The antidepressant-like effect of vagus nerve stimulation is mediated through the locus coeruleus

Grimonprez, Annelies; Raedt, Robrecht; Portelli, Jeanelle; Dauwe, Ine; Larsen, Lars Emil; Bouckaert, Charlotte; Delbeke, Jean; Carrette, Evelien; Meurs, Alfred; Herdt, Veerle De; Boon, Paul; Vonck, Kristl

doi:10.1016/j.jpsychires.2015.05.002

Cited by 60 publications

(47 citation statements)

References 68 publications

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“…However, these findings do not rule out the importance of other neuromodulatory systems in VNS-dependent plasticity. Several previous studies have indicated that the noradrenergic system is involved in the effects of VNS [23-28, 55]. Norepinephrine and acetylcholine often act synergistically to influence plasticity [32]; therefore, it is possible that both the noradrenergic and cholinergic systems contribute to VNS-dependent plasticity.…”

Section: Discussionmentioning

confidence: 99%

“…VNS drives release of norepinephrine throughout the brain [23-26]. Lesions of the LC prevent the seizure-attenuating and antidepressant effects of VNS, indicating the importance of noradrenergic signaling in the effects of VNS [27, 28]. Acute antagonism of muscarinic acetylcholine receptors prevents VNS-dependent desynchronization of cortical EEG, suggesting that VNS exerts an effect on cortical processing by engaging cholinergic transmission [29].…”

Section: Introductionmentioning

confidence: 99%

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Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation

et al. 2016

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Background Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. The mechanisms that underlie VNS-dependent enhancement of map plasticity are largely unknown. The cholinergic nucleus basalis (NB) is a critical substrate in cortical plasticity, and several studies suggest that VNS activates cholinergic circuitry. Objective We examined whether the NB is required for VNS-dependent enhancement of map plasticity in the motor cortex. Methods Rats were trained to perform a lever pressing task and then received injections of the immunotoxin 192-IgG-saporin to selectively lesion cholinergic neurons of the NB. After lesion, rats underwent five days of motor training during which VNS was paired with successful trials. At the conclusion of behavioral training, intracortical microstimulation was used to document movement representations in motor cortex. Results VNS paired with forelimb training resulted in a substantial increase in the representation of proximal forelimb in rats with an intact NB compared to untrained controls. NB lesions prevent this VNS-dependent increase in proximal forelimb area and result in representations similar to untrained controls. Motor performance was similar between groups, suggesting that differences in forelimb function cannot account for the difference in proximal forelimb representation. Conclusions Together, these findings indicate that the NB is required for VNS-dependent enhancement of plasticity in the motor cortex and may provide insight into the mechanisms that underlie the benefits of VNS therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation

et al. 2016

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“…Two major working hypotheses of VNS in depression were proposed: the 'monoaminergic' and the 'neural plasticity' hypotheses of depression [77]. Of note, noradrenergic neurons from the locus coeruleus play an important role in the antidepressant-like effect of VNS [78]. Furthermore, transcutaneous VNS modulates the default mode network in major depressive disorder [79].…”

Section: Vagus Nerve Stimulationmentioning

confidence: 99%

Nonlinear effects of respiration on the crosstalk between cardiovascular and cerebrovascular control systems

Bari

Marchi

Maria

et al. 2016

Phil. Trans. R. Soc. A.

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Cardiovascular and cerebrovascular regulatory systems are vital control mechanisms responsible for guaranteeing homeostasis and are affected by respiration. This work proposes the investigation of cardiovascular and cerebrovascular control systems and the nonlinear influences of respiration on both regulations through joint symbolic analysis (JSA), conditioned or unconditioned on respiration. Interactions between cardiovascular and cerebrovascular regulatory systems were evaluated as well by performing correlation analysis between JSA indexes describing the two control systems. Heart period, systolic and mean arterial pressure, mean cerebral blood flow velocity and respiration were acquired on a beat-to-beat basis in 13 subjects experiencing recurrent syncope episodes (SYNC) and 13 healthy individuals (non-SYNC) in supine resting condition and during head-up tilt test at 60° (TILT). Results showed that JSA distinguished conditions and groups, whereas time domain parameters detected only the effect of TILT. Respiration affected cardiovascular and cerebrovascular regulatory systems in a nonlinear way and was able to modulate the interactions between the two control systems with different outcome in non-SYNC and SYNC groups, thus suggesting that the analysis of the impact of respiration on cardiovascular and cerebrovascular regulatory systems might improve our understanding of the mechanisms underpinning the development of postural-related syncope.

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“…LC lesions block both the antiepileptic and antidepressant-like effects of VNS, demonstrating the requirement of noradrenergic engagement (Krahl et al, 1998, Grimonprez et al, 2015, Furmaga, Shah and Frazer., 2011). Moreover, 30 second trains of VNS increase firing rates of LC neurons over the course of minutes to hours (Groves, Bowman and Brown., 2005, Manta et al, 2009a, Manta et al, 2013, Dorr and Debonnel., 2006).…”

Section: Introductionmentioning

confidence: 97%

Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation

Hulsey

Riley

Loerwald

et al. 2017

Experimental Neurology

221

214

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Vagus nerve stimulation (VNS) has emerged as a therapy to treat a wide range of neurological disorders, including epilepsy, depression, stroke, and tinnitus. Activation of neurons in the locus coeruleus (LC) is believed to mediate many of the effects of VNS in the central nervous system. Despite the importance of the LC, there is a dearth of direct evidence characterizing neural activity in response to VNS. A detailed understanding of the brain activity evoked by VNS across a range of stimulation parameters may guide selection of stimulation regimens for therapeutic use. In this study, we recorded neural activity in the LC and the mesencephalic trigeminal nucleus (Me5) in response to VNS over a broad range of current amplitudes, pulse frequencies, train durations, inter-train intervals, and pulse widths. Brief 0.5 s trains of VNS drive rapid, phasic firing of LC neurons at 0.1 mA. Higher current intensities and longer pulse widths drive greater increases in LC firing rate. Varying the pulse frequency substantially affects the timing, but not the total amount, of phasic LC activity. VNS drives pulse-locked neural activity in the Me5 at current levels above 1.2 mA. These results provide insight into VNS-evoked phasic neural activity in multiple neural structures and may be useful in guiding the selection of VNS parameters to enhance clinical efficacy.

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The antidepressant-like effect of vagus nerve stimulation is mediated through the locus coeruleus

Cited by 60 publications

References 68 publications

Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation

Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation

Nonlinear effects of respiration on the crosstalk between cardiovascular and cerebrovascular control systems

Parametric characterization of neural activity in the locus coeruleus in response to vagus nerve stimulation

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