Paul Meurice

A three-dimensional digital segmented and deformable brain atlas of the domestic pig

We used high-magnetic field (4.7 T) magnetic resonance imaging (MRI) to build the first high-resolution (100 microm x 150 microm x 100 microm) three-dimensional (3D) digital atlas in stereotaxic coordinates of the brain of a female domestic pig (Sus scrofa domesticus). This atlas was constructed from one hemisphere which underwent a symmetrical transformation through the midsagittal plane. Concomitant construction of a 3D histological atlas based on the same scheme facilitated control of deep brain structure delimitation and enabled cortical mapping to be achieved. The atlas contains 178 individual cerebral structures including 42 paired and 9 single deep brain structures, 5 ventricular system areas, 6 paired deep cerebellar nuclei, 12 cerebellar lobules and 28 cortical areas per hemisphere. Given the increasing importance of pig brains in medical research, this atlas should be a useful tool for intersubject normalization in anatomical imaging as well as for precisely localizing brain areas in functional MR studies or electrode implantation trials. The atlas can be freely downloaded from our institutions Website.

Changes in Brain Activity After a Diet‐Induced Obesity

Compared to lean subjects, obese men have less activation in the dorsolateral prefrontal cortex, a brain area implicated in the inhibition of inappropriate behavior, satiety, and meal termination. Whether this deficit precedes weight gain or is an acquired feature of obesity remains unknown. An adult animal model of obesity may provide insight to this question since brain imaging can be performed in lean vs. obese conditions in a controlled study. Seven diet‐induced obese adult minipigs were compared to nine lean adult minipigs housed in the same conditions. Brain activation after an overnight fasting was mapped in lean and obese subjects by single photon emission computed tomography. Cerebral blood flow, a marker of brain activity, was measured in isoflurane‐anesthetized animals after the intravenous injection of 99mTc‐HMPAO (750 MBq). Statistical analysis was performed using statistical parametric mapping (SPM) software and cerebral blood flow differences were determined using co‐registered T1 magnetic resonance imaging (MRI) and histological atlases. Deactivations were observed in the dorsolateral and anterior prefrontal cortices in obese compared to lean subjects. They were also observed in several other structures, including the ventral tegmental area, the nucleus accumbens, and nucleus pontis. On the contrary, activations were found in four different regions, including the ventral posterior nucleus of the thalamus and middle temporal gyrus. Moreover, the anterior and dorsolateral prefrontal cortices as well as the insular cortex activity was negatively associated with the body weight. We suggested that the reduced activation of prefrontal cortex observed in obese humans is probably an acquired feature of obesity since it is also found in minipigs with a diet‐induced obesity.

Combined compared to dissociated oral and intestinal sucrose stimuli induce different brain hedonic processes

The characterization of brain networks contributing to the processing of oral and/or intestinal sugar signals in a relevant animal model might help to understand the neural mechanisms related to the control of food intake in humans and suggest potential causes for impaired eating behaviors. This study aimed at comparing the brain responses triggered by oral and/or intestinal sucrose sensing in pigs. Seven animals underwent brain single photon emission computed tomography (99mTc-HMPAO) further to oral stimulation with neutral or sucrose artificial saliva paired with saline or sucrose infusion in the duodenum, the proximal part of the intestine. Oral and/or duodenal sucrose sensing induced differential cerebral blood flow changes in brain regions known to be involved in memory, reward processes and hedonic (i.e., pleasure) evaluation of sensory stimuli, including the dorsal striatum, prefrontal cortex, cingulate cortex, insular cortex, hippocampus, and parahippocampal cortex. Sucrose duodenal infusion only and combined sucrose stimulation induced similar activity patterns in the putamen, ventral anterior cingulate cortex and hippocampus. Some brain deactivations in the prefrontal and insular cortices were only detected in the presence of oral sucrose stimulation. Finally, activation of the right insular cortex was only induced by combined oral and duodenal sucrose stimulation, while specific activity patterns were detected in the hippocampus and parahippocampal cortex with oral sucrose dissociated from caloric load. This study sheds new light on the brain hedonic responses to sugar and has potential implications to unravel the neuropsychological mechanisms underlying food pleasure and motivation.

Familiarity to a Feed Additive Modulates Its Effects on Brain Responses in Reward and Memory Regions in the Pig Model.

Brain responses to feed flavors with or without a feed additive (FA) were investigated in piglets familiarized or not with this FA. Sixteen piglets were allocated to 2 dietary treatments from weaning until d 37: the naive group (NAI) received a standard control feed and the familiarized group (FAM) received the same feed added with a FA mainly made of orange extracts. Animals were subjected to a feed transition at d 16 post-weaning, and to 2-choice feeding tests at d 16 and d 23. Production traits of the piglets were assessed up to d 28 post-weaning. From d 26 onwards, animals underwent 2 brain imaging sessions (positron emission tomography of 18FDG) under anesthesia to investigate the brain activity triggered by the exposure to the flavors of the feed with (FA) or without (C) the FA. Images were analyzed with SPM8 and a region of interest (ROI)-based small volume correction (p < 0.05, k ≥ 25 voxels per cluster). The brain ROI were selected upon their role in sensory evaluation, cognition and reward, and included the prefrontal cortex, insular cortex, fusiform gyrus, limbic system and corpus striatum. The FAM animals showed a moderate preference for the novel post-transition FA feed compared to the C feed on d 16, i.e., day of the feed transition (67% of total feed intake). The presence or absence of the FA in the diet from weaning had no impact on body weight, average daily gain, and feed efficiency of the animals over the whole experimental period (p ≥ 0.10). Familiar feed flavors activated the prefrontal cortex. The amygdala, insular cortex, and prepyriform area were only activated in familiarized animals exposed to the FA feed flavor. The perception of FA feed flavor in the familiarized animals activated the dorsal striatum differently than the perception of the C feed flavor in naive animals. Our data demonstrated that the perception of FA in familiarized individuals induced different brain responses in regions involved in reward anticipation and/or perception processes than the familiar control feed flavor in naive animals. Chronic exposure to the FA might be necessary for positive hedonic effects, but familiarity only cannot explain them.

Effects of Chronic Consumption of Sugar-Enriched Diets on Brain Metabolism and Insulin Sensitivity in Adult Yucatan Minipigs.

Excessive sugar intake might increase the risk to develop eating disorders via an altered reward circuitry, but it remains unknown whether different sugar sources induce different neural effects and whether these effects are dependent from body weight. Therefore, we compared the effects of three high-fat and isocaloric diets varying only in their carbohydrate sources on brain activity of reward-related regions, and assessed whether brain activity is dependent on insulin sensitivity. Twenty-four minipigs underwent 18FDG PET brain imaging following 7-month intake of high-fat diets of which 20% in dry matter weight (36.3% of metabolisable energy) was provided by starch, glucose or fructose (n = 8 per diet). Animals were then subjected to a euglycemic hyperinsulinemic clamp to determine peripheral insulin sensitivity. After a 7-month diet treatment, all groups had substantial increases in body weight (from 36.02±0.85 to 63.33±0.81 kg; P<0.0001), regardless of the diet. All groups presented similar insulin sensitivity index (ISI = 1.39±0.10 mL·min-1·μUI·kg). Compared to starch, chronic exposure to fructose and glucose induced bilateral brain activations, i.e. increased basal cerebral glucose metabolism, in several reward-related brain regions including the anterior and dorsolateral prefrontal cortex, the orbitofrontal cortex, the anterior cingulate cortex, the caudate and putamen. The lack of differences in insulin sensitivity index and body weight suggests that the observed differences in basal brain glucose metabolism are not related to differences in peripheral insulin sensitivity and weight gain. The differences in basal brain metabolism in reward-related brain areas suggest the onset of cerebral functional alterations induced by chronic consumption of dietary sugars. Further studies should explore the underlying mechanisms, such as the availability of intestinal and brain sugar transporter, or the appearance of addictive-like behavioral correlates of these brain functional characteristics.

fMRI-Based Brain Responses to Quinine and Sucrose Gustatory Stimulation for Nutrition Research in the Minipig Model: A Proof-of-Concept Study

The minipig model is of high interest for brain research in nutrition and associated pathologies considering the similarities to human nutritional physiology, brain structures, and functions. In the context of a gustatory stimulation paradigm, fMRI can provide crucial information about the sensory, cognitive, and hedonic integration of exteroceptive stimuli in healthy and pathological nutritional conditions. Our aims were (i) to validate the experimental setup, i.e., fMRI acquisition and SPM-based statistical analysis, with a visual stimulation; (ii) to implement the fMRI procedure in order to map the brain responses to different gustatory stimulations, i.e., sucrose (5%) and quinine (10 mM), and (ii) to investigate the differential effects of potentially aversive (quinine) and appetitive/pleasant (sucrose) oral stimulation on brain responses, especially in the limbic and reward circuits. Six Yucatan minipigs were imaged on an Avanto 1.5-T MRI under isoflurane anesthesia and mechanical ventilation. BOLD signal was recorded during visual or gustatory (artificial saliva, sucrose, or quinine) stimulation with a block paradigm. With the visual stimulation, brain responses were detected in the visual cortex, thus validating our experimental and statistical setup. Quinine and sucrose stimulation promoted different cerebral activation patterns that were concordant, to some extent, to results from human studies. The insular cortex (i.e., gustatory cortex) was activated with both sucrose and quinine, but other regions were specifically activated by one or the other stimulation. Gustatory stimulation combined with fMRI analysis in large animals such as minipigs is a promising approach to investigate the integration of gustatory stimulation in healthy or pathological conditions such as obesity, eating disorders, or dysgeusia. To date, this is the first intent to describe gustatory stimulation in minipigs using fMRI.

Obesogenic diets have deleterious effects on fat deposits irrespective of the nature of dietary carbohydrates in a Yucatan minipig model

The effects of digestible carbohydrates, fructose in particular, on the development of metabolic disturbances remain controversial. We explored the effects of prolonged consumption of high-fat diets differing in their carbohydrate source on fat deposits in the adult Yucatan minipig. Eighteen minipigs underwent computed tomographic imaging and blood sampling before and after 8 weeks of three isocaloric high-fat diets with different carbohydrate sources (20% by weight for starch in the control diet, glucose or fructose, n=6 per diet). Body adiposity, liver volume, and fat content were estimated from computed tomographic images (n=18). Liver volume and lipid content were also measured post mortem (n=12). We hypothesized that the quantity and the spatial distribution of fat deposits in the adipose tissue or in the liver would be altered by the nature of the carbohydrate present in the obesogenic diet. After 8 weeks of dietary exposure, body weight (from 26±4 to 58±3 kg), total body adiposity (from 38±1 to 47±1%; P<.0001), liver volume (from 1156±31 to 1486±66 mL; P<.0001), plasma insulin (from 10±1 to 14±2 mIU/L; P=.001), triacylglycerol (from 318±37 to 466±33 mg/L; P=.005), and free-fatty acids (from 196±60 to 396±59 μmol/L; P=.0001) increased irrespective of the carbohydrate type. Similarly, the carbohydrate type did not induce changes in the spatial repartition of the adipose tissue. Divergent results were obtained for fat deposits in the liver depending on the investigation method. In conclusion, obesogenic diets alter adipose tissue fat deposits and the metabolic profile independently of the nature of dietary carbohydrates.

O62: Détection combinée ou dissociée du sucre aux niveaux gustatif et/ou viscéral : conséquences sur les processus hédoniques cérébraux

Introduction et but de l’etude La caracterisation des reseaux cerebraux impliques dans le traitement des signaux sucres gustatifs et/ou visceraux chez un modele animal pertinent en nutrition humaine pourrait aider a mieux comprendre les mecanismes centraux lies au controle de l’ingestion et les causes potentielles de certains troubles du comportement alimentaire. Cette etude d’imagerie cerebrale avait pour objectif de comparer les reponses cerebrales induites par la detection dissociee ou combinee de saccharose aux niveaux oral et/ou intestinal, chez le porcelet en croissance. Materiel et methodes Sept animaux ont ete soumis, sous anesthe-sie generale a l’isoflurane, a quatre seances d’imagerie cerebrale par tomographie d’emission monophotonique ( 99m Tc-HMPAO) lors d’une exposition a une stimulation orale avec de la salive artificielle neutre (OS-) ou sucree (OS+), couplee a une infusion duodenale de serum physiologique (DS-) ou de saccharose (DS+). Trois contrastes cerebraux ont ete analyses via le logiciel SPM8 : OS+DS+ vs. OS-DS-, OS+DS- vs. OS-DS-, et OS-DS+ vs. OS-DS- pour etudier les reponses a des stimulations sucrees associant ou dissociant les modalites gusta-tives et viscerales, respectivement. Une analyse SVC (Small Volume Correction) a ete realisee sur la base de regions d’interet incluant les noyaux de la base, les cortex prefrontal, insulaire et cingulaire, l’hippocampe et le cortex parahippocampique, ainsi que l’amygdale. Le seuil de significativite des pics de clusters a ete fixe a P Resultats et Analyse statistique Les resultats de cette etude montrent que la detection du saccharose aux niveaux oral et/ou duodenal a induit des modifications du debit sanguin locoregional cerebral (indicateur de l’activite cerebrale) dans des regions connues pour etre impliquees dans la memoire, les processus hedoniques et motivationnels, ainsi que l’evaluation de stimuli sensoriels. Ces regions incluent le striatum dorsal, le cortex prefrontal, le cortex cingulaire, le cortex insulaire, l’hippocampe et le cortex parahippocampique. La detection duodenale de saccharose (avec ou sans perception gustative) a induit des activations specifiques dans le putamen, le cortex cingulaire ventral anterieur et l’hippocampe. Des baisses d’activite cerebrale ont ete detectees dans les cortex prefrontal et insulaire uniquement lorsque le gout sucre etait percu oralement (avec ou sans detection duodenale). Enfin, l’activation du cortex insulaire droit a seulement ete observee lors de la detection combinee du saccharose aux niveaux oral et duodenal, tandis que des activations specifiques ont ete enregistrees dans l’hippocampe et le cortex parahippocampique en contexte de stimulation gustative dissociee d’une charge calorique. Conclusion Cette etude apporte de nouveaux elements sur les reponses cerebrales au sucre et permet d’accroitre notre connaissance des mecanismes neuropsychologiques gouvernant plaisir et motivation alimentaire. Notamment, ces resultats demontrent l’importance de la detection multimodale du sucre sur la modulation du circuit de la recompense et permettent d’emettre des hypotheses quant aux consequences centrales et comportementales de l’utilisation de succedanes du sucre, comme les edulcorants, ou bien sur la consommation excessive de regimes sucres et hypercaloriques sur la mise en place de phenomenes addictifs.