Early-life undernutrition and depression later in life: a systematic review.

CONTEXT: Early adverse experience can have a long-term effect on growth and development and negative repercussions into adulthood. Among the various consequences of undernutrition is depression. OBJECTIVE: The present work aimed to evaluate the relationship between early-life undernutrition and depression in adult life. DATA SOURCES: Data were obtained from the PubMed, SCOPUS, and Web of Science databases in November 2021 and were selected using the systematic bibliographic review manager program State of the Art Through Systematic Review. DATA EXTRACTION: Data were extracted using the State of the Art Through Systematic Review program. DATA ANALYSIS: Of the 559 articles that were identified, 114 were duplicates, and 426 were excluded after inclusion and exclusion criteria were applied to the title and abstract. One other relevant study was included. From the 20 remaining articles, 8 were excluded after the full-text screening. Finally, 12 articles remained for review in the present work. The studies described in these articles investigated humans, rats, or mice, and correlated early-life malnutrition and depression in adulthood as the principal outcome. CONCLUSIONS: Undernutrition in early life and later depression are linked. Furthermore, the knowledge that the risk factors for depression start at the beginning of life points to public health policies starting in intrauterine life and extending throughout childhood and adolescence.

Effects of Early Weaning Associated with Alimentary Stress on Emotional and Feeding Behavior of Female Adult Wistar Rats.

Maternal lactation proves crucial for mammals' nutrition during their early development, influencing the development of adult physiological mechanisms. Its premature termination has been associated with several disorders, but these have been primarily documented in males, when they are most prevalent in women. Therefore, we subjected adult female Wistar rats to Early Weaning through maternal separation at age 15 days to acute alimentary stress in the form of visual and olfactory exposition to a cafeteria diet sans consumption for 22 days. We measured standard diet intake and water intake daily and cafeteria diet intake every 7 days. Additionally, we evaluated anxiety using the elevated plus maze and measured body weight in similar intervals. Results showed less consumption of the cafeteria diet among Early Weaning rats on day 2 and more time spent in the maze's central area by the Early Weaning rats during the basal evaluation and in the maze's open arms by control rats on day 7 when compared to the same group's basal time. No other significant differences were found. These results show the importance of determining the impact that female steroidal gonadal hormones such as estradiol have upon feeding behavior and anxiety and determining to what degree these parameters are influenced by hormonal action.

Maternal separation in the light or dark phase of the circadian cycle has different effects on the corticosterone levels and anxiety-like behavior in male adult rats.

Maternal care in early life is essential for the growth and development of an offspring. The light phase of the circadian cycle is the dam's most caring phase for her pups. Therefore, we hypothesized that, in the long term, maternal separation (an early-life stress model) in the light phase can be more deleterious than maternal separation in the dark phase. This study aims to compare the effects of maternal separation in the dark or light phase of the circadian cycle on the behavioral and physiological parameters of adult male Wistar rats. From the first to the fourteenth day of life, litters were separated from their mothers for six hours, forming the following experimental groups: Control (C), Maternal Separation in the Light (MSL), and Maternal Separation in the Dark (MSD). After weaning, these groups were left undisturbed until the start of behavioral tests in adulthood. Behavioral measures (standard diet intake, palatable diet intake, and anxiety-like behavior in the elevated plus maze), as well as retroperitoneal adipose tissue weight, and corticosterone levels in response to feeding stress, were assessed between the ages of 120 and 180 days. The results showed that, in adulthood, the food intake after an eight-hour fast or feeding stress had not changed. Anxiety behavior was analyzed by measuring time in the open or closed arms of the elevated plus-maze. The corticosterone levels were measured after food stress, and quantified by using the enzyme-linked immunosorbent assay (ELISA) method. The retroperitoneal adipose tissue weight was also measured. The MSD group presented higher corticosterone levels (MSD = 173.9 ± 12.7) when compared to the C (4.21 ± 0.3) and MSL (4.25 ± 0.28, p < 0.001) groups. In the anxiety test, we observed that the duration in the open arm was shorter for the MSL group (27.4 ± 3.7) compared to the control (112.9 ± 9.6, p < 00.1). There was no change in the MSD group compared to the control, with regard to the time spent in the open arm of the maze. An effect of maternal separation on the consumption of a palatable diet was observed. There was an increase in the palatable diet intake in the MSL (16.3 ± 1.9) and MSD (15.7 ± 0.5) groups compared to the control (11.4 ± 1.2, p < 0.05). In response to stress and food deprivation, there was no difference between groups in food consumption. The adipose tissue weight was higher in the MSD group (7.12 ± 0.29) compared to the control (4.21 ± 0.3) and MSL (4.25 ± 0.28, p < 0.001) groups. Based on the results observed, we concluded that the light-phase stress is more detrimental to emotional behavior during the first two weeks of life, and the dark-phase stress is more detrimental to Hypothalamus-Pituitary-Adrenal (HPA)-axis functioning. Furthermore, the higher intake of a palatable diet could be interpreted as a coping behavior to these early stress-related modifications.

Blockade of Opiodergic System During Early Weaning Reverts Feeding Behavior Altered Patterns.

Adverse experiences that occur during the early stages of life can have permanent repercussions in adulthood. Among these experiences, early weaning is one that can alter the molecular, cellular, and behavior patterns in later life. Centered on this fact, the objective of the current study was to evaluate the effect of early weaning at 15 days of life of Wistar rats on their feeding behavior and if the opioidergic system blockade would cause a reversal of these outcomes. Experimental groups were formed based on the weaning period of each litter. On postnatal day 15, the group D15 was weaned and, on postnatal day 30 (natural weaning), the group D30 was weaned. The rats weaned on postnatal day 15, and administered subcutaneous Naltrexone (3 mg/kg) were from group D15 + NTX. Those weaned at 15 days of age exhibited higher depressive-like behavior, lesser reactivity time to sucrose, and higher intake of palatable food than the control group. The Naltrexone administration was observed to reverse some outcomes, such as increasing the reactivity time to sucrose and decreasing the quantity of palatable food consumed, to levels similar to those of the control group. Together, the findings of the present study are indicative of the vital role played by the opioidergic system in inducing the changes noted in the eating behavior patterns during adulthood, post early weaning.

Early Life Stress and the Onset of Obesity: Proof of MicroRNAs' Involvement Through Modulation of Serotonin and Dopamine Systems' Homeostasis.

Healthy persons hold a very complex system for controlling energy homeostasis. The system functions on the interconnected way between the nutritional, endocrine, neural, and epigenetic regulation, which includes the microRNAs (miRNAs). Currently, it is well accepted that experiences of early life stress (ELS) carry modification of the central control of feeding behavior, one of the factors controlling energy homeostasis. Recently, studies give us a clue on the modulation of eating behavior, which is one of the main factors associated with the development of obesity. This clue connected the neural control through the serotonin (5HT) and dopamine (DA) systems with the fine regulation of miRNAs. The first pieces of evidence highlight the presence of the miR-16 in the regulation of the serotonin transporter (SERT) as well as the receptors 1a (5HT1A) and 2a (5HT2A). On the other hand, miR-504 is related to the dopamine receptor D2 (DRD2). As our knowledge advance, we expected to discover other important pathways for the regulation of the energy homeostasis. As both neurotransmission systems and miRNAs seem to be sensible to ELS, the aim of this review is to bring new insight about the involvement of miRNAs with a central role in the control of eating behavior focusing on the influences of ELS and regulation of neurotransmission systems.

Hypothalamic peptide and nutrient sensors gene expression in the hypothalamus of neonatal rat.

In the neonate, the main mediator for satiety or hunger is the information of distention or gastric contraction. Food intake controls has two types of a short-term one, based on the level of hydration, and another long-term one, dependent on the gastric stretch. The aim of this study is to evaluate the gene expression of peptides and nutrient sensors in the hypothalamus at 10 and 18 days of postnatal life. Male rats divided into groups: Fasting, Water, Milk, and Gavage.Two age groups had analyzed into 10 and 18 days. Gene expression of hypothalamic peptides, Neuropeptide Y(NPY), Agouti-related peptide(AgRP), proopiomelanocortin(POMC), cocaine-and amphetamine-regulated transcript(CART), and energy sensors mechanistic target of rapamycin(mTOR) and AMP-activated protein kinase(AMPK) in the hypothalamus was seen. During the fasting period, there was an increase in expression of AMPK seen in 10 and 18 days, also mTOR reduction. Expression of NPY, AgRP, and POMC suffered the fasting effect only at 18 days. The effect of gastric distention and energy loads, there was increased expression of AMPK at 10 and 18 days, but expression of mTOR showed only at 18 days. There was increased NPY expression at 18 days, but not at 10 days, while AgRP increased its expression at both ages. At 10 days gene expression of CART increased and POMC as well as 10-18 days. Data demonstrated a simultaneous responsiveness to hypothalamic nutrient sensing also, controlling peptide food consumption even at an early age. The mature standard of control only observed at 18 days of life.

Early life stress induced by maternal separation during lactation alters the eating behavior and serotonin system in middle-aged rat female offspring.

Stressful events occurring during early life have been related to behavioral and neurochemical disturbances. Maternal separation during the first two weeks of life is a traumatic event that strongly affects the feeding behavior and serotonergic system of the progeny in adulthood. As this system modulates the feeding behavior, the present study aimed at investigating the effects of maternal separation-induced stress on both the feeding behavior and serotonergic system of the middle-aged female rats by manipulating this system using fluoxetine, a selective serotonin transporter inhibitor. Lactating Wistar rats were separated from their litters from postnatal day 2 (PND 2) to PND 14 for 3 h in the dark phase of the circadian cycle. The maternally separated (MS) and control (C) groups were distinguished from each other based on the incidence or absence of maternal separation (early life stress). All the analyses were done on the female offspring from one-year of age. Maternal separation anticipated the satiety point in these females. This anticipation was linked to lower food intake, meal duration and meal size. These results mirrored the effects of fluoxetine in the control animals. Furthermore, maternal separation was associated with 5ht1b serotonin receptor hyperexpression in the hypothalamus. These findings demonstrate that maternal separation has long-lasting effects on the eating behavior and serotonergic system and that this system could be responsible for mediating these behavioral outcomes.

Early weaning modulates eating behavior and promotes hypofunction of the serotonergic (5HT) system in juvenile male rats.

Early life stress (ELS) has been associated with developmental impairments. Early weaning (EW) is a postnatal stress model consisting of interruption of lactation and maternal care. The 5HT-system has been associated with neurobehavioral modulations promoted by ELS. Thus, the present work aims to investigate the effects of early weaning on feeding behavior and serotonergic system of juvenile male rats. For this, rats were submitted to early (PND15) or natural (PND30) weaning and had the body weight, food intake in circadian phases, and food intake in response to fenfluramine assessed. mRNA expression of serotoninergic receptors (5HT1A and 5HT2C) and transporter (SERT) was assessed in the hypothalamus and brainstem, as well as NPY and POMC mRNA expression in hypothalamus. The results show that early weaning promoted changes in the percentage of weight gain during lactation period and increase in body weight at PND40. It was also observed that EW promoted increase and decrease in food intake in light and dark phase, respectively, and leads to a decreased action of fenfluramine on inhibition of food intake. In addition, early weaning promoted increased NPY and SERT mRNA expression in the hypothalamus and 5HT2C in the brainstem. Together, the data indicate that the stress caused by early weaning impairs the eating behavior of juvenile male rats through hypofunction of the 5HT-system.

Early weaning leads to disruption of homeostatic and hedonic eating behaviors and modulates serotonin (5HT) and dopamine (DA) systems in male adult rats.

Early weaning is associated with disruption of eating behavior. However, little is known about the mechanisms behind it. 5HT and DA systems are key regulators of homeostatic and hedonic eating behaviors, respectively. Thus, this study aims to evaluate the effects of early weaning on feeding behavior and 5HT and DA systems. For this, rats were submitted to regular (PND30) or early weaning (PND15) and between PND250 and PND300 were evaluated food intake of standard diet in response to 4 h food deprivation, during the 24 h period and per phase of the circadian cycle, in addition to the palatable food intake. Additionally, body mass and mRNA expression of 5HT1B, 5HT2C, SERT, DRD1 and DRD2 were evaluated in the hypothalamus and brainstem. The results demonstrate that early weaning promoted an increase in standard food intake in response to a 4 h food deprivation in the 24 h period and in the dark phase of the circadian cycle, in addition to an increased palatable food intake. No differences in body mass between regular or early weaning were observed. In the hypothalamus, increased mRNA expression of SERT and DRD1 was observed, but decreased 5HT1B mRNA expression. In the brainstem, the expression of 5HT1B, SERT, 5HT2C, DRD1 and DRD2 was increased in early weaned rats. In a nutshell, the stress promoted by early weaning has programmed the animals to be hyperphagic and to increase their palatable food intake, which was associated with modulation of 5HT and DA systems.

Early weaning disrupts feeding patterns in female juvenile rats through 5HT-system modulations.

Convergent evidence in literature shows that rapid disruption of maternal care and breastfeeding due to an early weaning protocol changes the development of several neurobehavioral patterns in rodents, including the circadian pattern of feeding. The serotoninergic system has been associated with the control of feeding patterns. Therefore, we aim to evaluate the patterns of feeding, the mRNA expression of 5 H T-1b, 5 H T-2c, and SERT on the hypothalamus, brainstem, and the body weight of female juvenile Wistar rats, submitted to early (PND15) or regular (PND30) weaning. The results demonstrate that early weaning promotes an increase in food intake in a 24 -h period, in the dark phase of the circadian cycle and in the four-hour time intervals at the beginning of the dark and light phases. Also, early weaning decreases the mRNA expression of 5 H T-1b, 5 H T-2c, and SERT on the hypothalamus, but increases it on the brainstem. Additionally, early weaning promotes an increase in body weight. Therefore, the present data demonstrate that early weaning changes the patterns of feeding in juvenile female rats and suggests that this behavioral modification is due to the modulations promoted in the 5 H T-system.

Dual exposure to stress in different stages of development affects eating behavior of male Wistar rats.

Maternal separation stress is a model of early life stress performed by the separation between dam and pups in the first days of life. The consequences of this early stress have been demonstrated on various behaviors, including feeding behavior. The results, however, are still controversial and it seems that a second exposure to stress later in life exacerbates the adverse outcomes. The present study aimed to determine the effects of maternal separation as a model of stress in early life, with or without a later life stress experience on eating behavior. Lactating Wistar rats were separated from their litters from postnatal day 2 (PND 2) to PND 14 for 3 h in the dark phase of the circadian cycle. The groups control (C) and separated (S) were composed. The assessment of food intake was performed between the ages of 60 and 150 days of life with a group that experienced only the early stress by maternal separation and with a second group that experienced the pre-weaning maternal separation stress and the food stress from 60 days of age. This food stress consisted of allowing visual and olfactory exposure of the animals to palatable food but did not allow the feeding. Maternal separation promoted higher palatable food and lower standard diet intake only after a double exposure to stress. Besides, the double exposure to stress promoted weight loss and an anxiety-like behavior. These outcomes were associated with a resistance to the anorectic effects of fluoxetine suggesting an alteration of the serotonergic system. Together, these findings indicate that maternal separation stress has long-lasting consequences on eating behavior, and that the dual exposure to stress seems more harmful to eating behavior outcomes. In addition, the results suggest that the serotonergic system is one candidate as the system mediating these alterations.

Pre-weaning maternal separation increases eating later in life in male and female offspring, but increases brainstem dopamine receptor 1a and 2a only in males.

Maternal separation stress (MS) is a model of early life stress performed by the separation between dam and pups in the first days of life. This model has been associated with eating behavior and dopaminergic system abnormal phenotypes. This study aims to investigate whether maternal separation in the light or dark phase of the circadian cycle promotes phenotypic adjustments in the eating behavior and the dopamine system in both males and females. Lactating Wistar rats were separated from their litters from postnatal day 1 (PND 1) to PND 14 for 6 h in the light or dark phase of the circadian cycle. The groups of female control (FC), male control (MC), female rat separated in the dark (FSD), male rat separated in the dark (MSD), female rat separated in the light (FSL), and male rat separated in the light (MSL) were composed. The assessment of food intake was performed at the age of 120-150 days and the analysis of brainstem drd1a and drd2a dopamine receptors expression at 180 days of life. Maternal separation promoted higher palatable diet intake independent on sex and circadian cycle. On the other hand, drd1a and drd2a dopamine receptors expression were higher only in males separated in the dark phase of the circadian cycle. These findings demonstrate that maternal separation effects on feeding behavior do not depend on sex and circadian cycle, but the effects on dopamine receptors expression depend on sex and circadian cycle.

Daytime increase in caloric intake without change in total 24-h caloric intake can increase adiposity but not total bodyweight in rats with inverted feeding pattern.

The goal of this study was to evaluate the effect of the food availability period on body weight, self-selection of macronutrients, adiposity, lipoprotein, and serum glucose profiles without changing energy intake. Young male rats were divided into 2 groups according to the availability of food during the light and dark phases of the cycle, forming 2 groups: control group (CG) and group with inverted feeding pattern (IFPG). Before inversion of food availability on the 80th day, circadian food intake was measured every 4 h over 24 h during 3 days. The glycemic curve, an oral test for glucose tolerance, and self-selection of macronutrients were evaluated. Blood samples were collected for analysis of fasting glucose, triglycerides, and total cholesterol fractions. The IFPG showed an increase in fasting glucose in the dark phase of the cycle, changes in the glycemic curve, and oral glucose tolerance test. It also showed increased abdominal and liver fat and distinct choice of macronutrients compared with the CG. A change in the availability of food according to the phase of the circadian cycle produces changes in glucose and feeding circadian rhythm culminating in increased abdominal and hepatic fat. These effects can increase the risk of metabolic disorders and installation of chronic diseases.

Low protein diet during gestation and lactation increases food reward seeking but does not modify sucrose taste reactivity in adult female rats.

INTRODUCTION: Nutritional deficiencies during neural development may lead to irreversible changes, even after nutritional rehabilitation, promoting morphological and functional adaptations of structures involved with various behaviours including feeding behaviour. However, the ability of the exposure low protein diet during gestation and lactation to affect the hedonic component of food intake is still poorly understood, especially in females. METHODS: Wistar rats were divided into two groups according to the diet offered to the dams during pregnancy and lactation: control female (CF; diet with 17% protein, n=7) and low protein female (LPF; diet with 8% protein, n=7). The following parameters were evaluated: (a) body weight during weaning, 30, 45, 60, 75, 90 days of life; (b) standard diet intake from 110 to 132 days of life; (c) fat diet and consumption of simple carbohydrates (HFHS) for 1h at 145 days of life; (d) incentive runway task 60 days after 82 days of life; (e) taste reactivity at 90 days of life; and (f) neuronal activation in the caudate putamen, amygdala, paraventricular nucleus of the hypothalamus under stimulus HFHS at 145 days of life. RESULTS: The exposure, a low protein diet during gestation and lactation, decreased the body weight throughout the study period from weaning to 90 days of life. However, there was no significant change in the body weight of low protein females from 110 to 132 days of life compared with the control females. There was an increase in the rate of the search for reward and reduced the latency of the perception of bitter taste. The exposure, a low protein diet during gestation and lactation, also promoted hypophagy in adult females compared with control animals. The low protein female had increased HFHS diet consumption compared with the control. Undernutrition increased neuronal activation in response to HFHS diet consumption compared with female controls in the amygdala and in the caudate putamen. CONCLUSION: Females subjected to the exposure, a low protein diet during gestation and lactation, exhibit hypophagy on a standard diet but a higher consumption of a diet rich in lipids and simple carbohydrates. And also were more motivated by the pursuit of reward and reduced latency of the bitter taste reactivity, and increased the number of immunoreactive cells c-fos protein activated in the caudate putamen, amygdala and paraventricular nucleus.