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

Alvarez-Dieppa, Amanda; Griffin, Kimberly; Cavalier, Sheridan; McIntyre, Christa K.

doi:10.1155/2016/4273280

Cited by 64 publications

(50 citation statements)

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“…A two-tailed t-test indicated no significant effect of VNS Alone (VNS Alone vs. Pre-Extinction freezing, t(11)=1.8 p=0.16), demonstrating that VNS Alone was not sufficient to reduce conditioned fear to either CS (Figure 2d). These findings are consistent with previous results and indicate that VNS reduces conditioned fear by enhancing fear extinction [28]. …”

Section: Resultssupporting

confidence: 94%

“…The CFRTs could allow for extinction learning because they involve four non-reinforced exposures to both stimuli on each test day. However, we find a significant effect when only four of the exposures are paired with VNS [28–31]. Although we have not observed locomotor or other performance effects that may obscure measurement of conditioned fear, taking the CFRT before and after VNS treatment prevents mistaking of immediate performance disturbances for VNS effects on extinction.…”

Section: Methodsmentioning

confidence: 74%

“…VNS can enhance memory consolidation in rats and humans and it also facilitates experience-dependent plasticity [23–24; 27; 45–54]. We have observed similarities and differences in plasticity related to VNS-enhanced and Extended Extinction [28, 30]. For example, VNS administration during extinction training predisposes field potentials in the basolateral complex of the amygdala (BLA) to LTP following high-frequency stimulation of the infralimbic region (IL) of the prefrontal cortex, whereas the same stimulation of the IL did not produce LTP in the BLA of animals given Extended Extinction training with sham stimulation [30].…”

Section: Discussionmentioning

confidence: 99%

“…VNS-treated rats received four presentations of the CS that overlapped with VNS (VNS+Extinction group; n=14). The parameters used for VNS were the same as those used to enhance memory consolidation and the consolidation of extinction of conditioned fear [28–31] and they are within the range of stimulation parameters approved by the FDA for seizure prevention in humans [33]. For seizure prevention, a 30 sec train of VNS is given every 5 min throughout the day and night.…”

Section: Methodsmentioning

confidence: 99%

“…Vagus nerve stimulation (VNS) paired with specific stimuli has emerged as a strategy to enhance memory consolidation [26–27] as well as consolidation of extinction memory in healthy rats [28–30]. Additionally, VNS administration paired with exposure to conditioned cues accelerates the extinction of conditioned fear and attenuates reinstatement in a rat model of PTSD [31].…”

Section: Introductionmentioning

confidence: 99%

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Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

et al. 2019

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Background: Exposure-based therapies are used to treat a variety of trauma- and anxiety-related disorders by generating successful extinction following cue exposure during treatment. The development of adjuvant strategies that accelerate extinction learning, improve tolerability, and increase efficiency of treatment could increase the efficacy of exposure-based therapies. Vagus nerve stimulation (VNS) paired with exposure can enhance fear extinction, in rat models of psychiatric disorders, and chronic administration of VNS reduces anxiety in rats and humans. Objective: We tested whether VNS, like other cognitive enhancers, could produce generalization of extinction for stimuli that are not presented during the extinction sessions, but are associated with the fear event. Methods: Male Sprague Dawley rats underwent auditory fear conditioning with two easily discriminable auditory stimuli. Following fear conditioning, extinction training consisted of exposure to only one of the conditioned sounds. Half of the rats received VNS and half received sham stimulation during with sound presentations. VNS effects on anxiety were examined in a separate study where VNS was administered prior to testing on the elevated plus maze. Results: Sham stimulated rats given 20 presentations of a conditioned stimulus (CS) during the extinction session showed performance that was matched to VNS-treated rats given only 4 presentations of the CS. Despite comparable levels of freezing to the presented CS, only the VNS-treated rats showed a significant decrease in freezing to the CS that was not presented. VNS-induced generalization of extinction was observed only when the two sounds were paired with footshock within the same fear conditioning session; VNS did not promote generalization of extinction when the two sounds were conditioned on different days or in different contexts. On the anxiety test, VNS administration significantly increased time spent in the open arms of the elevated plus maze. Conclusion: These results provide evidence that VNS can promote generalization of extinction to other stimuli associated with a specific fear experience. Furthermore, non-contingent VNS appears to reduce anxiety. The ability to generalize extinction and reduce anxiety makes VNS a potential candidate for use as an adjunctive strategy to improve the efficacy and tolerability of exposure-based therapies.

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Section: Resultssupporting

confidence: 94%

Section: Methodsmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

et al. 2019

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Ascending Vagal Sensory and Central Noradrenergic Pathways Modulate Retrieval of Passive Avoidance Memory in Male Rats

Edwards,

Guerrero,

Thompson

et al. 2024

J of Neuroscience Research

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Visceral feedback from the body is often subconscious, but plays an important role in guiding motivated behaviors. Vagal sensory neurons relay “gut feelings” to noradrenergic (NA) neurons in the caudal nucleus of the solitary tract (cNTS), which in turn project to the anterior ventrolateral bed nucleus of the stria terminalis (vlBNST) and other hypothalamic‐limbic forebrain regions. Prior work supports a role for these circuits in modulating memory consolidation and extinction, but a potential role in retrieval of conditioned avoidance remains untested. To examine this, adult male rats underwent passive avoidance conditioning. We then lesioned gut‐sensing vagal afferents by injecting cholecystokinin‐conjugated saporin toxin (CSAP) into the vagal nodose ganglia (Experiment 1), or lesioned NA inputs to the vlBNST by injecting saporin toxin conjugated to an antibody against dopamine‐beta hydroxylase (DSAP) into the vlBNST (Experiment 2). When avoidance behavior was later assessed, rats with vagal CSAP lesions or NA DSAP lesions displayed significantly increased conditioned passive avoidance. These new findings support the view that gut vagal afferents and the cNTSNA‐to‐vlBNST circuit play a role in modulating the expression/retrieval of learned passive avoidance. Overall, our data suggest a dynamic modulatory role of vagal sensory feedback to the limbic forebrain in integrating interoceptive signals with contextual cues that elicit conditioned avoidance behavior.

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Contemporary Approaches Toward Neuromodulation of Fear Extinction and Its Underlying Neural Circuits

Becker,

Milad

2023

Current Topics in Behavioral Neurosciences

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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

Cited by 64 publications

References 55 publications

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats

Ascending Vagal Sensory and Central Noradrenergic Pathways Modulate Retrieval of Passive Avoidance Memory in Male Rats

Contemporary Approaches Toward Neuromodulation of Fear Extinction and Its Underlying Neural Circuits

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