The impact of poor fetal growth and chronic hyperpalatable diet exposure in adulthood on hippocampal function and feeding patterns in male rats.

Poor fetal growth affects eating behavior and the mesocorticolimbic system; however, its influence on the hippocampus has been less explored. Brain insulin sensitivity has been linked to developmental plasticity in response to fetal adversity and to cognitive performance following high-fat diet intake. We investigated whether poor fetal growth and exposure to chronic hyperpalatable food in adulthood could influence the recognition of environmental and food cues, eating behavior patterns, and hippocampal insulin signaling. At 60 days of life, we assigned male offspring from a prenatal animal model of 50% food restriction (FR) to receive either a high-fat and -sugar (HFS) diet or standard chow (CON) diet. Behavioral tests were conducted at 140 days, then tissues were collected. HFS groups showed a diminished hippocampal pAkt/Akt ratio. FR-CON and FR-HFS groups had higher levels of suppressor of cytokine signaling 3, compared to control groups. FR groups showed increased exploration of a novel hyperpalatable food, independent of their diet, and HFS groups exhibited overall lower entropy (less random, more predictable eating behavior) when the environment changed. Poor fetal growth and chronic HFS diet in adulthood altered hippocampal insulin signaling and eating patterns, diminishing the flexibility associated with eating behavior in response to extrinsic changes in food availability in the environment.

Relationship between insulin and Netrin-1/DCC guidance cue pathway regulation in the prefrontal cortex of rodents exposed to prenatal dietary restriction.

Fetal restriction (FR) alters insulin sensitivity, but it is unknown how the metabolic profile associated with restriction affects development of the dopamine (DA) system and DA-related behaviors. The Netrin-1/DCC guidance cue system participates in maturation of the mesocorticolimbic DA circuitry. Therefore, our objective was to identify if FR modifies Netrin-1/DCC receptor protein expression in the prefrontal cortex (PFC) at birth and mRNA in adulthood in rodent males. We used cultured HEK293 cells to assess if levels of miR-218, microRNA regulator of DCC, are sensitive to insulin. To assess this, pregnant dams were subjected to a 50% FR diet from gestational day 10 until birth. Medial PFC (mPFC) DCC/Netrin-1 protein expression was measured at P0 at baseline and Dcc/Netrin-1 mRNA levels were quantified in adults 15 min after a saline/insulin injection. miR-218 levels in HEK-293 cells were measured in response to insulin exposure. At P0, Netrin-1 levels are downregulated in FR animals in comparison to controls. In adult rodents, insulin administration results in an increase in Dcc mRNA levels in control but not FR rats. In HEK293 cells, there is a positive correlation between insulin concentration and miR-218 levels. Since miR-218 is a Dcc gene expression regulator and our in vitro results show that insulin regulates miR-218 levels, we suggest that FR-induced changes in insulin sensitivity could be affecting Dcc expression via miR-218, impacting DA system maturation and organization. As fetal adversity is linked to nonadaptive behaviors later in life, this may contribute to early identification of vulnerability to chronic diseases associated with fetal adversity.

Brain structural abnormalities in six major psychiatric disorders: shared variation and network perspectives.

Common brain abnormalities are a possible explanation for comorbidities in psychiatric disorders. Challenges in understanding these conditions are likely due to the paucity of studies able to analyze the extent and regional distribution of shared morphometric abnormalities between disorders. Recently, Opeal et al. presented an elegant rationale to investigate shared and specific morphometric measures of cortical thickness and subcortical gray matter volume between healthy individuals and subjects across six major psychiatric disorders. Although their approach has the potential to systematically portrait shared brain alterations, the chosen principal component analysis solution may not address the central question of the observed shared versus specific brain alterations due to misspecification of the number of components. Given how this misspecification can lead to different conclusions, we reanalyzed Opel et al. data to thoroughly determine the number of factors to be considered, explore the alternative solution, and visualize the patterns of shared brain matter correlations using network analysis. Our approach suggests that a unidimensional solution was appropriate in this situation. The unidimensional solution indicated that brain alterations in autism spectrum disorder (ASD) had a significant negative component loading, suggesting that brain abnormalities found in ASD carry more similarities with major depressive disorder (MDD), bipolar disorder (BD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) than demonstrated by the original work. Network analysis indicated that SCZ had the highest strength, BD the highest closeness, and BD and MDD had the highest betweenness in the network. This work highlights how different component solutions can lead to different conclusions, with important implications for the understanding of overlapped patterns of symptoms among six major psychiatric diseases. The network approach is complementary in indicating central markers of specific psychopathology domains. Investigations using shared-variation and network perspectives are promising for the study of pathophysiological patterns of common brain alterations.

Intrauterine growth restriction increases impulsive behavior and is associated with altered dopamine transmission in both medial prefrontal and orbitofrontal cortex in female rats.

Recent studies have implicated a role for impulsivity in the altered eating behaviors and the increased risk for obesity consistently associated with intrauterine growth restriction (IUGR). Changes in dopamine transmission within prefrontal areas are believed to contribute to these adverse outcomes. Here we investigated the impulsive behavior toward a delayed reward and evaluated dopamine levels and its receptors in the medial prefrontal (mPFC) and orbitofrontal (OFC) cortex of female adult rats exposed to IUGR. From day 10 of pregnancy and until birth, Sprague-Dawley dams received either an ad libitum (Adlib) or a 50% food-restricted (FR) diet. At birth, all pups were adopted by Adlib mothers, generating the groups Adlib/Adlib (control) and FR/Adlib (intrauterine growth-restricted). Adult impulsive behavior was evaluated using a Tolerance to Delay of Reward Task. In vivo dopamine responses to sweet food intake were measured by voltammetry, and D1, D2 and DAT levels were accessed by Western Blot. Animals from FR group showed a pronounced aversion to delayed rewards. DA response to sweet food was found to be blunted in the mPFC of FR animals, whereas in the OFC, the DA levels appear to be unaffected by reward consumption. Moreover, FR animals presented reduced D1 receptors in the OFC and a later increase in the mPFC D2 levels. These findings suggest that IUGR female rats are more impulsive and that the associated mechanism involves changes in the dopamine signaling in both the mPFC and OFC.

Methylphenidate administration reverts attentional inflexibility in adolescent rats submitted to a model of neonatal hypoxia-ischemia: Predictive validity for ADHD study.

Perinatal complications such as birth asphyxia were associated with a higher risk for Attention-Deficit/Hyperactivity Disorder (ADHD) in humans. Data from a rat model of neonatal hypoxia-ischemia (HI) have revealed inattention, impulsive behavior and dopamine (DA) disturbances in the prefrontal cortex (PFC), confirming the face validity and construct validity for ADHD study. However, the predictive validity (similar therapeutic efficacy of the pharmacological treatment available in the clinic) should be considered. Therefore, we aimed to investigate the effects of methylphenidate (MPH) - the treatment of choice for ADHD - on exploratory and attentional flexibility behaviors and DA-related proteins in the PFC of animals submitted to neonatal HI. Male Wistar rats were divided into four groups: control saline (CTS, n = 12), control MPH (CTMPH, n = 12), HI saline (HIS, n = 13) and HIMPH (n = 12). The HI procedure was conducted at postnatal day (PND) 7 and behavioral measures between PND 30-40, followed by protein analysis in the PFC. The MPH administration (2.5 mg/kg, i.p.) occurred 30 min prior each behavioral session and euthanasia for western blot analysis. We observed that the MPH increased the locomotor activity in the open field especially in HI rats. In the attentional-set shifting task, the MPH reversed the HI- induced attentional inflexibility, but impaired the task acquisition in control rats. Neonatal HI resulted in lower DA D2 receptors expression but also decreased DA transporter (responsible for DA reuptake) and increased pTH (phosphorylated-tyrosine hydroxylase) levels in the PFC, probably to compensate the dysfunctional DA transmission. This compensation was higher in the HIMPH group and it could explain the improvement in the attentional flexibility as well as the increased locomotor activity in this group. Taken this data together, we can assume the predictive validity of the HI model for the ADHD study concerning the impact of MPH treatment on attentional parameters.

Intrauterine growth restriction increases the preference for palatable foods and affects sensitivity to food rewards in male and female adult rats.

Clinical evidence suggests that intrauterine growth restriction (IUGR) can cause persistent changes in the preference for palatable foods. In this study, we compared food preferences, the response to food rewards, and the role of the mesolimbic dopaminergic system in feeding behavior, between IUGR and control rats. Time-mated pregnant Sprague-Dawley rats were randomly allocated to a control group (standard chow ad libitum) or a 50% food restriction (FR) group, which received 50% of the control dams׳ habitual intake. These diets were provided from gestation day 10 to the 21st day of lactation. Within 24h of birth, pups were cross-fostered and divided into four groups: Adlib/Adlib, FR/Adlib, FR/FR, Adlib/FR. Standard chow consumption was compared between all groups. Food preferences, conditioned place preference to a palatable diet, and the levels of tyrosine hydroxylase (TH) phosphorylation and D2 receptors in the nucleus accumbens were analyzed and compared between the two groups of interest: Adlib/Adlib (control) and FR/Adlib (exposed to growth restriction during the fetal period only). IUGR adult rats had a stronger preference for palatable foods, but showed less conditioned place preference to a palatable diet than controls. D2 receptors levels were lower in IUGR rats. At baseline, TH and pTH levels were higher in FR/Adlib than control males. Measurements taken after exposure to sweet foods revealed higher levels of TH and pTH in FR/Adlib than control females. These data showed that IUGR rats exhibited a preference for palatable foods, potentially due to alterations in their mesolimbic reward pathway. Additionally, the changes observed in the mesolimbic dopaminergic system of IUGR rats proved to be sex-specific. This article is part of a Special Issue entitled 1618.

Increased palatable food intake and response to food cues in intrauterine growth-restricted rats are related to tyrosine hydroxylase content in the orbitofrontal cortex and nucleus accumbens.

Intrauterine growth restriction (IUGR) is associated with altered food preferences, which may contribute to increased risk of obesity. We evaluated the effects of IUGR on attention to a palatable food cue, as well as tyrosine hydroxylase (TH) content in the orbitofrontal cortex (OFC) and nucleus accumbens (NAcc) in response to sweet food intake. From day 10 of gestation and through lactation, Sprague-Dawley rats received either an ad libitum (Adlib) or a 50% food-restricted (FR) diet. At birth, pups were cross-fostered, generating four groups (gestation/lactation): Adlib/Adlib (control), FR/Adlib (intrauterine growth-restricted), Adlib/FR, and FR/FR. Adult attention to palatable food cues was measured using the Attentional Set-Shifting Task (ASST), which uses a sweet pellet as reward. TH content in the OFC and NAcc was measured at baseline and in response to palatable food intake. At 90 days of age, FR/Adlib males ate more sweet food than controls, without differences in females. However, when compared to Controls, FR/Adlib females needed fewer trials to reach criterion in the ASST (p=0.04) and exhibited increased TH content in the OFC in response to sweet food (p=0.03). In the NAcc, there was a differential response of TH content after sweet food intake in both FR/Adlib males and females (p<0.05). Fetal programming of adult food preferences involves the central response to palatable food cues and intake, affecting dopamine release in select structures of the brain reward system.