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Previous studies in animal models and humans have shown that exposure to nutritional deficiencies in the perinatal period increases the risk of psychiatric disease. Less well understood is how such effects are modulated by the combination of genetic background and parent‐of‐origin (PO). To explore this, we exposed female mice from 20 Collaborative Cross (CC) strains to protein deficient, vitamin D deficient, methyl donor enriched or standard diet during the perinatal period. These CC females were then crossed to a male from a different CC strain to produce reciprocal F1 hybrid females comprising 10 distinct genetic backgrounds. The adult F1 females were then tested in the open field, light/dark, stress‐induced hyperthermia, forced swim and restraint stress assays. Our experimental design allowed us to estimate effects of genetic background, perinatal diet, PO and their interactions on behavior. Genetic background significantly affected all assessed phenotypes. Perinatal diet exposure interacted with genetic background to affect body weight, basal body temperature, anxiety‐like behavior and stress response. In 8 of 9 genetic backgrounds, PO effects were observed on multiple phenotypes. Additionally, we identified a small number of diet‐by‐PO effects on body weight, stress response, anxiety‐ and depressive‐like behavior. Our data show that rodent behaviors that model psychiatric disorders are affected by genetic background, PO and perinatal diet, as well as interactions among these factors. [ABSTRACT FROM AUTHOR]

Schizophrenia is a debilitating neuropsychiatric disorder that affects 1% of the US population. Based on twin and genome-wide association studies, it is clear that both genetics and environmental factors increase the risk for developing schizophrenia. Moreover, there is evidence that conditions in utero, either alone or in concert with genetic factors, may alter neurodevelopment and lead to an increased risk for schizophrenia. There has been progress in identifying genetic loci and environmental exposures that increase risk, but there are still considerable gaps in our knowledge. Furthermore, very little is known about the specific neurodevelopmental mechanisms upon which genetics and the environment act to increase disposition to developing schizophrenia in adulthood. Vitamin D deficiency during the perinatal period has been hypothesized to increase risk for schizophrenia in humans. The developmental vitamin D ( DVD) deficiency hypothesis of schizophrenia arises from the observation that disease risk is increased in individuals who are born in winter or spring, live further from the equator or live in urban vs. rural settings. These environments result in less exposure to sunlight, thereby reducing the initial steps in the production of vitamin D. Rodent models have been developed to characterize the behavioral and developmental effects of DVD deficiency. This review focuses on these animal models and discusses the current knowledge of the role of DVD deficiency in altering behavior and neurobiology relevant to schizophrenia. [ABSTRACT FROM AUTHOR]

Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine ( COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic ( PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC. [ABSTRACT FROM AUTHOR]

Catechol-O-methyltransferase (COMT) is a ubiquitously expressed enzyme that maintains basic biologic functions by inactivating catechol substrates. In humans, polymorphic variance at the COMT locus has been associated with modulation of pain sensitivity and risk for developing psychiatric disorders. A functional haplotype associated with increased pain sensitivity was shown to result in decreased COMT activity by altering mRNA secondary structure-dependent protein translation. However, the exact mechanisms whereby COMT modulates pain sensitivity and behavior remain unclear and can be further studied in animal models. We have assessed Comt1 gene expression levels in multiple brain regions in inbred strains of mice and have discovered that Comt1 is differentially expressed among the strains, and this differential expression is cis-regulated. A B2 short interspersed nuclear element (SINE) was inserted in the 3 -untranslated region (3′-UTR) of Comt1 in 14 strains generating a common haplotype that correlates with gene expression. Experiments using mammalian expression vectors of full-length cDNA clones with and without the SINE element show that strains with the SINE haplotype (+SINE) have greater Comt1 enzymatic activity. +SINE mice also exhibit behavioral differences in anxiety assays and decreased pain sensitivity. These results suggest that a haplotype, defined by a 3 -UTR B2 SINE element, regulates Comt1 expression and some mouse behaviors. [ABSTRACT FROM AUTHOR]

The identification of genes influencing sensitivity to stimulants and opioids is important for determining their mechanism of action and may provide fundamental insights into the genetics of drug abuse. We used a panel of C57BL/6J (B6; recipient)× A/J (donor) chromosome substitution strains (CSSs) to identify quantitative trait loci (QTL) for both open field activity and sensitivity to the locomotor stimulant response to methamphetamine (MA). Mice were injected with saline (days 1 and 2) and MA (day 3; 2 mg/kg i.p.). We analyzed the total distance traveled in the open field for 30 min following each injection. CSS-8, -11 and -16 showed reduced MA-induced locomotor activity relative to B6, whereas CSS-10 and -12 showed increased MA-induced locomotor activity. Further analysis focused on CSS-11 because it was robustly different from B6 following MA injection, but did not differ in activity following saline injection and because it also showed reduced locomotor activity in response to the mu-opioid receptor agonist fentanyl (0.2 mg/kg i.p.). Thus, CSS-11 captures QTLs for the response to both psychostimulants and opioids. Using a B6 × CSS-11 F2 intercross, we identified a dominant QTL for the MA response on chromosome 11. We used haplotype association mapping of cis expression QTLs and bioinformatic resources to parse among genes within the 95% confidence interval of the chromosome 11 QTL. Identification of the genes underlying QTLs for response to psychostimulants and opioids may provide insights about genetic factors that modulate sensitivity to drugs of abuse. [ABSTRACT FROM AUTHOR]

We carried out a quantitative trait loci (QTL) mapping experiment in two phenotypically similar inbred mouse strains, C57BL/6J and C58/J, using the open-field assay, a well-established model of anxiety-related behavior in rodents. This intercross was initially carried out as a control cross for an ethylnitrosurea mutagenesis mapping study. Surprisingly, although open-field behavior is similar in the two strains, we identified significant QTL in their F2 progeny. Marker regression identified a locus on Chr 8 having associations with multiple open-field measures and a significant interaction between loci on Chr 13 and 17. Together, the Chr 8 locus and the interaction effect form the core set of QTL controlling these behaviors with additional loci on Chr 1 and 6 present in a subset of the behaviors. [ABSTRACT FROM AUTHOR]

The incidence of spontaneous and types of positional nystagmus in 302 patients with end organ, nerve, brain stem and cerebellar lesions is analyzed. All types of these nystagmus are frequently encountered in peripheral and central lesions. By itself the type of vestibular nystagmus (except vertical spontaneous seen in this series in only central lesions) is not diagnostic of any lesion. It should be considered with other findings. Based on these findings, the discontinuation of the term benign paroxysmal nystagmus is suggested. In a small number of cases retested over a year, a change from spontaneous to positional to paroxysmal positional nystagmus is shown. These changes are considered to reflect the degrees of vestibular compensation that occur over a period of time. [ABSTRACT FROM AUTHOR]

An F2 intercross derived from C57BL/6 and DBA/2 progenitor inbred strains was used to test for replication of quantitative trait loci (QTLs) for alcohol preference nominated by a previous study using BXD recombinant inbred (RI) strains (Rodriguez et al., Alcohol. Clin. Exp. Res. 19:367-379, 1995). Fourteen provisional QTLs were nominated in the original RI study with a p < 0.05 criterion. In the present study, a genome scan (101 microsatellite markers) was conducted on an F2 population (n = 218). Three significant QTLs were detected on chromosomes 1, 4, and 9, and three suggestive QTLs were detected on chromosomes 2, 3, and 10. Of these six QTLs, four were consistent with the previous RI nominations. The replication rate of 28.6% (4 of 14) is in agreement with the results of simulation studies performed by Belknap et al. (Behav. Genet. 26:149-160, 1996) and supports the methodological argument for a multistage research design for nominating and replicating QTLs.