Functional changes in neural mechanisms underlying post-traumatic stress disorder in World Trade Center responders

Invernizzi, Azzurra; Rechtman, Elza; Curtin, Paul; Papazaharias, Demetrios M.; Jalees, Maryam; Pellecchia, Alison C.; Santiago-Michels, Stephanie; Bromet, Evelyn J.; Lucchini, Roberto; Luft, Benjamin J.; Clouston, Sean; Tang, Cheuk Y.; Horton, Megan

doi:10.1038/s41398-023-02526-y

Cited by 1 publication

(1 citation statement)

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“…Pioneering studies using neuroimaging approaches have identified functional changes in multiple brain areas, including the hippocampus, amygdala, anterior cingulate cortex (ACC), insular cortex, and ventromedial prefrontal cortex, in patients with PTSD. [ 4 , 5 ] However, the brain areas and circuits involved in abnormal fear memory extinction are poorly understood. Clinical studies have revealed no differences in the acquisition phase of memory in patients with PTSD, [ 6 , 7 ] suggesting the presence of specific areas beyond the well‐known memory control centers in the brain.…”

Section: Introductionmentioning

confidence: 99%

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model

Xiao,

Xi,

Wang

et al. 2023

Advanced Science

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Impaired extinction of fear memory is one of the most common symptoms in post‐traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD‐ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle‐based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD‐related impaired extinction of fear memory and provide therapeutic insights into Kv3.2‐targeted RNA therapy for PTSD.

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