Investigating Vagal Afferent Facilitating Cognition: The Role of Electrical Vagus Nerve Stimulation and Peripheral Cholecystokinin


Student thesis: Doctoral Thesis

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Award date17 May 2017


Evidences from the animal and human studies indicated that activating vagal afferent could modulate the cognitive functions such as learning and memory as well as decision-making behavior. Cholecystokinin-octapeptide (CCK-8) is a major gastrointestinal hormone released during feeding. Our series of studies demonstrate that peptone in the duodenum stimulates the secretion of the CCK-releasing peptide (CCK-RP) which mediates CCK-8 release. CCK-8 acting on vagal afferent fibers mediates various physiological functions. In a T-maze task combined with electric foot shock, mice access to food immediately after training session or intraperitoneal administration of CCK-8 could enhance memory retention. Vagotomy blocked the CCK-8 induced memory enhancement. Combining the colorectal distension (CRD) with the conditioned place avoidance (CPA) in rats as a visceral pain-related behavioral paradigm, we directly assessed a learned behavior that reflects the affective component of visceral pain. Furthermore, we demonstrated that activation of perigenual anterior cingulate cortex (pACC) is crucial for memory processing involved in long-term negative visceral emotion and predicting the aversive stimuli through contextual cues. In the current study, we hypothesize that activation of vagal afferent by CCK-8 facilitates the visceral pain-related memory consolidation involved in long-term negative affective state. Using CRD-induced CPA paradigm, we assessed the effects of exogenous CCK-8 and endogenous CCK-8 at postprandial plasma concentration on visceral pain induced negative memory retention.

In addition, stimulating vagal afferents directly by electricity could be an alternative method to modulate vagus nerve mediated psychophysiological processing. Electrical vagus nerve stimulation (VNS) has become an established therapy for treatment of resistant epilepsy and resistant depression. Previous studies have shown the effects of VNS on enhancing memory performance in both rats and humans. By using behavioral paradigms to assess visceral pain in conscious rats, we have characterized the visceral analgesic properties of subdiaphragmatic VNS in rats. We demonstrated that electrical VNS in low-intensity activated vagal afferent A-δ fibers to reduce the CRD induced visceral pain. Based on findings in rat and human we hypothesize that activation of vagal afferent enhances visceral pain-related affective memory. In the current study using CRD-induced CPA, we examined the learned behavior and aversive memory in freely moving rats. In combination with CRD–CPA with electrical VNS in different intensities, this approach enables one to determine whether VNS modulates “aversive memory” of visceral pain.

Making a decision under intricate and indeterminate conditions is an essential cognitive process for adaption dependent on the incorporation of several executive functions. A human experimental study investigated the effect of VNS on decision-making. Improved performances were shown in participants but despite this the underlying mechanisms are unknown. By employing a conscious rat model equipped with vagus nerve cuff electrode, we assess the role of chronic VNS on decision-making in rat gambling task (RGT). Recent animal studies have shown that decision-making performances in the RGT depend on the integrated function of several subregions of the PFC, especially the prelimbic, cingulated and orbitofrontal cortices, and amygdala. The anterior cingulate cortex (ACC) is a major cortical area of the limbic loop system, integrating emotion and cognition. It has been shown that the basolateral amygdala (BLA) and the ACC form an interconnected neural circuit that may mediate certain types of decision-making processes. These data suggest that VNS may be affecting areas of the brain involved in decision-making. Accordingly, simultaneous multichannel-recordings were used in conscious rats to test the hypothesis that VNS may induce alterations of in both spike-field-coherence and synchronization of theta oscillations across brain areas in the ACC and BLA.

Main findings of the present study are: (1) Intravenous infusion of CCK-8 at physiological concentration or intraduodenal perfusion of peptone combining with conditioned training markedly enhanced the CRD-induced CPA scores which represented the reinforcement of pain-related affective memory retention. (2) Administration of CCK-A receptor antagonist CR-1409 or perivagal application of capsaicin disrupted the effect of CCK-8 on aversive visceral pain memory, which was consistent with the notion that vagal afferent modulates affective aspects of visceral pain. (3) Performing VNS in high-intensity (400 μA) immediately following conditioned training increased the CRD-induced CPA scores significantly. In contrast, low-intensity VNS (40 μA) did not alter the CRD-induced CPA. Furthermore, (4) daily VNS, administered immediately following training sessions of RGT, caused an increase in ‘good decision-maker’ rats. (5) Neural spikes in the ACC became synchronized with the ongoing theta oscillations of local field potential (LFP) in BLA following VNS. Moreover, cross-correlation analysis revealed synchronization between the ACC and BLA was increased after VNS.

In conclusions, vagus verve stimulation facilities visceral pain-related affective memory, underscore the importance of memory in visceral pain perception. In particular, postprandial CCK activating vagal afferent C fibers enhances visceral pain-related affective processing and memory. Moderate electrical vagus nerve stimulation following training sessions facilitates decision making in rats paralleled with enhanced phase locking of the theta oscillations in the BLA to the ACC spikes immediately following VNS. The data may serve as a basis to develop fundamental notions regarding neurophysiologic biomarkers for therapeutic VNS in cognitive impairments.