Calorie restriction and pravastatin administration during pregnancy in obese rhesus macaques modulates maternal and infant metabolism and infant brain and behavioral development.

Background: Maternal obesity has been associated with a higher risk of pregnancy-related complications in mothers and offspring; however, effective interventions have not yet been developed. We tested two interventions, calorie restriction and pravastatin administration, during pregnancy in a rhesus macaque model with the hypothesis that these interventions would normalize metabolic dysregulation in pregnant mothers leading to an improvement in infant metabolic and cognitive/social development.

Methods: A total of 19 obese mothers were assigned to either one of the two intervention groups ( = 5 for calorie restriction;  = 7 for pravastatin) or an obese control group ( = 7) with no intervention, and maternal gestational samples and postnatal infant samples were compared with lean control mothers ( = 6) using metabolomics methods.

Delineation of biomarkers and molecular pathways of residual effects of fluoxetine treatment in juvenile rhesus monkeys by proteomic profiling.

Fluoxetine (Prozac™) is the only antidepressant approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) in children. Despite its considerable efficacy as a selective serotonin reuptake inhibitor, the possible long-term effects of fluoxetine on brain development in children are poorly understood. In the current study, we aimed to delineate molecular mechanisms and protein biomarkers in the brains of juvenile rhesus macaques () one year after the discontinuation of fluoxetine treatment using proteomic and phosphoproteomic profiling.

Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models.

Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain.

Impact of Maternal Obesity on the Gestational Metabolome and Infant Metabolome, Brain, and Behavioral Development in Rhesus Macaques.

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.

Long-Term Fluoxetine Administration Causes Substantial Lipidome Alteration of the Juvenile Macaque Brain.

Fluoxetine is an antidepressant commonly prescribed not only to adults but also to children for the treatment of depression, obsessive-compulsive disorder, and neurodevelopmental disorders. The adverse effects of the long-term treatment reported in some patients, especially in younger individuals, call for a detailed investigation of molecular alterations induced by fluoxetine treatment. Two-year fluoxetine administration to juvenile macaques revealed effects on impulsivity, sleep, social interaction, and peripheral metabolites.

Statistical modeling with litter as a random effect in mixed models to manage "intralitter likeness".

"Intralitter likeness," the possibility that the shared genetics and/or maternal environment in multiparous species causes strong similarity for outcome variables in littermates, violates a core statistical assumption, that of observation independence, when littermate outcomes are analyzed. Intralitter likeness has been of major concern to investigators for several decades. Despite consensus and guidance, many research reports in the rodent literature continue to ignore intralitter likeness.

Serotonin Transporter Binding Potentials in Brain of Juvenile Monkeys 1 Year After Discontinuation of a 2-Year Treatment With Fluoxetine.

Background: The potential long-term effects of childhood fluoxetine therapy on brain serotonin systems were studied using a nonhuman primate model, the rhesus monkey.

Methods: Juvenile male rhesus (1-4 years of age, corresponding to 4-11 years of age in children) were treated orally with fluoxetine (2 mg/kg) or vehicle daily for 2 years and removed from treatment during the third year. Each treatment group was assigned an equal number of subjects with low and high transcription polymorphisms of MAOA.

Fluoxetine Administration in Juvenile Monkeys: Implications for Pharmacotherapy in Children.

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.

Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet.

Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze.

Effects of Acyclovir and IVIG on Behavioral Outcomes after HSV1 CNS Infection.

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.

Cognitive performance of juvenile monkeys after chronic fluoxetine treatment.

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.

Peripheral fibroblast metabolic pathway alterations in juvenile rhesus monkeys undergoing long-term fluoxetine administration.

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.

Sleep disturbance as detected by actigraphy in pre-pubertal juvenile monkeys receiving therapeutic doses of fluoxetine.

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.

Peer social interaction is facilitated in juvenile rhesus monkeys treated with fluoxetine.

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.

Bone growth in juvenile rhesus monkeys is influenced by 5HTTLPR polymorphisms and interactions between 5HTTLPR polymorphisms and fluoxetine.

Male rhesus monkeys received a therapeutic oral dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine daily from 1 to 3 years of age. Puberty is typically initiated between 2 and 3 years of age in male rhesus and reproductive maturity is reached at 4 years. The study group was genotyped for polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (SERT) genes that affect serotonin neurotransmission.

Fetal iron deficiency and genotype influence emotionality in infant rhesus monkeys.

Background: Anemia during the third trimester of fetal development affects one-third of the pregnancies in the United States and has been associated with postnatal behavioral outcomes. This study examines how fetal iron deficiency (ID) interacts with the fetal monoamine oxidase A (MAOA) genotype. MAOA metabolizes monoamine neurotransmitters.

Sleep patterns in male juvenile monkeys are influenced by gestational iron deprivation and monoamine oxidase A genotype.

Individual differences in sleep patterns of children may have developmental origins. In the present study, two factors known to influence behavioural development, monoamine oxidase A (MAOA) genotype and prenatal Fe-deficient (ID) diet, were examined for their influences on sleep patterns in juvenile rhesus monkeys. Sleep patterns were assessed based on a threshold for inactivity as recorded by activity monitors.

Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model.

Rationale: The selective serotonin reuptake inhibitor (SSRI) fluoxetine is the only psychopharmacological agent approved for use in children. While short-term studies of side effects have been performed, long-term consequences for brain development are not known. Such studies can be performed in appropriate animal models if doses modeling therapeutic use in children are known.

Developmental plasticity of red blood cell homeostasis.

Most human physiologic set points like body temperature are tightly regulated and show little variation between healthy individuals. Red blood cell (RBC) characteristics such as hematocrit and mean cell volume are stable within individuals but can vary by 20% from one healthy person to the next. The mechanisms for the majority of this inter-individual variation are unknown and do not appear to involve common genetic variation.

Prenatal iron deficiency and monoamine oxidase A (MAOA) polymorphisms: combined risk for later cognitive performance in rhesus monkeys.

Monoamine oxidase A (MAOA) gene polymorphisms resulting in high and low transcription rates are associated with individual differences in reward efficacy and response inhibition. Iron deficiency (ID) is the most frequent single-nutrient deficiency worldwide, and prenatal ID has recently been shown to carry a risk for lower mental development scores in infants. In this study, a potential interaction of MAOA genotype and prenatal ID was studied in young male rhesus monkeys.

Mice with an isoform-ablating Mecp2 exon 1 mutation recapitulate the neurologic deficits of Rett syndrome.

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750). Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3 and 4 encodes MeCP2-e1 or MeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT.

Binge drinking prior to pregnancy detection in a nonhuman primate: behavioral evaluation of offspring.

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.