Chronic Pain Induces Hypomyelination: A Causal Mechanism for Brain Circuitry Desynchronization and Impaired Decision Making.

Using well established visceral hypersensitive (VH) rat model of colonic anaphylaxis, our previous electrophysiological studies using multiple-electrode array recordings have demonstrated that functional disturbances in basolateral amygdala (BLA)-anterior cingulate cortex (ACC) neural circuitry in chronic pain. However, the biological mechanism has not been investigated. Myelin is a modifiable structure regulating neural network synchrony and information transmission. Defects in myelin biosynthesis and structure would affect the precise interactions and synchronization between brain regions. Oligodendroglia are particularly susceptible to excitotoxicity induced by inflammation. In the current proposal we will show an increase in the levels of pro-inflammatory cytokines in the ACC. Performing studies of immunohistochemistry, confocal and TEM microscopy we will determine decrease of myelin basic protein, oligodendrocyte precursor cells, mature oligodendrocytes, and ACC myelin thickness in VH. Consistent with our previous reports, the decision-making deficits in VH will be confirmed. To ensure that myelination is necessary for the synchronization of ACC circuitry and cognitive function lysolecithin-induced demyelination will be performed to mimicking the impairments observed in chronic visceral pain. Clemastine is a leading drug candidate for myelin formation approved by Food and Drug Administration. Next, we plan to expand recent report that the dysregulation of interactions between BLA and ACC associated with impaired decision making in VH rats were repairs by administration of clemastine. Astrocytes function as cellular mediators of myelination and remyelination of oligodendrocytes by releasing various factors (PDGF, FGF2, CNTF, LIF, etc). In astrocytes, glycogen is catabolized to lactate. Notice, myelinating oligodendrocytes also release lactate through the monocarboxylate transporter MCT1. Oligodendrocytes utilize lactate as a metabolite. Finally, we will focus on using optogenetic activation of astrocytes to test our hypotheses that astrocyte -lactate-oligodendrocyte supply promotes oligodendrogenesis and adaptive myelination. We expect to show that local infusion of lactate and optogenetic stimulation of astrocytes could release lactate, which is able to repair the dysfunction of ACC network and rescue impaired decision making under pain state suggesting astrocytic lactates supply plays a critical role in modulating spike timing accuracy of ACC neuronal network and cognition. The HMRF Reviewer’s concern on our model regarding the causes or consequence of pain–desynchrony–demyelination vs. pain ̶̶ demyelination ̶̶ desynchrony has clearly addressed. Understanding the mechanism of hypomyelination leads to desynchronization in ACC circuitry and impairs cognition in chronic visceral pain state could facilitate the identification of potential therapeutic targets in the brain cortex for cognitive deficits for human chronic visceral pain.