Maternal separation with early weaning: a novel mouse model of early life neglect

<p>Abstract</p> <p>Background</p> <p>Childhood adversity is associated with increased risk for mood, anxiety, impulse control, and substance disorders. Although genetic and environmental factors contribute to the development of such disorders, the neurobiological mechanisms involved are poorly understood. A reliable mouse model of early life adversity leading to lasting behavioral changes would facilitate progress in elucidating the molecular mechanisms underlying these adverse effects. Maternal separation is a commonly used model of early life neglect, but has led to inconsistent results in the mouse.</p> <p>Results</p> <p>In an effort to develop a mouse model of early life neglect with long-lasting behavioral effects in C57BL/6 mice, we designed a new maternal separation paradigm that we call Maternal Separation with Early Weaning (MSEW). We tested the effects of MSEW on C57BL/6 mice as well as the genetically distinct DBA/2 strain and found significant MSEW effects on several behavioral tasks (i.e., the open field, elevated plus maze, and forced swim test) when assessed more than two months following the MSEW procedure. Our findings are consistent with MSEW causing effects within multiple behavioral domains in both strains, and suggest increased anxiety, hyperactivity, and behavioral despair in the MSEW offspring. Analysis of pup weights and metabolic parameters showed no evidence for malnutrition in the MSEW pups. Additionally, strain differences in many of the behavioral tests suggest a role for genetic factors in the response to early life neglect.</p> <p>Conclusions</p> <p>These results suggest that MSEW may serve as a useful model to examine the complex behavioral abnormalities often apparent in individuals with histories of early life neglect, and may lead to greater understanding of these later life outcomes and offer insight into novel therapeutic strategies.</p

Functional Genomic and Proteomic Analysis Reveals Disruption of Myelin-Related Genes and Translation in a Mouse Model of Early Life Neglect

Early life neglect is an important public health problem which can lead to lasting psychological dysfunction. Good animal models are necessary to understand the mechanisms responsible for the behavioral and anatomical pathology that results. We recently described a novel model of early life neglect, maternal separation with early weaning (MSEW), that produces behavioral changes in the mouse that persist into adulthood. To begin to understand the mechanism by which MSEW leads to these changes we applied cDNA microarray, next-generation RNA-sequencing (RNA-seq), label-free proteomics, multiple reaction monitoring (MRM) proteomics, and methylation analysis to tissue samples obtained from medial prefrontal cortex to determine the molecular changes induced by MSEW that persist into adulthood. The results show that MSEW leads to dysregulation of markers of mature oligodendrocytes and genes involved in protein translation and other categories, an apparent downward biasing of translation, and methylation changes in the promoter regions of selected dysregulated genes. These findings are likely to prove useful in understanding the mechanism by which early life neglect affects brain structure, cognition, and behavior

Brief Prenatal Ethanol Exposure Alters Behavioral Sensitivity to the Kappa Opioid Receptor Agonist (U62,066E) and Antagonist (Nor-BNI) and Reduces Kappa Opioid Receptor Expression

Background Approximately 10 to 15% of women consume alcohol (ethanol [EtOH]) during pregnancy in the United States. Even low amounts of EtOH consumption during pregnancy can elicit long-term consequences. Prenatal experience with as few as 3 drinks has been associated with increase problem drinking in adulthood. Such effects are corroborated in rodents; however, the underlying neural adaptations contributing to this effect are not clear. In the current set of experiments, we investigated whether changes in EtOH responding following prenatal EtOH exposure involved kappa opioid receptor activation and expression. Methods Sprague–Dawley rats were prenatally exposed to low levels of alcohol (1.0 g/kg) during late gestation (gestational days 17 to 20 [GD17–20]) via intragastric intubation of pregnant dams. Following birth, EtOH intake, kappa- and mu-opioid-induced place conditioning, and kappa opioid receptor expression in mesolimbic brain regions were assessed in infant rats (postnatal days 14 to 15 [PD14–15]) that were offspring of dams given EtOH, vehicle, or untreated, during pregnancy. Results Animals exposed to prenatal alcohol drank more alcohol later in life and exhibited significant changes in the kappa opioid system. While control subjects found kappa opioid activation aversive, animals exposed to EtOH prenatally exhibited either no aversion or appetitive responding. Further analysis revealed that synaptosomal kappa opioid receptor expression was significantly decreased in brain areas implicated in responding to EtOH. Conclusions Overall, these data suggest that prenatal EtOH affects kappa opioid function and expression and that these changes may be involved in increased drinking later in life.Fil: Nizhnikov, Michael. Bio-behavioral Institute; Estados UnidosFil: Pautassi, Ricardo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Carter, Jenna M.. Bio-behavioral Institute; Estados UnidosFil: Landine, Justine. Bio-behavioral Institute; Estados UnidosFil: Varlinskaya, Elena I.. Bio-behavioral Institute; Estados UnidosFil: Bordner, Kelly A.. University Of Connecticut; Estados UnidosFil: Werner, David F.. Bio-behavioral Institute; Estados UnidosFil: Spear, Norma E.. Bio-behavioral Institute; Estados Unido

DETERMINATION OF N-HETEROCYCLIC CARBENE NHC STERIC AND ELECTRONIC PARAMETERS USING THE (NHC)(IR)(CO)CL SYSTEM

Complexes of iridium bearing NHC (NHC = N-heterocyclic carbene) ligands were synthesized and fully characterized. The series [(NHC)Ir(cod)Cl] were obtained by simple cleavage of [Ir(cod)Cl]2. The [(NHC)Ir(cod)Cl] complexes were reacted with excess carbon monoxide, leading to [(NHC)Ir(CO)2Cl]. The infrared carbonyl stretching frequencies of these were recorded to quantify the electronic parameter of NHC ligands. X-ray diffraction study results allow for determination of NHC steric parameters within this series. These data allow for comparison with other ligand families