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M1278

Depression and Sensitivity to Stress Can Be Induced by Transient GastricIrritation in the Neonatal Period: Behavioral and Molecular CorrelatesLiansheng Liu, Qian Li, Mohan M. Shenoy, Tugba Colak, Kshama R. Mehta, Pankaj J.Pasricha

Background: Patients with functional dyspepsia (FD) tend to be more depressed and anxiousthan healthy controls but what comes first is not clear. We hypothesized that psychologicalmorbidity can be secondary to abnormal gastrointestinal afferent signaling. We thereforeevaluated depression-like and anxiety-like behaviors and the sensitivity to stress in a previ-ously described rat model of FD. Methods: 10 days old male Sprague-Dawley rats received0.2 ml of 0.1% iodoacetamide (IA) in 2% sucrose daily by oral gavages for 6 days. Controlgroup received 2% sucrose. At 8-10 weeks of age, sucrose preference test (SPT) and forced-swim test (FST) were used for testing depression-like behavior and elevated plus maze (EPM)and open field test (OFT) were used to test anxiety-like behaviors. Subsequently plasmaACTH, corticosterone and oxytocin levels in response to a minor stressor (subcutaneoussaline injection) were measured. RNA was extracted from various brain regions. Results:Rats with neonatal gastric irritation (NGI) showed several abnormalities on the FST ascompared with control (Immobility: 32.4± 3.95 vs. 12.95±2.80, climbing: 7.05± 1.18 vs.18.65 ±1.9 and swimming: 20.6± 3.02 vs. 28.35± 2.1, P <0.05). Sucrose preference (definedas > 75% of total intake) was decreased in NGI rats (45% versus 80%; p <0.05). Nosignificant change between NGI and control animals was observed in EPM test. On theother hand, OFT showed that the time at center and total distance moved were significantlydecreased in NGI rats compared to control rats (16± 4. vs 30±5 and 9182±655 vs 11548±332, P <0.05). The basal level of plasma corticosterone in NGI rats was significantly higherthan that in control rats (3.05±0.74 vs. 1.41±0.25, P<0.05) although stress did not inducea further elevation. Further, while stress did not alter the plasma ACTH and oxytocinconcentration in control rats, the hormone levels were significantly increased in stressedNGI rats compared to non-stressed FD rats (49.45±11.42 vs 22.76±2.05 and 14.87±1.50vs 7.07±0.62, P<0.05). Gene array data showed significant changes in key molecules thatmodulate stress and depression including 5-HT1A, 5-HT2A, TrkB, NPYr1 and oxytocin.Conclusions: These results suggest that transient gastric irritation in the neonatal periodcan induce long lasting depressive behavior as well as sensitivity to stress, associated withspecific molecular correlates. These findings have major implications for the pathogenesisand treatment of psychological co-morbidity in patients with FD. Thus, gastric hypersensitiv-ity could be a cause rather than an effect of depression.

M1279

Overlapped Heartburn/Regurgitation Amplifies Abdominal Pain andIndigestion via Common Central Serotonin Neurotransmission Disorders inPatients With Functional DyspepsiaKazunari Tominaga, Chikako Tsumoto, Suzuka Ataka, Hirohisa Machida, HirotoshiOkazaki, Hirokazu Yamagami, Tetsuya Tanigawa, Kenji Watanabe, Toshio Watanabe,Yasuhiro Fujiwara, Susumu Shiomi, Yasuyoshi Watanabe, Tetsuo Arakawa

Background & Aims:Heartburn/regurgitation often overlaps abdominal pain and indigestionand affects each other in functional dyspepsia (FD) patients. Thus, upper abdominal dyspepticsymptoms may be mediated by similar neurotransmission pathways based on the brain-gutinteraction. Central serotonergic abnormalities are associated with the pathophysiology offunctional gastrointestinal disorders or psychiatric depression and anxiety. To evaluate theroles of the cerebral serotonin (5-HT) neurotransmission systems in overlapped heartburn/regurgitation of FD patients, we examined both 5-HT transporter (5-HTT) binding potentialin the brain and correlation of 5-HTT binding potential to overlapped heartburn/regurgitationbetween FD patients and controls. Methods: Patients with FD diagnosed according to theRome III criteria (N=9, female: 6, age range 36-76 yrs) were recruited for this study. Therewere 8 healthy controls (female: 2, age range 25-61 yrs). To measure 5-HTT binding potentialin areas of the thalamus, putamen, amygdala, midbrain, and cerebellum (as a referenceregion), positron emission tomography (PET) with [11C]N,N-dimethyl-2-(2-amino-4-cyano-phenylthio) benzylamine ([11C]DASB), which binds specifically to 5-HTT, was performed.We used the Multi-linear Reference Tissue Mode method within the standard softwarepackage of PMOD Technologies for analysis of [11C]DASB with reference to the co-registeredMRI images. Abdominal symptoms reflux, abdominal pain, and indigestion were evaluatedon the Gastrointestinal Symptoms Rating Scale (GSRS). Results: All scores for heartburn/regurgitation, abdominal pain, and indigestion were higher for FD patients than for controls(p<0.01). In FD patients, the binding potential of [11C]DASB in the midbrain (p=0.041)and thalamus (p=0.031) was higher than in the corresponding areas in controls. Bindingpotential of [11C]DASB in the midbrain was correlated with reflux scores (p=0.012, r=0.568)as well as abdominal pain (p=0.050, r=0.410) scores and indigestion (p=0.029, r=0.475).In the thalamus, however, it was correlated with reflux scores (p=0.019, r=0.521) differentfrom a tendency to abdominal pain (p=0.051, r=0.401) scores and indigestion (p=0.062,r=0.384). Scores of abdominal pain and indigestion in FD patients overlappedwith heartburn/regurgitation were higher than those of FD patients without it (p<0.05). Conclusion: These

S-370AGA Abstracts

findings suggest that disorders of central 5-HT neurotransmission in the midbrain andthalamus are correlated with heartburn/regurgitation in FD patients, which may amplifyabdominal pain and indigestion symptoms.

M1280

Treating Chronic Dysphagia Post Stroke With Neurostimulation BasedInterventions: A Preliminary StudyEmilia Michou, Satish Mistry, Samantha Jefferson, Salil Singh, Shaheen Hamdy

Background:Oropharyngeal dysphagia after stroke has an incidence up to 45% and whenchronic, leads to increased risk of institutionalisation and death in the long term. PharyngealElectrical Stimulation(PES)[1],repetitive Transcranial Magnetic Stimulation(rTMS)[2]andPaired Associative Stimulation(PAS)[3]are three neurostimulation techniques developed toincrease cortical excitability of pharyngeal motor cortex, with therapeutic potential. Howeverthe effects of neurostimulation on chronic but stable dysphagia in stroke patients remainunknown. We therefore investigated the effects of these interventions in stroke patients withdysphagia persisting for more than 6 weeks.Methods:In 12 dysphagic stroke patients(69±9years old,79±25 weeks post stroke(mean±SD), 6 left, 5 right hemispheric, 1 undeter-mined)pharyngeal electromyographic responses were recorded using an intraluminal catheterafter the application of single TMS pulses over pharyngeal motor cortex, in order to measurecortico-bulbar excitability before, immediately and 30 minutes after real and sham applica-tions of either:a)PES(10 mins of 5Hz),b)rTMS(250 repeated TMS pulses at 5Hz),or c)PAS(10mins of repeated pairs of pharyngeal and TMS pulse every 20sec). In 9 subjects, swallowingperformance and safety(aspiration-penetration scores,APs) were assessed with videofluoro-scopy before and after both real and sham neurostimulation techniques.Results:Comparedto sham, the application of all neurostimulation interventions significantly increased thecortical excitability in the unaffected hemisphere by 54±17%(mean±SEM) immediately post(-repeated ANOVA,p<0.001,Time*Treatment,p=0.005) not observed in the affected hemi-sphere(p=0.12). In addition, after active neurostimulation, APs were reduced by-14±6%(mean±SEM)compared to sham(Wilcoxon's test,p=0.05). Moreover, the delaybetween the oral and pharyngeal phases of swallowing, important for swallowing safety,was shortened by -56±13%(mean±SEM)after real neurostimulation(Wilcoxon's test,p=0.01)compared to sham. There was no consistent difference in cortical or swallowing responsebetween the interventions.Conclusion:These preliminary results show that neurostimulationinterventions have beneficial neurophysiological and behavioural effects in chronic strokepatients with dysphagia, increasing cortical excitability and improving swallowing safety.These findings provide support for neurostimulation being a useful adjunct in swallowingrehabilitation, even in chronic neurologic illness, and lay the foundation for further clinicaltrials of these forms of intervention.References:1.Fraser et al,Neuron 2002,2.Jefferson etal,Gastro 2009,3.Singh et al,Gastro 2009.

M1281

Chronic Repeated Stress Restores Impaired Gastric Motility in Wild TypeMice, but Not Oxytocin Knockout MiceReji Babygirija, Jun Zheng, Mehmet Bulbul, Kirk A. Ludwig, Toku Takahashi

Background: Stress is highly associated with common gastrointestinal disorders. The non-apeptide oxytocin is known to facilitate anxiolysis and to attenuate stress responses viainhibiting corticotrophin-releasing factor (CRF) expression of the hypothalamus. We haverecently shown that impaired gastric motility observed in acute restraint stress was restoredfollowing chronic repeated stress in mice. Chronic repeated stress upregulates oxytocinmRNA expression at the hypothalamus, resulting in downregulation of CRFmRNA expression(Am J Physiol, in press). Oxytocin knockout mice (OXT-KO) have been widely used tostudy the central oxytocin signaling pathways in response to various stressors. Previousstudies have shown that OXT-KO had higher corticosterone release and greater anxietybehaviours, compared to the wild type mice (Prog Brain Res. 170, 53-64, 2008). Westudied the effects of acute stress and chronic repeated stress on solid gastric emptying andhypothalamic CRFmRNA expression in wild type andOXT-KOmice.Methods: Heterozygousparents (B6; 129S-Oxt tm1Wsy/J mice) were obtained from Jackson lab (Bar Harbor, Maine)and were bred in our animal facility. The off springs were genotyped using DNA preparedfrom tail extracts using polymerase chain reaction (PCR). Male OXT-KO, wild type andheterozygous littermates were used for the study. Solid gastric emptying was measuredfollowing acute restraint stress (for 90 min) or chronic repeated restraint stress for 5 consecut-ive days. The expression of CRF mRNA in the paraventricular nucleus (PVN) and supraopticnucleus (SON) was measured using real time RT-PCR. Results: There were no significantdifferences of gastric emptying in wild type (68.4±4.1%, n= 6), heterozygous (71.8±3.1%, n=6) and OXT-KO (70.6±3.1%, n=6) mice in non-stressed conditions. Acute stress significantlydelayed gastric emptying in these mice. The degree of delayed emptying was significantlylower in OXT-KO mice (29.8±1.2%, n=6, P<0.01) than that of wild type (40.8±0.8%, n=6) and heterozygous mice (35.8±1.2%, n=6). Following chronic repeated stress loading,gastric emptying was significantly restored in wild type (67.3±2.4%, n=6) and heterozygousmice (66.6±4.2%, n=6). In contrast, delayed gastric emptying was still observed in OXT-KO mice (34.7±1.3%, n=6) following chronic repeated stress. The increase in CRF mRNAexpression at the PVN and SON was much pronounced in OXT-KO mice, compared to thewild type mice following chronic repeated stress. Conclusion: These findings suggest thatcentral oxytocin attenuates CRF expression and plays a pivotal role in mediating the adapta-tion mechanism following chronic stress in mice.