Targeting Vagal Afferent in Learning and Memory Impairments Associated with Chronic Visceral Pain: The Role of Cholecystokinin

In the animal and human, available evidences indicated that activation of vagalafferents plays a role in the behavioral control learning and memory storage. Clinicalevidence has shown that patients with irritable bowel syndrome (IBS) who seektreatment have psychiatric comorbidity, usually suffer from memory deficiency.Dysfunction of vagal nerve has reported in IBS patients. Until now there has been noexperimental animal model to study visceral pain related cognitive deficits, and little isknown about the underlying mechanisms.Cholecystokinin-octapeptide, which is a gastrointestinal hormone released duringfeeding, has been shown to enhance memory retention. Our series of publishedobservations have shown CCK acting on vagal afferent fibers mediates variousphysiological functions.Our recent ongoing studies have clearly shown the impairments of the spatial andworking memory in viscerally hypersensitive (VH) rat model. We hypothesize that CCKacting via vagal afferent facilities learning and memory process in normal subjects.Further, exogenous or endogenous released CCK enables to rescue memory deficitsassociated with chronic visceral pain.To test these hypotheses vagal afferent neural responses to CCK-8 will be examined byelectrophysiological recorded single-neuronal firings in the nodose ganglia followingneurobiotin labeling and double staining to characterize the neurochemical coding.Various behavioral experiments will be performed to establish a visceral pain animalmodel with cognitive deficits. The effects of CCK on rescuing learning and memoryimpairment will be examined. The physiological implications will be further strengthenedby the similar effects observed in the rats with gastric infusion of peptone, which hasbeen shown to induce increases in plasma CCK levels.Oscillatory of local field potential (LFP), coherent of LFP and neural spikes activity areincreasingly recognized as a fundamental hallmark of cortical integrative functions.Given the fact that our ongoing project (GRF11100914) showed for the first time that block of LTP, suppresses phase-locking of anterior cingulate cortex (ACC) neurons anddesynchronization between medial thalamus (MT)-ACC pathway in VH rats, in the lastphase of our experiment, we will perform multi-electrophysiological recording to clarifythat the CCK enables to restore the reduced coherences, and repair theta-phase-lockingof ACC neurons and further maintain the synchrony in MT-ACC pathway in VH rats.These results reinforce the view that gut-brain axis plays an important role inmodulating learning and memory, and may help the design of experimental approachesaimed at exploiting synaptic reinforcement as a means for ameliorating the impact ofvisceral pain on learning and memory dysfunction.?