"Comfort-foods" chronic intake has different behavioral and neurobiological effects in male rats exposed or not to early-life stress.

The ability of "comfort-food" (CF) diet to revert long-term effects of early-life stress (ELS) is less well known. The objective of this study was to verify if the chronic exposure to CF diet in animals submitted to ELS could relief the stress response at behavioral, neuroendocrine, and neurobiochemical levels, via differences in glucocorticoid receptors expression in brain areas involved in the stress response. From the second day of life, litters of Wistar rats and their mothers were submitted to the reduced nesting material protocol (ELS). In adult life, ELS and a control group were exposed chronically to two diet schemes: standard rat chow only or both "CF" diet, containing fat (34%) and sugar (20%) and a diet similar to the standard diet. Anxiety-like behavior, neuroendocrine response stress, leptin, GR, SOCS-3, pSTAT3, and the abdominal fat were evaluated. The anxiety-like behavior results showed that ELS group when exposed to comfort food were not different from the others groups. Chronic exposure to CF diet induced an anxiety-like behavior in the control group. Groups chronically exposed to CF diet had lower levels of corticosterone over time independent of the neonatal group. The ELS group exposed to the "CF" diet had higher levels of hippocampal GR, lower levels of hypothalamic SOCS-3 and greater accumulation of abdominal fat. Chronic CF diet consumption is able to reduce corticosterone levels independent of the neonatal history, but is associated with anxiety-like behavior in animals without previous history of trauma. Metabolic disturbances like increased adiposity and altered SOCS-3 seem to be a result of multiple insults (neonatal trauma followed by chronic CF diet). We highlight that the Control-chow and ELS-chow data were previously published, and are included in this study for comparative analysis.

Intrauterine Growth Restriction Modifies the Accumbal Dopaminergic Response to Palatable Food Intake.

Intrauterine growth restriction (IUGR) associates with increased preference for palatable foods and altered insulin sensitivity. Insulin modulates the central dopaminergic response and changes behavioral responses to reward. We measured the release of dopamine in the accumbens during palatable food intake in IUGR rats both at baseline and in response to insulin. From pregnancy day 10 until birth, gestating Sprague-Dawley rats received either an ad libitum (Control), or a 50% food restricted (FR) diet. In adulthood, palatable food consumption and feeding behavior entropy was assessed using an electronic food intake monitor (BioDAQ®), and dopamine response to palatable food was measured by chronoamperometry recordings in the nucleus accumbens (NAcc). FR rats eat more palatable foods during the dark phase, and their eating pattern has a higher entropy compared to control rats. There was a delayed dopamine release in the FR group in response to palatable food and insulin administration reverted this delayed effect. Western blot showed a decrease in suppressor of cytokine signaling 3 protein (SOCS3) in the ventral tegmental area (VTA) and an increase in the ratio of phospho-tyrosine hydroxylase to tyrosine hydroxylase (pTH/TH) in the NAcc of FR rats. Administration of insulin also abolished this latter effect in FR rats. FR rats showed metabolic alterations and a delay in the dopaminergic response to palatable foods. This could explain the increased palatable food intake and behavioral entropy found in FR rats. IUGR may lead to binge eating, obesity and its metabolic consequences by modifying the central dopaminergic response to sweet food.

Intrauterine growth restriction modifies the hedonic response to sweet taste in newborn pups - Role of the accumbal µ-opioid receptors.

Intrauterine growth restriction (IUGR) is associated with increased preference for palatable foods. The hedonic response to sweet taste, modulated by the nucleus accumbens µ-opioid-receptors, may be involved. We investigated hedonic responses and receptor levels in IUGR and Control animals. From pregnancy day 10, Sprague-Dawley dams received either an ad libitum (Control), or a 50% food restricted (FR) diet. At birth, pups were cross-fostered, and nursed by Adlib fed dams. The hedonic response was evaluated at 1 day after birth and at 90 days of life, by giving sucrose solution or water and analyzing the hedonic facial responses (within 60s). Control pups exposed either to water or sucrose resolved their hedonic responses after 16 and 18s, respectively, while FR hedonic responses to sucrose persisted over 20s. FR pups had deceased phospho-µ-opioid-receptor (p=0.009) and reduced phosphor:total mu opioid receptor ratio compared to controls pups (p=0.003). In adults, there was an interaction between group and solution at the end of the evaluation (p=0.044): Control decreased the response after sucrose solution, FR did not change over time. There were no differences in phosphorylation of µ-opioid-receptor in adults. These results demonstrate IUGR newborn rats exhibit alterations in hedonic response accompanied by a decrease in µ-opioid-receptor phosphorylation, though these alterations do not persist at 3 months of age. Opioid system alterations in early life may contribute to the development of preference for highly palatable foods and contribute to rapid weight gain and obesity in IUGR offspring.

Litter size reduction alters insulin signaling in the ventral tegmental area and influences dopamine-related behaviors in adult rats.

Postnatal overfeeding is a well-known model of early-life induced obesity and glucose intolerance in rats. However, little is known about its impact on insulin signaling in specific brain regions such as the mesocorticolimbic system, and its putative effects on dopamine-related hedonic food intake in adulthood. For this study, rat litters were standardized to 4 (small litter - SL) or 8 pups (control - NL) at postnatal day 1. Weaning was at day 21, and all tests were conducted after day 60 of life in male rats. In Experiment 1, we demonstrated that the SL animals were heavier than the NL at all time points and had decreased AKT/pAKT ratio in the Ventral Tegmental Area (VTA), without differences in the skeletal muscle insulin signaling in response to insulin injection. In Experiment 2, the standard rat chow intake was addressed using an automated system (BioDAQ, Research Diets(®)), and showed no differences between the groups. On the other hand, the SL animals ingested more sweet food in response to the 1 min tail-pinch challenge and did not develop conditioned place preference to sweet food. In Experiment 3 we showed that the SL rats had increased VTA TH content but had no difference in this protein in response to a sweet food challenge, as the NL had. The SL rats also showed decreased levels of dopamine D2 receptors in the nucleus accumbens. Here we showed that early postnatal overfeeding was linked to an altered functioning of the mesolimbic dopamine pathway, which was associated with altered insulin signaling in the VTA, suggesting increased sensitivity, and expression of important proteins of the dopaminergic system.