A maternal Western diet during gestation and lactation modifies offspring's microglial cell density and morphology in the hippocampus and prefrontal cortex in Yucatan minipigs.

Changes in microglial development and morphology can be induced by inflammatory conditions and associated with eating or mood disorders, such as hyperphagia or depression. In a previous paper in the minipig model, we showed that maternal Western diet during gestation and lactation decreased hippocampus neurogenesis and food-rewarded cognitive abilities in the progeny. Whether these alterations are concomitant with a central inflammatory process in brain structures involved in learning and memory (hippocampus, HPC), cognitive (prefrontal cortex, PFC), or hedonic (orbitofrontal cortex, OFC) control of food intake is still unknown. In the present study, Yucatan minipigs (Sus scrofa) sows were exposed to two different diets during gestation and lactation (standard, SD N = 7 vs. Western diet, WD N = 9). Iba1 is a calcium-binding protein specifically expressed in microglia in the brain, which plays an important role in the regulation of the microglia function. Iba1 expression was examined by immunohistochemical analyses in the PFC, OFC and HPC of piglets. The density of microglial cells, as well as their morphology, were assessed in order to have an indirect insight of microglial cell activation state possibly in relationship with neuroinflammation. The density of Iba1-positive cells was higher in the PFC but not in the HPC of WD compared to SD piglets (p < 0.001). In the HPC, anterior and dorsolateral PFC, WD piglets had more unipolar cells, contrary to SD that had more multipolar cells (P < 0.0001). Opposite effects were observed in the OFC, with SD presenting more unipolar (P < 0.001) microglial cells compared to WD. We showed here that maternal diet during pregnancy and lactation had significant effects on morphological changes of microglial cells in the offspring, and that these effects differed between the HPC and PFC, suggesting different response mechanisms to the early nutritional environment.

A maternal Western diet during gestation and lactation modifies offspring's microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs.

A suboptimal early nutritional environment (i.e., excess of energy, sugar, and fat intake) can increase susceptibility to diseases and neurocognitive disorders. The purpose of this study was to investigate in nonobese Yucatan minipigs (Sus scrofa) the impact of maternal diet [standard diet (SD) vs. Western diet (WD)] during gestation and 25 d of lactation on milk composition, blood metabolism, and microbiota activity of sows (n = 17) and their piglets (n = 65), and on spatial cognition (n = 51), hippocampal plasticity (n = 17), and food preferences/motivation (n = 51) in the progeny. Milk dry matter and lipid content, as well as plasma total cholesterol and free fatty acid (FFA) concentrations (P < 0.05) were higher in WD than in SD sows. Microbiota activity decreased in both WD sows and 100-d-old piglets (P < 0.05 or P < 0.10, depending on short-chain FAs [SCFAs]). At weaning [postnatal day (PND) 25], WD piglets had increased blood triglyceride and FFA levels (P < 0.01). Both SD and WD piglets consumed more of a known SD than an unknown high-fat and -sucrose (HFS) diet (P < 0.0001), but were quicker to obtain HFS rewards compared with SD rewards (P < 0.01). WD piglets had higher working memory (P = 0.015) and reference memory (P < 0.001) scores, which may reflect better cognitive abilities in the task context and a higher motivation for the food rewards. WD piglets had a smaller hippocampal granular cell layer (P = 0.03) and decreased neurogenesis (P < 0.005), but increased cell proliferation (P < 0.001). A maternal WD during gestation and lactation, even in the absence of obesity, has significant consequences for piglets' blood lipid levels, microbiota activity, gut-brain axis, and neurocognitive abilities after weaning.-Val-Laillet, D., Besson, M., Guérin, S., Coquery, N., Randuineau, G., Kanzari, A., Quesnel, H., Bonhomme, N., Bolhuis, J. E., Kemp, B., Blat, S., Le Huërou-Luron, I., Clouard, C. A maternal Western diet during gestation and lactation modifies offspring's microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs.

The peptidic antidepressant spadin interacts with prefrontal 5-HT(4) and mGluR(2) receptors in the control of serotonergic function.

This study investigates the mechanism of action of spadin, a putative fast-acting peptidic antidepressant (AD) and a functional blocker of the K(+) TREK-1 channel, in relation with the medial prefrontal cortex (mPFC)-dorsal raphé (DRN) serotonergic (5-HT) neurons connectivity. Spadin increased 5-HT neuron firing rate by 113%, an augmentation abolished after electrolytic lesion of the mPFC. Among the few receptor subtypes known to modulate TREK-1, the stimulation of 5-HT4 receptors and the blockade of mGluR2/3 ones both activated 5-HT impulse flow, effects also suppressed by mPFC lesion. The combination of spadin with the 5-HT4 agonist RS 67333 paradoxically reduced 5-HT firing, an effect reversed by acutely administering the 5-HT1A agonist flesinoxan. It also had a robust synergetic effect on the expression of Zif268 within the DRN. Together, these results strongly suggest that 5-HT neurons underwent a state of depolarization block, and that the mechanisms underlying the influences exerted by spadin and RS 67333 are additive and independent from each other. In contrast, the mGluR2/3 antagonist LY 341495 occluded the effect of spadin, showing that it likely depends on mPFC TREK-1 channels coupled to mGluR2/3 receptors. These in vivo electrophysiological data were confirmed by in vitro Ca(2+) cell imaging performed in cultured cortical neurons. Altogether, our results indicate that spadin, as a natural compound, constitutes a very good candidate to explore the "glutamatergic path" of fast-acting AD research. In addition, they provide the first evidence of 5-HT depolarization block, showing that the combination of 5-HT activators for strategies of AD augmentation should be performed with extreme caution.