VNS-tone pairing alters brain proteins in Rett syndrome rat model
Findings may guide research into communication deficits in Rett
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Stimulating the vagus nerve, part of the autonomic nervous system that regulates involuntary functions, paired with sound tones, may support the development of future therapies for communication deficits in Rett syndrome.
Researchers found that VNS-tone pairing changed protein levels in the brain’s sound-processing region in a rat model of Rett syndrome, with many affected proteins involved in synaptic signaling — communication between nerve cells — and metabolism, processes that can be impaired in Rett.
“The molecular pathways identified here will guide future research in pharmaceutical intervention and act as biomarkers in an effort to alleviate the auditory processing deficits observed in Rett syndrome and ultimately improve communication,” the researchers wrote.
VNS may help shape auditory cortex activity
The study, “Vagus Nerve Stimulation Paired With Tones Alters the Auditory Cortex Proteome in a Rat Model of Rett Syndrome,” was published in Developmental Neurobiology.
Rett syndrome is a neurodevelopmental disorder that mostly affects girls. In roughly 95% of cases, it’s caused by a mutation in the MeCP2 gene, which regulates the activity of other genes involved in brain development and the communication between brain cells.
After 6 to 18 months of apparently typical development, children experience a regression characterized by language loss, seizures, and sensory processing problems. According to caregivers, the lack of effective communication is the most impactful concern across the lifespan.
Prior research has shown that the auditory cortex, the part of the brain that processes sound, plays a substantial role in communication deficits present in Rett syndrome.
Because the loss of MeCP2 affects the activity of other genes, and thus the levels of many proteins, researchers performed a broad analysis of protein levels, known as the proteome, in the auditory cortex of a rat model of Rett syndrome.
Some rats from the Rett syndrome model were treated with vagus nerve stimulation (VNS) paired with tones. VNS refers to applying mild electrical impulses to the vagus nerve. This large nerve runs through the neck and is part of the autonomic nervous system, which controls involuntary functions in the body.
Tone pairing may promote brain plasticity
In VNS-tone pairing, a specific sound is played at the exact moment of a VNS pulse, which can promote changes in how the brain responds to sound, a concept known as neuroplasticity. In fact, this approach has been shown to drive changes in the auditory cortex in rats used to model Rett syndrome and has the potential to enhance communication abilities in people with Rett.
“Changes in protein expression induced by VNS-tone pairing help uncover possible underlying mechanisms of VNS-induced plasticity in the auditory cortex,” the team wrote.
VNS was delivered to some rats from the Rett syndrome model via a small, surgically implanted electrode and paired with tones played at seven different frequencies, each matched to the rat’s hearing range. Rats received about 300 VNS-tone pairings per day, five days a week, for four weeks, totaling about 6,000 stimulations across 20 sessions. Untreated healthy rats served as controls, and untreated rats from the Rett syndrome model were included for comparison.
Results showed 91 proteins were differentially expressed (present at meaningfully different levels) in the auditory cortex of untreated rats from the Rett model compared with healthy rats.
Of those, about two-thirds (62%) were at lower levels and primarily involved in synaptic signaling and cellular differentiation (the process by which cells develop specialized functions). The remaining 38% were at higher levels and mainly involved in metabolism (the chemical processes that produce energy in cells).
VNS altered protein levels in Rett model rats
When the researchers compared rats from the Rett model, with or without VNS, 151 proteins were differentially expressed. Of those, 76% were higher in the VNS-treated group, and 24% were lower, indicating that VNS-tone pairing largely increased protein levels, the team noted. The proteins with the largest increases were primarily involved in synaptic signaling and metabolism.
The team then compared VNS-treated rats from the Rett model directly to healthy controls to determine whether VNS-tone pairing brought the Rett auditory cortex proteome closer to healthy control levels.
There were still 121 proteins that differed between the two groups, with 74% higher and 26% lower in the VNS-treated rats from the Rett model than in controls. This indicates that VNS-tone pairing substantially altered the proteome but did not restore it to healthy control levels.
Across all differentially expressed proteins identified in the study, 88 were found to be directly relevant to synaptic function using a specialized database called SYNGO.
“The results from this proteomic analysis describe synaptic and metabolic dysregulation in the [Rett] auditory cortex, which points to potential mechanisms involved in the auditory dysfunction present in Rett syndrome,” the researchers concluded. “The work shown here points to an optimistic future for the treatment of auditory processing in girls with Rett syndrome.”
