Pex3 is involved in the genetic regulation of Nr3c2 expression in the amygdala of mice.

The mineralocorticoid receptor (Nr3c2) has received increased attention as an important stress-related gene. Here, we sought to uncover candidate genes regulating the expression of Nr3c2. Using a genetical genomics approach, we identified a significant trans-regulated expression quantitative trait locus (eQTL) at Chromosome 10 for Nr3c2 expression in the amygdala of BXD RI strains.

Arachidonoyl serotonin (AA-5-HT) modulates general fear-like behavior and inhibits mesolimbic dopamine release.

Cannabinergic and vanilloidergic signaling are potential mechanisms for the treatment of anxiety symptoms because of the anxiolytic properties of cannabinoid type 1 receptor (CBR) activation and transient potential vanilloid type 1 channel (TRPV) inhibition. Arachidonoyl serotonin (AA-5-HT), a fatty acid amide hydrolase and TRPV inhibitor provides a means of modulating these systems. We examined the effects of AA-5-HT on anxiety- and fear-like behaviors in male low (C57BL/6 J; [B6]) and high (BALB/cJ; [BCJ]) anxiety mice in light/dark box (LDB), open-field (OF), and fear extinction (FE) paradigms.

Ethanol's Effect on Expression in the Hippocampus of Mice.

Coenzyme Q (CoQ) is a well-studied molecule, present in every cell membrane in the body, best known for its roles as a mitochondrial electron transporter and a potent membrane anti-oxidant. Much of the previous work was done in yeast and more recent work has suggested that CoQ may have additional roles prompting calls for a re-assessment of its role using systems in mammals. Here we investigated the putative role of Coenzyme Q in ethanol-induced effects using BXD RI mice.

Integrating Genetic and Gene Co-expression Analysis Identifies Gene Networks Involved in Alcohol and Stress Responses.

Although the link between stress and alcohol is well recognized, the underlying mechanisms of how they interplay at the molecular level remain unclear. The purpose of this study is to identify molecular networks underlying the effects of alcohol and stress responses, as well as their interaction on anxiety behaviors in the hippocampus of mice using a systems genetics approach. Here, we applied a gene co-expression network approach to transcriptomes of 41 BXD mouse strains under four conditions: stress, alcohol, stress-induced alcohol and control.

The effect of alcohol on the differential expression of cluster of differentiation 14 gene, associated pathways, and genetic network.

Alcohol consumption affects human health in part by compromising the immune system. In this study, we examined the expression of the Cd14 (cluster of differentiation 14) gene, which is involved in the immune system through a proinflammatory cascade. Expression was evaluated in BXD mice treated with saline or acute 1.

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice.

Alcohol abuse is a complex disorder, which is confounded by other factors, including stress. In the present study, we examined gene expression in the hippocampus of BXD recombinant inbred mice after exposure to ethanol (NOE), stress (RSS), and the combination of both (RSE). Mice were given an intraperitoneal (i.

A novel heat shock protein alpha 8 (Hspa8) molecular network mediating responses to stress- and ethanol-related behaviors.

Genetic differences mediate individual differences in susceptibility and responses to stress and ethanol, although, the specific molecular pathways that control these responses are not fully understood. Heat shock protein alpha 8 (Hspa8) is a molecular chaperone and member of the heat shock protein family that plays an integral role in the stress response and that has been implicated as an ethanol-responsive gene. Therefore, we assessed its role in mediating responses to stress and ethanol across varying genetic backgrounds.

Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel.

Rationale: Cocaine addiction is a major public health problem with a substantial genetic basis for which the biological mechanisms remain largely unknown. Systems genetics is a powerful method for discovering novel mechanisms underlying complex traits, and intravenous drug self-administration (IVSA) is the gold standard for assessing volitional drug use in preclinical studies. We have integrated these approaches to identify novel genes and networks underlying cocaine use in mice.

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons.

Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions.

Alcoholism, stress, and anxiety are strongly interacting heritable, polygenetic traits. In a previous study, we identified a quantitative trait locus (QTL) on murine chromosome (Chr) 1 between 23.0 and 31.

Treatment- and population-dependent activity patterns of behavioral and expression QTLs.

Genetic control of gene expression and higher-order phenotypes is almost invariably dependent on environment and experimental conditions. We use two families of recombinant inbred strains of mice (LXS and BXD) to study treatment- and genotype-dependent control of hippocampal gene expression and behavioral phenotypes. We analyzed responses to all combinations of two experimental perturbations, ethanol and restraint stress, in both families, allowing for comparisons across 8 combinations of treatment and population.

Effects of an early handling-like procedure and individual housing on anxiety-like behavior in adult C57BL/6J and DBA/2J mice.

Manipulations of rearing conditions have been used to examine the effects of early experience on adult behavior with varying results. Evidence suggests that postnatal days (PND) 15-21 are a time of particular susceptibility to environmental influences on anxiety-like behavior in mice. To examine this, we subjected C57BL/6J and DBA/2J mice to an early handling-like procedure.

Linking genetically defined neurons to behavior through a broadly applicable silencing allele.

Tools for suppressing synaptic transmission gain power when able to target highly selective neuron subtypes, thereby sharpening attainable links between neuron type, behavior, and disease; and when able to silence most any neuron subtype, thereby offering broad applicability. Here, we present such a tool, RC::PFtox, that harnesses breadth in scope along with high cell-type selection via combinatorial gene expression to deliver tetanus toxin light chain (tox), an inhibitor of vesicular neurotransmission. When applied in mice, we observed cell-type-specific disruption of vesicle exocytosis accompanied by loss of excitatory postsynaptic currents and commensurately perturbed behaviors.

Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior.

No animal models replicate the complexity of human depression. However, a number of behavioral tests in rodents are sensitive to antidepressants and may thus tap important underlying biological factors. Such models may also offer the best opportunity to discover novel treatments.

Acute mild footshock alters ethanol drinking and plasma corticosterone levels in C57BL/6J male mice, but not DBA/2J or A/J male mice.

Stress is an often-reported cause for alcohol consumption in humans. Acute intermittent footshock is a frequently used paradigm to produce stress in laboratory animals including mice. The effect produced by intermittent footshock stress on ethanol self-administration has been inconsistent: both increases and decreases in ethanol consumption have been reported.

Genetic mapping of vocalization to a series of increasing acute footshocks using B6.A consomic and B6.D2 congenic mouse strains.

Footshock response is used to study a variety of biological functions in mammals including drug self-administration, learning and memory and nociception. However, the genetics underlying variability in footshock sensitivity are not well understood. In the current studies, a panel of B6.

Nogo Receptor 1 (RTN4R) as a candidate gene for schizophrenia: analysis using human and mouse genetic approaches.

Background: NOGO Receptor 1 (RTN4R) regulates axonal growth, as well as axon regeneration after injury. The gene maps to the 22q11.2 schizophrenia susceptibility locus and is thus a strong functional and positional candidate gene.

Neurobehavioral mutants identified in an ENU-mutagenesis project.

We report on a battery of behavioral screening tests that successfully identified several neurobehavioral mutants among a large-scale ENU-mutagenized mouse population. Large numbers of ENU-mutagenized mice were screened for abnormalities in central nervous system function based on abnormal performance in a series of behavior tasks. We developed and used a high-throughput screen of behavioral tasks to detect behavioral outliers.

The Collaborative Cross, a community resource for the genetic analysis of complex traits.

The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Behavioral differences among 129 substrains: implications for knockout and transgenic mice.

Most knockout (KO) mice are produced with embryonic stem cells derived from a 129 strain. Because most KO strains are backcrossed to B6 yet retain a portion of their genome from 129, especially around the ablated target locus, phenotypes previously attributed to the ablated locus may be due to passenger 129 genes. Thus, the authors decided to test several 129 substrains for their behavioral characteristics.

Anxiety in the elevated zero-maze is augmented in mice after repeated daily exposure.

We recently tested three inbred mouse strains (C57BL/6J, DBA/2J, C3H/HeJ) and two F1 hybrids (B6C3F1/J, C3D2F1/J) in an elevated zero-maze for 3 consecutive days. As measured by the latency to enter an open quadrant and percentage of time spent in the open, anxiety increased over the three trials. Furthermore, we observed that some strains used visual cues to avoid the open arms of the zero-maze on the initial exposure, while other strains may have used other sensory cues.