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Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala

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ABSTRACT

Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction.

No MeSH data available.


Increased expression of GluN2B in the BLA of rats given VNS during fear extinction training. (a) Rats given VNS during extinction training show higher levels of GluN2B compared to rats given sham stimulation (∗p < 0.05). (b–e) No significant difference in expression of GluN2A, p-GluA1 at S845 or S831, or p-ERK across groups.
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fig2: Increased expression of GluN2B in the BLA of rats given VNS during fear extinction training. (a) Rats given VNS during extinction training show higher levels of GluN2B compared to rats given sham stimulation (∗p < 0.05). (b–e) No significant difference in expression of GluN2A, p-GluA1 at S845 or S831, or p-ERK across groups.

Mentions: To further elucidate molecular effects of VNS-enhanced extinction, we assessed expression of downstream targets of p-CaMKII and proteins known to be affected by Arc expression that play important roles in synaptic plasticity. p-CaMKII can affect LTP through indirect phosphorylation of ERK and via interactions with both NMDA and AMPA receptors [11, 12, 14–17]. Rats given VNS during extinction training showed a significant increase in expression of the GluN2B subunit of NMDA receptors compared to sham-extinction rats (Figure 2(a); t(12) = 2.272, p = 0.042). No difference was seen in expression of the GluN2A subunit of NMDA receptors (Figure 2(b); t(14) = 0.662, p = 0.518), in phosphorylation of the GluA1 subunit of AMPA receptors at either the Ser831 (Figure 2(c); t(23) = 1.463, p = 0.157) or Ser845 site (Figure 2(d); t(10) = 0.811, p = 0.435), or in phosphorylation of ERK protein (Figure 2(e); t(23) = 0.659, p = 0.515).


Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala
Increased expression of GluN2B in the BLA of rats given VNS during fear extinction training. (a) Rats given VNS during extinction training show higher levels of GluN2B compared to rats given sham stimulation (∗p < 0.05). (b–e) No significant difference in expression of GluN2A, p-GluA1 at S845 or S831, or p-ERK across groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC5120198&req=5

fig2: Increased expression of GluN2B in the BLA of rats given VNS during fear extinction training. (a) Rats given VNS during extinction training show higher levels of GluN2B compared to rats given sham stimulation (∗p < 0.05). (b–e) No significant difference in expression of GluN2A, p-GluA1 at S845 or S831, or p-ERK across groups.
Mentions: To further elucidate molecular effects of VNS-enhanced extinction, we assessed expression of downstream targets of p-CaMKII and proteins known to be affected by Arc expression that play important roles in synaptic plasticity. p-CaMKII can affect LTP through indirect phosphorylation of ERK and via interactions with both NMDA and AMPA receptors [11, 12, 14–17]. Rats given VNS during extinction training showed a significant increase in expression of the GluN2B subunit of NMDA receptors compared to sham-extinction rats (Figure 2(a); t(12) = 2.272, p = 0.042). No difference was seen in expression of the GluN2A subunit of NMDA receptors (Figure 2(b); t(14) = 0.662, p = 0.518), in phosphorylation of the GluA1 subunit of AMPA receptors at either the Ser831 (Figure 2(c); t(23) = 1.463, p = 0.157) or Ser845 site (Figure 2(d); t(10) = 0.811, p = 0.435), or in phosphorylation of ERK protein (Figure 2(e); t(23) = 0.659, p = 0.515).

View Article: PubMed Central - PubMed

ABSTRACT

Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc protein in VNS-enhanced extinction.

No MeSH data available.