Sleep disturbance is a reported side effect of antidepressant drugs in children. Using a nonhuman primate model of childhood selective serotonin reuptake inhibitor (SSRI) therapy, sleep was studied quantitatively with actigraphy. Two 48-h sessions were recorded in the home cage environment of juvenile male rhesus monkeys at two and three years of age, after one and two years of treatment with a therapeutic dose of the SSRI fluoxetine, and compared to vehicle treated controls. A third session was conducted one year after discontinuation of treatment at four years of age. During treatment, the fluoxetine group demonstrated sleep fragmentation as indexed by a greater number of rest-activity transitions compared to controls. In addition fluoxetine led to more inactivity during the day as indexed by longer duration of rest periods and the reduced activity during these periods. The fluoxetine effect on sleep fragmentation, but not on daytime rest, was modified by the monkey's genotype for polymorphisms of monoamine oxidase A (MAOA), an enzyme that metabolizes serotonin. After treatment, the fluoxetine effect on nighttime rest-activity transitions persisted, but daytime activity was not affected. The demonstration in this nonhuman primate model of sleep disturbance in connection with fluoxetine treatment and specific genetic polymorphisms, and in the absence of diagnosed psychopathology, can help inform use of this drug in children.

Fluoxetine improves social interactions in children with autism, social anxiety and social phobia. It is not known whether this effect is mediated directly or indirectly by correcting the underlying pathology. Genetics may also influence the drug effect. Polymorphisms of the MAOA (monoamine oxidase A) gene interact with fluoxetine to influence metabolic profiles in juvenile monkeys. Juvenile nonhuman primates provide an appropriate model for studying fluoxetine effects and drug*gene interactions in children. Male rhesus monkeys 1-3 years of age living in permanent social pairs were treated daily with a therapeutic dose of fluoxetine or vehicle (n = 16/group). Both members of each social pair were assigned to the same treatment group. They were observed for social interactions with their familiar cagemate over a 2-year dosing period. Subjects were genotyped for MAOA variable number of tandem repeats (VNTR) polymorphisms categorized for high or low transcription rates (hi-MAOA, low-MAOA). Fluoxetine-treated animals spent 30% more time in social interaction than vehicle controls. Fluoxetine significantly increased the duration of quiet interactions, the most common type of interaction, and also of immature sexual behavior typical of rhesus in this age group. Specific behaviors affected depended on MAOA genotype of the animal and its social partner. When given fluoxetine, hi-MOAO monkeys had more social invitation and initiation behaviors and low-MAOA subjects with low-MAOA partners had more grooming and an increased frequency of some facial and vocal expressive behaviors. Fluoxetine may facilitate social interaction in children independent of remediation of psychopathology. Common genetic variants may modify this effect.

Background

Minimal scientific information is available to inform public health policy on binge drinking prior to pregnancy detection. The nonhuman primate provides a valuable animal model for examining consequences to reproduction and offspring function that may result from this common pattern of alcohol abuse.

Methods

Adult female rhesus monkeys were dosed with 1.5 g/kg per day ethanol (EtOH) by gavage 2 d/wk beginning 7 months prior to mating and continuing to pregnancy detection at 19 to 20 days gestation. Postnatal evaluation of control (n = 6) and EtOH-treated (n = 4) infants included a neonatal neurobehavioral assessment, a visual paired comparison (cognitive) test at 35 days of age, and mother-infant interaction at 100 to 112 days of age.

Results

Alcohol-exposed neonates did not differ from controls in posture and reflex measures. Longer durations of visual fixation, suggesting slower visual processing, and greater novelty preference were seen in the alcohol group. At early weaning age, as infants spent more time away from their dams, more of the reunions between mother and infant were initiated by the mothers in the alcohol-exposed group, suggesting a more immature mother-infant interaction.

Conclusions

Intermittent high-dose alcohol exposure (binge drinking) discontinued at early pregnancy detection in rhesus monkey can result in altered behavioral function in the infant. Mediating effects on ovum, reproductive tract, and early embryo can be explored in this model. Studies of longer-term consequences in human populations and animal models are needed.

We report on biochemical pathways perturbed upon chronic fluoxetine administration to juvenile macaques using global metabolomics analyses of fibroblasts derived from skin biopsies. After exposure to tissue culture conditions confounding environmental factors are eliminated and identification of metabolites whose levels are affected by the drug become apparent with a better signal-to-noise ratio compared to data obtained from plasma and cerebrospinal fluid (CSF). Levels of more than 200 metabolites were analyzed to interrogate affected molecular pathways and identify biomarkers of drug response. In addition, we have correlated the metabolomics results with monoamine oxidase (MAOA) genotype and impulsivity behavioral data. Affected pathways include Purine and Pyrimidine metabolisms that have been previously implicated to contribute to neuropsychiatric disorders.

Concern that synthetic food dyes may impact behavior in children prompted a review by the California Office of Environmental Health Hazard Assessment (OEHHA). OEHHA conducted a systematic review of the epidemiologic research on synthetic food dyes and neurobehavioral outcomes in children with or without identified behavioral disorders (particularly attention and activity). We also conducted a search of the animal toxicology literature to identify studies of neurobehavioral effects in laboratory animals exposed to synthetic food dyes. Finally, we conducted a hazard characterization of the potential neurobehavioral impacts of food dye consumption. We identified 27 clinical trials of children exposed to synthetic food dyes in this review, of which 25 were challenge studies. All studies used a cross-over design and most were double blinded and the cross-over design was randomized. Sixteen (64%) out of 25 challenge studies identified some evidence of a positive association, and in 13 (52%) the association was statistically significant. These studies support a relationship between food dye exposure and adverse behavioral outcomes in children. Animal toxicology literature provides additional support for effects on behavior. Together, the human clinical trials and animal toxicology literature support an association between synthetic food dyes and behavioral impacts in children. The current Food and Drug Administration (FDA) acceptable daily intakes are based on older studies that were not designed to assess the types of behavioral effects observed in children. For four dyes where adequate dose-response data from animal and human studies were available, comparisons of the effective doses in studies that measured behavioral or brain effects following exposure to synthetic food dyes indicate that the basis of the ADIs may not be adequate to protect neurobehavior in susceptible children. There is a need to re-evaluate exposure in children and for additional research to provide a more complete database for establishing ADIs protective of neurobehavioral effects.

Fluoxetine therapy has been approved for children with major depressive disorder and obsessive compulsive disorder for over 14 years and has expanded to other childhood behavior disorders. As use increases, more detail on fluoxetine effects during juvenile brain development can help maintain safe and effective use of this therapy. Here, a narrative review is provided of previously published findings from a large nonhuman primate project. Fluoxetine was administered to juvenile male rhesus monkeys for an extended period (2 years) prior to puberty. Compared to controls, treated monkeys showed sleep disruption, facilitated social interaction, greater impulsivity, and impaired sustained attention during treatment. No effects on growth were seen. Metabolomics assays characterized a distinctive response to fluoxetine and demonstrated individual differences that were related to the impulsivity measure. Fluoxetine interactions with monoamine oxidase A polymorphisms that influenced behavior and metabolomics markers were an important, previously unrecognized finding of our studies. After treatment was discontinued, some behavioral effects persisted, but short-term memory and cognitive flexibility testing did not show drug effects. This detailed experimental work can contribute to clinical research and continued safe and effective fluoxetine pharmacotherapy in children.

Herpes simplex virus 1 (HSV) encephalitis (HSE) has serious neurological complications, involving behavioral and cognitive impairments that cause significant morbidity and a reduced quality of life. We showed that HSE results from dysregulated central nervous system (CNS) inflammatory responses. We hypothesized that CNS inflammation is casually involved in behavioral abnormalities after HSE and that treatment with ACV and pooled human immunoglobulin (IVIG), an immunomodulatory drug, would improve outcomes compared to mice treated with phosphate buffered saline (PBS) or ACV alone. Anxiety levels were high in HSV-infected PBS and ACV-treated mice compared to mice treated with ACV + IVIG, consistent with reports implicating inflammation in anxiety induced by lipopolysaccharide (LPS) or stress. Female, but not male, PBS-treated mice were cognitively impaired, and unexpectedly, ACV was protective, while the inclusion of IVIG surprisingly antagonized ACV's beneficial effects. Distinct serum proteomic profiles were observed for male and female mice, and the antagonistic effects of ACV and IVIG on behavior were paralleled by similar changes in the serum proteome of ACV- and ACV + IVIG-treated mice. We conclude that inflammation and other factors mediate HSV-induced behavioral impairments and that the effects of ACV and IVIG on behavior involve novel mechanisms.

Potential long term effects on brain development are a concern when drugs are used to treat depression and anxiety in childhood. In this study, male juvenile rhesus monkeys (three-four years of age) were dosed with fluoxetine or vehicle (N=16/group) for two years. Histomorphometric examination of cortical dendritic spines conducted after euthanasia at one year postdosing (N=8/group) suggested a trend toward greater dendritic spine synapse density in prefrontal cortex of the fluoxetine-treated monkeys. During dosing, subjects were trained for automated cognitive testing, and evaluated with a test of sustained attention. After dosing was discontinued, sustained attention, recognition memory and cognitive flexibility were evaluated. Sustained attention was affected by fluoxetine, both during and after dosing, as indexed by omission errors. Response accuracy was not affected by fluoxetine in post-dosing recognition memory and cognitive flexibility tests, but formerly fluoxetine-treated monkeys compared to vehicle controls had more missed trial initiations and choices during testing. Drug treatment also interacted with genetic and environmental variables: MAOA genotype (high- and low transcription rate polymorphisms) and testing location (upper or lower tier of cages). Altered development of top-down cortical regulation of effortful attention may be relevant to this pattern of cognitive test performance after juvenile fluoxetine treatment.

Basic helix-loop-helix transcription factors Olig1 and Olig2 critically regulate oligodendrocyte development. Initially identified as a downstream effector of Olig1, an oligodendrocyte-specific zinc finger transcription repressor, Zfp488, cooperates with Olig2 function. Although Zfp488 is required for oligodendrocyte precursor formation and differentiation during embryonic development, its role in oligodendrogenesis of adult neural progenitor cells is not known. In this study, we tested whether Zfp488 could promote an oligodendrogenic fate in adult subventricular zone (SVZ) neural stem/progenitor cells (NSPCs). Using a cuprizone-induced demyelination model in mice, we examined the effect of retrovirus-mediated Zfp488 overexpression in SVZ NSPCs. Our results showed that Zfp488 efficiently promoted the differentiation of the SVZ NSPCs into mature oligodendrocytes in vivo. After cuprizone-induced demyelination injury, Zfp488-transduced mice also showed significant restoration of motor function to levels comparable to control mice. Together, these findings identify a previously unreported role for Zfp488 in adult oligodendrogenesis and functional remyelination after injury.

Maternal gestational obesity is associated with elevated risks for neurodevelopmental disorder, including autism spectrum disorder. However, the mechanisms by which maternal adiposity influences fetal developmental programming remain to be elucidated. We aimed to understand the impact of maternal obesity on the metabolism of both pregnant mothers and their offspring, as well as on metabolic, brain, and behavioral development of offspring by utilizing metabolomics, protein, and behavioral assays in a non-human primate model. We found that maternal obesity was associated with elevated inflammation and significant alterations in metabolites of energy metabolism and one-carbon metabolism in maternal plasma and urine, as well as in the placenta. Infants that were born to obese mothers were significantly larger at birth compared to those that were born to lean mothers. Additionally, they exhibited significantly reduced novelty preference and significant alterations in their emotional response to stress situations. These changes coincided with differences in the phosphorylation of enzymes in the brain mTOR signaling pathway between infants that were born to obese and lean mothers and correlated with the concentration of maternal plasma betaine during pregnancy. In summary, gestational obesity significantly impacted the infant systemic and brain metabolome and adaptive behaviors.