes the formation of ligands in the ECM for β3-integrin receptors that produces postsynaptic transient potentiation. Red lettering refers to proven targets for disrupting transient tetrapartite synaptic plasticity and preventing cue-induced drug/stress, but not sucrose seeking.