Investigating Intra-Individual Networks of Response Inhibition and Interference Resolution using 7T MRI.

Response inhibition and interference resolution are often considered subcomponents of an overarching inhibition system that utilizes the so-called cortico-basal-ganglia loop. Up until now, most previous functional magnetic resonance imaging (fMRI) literature has compared the two using between-subject designs, pooling data in the form of a meta-analysis or comparing different groups. Here, we investigate the overlap of activation patterns underlying response inhibition and interference resolution on a within-subject level, using ultra-high field MRI. In this model-based study, we furthered the functional analysis with cognitive modelling techniques to provide a more in-depth understanding of behaviour. We applied the stop-signal task and multi-source interference task to measure response inhibition and interference resolution, respectively. Our results lead us to conclude that these constructs are rooted in anatomically distinct brain areas and provide little evidence for spatial overlap. Across the two tasks, common BOLD responses were observed in the inferior frontal gyrus and anterior insula. Interference resolution relied more heavily on subcortical components, specifically nodes of the commonly referred to indirect and hyperdirect pathways, as well as the anterior cingulate cortex, and pre-supplementary motor area. Our data indicated that orbitofrontal cortex activation is specific to response inhibition. Our model-based approach provided evidence for the dissimilarity in behavioural dynamics between the two tasks. The current work exemplifies the importance of reducing inter-individual variance when comparing network patterns and the value of UHF-MRI for high resolution functional mapping.

Antiretroviral activities of hypericin and rose bengal: photodynamic effects on Friend leukemia virus infection of mice.

The ability of hypericin to protect mice from splenomegaly resulting from infection with Friend leukemia virus (FLV) was re-examined in light of recent evidence showing that light is absolutely required for this drug's antiviral activity. FLV-induced splenomegaly was not prevented or ameliorated in mice injected with 100 micrograms hypericin, either mixed with the FLV inoculum or administered 1 day p.i., either under normal laboratory light or in the dark. These results contradict previous findings. Both hypericin and rose bengal, however, inactivated the FLV inoculum at low doses (< 11 micrograms), provided that the mixture was illuminated for 1 h under a normal fluorescent desk lamp. This procedure protected mice completely from FLV-induced splenomegaly, and provided a possible explanation for the discrepancy between our results and those reported previously. We conclude that for FLV, as for other enveloped viruses studied previously, illumination of hypericin with the virus is absolutely required for hypericin's antiviral (virucidal) effects, thus limiting its potential usefulness as an antiretroviral agent.

The effects of polyoxyethylated cholesterol on fecal bile acids and nitrogen and on cholesterol balance in rats.

Polyoxyethylated cholesterol (POEC) is a water soluble derivative of cholesterol which decreases cholesterol absorption in rats without affecting body weight, fatty acid excretion, or intestinal histology. In the present study rat feces were analyzed for cholic, deoxycholic, chenodeoxycholic, muricholic and lithocholic acid following 3 months of feeding a standard or a 2% enriched cholesterol diet with or without 1.5% POEC. In rats maintained on the cholesterol free diet, POEC increased total bile acids (mg/day) by 50% from 14 +/- 3 to 21 +/- 3 (mean +/- SEM) but only the increase in chenodeoxycholic acid was significant (P less than 0.05). The corresponding POEC effect in the 2% cholesterol diet was 31% (70 +/- 8 to 93 +/- 3, P less than 0.01). Fecal nitrogen and serum cholesterol did not vary among groups. Comparing these data with neutral steroid excretion previously determined showed that POEC in the cholesterol-free diet increased the negative cholesterol balance more than three-fold (34 +/- 7 vs 118 +/- 13 P less than 0.01). In rats fed 2% cholesterol, POEC caused a negative cholesterol balance of 222 +/- 8 compared to the control of 27 +/- 52 (P less than 0.01). The data indicate that POEC exerts complex effects in the intestinal tract which increase both bile acid and cholesterol excretion.

Blood flow, O2 extraction and O2 consumption along the rat small intestine.

Differences in O2 delivery and consumption along the fed and fasted small intestine are described. Total wall blood flow was determined in sequential segments of small intestine from 5 to 6-month-old male, anesthetized Fischer 344 rats either 75-80 min before or after feeding, using radioactive microspheres. Oxygen saturation in submucosal arterioles and venules (50-60 micron diam) was determined throughout the intestine, using a microspectrophotometric technique. Venous O2 saturations showed considerable heterogeneity in all regions, and ranged from 0 to 77%. Arterial-venous O2 content differences (CaO2-CvO2) did not change along the fasted rat intestine, and averaged 8.2 ml O2/100 ml blood. However, CaO2-CvO2 followed a small proximal to distal gradient (proximal greater than distal) in the fed rats. Larger proximal to distal gradients (proximal greater than distal) occurred in both blood flow and O2 consumption in both groups. Feeding did not change intestinal average CaO2-CvO2. However, feeding induced a 53% increase in average O2 consumption, with the greatest increase (130%) occurring in the middle third of the intestine. Feeding induced a 42% increase in average blood flow, with the greatest increase (70%) occurring in the distal third of the intestine. The increased O2 used by the fed intestine was primarily provided by the increased blood flow. The O2 consumption gradient is assumed to reflect differences in mucosal mass along the intestine and/or differences in metabolic activity.

The effects of polyoxyethylated cholesterol feeding on hepatic cholesterol synthesis and intestinal cholesterol absorption in rats.

Adduction of ethylene glycol moieties to the 3-hydroxy position of cholesterol produces polyoxyethylated cholesterol (POEC), a water-soluble compound that suppresses cholesterol synthesis and esterification in cultured human fibroblasts. Feeding Sprague-Dawley rats a diet containing 2% (wt/wt) POEC with 10 ethoxy groups resulted in a 3-fold increase in hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity compared to activity in rats pair-fed a diet of standard rat chow. POEC with an average of 20 ethoxy groups (POEC-20) caused comparable changes in hepatic [2-14C]acetate incorporation into non-saponifiable lipids under ad libitum feeding conditions, significantly reduced cholesterol absorption (18% vs 57%), and increased fecal excretion of neutral steroids (5.1 vs 2.0 mg/g food intake). POEC-20 also reduced cholesterol absorption in rats fed a diet enriched with 2% cholesterol (11% vs 31%). Histologic studies of intestinal mucosa and hepatic tissues from rats fed POEC showed no pathologic changes. These experiments indicate that POEC reduces cholesterol absorption and causes compensatory increases in hepatic cholesterol synthesis.

Circadian changes in serum and liver metabolites and liver lipogenic enzymes in ad libitum- and meal-fed, lean and obese Zucker rats.

Circadian rhythms were studied in ad libitum- and meal-fed Zucker rats. Lean and obese female rats were fed ad libitum or in a single meal from 1400-1800 for 12 d. Both groups of ad libitum-fed rats exhibited a nocturnal feeding pattern; obese rats ate more than the lean rats during the light and dark parts of the cycle. After 12 d, groups of rats were killed at 4-h intervals over a 24-h period, inclusively, and the presence of circadian rhythms was evaluated for the serum metabolites, liver constituents and the liver lipogenic enzymes. The obese ad libitum-fed rats demonstrated rhythms for serum triglycerides, serum cholesterol, liver protein and glycogen, and the activities of fatty acid synthetase, citrate cleavage enzyme (EC 4.1.3.8), and glucose-6-P dehydrogenase (EC 1.1.1.49). Meal feeding the obese rats modified the rhythms for serum cholesterol, liver glycogen and the activities of glucose-6-P dehydrogenase, and citrate cleavage enzyme and a rhythm was established for serum glucose. The feeding schedule did not cue a rhythm for serum triglycerides and phosphogluconate dehydrogenase (EC 1.1.1.44) or modify the rhythm for liver protein. The lean ad libitum-fed rats displayed rhythms for all the measured parameters except serum glucose. Feeding-cued rhythms for all metabolites except serum cholesterol were observed when the lean rats were meal-fed. These data suggest that the rhythms of the ad libitum-fed obese rats may not be similar to those observed in the lean rat. Yet, changing the feeding schedule may be important in establishing rhythm patterns that will alter the anabolic profile characteristic of the Zucker obese rat.

Changes in circadian rhythmicity of liver and serum parameters in rats fed a total parenteral nutrition solution by continuous and discontinuous intravenous or intragastric infusion.

Circadian rhythms were assessed in rats (224-246 grams) receiving either an intragastric (IG) or intravenous (IV) infusion continuously (C), or IG or IV infusions discontinuously (D) from 0000 to 1400 hours daily. A control group was maintained on a stock diet ad libitum. IV- and IG-fed rats were infused with 50 milliliters per day of a solution containing 25% dextrose and 4.25% amino acids plus vitamins and minerals. After 10 to 11 days, groups of rats were killed from each treatment every 6 hours over a 24-hour period. Results showed that IG feeding promoted better growth and nitrogen retention than IV feeding. Rhythm patterns for liver weight, glycogen, and protein content were similar between D-IG and D-IV infused rats. All groups except the D-IV fed rats exhibited fluctuations of serum insulin. A rhythm was not present for serum glucose in C-IV fed rats and a rhythm was also absent for serum albumin in both C-IV and D-IV fed rats. C-IV feeding increased serum glucose and insulin levels and decreased serum albumin levels in comparison to IG feeding. In comparison to the ad libitum-fed, control rats, C-IV or D-IV or IG infusions led to alterations in liver and serum parameters.

Circadian rhythmicity in several small intestinal functions is independent of use of the intestine.

Fifty milliliters of a liquid diet were administered daily to rats in three different ways: 1) orally, beginning at 0000 h; 2) by continuous intravenous infusion; and 3) by discontinuous intravenous infusion from 0000 to 1400 h. Animals were killed every 6 h over a 24-h period. Activity profiles as a function of time of day were determined for the following small intestinal parameters; monosaccharide transport; five disaccharidases; alkaline phosphatase; gamma-glutamyltransferase; leucylnaphthylamide hydrolyzing activity; villus height and width; and number of columnar cells lining a villus section. Circadian rhythmicity as previously reported was observed for all parameters in rats fed orally for 7 days but was not observed in any parameters in rats fed by continuous infusion for 9 days. Rats fed by discontinuous infusion for 10 days maintained circadian rhythmicity in the following functions: monosaccharide transport; disaccharidase activities; and columnar cell number. Thus, rhythmicity in these functions can exist without nutrient delivery to the alimentary tract and presumably arises from involvement of a neuro-endocrine component. The other activities tested appear to require the alimentary tract for the existence of circadian rhythmicity.

Regional variability in circadian rhythmicity of intestinal digestive-absorptive functions.

The circadian rhythms of sucrase, maltase, isomaltase, trehalase, lactase, gamma-glutamyltransferase, leucylnaphthylamide hydrolyzing activity, alkaline phosphatase and monosaccharide transport were assessed in each fifth of the small intestine of the rat in order to determine if an entire enzyme or transport system population responded in a similar manner or if there were regional differences. Animals were maintained under a light-dark cycle and fed from 1400-1800, EST for 7 days. Functional activities were assessed every 4 h for 24 h, inclusively. Quantitative, and in a few instances, qualitative differences in different areas of the intestine were found for all functions. There were portions of the lactase and alkaline phosphatase populations which displayed no rhythmicity in activity. When rhythmicity was observed there were differences in the activity patterns along the intestine for all functions. Thus, the rhythm patterns obtained from homogenates of the entire small intestine are a composite of the patterns in regions of high average activity. Also, there appears to be a reasonable amount of local control of the various functions.

Evidence for circadian rhythmicity in guanyl cyclase of the rat intestinal epithelial cell.

The activity of the enzyme, guanyl cyclase, associated with the rat intestinal brush border membrane, has an endogenous circadian rhythm which is observed in the absence of oral intermittent feeding and of a dark period. This rhythm is cued by the feeding schedule but is essentially unaffected by a light-dark cycle.

Circadian rhythmicity in rat intestinal villus length and cell number.

Circadian rhythmicity has been reported in various small intestinal digestive-absorptive functions and in the mitotic activity of intestinal crypt cells. These functional activity rhythms and perhaps the mitotic rhythms are cued by the feeding schedule. We now report that circadian rhythms also occurred in both the villus height and cell number in rats maintained on morning or afternoon feeding schedules for 7 days. Villus width was constant. In afternoon-fed rats both villus height and cell number were 50% greater just before feeding than 12 h later. The amplitudes of the two rhythms in the morning fed rats were decreased, the general shape of the cycles were changed and the average number of cells was increased. These changes between morning and afternoon feeding are attributed to incomplete phase shifting due to an insufficient adaptation span for the morning fed rats. We conclude that circadian rhythms occurring in villus height and cell number are affected by the feeding schedule. Similarities to some previously reported functional rhythms suggest that fluctuations in cell number and/or villus length might be related to the functional changes.

The effects of meal-feeding at different times of the day on daily changes in serum insulin, gastrin and liver enzymes in the rat.

Restricted feeding at two distinct times of the day was associated with different adaptive responses in rats. Animals meal-fed from 1400 to 1800 hours for 6 days demonstrated feeding-cued circadian rhythms in liver weight and in liver transaminase and lactic dehydrogenase enzyme activities. Daily fluctuations in the levels of blood immunoreactive insulin and gastrin were also found to be cued by food intake. By comparison, rats fed from 0700 to 1100 hours for 6 days exhibited altered liver function and blood immunoreactive gastrin patterns. It is suggested that meal-feeding in rats is associated with certain adaptive responses which are dependent upon the timing of the meal. The observed metabolic alterations consequent to meal-feeding are much more apparent in morning-fed than in afternoon-fed animals.

Circadian rhythms of intestinal sucrase and glucose transport: cued by time of feeding.

In the rat, under constant illumination, the activities of the digestive enzyme sucrase and the absorptive transport system for glucose follow circadian rhythms on ad lib. and controlled feeding regimens. In response to controlled feeding, (1400-1800 h or 0200-0600 h, EST), both rhythms shift with time and the general level of activities are enhanced. Sucrase activity peaks before feeding and transport activity peaks during feeding. Feeding is a synchronizer for these digestive-absorptive functions, and the maximum activity of a function may occur prior to as well as subsequent to the daily onset of the synchronizer. The rhythms of these functions results from previous days' feeding patterns.

Effect of changes in feeding schedule on the diurnal rhythms and daily activity levels of intestinal brush border enzymes and transport systems.

The activities of rat intestinal enzymes, sucrase, lactase, maltase, trehalase, gamma-glutamyltransferase, leucylnaphthylamide-hydrolyzing activity, and the transport system for glucose follow diurnal rhythms on ad libitum and restricted feeding regimes. In response to 6 days of restricted feeding, food available between 1400 and 1800 Eastern Standard Time, all rhythms shifted in time and the daily levels of activities were changed. Alkaline phosphatase activity followed a diurnal rhythm only in restricted fed animals. In restricted fed rats several activity patterns were observed, some with short periods of maximum activity, 3 h or less, and some with plateaus of maximum activity, 5-9 h long. In respect to the time of day of the synchronizer, sucrase peaked before feeding, glucose transport peaked during feeding, alkaline phosphatase peaked after feeding, and the other enzymes had higher levels of activity before, during and after feeding. The effect of restricted feeding on the daily activity levels were: a decrease in leucylnaphthylamide-hydrolyzing activity, no change in alkaline phosphatase, and increases in the others. These enzyme and transport systems exhibit a large amount of individual regulation or control as reflected by the lack of a uniform activity pattern and response to the synchronizer, and the variation in direction and magnitude of the adaptations to restricted feeding.