Efcab7 deletion sensitizes mice to the teratogenic effects of gastrulation-stage alcohol exposure.

Alcohol exposure during the gastrulation stage of development can disrupt Sonic hedgehog (Shh) signaling and cause eye, craniofacial, and brain defects. One of the genes that regulates Shh signaling is Efcab7, which encodes a protein that facilitates the actions of Smoothened (Smo), a critical component of the Shh pathway. Previous work from our lab has demonstrated that Efcab7 is differentially expressed between two sub-strains of C57BL/6 mice that differ in their sensitivity to gastrulation-stage alcohol exposure.

Gastrulation-stage alcohol exposure induces similar rates of craniofacial malformations in male and female C57BL/6J mice.

Background: Prenatal alcohol exposure during gastrulation (embryonic day [E] 7 in mice, ~3rd week of human pregnancy) impairs eye, facial, and cortical development, recapitulating birth defects characteristic of Fetal Alcohol Syndrome (FAS). However, it is not known whether the prevalence or severity of craniofacial features associated with FAS is affected by biological sex.

Methods: The current study administered either alcohol (2.

Short-term transcriptomic changes in the mouse neural tube induced by an acute alcohol exposure.

Alcohol exposure during the formation and closure of the neural tube, or neurulation (embryonic day [E] 8-10 in mice; ∼4th week of human pregnancy), perturbs development of midline brain structures and significantly disrupts gene expression in the rostroventral neural tube (RVNT). Previously, alcohol exposure during neurulation was found to alter gene pathways related to cell proliferation, p53 signaling, ribosome biogenesis, immune signaling, organogenesis, and cell migration 6 or 24 h after administration. Our current study expands upon this work by investigating short-term gene expression changes in the RVNT following a single binge-like alcohol exposure during neurulation.

The pro-apoptotic Bax gene modifies susceptibility to craniofacial dysmorphology following gastrulation-stage alcohol exposure.

Background: During early development, alcohol exposure causes apoptotic cell death in discrete regions of the embryo which are associated with distinctive patterns of later-life abnormalities. In gastrulation, which occurs during the third week of human pregnancy, alcohol targets the ectoderm, the precursor of the eyes, face, and brain. This midline tissue loss leads to the craniofacial dysmorphologies, such as microphthalmia and a smooth philtrum, which define fetal alcohol syndrome (FAS).

Prenatal alcohol exposure disrupts Sonic hedgehog pathway and primary cilia genes in the mouse neural tube.

Neurulation-stage alcohol exposure (NAE; embryonic day [E] 8-10) is associated with midline craniofacial and CNS defects that likely arise from disruption of morphogen pathways, such as Sonic hedgehog (Shh). Notably, midline anomalies are also a hallmark of genetic ciliopathies such as Joubert syndrome. We tested whether NAE alters Shh pathway signaling and the number and function of primary cilia, organelles critical for Shh pathway transduction.

Transcriptomic analyses of gastrulation-stage mouse embryos with differential susceptibility to alcohol.

Genetics are a known contributor to differences in alcohol sensitivity in humans with fetal alcohol spectrum disorders (FASDs) and in animal models. Our study profiled gene expression in gastrulation-stage embryos from two commonly used, genetically similar mouse substrains, C57BL/6J (6J) and C57BL/6NHsd (6N), that differ in alcohol sensitivity. First, we established normal gene expression patterns at three finely resolved time points during gastrulation and developed a web-based interactive tool.

Transcriptome-Wide Regulation of Key Developmental Pathways in the Mouse Neural Tube by Prenatal Alcohol Exposure.

Background: Early gestational alcohol exposure is associated with severe craniofacial and CNS dysmorphologies and behavioral abnormalities during adolescence and adulthood. Alcohol exposure during the formation of the neural tube (gestational day [GD] 8 to 10 in mice; equivalent to4th week of human pregnancy) disrupts development of ventral midline brain structures such as the pituitary, septum, and ventricles. This study identifies transcriptomic changes in the rostroventral neural tube (RVNT), the region of the neural tube that gives rise to the midline structures sensitive to alcohol exposure during neurulation.

Cannabinoids Exacerbate Alcohol Teratogenesis by a CB1-Hedgehog Interaction.

We tested whether cannabinoids (CBs) potentiate alcohol-induced birth defects in mice and zebrafish, and explored the underlying pathogenic mechanisms on Sonic Hedgehog (Shh) signaling. The CBs, Δ-THC, cannabidiol, HU-210, and CP 55,940 caused alcohol-like effects on craniofacial and brain development, phenocopying Shh mutations. Combined exposure to even low doses of alcohol with THC, HU-210, or CP 55,940 caused a greater incidence of birth defects, particularly of the eyes, than did either treatment alone.

Knockdown of Mns1 Increases Susceptibility to Craniofacial Defects Following Gastrulation-Stage Alcohol Exposure in Mice.

Background: MNS1 (meiosis-specific nuclear structural protein 1) is necessary for motile cilia function, such as sperm flagella or those found in the embryonic primitive node. While little is known regarding the function or expression pattern of MNS1 in the embryo, co-immunoprecipitation experiments in sperm have determined that MNS1 interacts with ciliary proteins, which are also important during development. Establishment of morphogenic gradients is dependent on normal ciliary motion in the primitive node beginning during gastrulation (gestational day [GD] 7 in the mouse, second-third week of pregnancy in humans), a critical window for face, eye, and brain development and particularly susceptible to perturbations of developmental signals.

Activity and social behavior in a complex environment in rats neonatally exposed to alcohol.

Environmental complexity (EC) is a powerful, stimulating paradigm that engages animals through a variety of sensory and motor pathways. Exposure to EC (30 days) following 12 days of wheel running preserves hippocampal neuroplasticity in male rats neonatally exposed to alcohol during the third-trimester equivalent (binge-like exposure on postnatal days [PD] 4-9). The current experiment investigates the importance of various components of EC (physical activity, exploration, social interaction, novelty) and examines whether neonatal alcohol exposure affects how male rats interact with their environment and other male rats.

Housing in environmental complexity following wheel running augments survival of newly generated hippocampal neurons in a rat model of binge alcohol exposure during the third trimester equivalent.

Background: Binge-like alcohol exposure in neonatal rats during the brain growth spurt causes deficits in adult neurogenesis in the hippocampal dentate gyrus (DG). Previous data from our laboratory demonstrated that 12 days of voluntary wheel running (WR) beginning on postnatal day (PD) 30 significantly increased the number of newly generated cells evident in the DG on PD42 in both alcohol-exposed (AE) and control rats, but 30 days later a sustained beneficial effect of WR was evident only in control rats. This study tested the hypothesis that housing rats in environmental complexity (EC) following WR would promote the survival of the newly generated cells stimulated by WR, particularly in AE rats.

Long-term consequences of developmental alcohol exposure on brain structure and function: therapeutic benefits of physical activity.

Developmental alcohol exposure both early in life and during adolescence can have a devastating impact on normal brain structure and functioning, leading to behavioral and cognitive impairments that persist throughout the lifespan. This review discusses human work as well as animal models used to investigate the effect of alcohol exposure at various time points during development, as well as specific behavioral and neuroanatomical deficits caused by alcohol exposure. Further, cellular and molecular mediators contributing to these alcohol-induced changes are examined, such as neurotrophic factors and apoptotic markers.

Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors in the nucleus accumbens shell regulate progressive ratio responding maintained by nicotine.

Beta2 subunit containing nicotinic acetylcholine receptors (beta2(*)nAChRs; asterisk ((*)) denotes assembly with other subunits) are critical for nicotine self-administration and nicotine-associated dopamine (DA) release that supports nicotine reinforcement. The alpha6 subunit assembles with beta2 on DA neurons where alpha6beta2(*)nAChRs regulate nicotine-stimulated DA release at neuron terminals. Using local infusion of alpha-conotoxin MII (alpha-CTX MII), an antagonist with selectivity for alpha6beta2(*)nAChRs, the purpose of these experiments was to determine if alpha6beta2(*)nAChRs in the nucleus accumbens (NAc) shell are required for motivation to self-administer nicotine.

Systemic and intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, disrupts attentional performance in rats.

Rationale: Orexin neurons project to a number of brain regions, including onto basal forebrain cholinergic neurons. Basal forebrain corticopetal cholinergic neurons are known to be necessary for normal attentional performance. Thus, the orexin system may contribute to attentional processing.