Mariana Schroeder

The reward system and maternal behavior in an animal model of depression: a microdialysis study

Rationale and objectivesFlinders sensitive line (FSL) rats, an animal model of depression, display a different pattern of maternal behavior compared to Sprague-Dawley (SD) controls. In this study, we examined the rewarding value of mother–infant interaction for FSL dams.Materials and methodsIn the main study, we measured monoamine levels in the nucleus accumbens (NAc) of early postpartum FSL and SD dams during an interaction with pups, using the microdialysis technique. In addition, we compared the preference patterns of FSL and SD rats using the conditioned place preference paradigm, with pups as the unconditioned stimuli.ResultsDopamine (DA) levels in dialysates from the NAc of SD dams but not FSL dams were elevated while interacting with pups but the metabolism of DA to dihydroxyphenylacetic acid was greater in FSL than in SD dams. While SD dams showed a conditioned preference for a region that was associated with SD pups, FSL dams did not show a preference for regions associated either with SD or FSL pups, but water deprived FSL rats demonstrated a preference to a region associated with water, eliminating an alternative explanation of learning deficit in FSL rats.ConclusionsTaken together, these results suggest that FSL dams are less rewarded by pups, compared to control dams.

Weight gain and maternal behavior in CCK1 deficient rats

The OLETF rat model of obesity has been extensively studied as an adult model of hyperphagia-induced obesity. In order to better understand the early circumstances that make OLETF pups obese, we investigated body weight from postnatal day (PND) 1 and examined diurnal maternal behavior over the first three postpartum weeks by undisturbed observations. Male and female OLETF rats weighed significantly more than LETO controls from PND 1 until adulthood. Differences in nursing behavior were observed only in the third postnatal week: OLETF dams exhibited more frequent nursing. OLETF dams displayed less self-directed behaviors and activity, over the entire postpartum period examined. Taken together, these data demonstrate that OLETF males and females are heavier from birth and suggest that maternal factors may contribute to weight differences between the strains.

Attenuation of obesity by early life food-restriction in genetically hyperphagic male OLETF rats: Peripheral mechanisms

The alarming increase in childhood, adolescent and adult obesity has exposed the need for understanding early factors affecting obesity and for treatments that may help prevent or moderate its development. In the present study, we used the OLETF rat model of early-onset hyperphagia induced obesity, which become obese as a result of the absence of CCK(1) receptors, to examine the influence of partial food restriction on peripheral adiposity-related parameters during and after chronic and early short-term food restriction. Pair feeding (to the amount of food eaten by control, LETO rats) took place from weaning until postnatal day (PND) 45 (early) or from weaning until PND90 (chronic). We examined fat pad weight (brown, retroperitoneal, inguinal and epididymal); inguinal adipocyte size and number; and plasma leptin, oxytocin and creatinine levels. We also examined body weight, feeding efficiency and spontaneous intake after release from food-restriction. The results showed that chronic food restriction produced significant reductions in adiposity parameters, hormones and body weight, while early food restriction successfully reduced long-term body weight, intake and adiposity, without affecting plasma measurements. Early (and chronic) dieting produced promising long-term effects that may imply the reorganization of both peripheral and central mechanisms that determine energy balance and further support the theory suggesting that early interventions may effectively moderate obesity, even in the presence of a genetic tendency.

Examining maternal influence on OLETF rats’ early overweight: Insights from a cross-fostering study

Obese female Otsuka Long Evans Tokushima Fatty (OLETF) rats display increased nursing time and frequency compared to lean LETO controls, suggesting a maternal contribution to pup preobesity. In previous studies, OLETF pups presented high adiposity, showed greater suckling efficiency, initiative and weight gain from nursing than controls throughout lactation. To further elucidate maternal-infant interactions contributing to pup preobesity, we cross-fostered pups a day after birth and examined maternal behavior. Nursing frequency decreased in OLETF dams raising LETO pups (OdLp) in the third postnatal week, while LETO dams raising OLETF pups showed no significant changes. Fat % was greater in the milk of OLETF versus LETO dams. OdLp pups showed long-term body weight (BW) increase, suggesting that maternal environment can induce BW increases even in the absence of a genetic tendency. Additionally, interaction between OLETF dams and pups produces high nursing frequency, exposing the pups to abundant high-fat milk, thus strengthening their preobese phenotype.

Adaptation to lactation in OLETF rats lacking CCK-1 receptors: body weight, fat tissues, leptin and oxytocin

Objective:To understand the adaptation to lactation of obese rats, by studying the interplay among the gut hormone cholecystokinin (CCK), the adiposity hormone leptin and the affiliation hormone oxytocin in modulating body mass and fat storage.Design:Strain differences were examined between Otsuka Long Evans Tokushima Fatty (OLETF) rats lacking expression of functional CCK-1 receptors and Long Evans Tokushima Otsuka (LETO) controls, tested as nulliparous dams, at the 7 and 15th lactation day, at weaning (lactation day 22) or 8 weeks postweaning.Measurements:We measured body mass, fat pads (brown, retroperitoneal and inguinal) and inguinal adipocytes. Plasma levels of leptin and oxytocin were determined.Results:Fat depots of LETO female rats were larger during lactation compared to the levels found in postweaning and nulliparous female rats. LETO female rats gained weight and accumulated fat during pregnancy and lactation, returning to their normal fat levels postweaning. In contrast, OLETF female rats presented lower body weight and fat depots during the lactation period than nulliparous dams, and regained the weight and fat postweaning. Plasma leptin and oxytocin were highly correlated and followed the same pattern. OLETF leptin levels were highly correlated with fat depot and inguinal cell surface. No significant correlation was found for LETO parameters.Conclusions:Pregnancy and lactation are energy-consuming events, which naturally induce female rats to increase food intake and accumulate fat. When challenged by the demands of rapidly growing preobese OLETF pups, OLETF dams’ fat stores are reduced to lean, LETO levels. During lactation, sensitivity of the oxytocinergic neurons descending from the paraventricular nuclei to the nucleus of the solitary tract to CCK is reduced. We theorized that this pathway is not available to OLETF female rats that lack functional CCK-1 receptors to mediate the signal. The current study contributes to the understanding of the female bodys adaptation to lactation.

Long-term obesity levels in female OLETF rats following time-specific post-weaning food restriction

Obesity and the metabolic syndrome represent serious health threats affecting increasing numbers of individuals, with females being more affected than males and with growing incidence among children and adolescents. In the present study, we used the OLETF rat model of early-onset obesity to examine the influence of different timing of food restriction on long-term obesity levels in females. Food restriction took place at different time windows: from weaning until postnatal day (PND) 45 (early); from weaning until PND90 (chronic); or from PND45 until PND70 (late). Follow-up continued until PND90. During and after the termination of the diet-restriction period, we focused on peripheral adiposity-related measures such as fat pad weight (brown, retroperitoneal and inguinal); inguinal adipocyte size and number; and leptin, oxytocin and glucose levels. We also examined body weight, feeding efficiency, spontaneous intake after release from diet-restriction, and plasma creatinine levels and estrous cycle characteristics as a result of the chronic diet. The results suggest that while food restriction produced significant weight and adiposity loss, OLETF females presented poor weight loss retention after the early and late short-term diets. The estrous cycle structure and time of first estrous of the OLETF rats were normalized by chronic food restriction. Females responded to early food restriction in a different manner than males did in previous studies, further emphasizing the importance of sex-appropriate approaches in the investigation and treatment of the pathologies related to obesity and the metabolic syndrome.

Effects of CCK-8 on independent ingestion and central c-Fos-like immunoreactivity in rats on postnatal days 10 and 11.

Controls of the independent ingestion of food in the preweanling rat emerge in the second postnatal week. We investigated the effects of CCK-8 (0, 1, 5, or 10 microg/kg IP) on intake and c-Fos-like immunoreactive (CFLI) cells in hindbrain and forebrain on postnatal days 10 and 11. Five micrograms per kilogram decreased intake and increased the number of CFLI cells in four subnuclei of the nucleus tractus solitarius (NTS), in arcuate nucleus (ARC), and in central nucleus of the amygdala (CeA). Ten micrograms per kilogram decreased intake and increased CFLI in three NTS subnuclei as much as 5 microg/kg did, but was more potent than 5 microg/kg in the medial NTS subnucleus. Ten micrograms per kilogram increased CFLI in paraventricular (PVN) and supraoptic (SON) nuclei, but 5 microg/kg did not. Thus, reduction of intake by CCK-8 on days 10 and 11 is associated with increased hindbrain and forebrain CFLI.

Stress and pain responses in rats lacking CCK1 receptors

UNLABELLED CCK involvement in stress- and pain-responsiveness was examined by studying the behavior of infant (11-12-days-old) and adult OLETF rats that do not express CCK1 receptors. Infant odor- and texture-preferences were also assessed. We hypothesized that OLETF rats will show behavioral patterns similar to those previously observed after CCK1 antagonist administration. Rate of separation-induced ultrasonic vocalization was significantly greater in OLETF compared to controls, in two separate studies. Infant pups of the two strains did not differ in odor- and texture-preference tests. OLETF rats showed consistently longer hot-plate paw-lift (as infants, in two separate studies) and paw-lick (as adults) latencies. SUMMARY OLETF pups vocalized in isolation more than controls and showed relative hypoalgesic responses, evident also in adulthood, in concordance with the pharmacological literature.

Microstructural pattern of palatable food intake from weaning to adulthood in male and female OLETF rats.

Ontogenetic trajectories from weaning to adulthood and sex differences in feeding patterns were examined in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of early onset overeating-induced obesity, and a natural cholecystokinin-1 receptor knockout. Overnight patterns of licking a palatable liquid diet (Ensure) were analyzed on Postnatal Days 22, 38, 60, and 90. Because different microstructure profiles may reflect alterations in the influence of positive and negative signals, we examined meal parameters to uncover developing mechanisms underlying eating behavior in this strain. OLETF rats displayed significantly greater caloric intake, larger meals (in number of licks), and more (within-meal) clusters of feeding (which were shorter in duration and contained fewer licks per cluster) than did Long-Evans Tokushima Ohtsuka (LETO) strain controls. OLETF rats also had significantly lower satiety ratios than LETO rats. Moreover, we identified sex differences in the age of emergence of microstructural patterns of obesity-related overeating, suggesting that systems other than cholecystokinin may be disrupted, possibly worsening the OLETF strains obesity phenotype.

Selective Leptin Insensitivity and Alterations in Female-Reproductive Patterns Linked to Hyperleptinemia during Infancy

The dramatic increase in the prevalence of childhood obesity worldwide makes the investigation of its early developmental stages and effective prevention strategies an urgent issue. CCK1 deficient OLETF rats are a model of obesity previously used to study the early phases of this disorder. Here, we exposed wild type (LETO) females to an early obesogenic environment and genetically obese OLETF females to a lean postnatal environment, to assess long term alterations in leptin sensitivity, predisposition to diet induced obesity and adult female health. We found that genetically lean females reared by obese mothers presented early postnatal hyperleptemia, selectively reduced response to leptin and sensitivity to diet induced obesity when exposed to a high palatable diet as adults. The estrous cycle structure and intake profile were permanently disrupted, despite presenting normal adiposity/body weight/food intake. Genetically obese females reared by lean dams showed normalized early levels of leptin and reduced body weight, food intake and body fat at adulthood; normalized estrous cycle structure and food intake across the cycle, improved hormonal profile and peripheral leptin sensitivity and a remarkable progress in self-control when exposed to a high fat/palatable diet. Altogether, it appears that the early postnatal environment plays a critical role in determining later life coping with metabolic challenges and has an additive effect on the genetic predisposition that makes OLETF females morbidly obese as adults. This work also links, for the first time, alterations in the leptin system during early development to later life abnormalities related to female reproduction and health.