Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

Childs, Jessica E.; Alvarez-Dieppa, Amanda; McIntyre, Christa K.; Kroener, Sven

doi:10.3791/53032

Cited by 30 publications

(25 citation statements)

References 51 publications

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“…The fact that VNS can facilitate extinction from various reinforcers and across a range of stimulation parameters is consistent with the idea that VNS promotes plasticity by altering neurotransmission selectively in those brain regions actively engaged in a task (Kilgard 2012;Childs et al 2015). Temporally precise modulation of active networks could explain how the effects of VNS can generalize to motor functions, as well as a range of conditioned and unconditioned stimuli (Engineer et al 2011;Porter et al 2012;Hays et al 2014a,b).…”

Section: Discussionsupporting

confidence: 66%

“…connected to a back-mounted cannula (Plastics One). During the same surgery, a custom-made cuff electrode was placed around the left vagus nerve for the delivery of VNS (Childs et al 2015). Catheters were flushed daily with heparinized saline (0.2 mL of 100 IU) and gentamycin (0.2 mL of 0.1 g/ mL) to maintain catheter patency, which was assessed weekly by infusing 1.0 mg/0.1 mL of the fast-acting anesthetic methohexital sodium and noting the presence or absence of a brief period of sedation.…”

Section: Jugular Vein Catheterization and Vagus Nerve Electrode Implantmentioning

confidence: 99%

“…Twenty-four hours after the last treatment, a bipolar matrix stimulation electrode (FHC) was placed in the IL (D/V: 4.6, A/P: 3.0, M/L: 0.6 from bregma) and evoked local field potentials (eLFPs) were recorded in the BLA (D/V: 7.3, A/P:22.76, M/L: 24.9 from bregma) of urethane-anesthetized (1.5 g/kg IP) rats, using glass microelectrodes (2 M KCl; 1 -2 MOhms resistance), following previously published protocols (Peña et al 2014;Childs et al 2015). Baseline data were collected for a minimum of 10 min before longterm depression (LTD) was induced using low-frequency stimulation (1 Hz for 15 min) at the same stimulation intensity used for baseline recordings (23).…”

Section: In Vivo Lfp Recordingmentioning

confidence: 99%

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Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network

et al. 2016

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Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drugseeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug-and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects.Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in networks that regulate motivated behavior (Moussawi et al. 2009). As a result of this, recovery from drug addiction is frequently hampered by craving and relapse. Learning to inhibit, or extinguish, drug-seeking in response to drug-associated cues can reduce relapse. Extinction can reverse neuroadaptations caused by drug self-administration (Self et al. 2004;Millan et al. 2011). However, extinction training alone is often insufficient to prevent drug relapse (Weiss et al. 2001;Conklin and Tiffany 2002), potentially because the corticolimbic networks that are important for cue and reward processing, which include the nucleus accumbens, the prefrontal cortex (PFC), and the amygdala (Jentsch and Taylor 1999), become dysregulated by chronic drug use themselves (Fowler et al. 2007;Sinha and Li 2007;Liu et al. 2009;Nic Dhonnchadha and Kantak 2011). Modulating extinction processes to better consolidate the new-formed memories thus has clinical potential to reshape maladaptive behavior and to prevent relapse (Taylor et al. 2009). Vagus nerve stimulation (VNS) is a minimally invasive neuroprosthetic treatment which can induce targeted plasticity in active networks (Hays et al. 2013). VNS is FDA-approved for the treatment of epilepsy and depression, and it can improve sensory and motor function in models of tinnitus and stroke (Engineer et al. 2011;Porter et al. 2012; Hays et al. 2014a,b). VNS has also already been shown ...

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Section: Discussionsupporting

confidence: 66%

Section: Jugular Vein Catheterization and Vagus Nerve Electrode Implantmentioning

confidence: 99%

Section: In Vivo Lfp Recordingmentioning

confidence: 99%

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Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network

et al. 2016

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“…Surgery protocols are described in detail elsewhere [35]. In brief, rats were anesthetized with isoflurane (2% at an oxygen flow rate of 600–800 ml/min).…”

Section: Methodsmentioning

confidence: 99%

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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“…The VNS surgeries were performed as previously described [27, 28]. Briefly, platinum-iridium wire electrodes were housed in custom-made Micro-Renathane cuffs (0.04 in.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2016

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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.

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Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

Cited by 30 publications

References 51 publications

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network

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

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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