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Maternal Brain TNF-α Programs Innate Fear in the Offspring.

ABSTRACT: Tumor necrosis factor alpha (TNF-α) is a cytokine that not only coordinates local and systemic immune responses [1, 2] but also regulates neuronal functions. Most prominently, glia-derived TNF-α has been shown to regulate homeostatic synaptic scaling [3-6], but TNF-α-null mice exhibited no apparent cognitive or emotional abnormalities. Instead, we found a TNF-α-dependent intergenerational effect, as mothers with a deficit in TNF-α programmed their offspring to exhibit low innate fear. Cross-fostering and conditional knockout experiments indicated that a TNF-α deficit in the maternal brain, rather than in the hematopoietic system, and during gestation was responsible for the low-fear offspring phenotype. The level of innate fear governs the balance between exploration/foraging and avoidance of predators and is thus fundamentally important in adaptation, fitness, and survival [7]. Because maternal exercise and activity are known to reduce both brain TNF-α [8] and offspring innate fear [9], whereas maternal stress has been reported to increase brain TNF-α [10] and offspring fear and anxiety [11, 12], maternal brain TNF-α may report environmental conditions to promote offspring behavioral adaptation to their anticipated postnatal environment.

SUBMITTER: Zupan B

PROVIDER: S-EPMC6170164 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Maternal Brain TNF-α Programs Innate Fear in the Offspring.

Zupan Bojana B Liu Bingfang B Taki Faten F Toth Judit Gal JG Toth Miklos M

Current biology : CB 20171130 24

Tumor necrosis factor alpha (TNF-α) is a cytokine that not only coordinates local and systemic immune responses [1, 2] but also regulates neuronal functions. Most prominently, glia-derived TNF-α has been shown to regulate homeostatic synaptic scaling [3-6], but TNF-α-null mice exhibited no apparent cognitive or emotional abnormalities. Instead, we found a TNF-α-dependent intergenerational effect, as mothers with a deficit in TNF-α programmed their offspring to exhibit low innate fear. Cross-fost ...[more]

PMID: 29199072

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Project description:Understanding the link between mother's obesity and regulation of the child's appetite is a prerequisite for the design of successful preventive strategies. Beyond the possible contributions of genetic heritage, family culture, and hormonal and metabolic environment during pregnancy, we investigate in the present paper the causal role of the transmission of the maternal microbiotas in obesity as microbiotas differ between lean and obese mothers, maternal microbiotas are the main determinants of a baby's gut colonization, and the intestinal microbiota resulting from the early colonization could impact the feeding behavior of the offspring with short- and long-term consequences on body weight. We thus investigated the potential role of vertical transfers of maternal microbiotas in programming the eating behavior of the offspring. Selectively bred obese-prone (OP)/obese-resistant (OR) Sprague-Dawley dams were used since differences in the cecal microbiota have been evidenced from males of that strain. Microbiota collected from vagina (at the end of gestation), feces, and milk (at postnatal days 1, 5, 10, and 15) of OP/OR dams were orally inoculated to conventional Fischer F344 recipient pups from birth to 15 days of age to create three groups of pups: F-OP, F-OR, and F-Sham group (that received the vehicle). We first checked microbiotal differences between inoculas. We then assessed the impact of transfer (from birth to adulthood) onto the intestinal microbiota of recipients rats, their growth, and their eating behavior by measuring their caloric intake, their anticipatory food reward responses, their preference for sweet and fat tastes in solutions, and the sensations that extend after food ingestion. Finally, we searched for correlation between microbiota composition and food intake parameters. We found that maternal transfer of microbiota differing in composition led to alterations in pups' gut microbiota composition that did not last until adulthood but were associated with specific eating behavior characteristics that were predisposing F-OP rats to higher risk of over consuming at subsequent periods of their life. These findings support the view that neonatal gut microbiotal transfer can program eating behavior, even without a significant long-lasting impact on adulthood microbiota composition.

Project description:Gestational exposure to maternal overweight (OW) influences the risk of obesity in adult life. Male offspring from OW dams gain greater body weight and fat mass and develop insulin resistance when fed high-fat diets (45% fat). In this report, we identify molecular targets of maternal OW-induced programming at postnatal d 21 before challenge with the high-fat diet. We conducted global transcriptome profiling, gene/protein expression analyses, and characterization of downstream signaling of insulin and adiponectin pathways in conjunction with endocrine and biochemical characterization. Offspring born to OW dams displayed increased serum insulin, leptin, and resistin levels (P < 0.05) at postnatal d 21 preceding changes in body composition. A lipogenic transcriptome signature in the liver, before development of obesity, was evident in OW-dam offspring. A coordinated locus of 20 sterol regulatory element-binding protein-1-regulated target genes was induced by maternal OW. Increased nuclear levels of sterol regulatory element-binding protein-1 and recruitment to the fatty acid synthase promoter were confirmed via ELISA and chromatin immunoprecipitation analyses, respectively. Higher fatty acid synthase and acetyl coenzyme A carboxylase protein and pAKT (Thr(308)) and phospho-insulin receptor-beta were confirmed via immunoblotting. Maternal OW also attenuated AMP kinase/peroxisome proliferator-activated receptor-alpha signaling in the offspring liver, including transcriptional down-regulation of several peroxisome proliferator-activated receptor-alpha-regulated genes. Hepatic mRNA and circulating fibroblast growth factor-21 levels were significantly lower in OW-dam offspring. Furthermore, serum levels of high-molecular-weight adiponectin (P < 0.05) were decreased in OW-dam offspring. Phosphorylation of hepatic AMP-kinase (Thr(172)) was significantly decreased in OW-dam offspring, along with lower AdipoR1 mRNA. Our results strongly suggest that gestational exposure to maternal obesity programs multiple aspects of energy-balance regulation in the offspring.

Dataset Information

Maternal Brain TNF-α Programs Innate Fear in the Offspring.

Publications

Maternal Brain TNF-α Programs Innate Fear in the Offspring.

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