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To explore the genetic dimensions of the stress response in rodents, we tested 12 inbred strains of mice and an F2 intercross (n=745) on the Tail Suspension Test (TST) and the Tail Suspension-Induced Hyperthermia (TSIH) paradigm. These selected 12 strains provide a representative sampling of the genetic heterogeneity of mousedom. An F2 intercross was derived from NMRI and 129S6 strains, which differ in their responses on the TST. Both inbred strains and F2 mice underwent a standardized protocol of automated TST with two sessions: (1) baseline and (2) imipramine TST. The duration of immobility and the body temperature after TST were recorded. The inbred strains were also tested in the Light–Dark Transition (LDT) test and in the Open Field Test (OFT), measuring the distance traveled, vertical movements, and center time as independent variables. The F2 mice were measured for core temperature after TST (TSIH). High intercorrelations among strain means were found for the LDT and OFT measures. Principal components analysis extracted four factors: “exploratory fear,” body weight, imipramine response on immobility, and “stress reactivity.” These dimensions were largely confirmed in the F2 population with one additional factor: imipramine response on TSIH. The results support a distinction between “stress reactivity” as measured by the TST and “exploratory fear” behavior as measured by the LDT and OFT. [Copyright &y& Elsevier]

By performing a whole genome screen in an F2 intercross of two strains of mice (A/J and C57BL/6J), which differ markedly in their behavioral response to a brightly lit open field (O-F), we have mapped several quantitative trait loci (QTL) for this complex behavioral phenotype. QTL on chromosomes 1 and 10 were identified that affect both initial ambulation in the O-F (initial “response to novelty” ambulation) (lod of 7.1 and 8.8, respectively) and vertical rearings (lod of 4.5 and 8.5, respectively). For habituated O-F behavior, QTL were identified on chromosomes 3 and 10 for ambulation (lod of 4.1 and 14.7, respectively) and on chromosomes 1, 10, and 19 for vertical rearings (lod of 5.8, 6.0, and 4.7, respectively). The QTL on chromosome 1 (near D1Mit1 16; 101 cM) was specific for initial O-F ambulation behavior, whereas the QTL on chromosome 10 (near D10Mit237; 74 cM) affected both initial and habituated rearing behavior. Additional suggestive QTL (lod, >2.8) were mapped to chromosomes 1, 8, 11, 15, and 19. The QTL on chromosomes 1, 10, and 19 individually explain from 3.2 to 12.7%. Collectively, the multiple independent QTL explain from 16.3 to 24.1% of the F2 population's phe-notypic variance, depending on the trait. These identified QTL should prove useful for dissecting the genetic and behavioral dimensions of O-F behavior, fostering an understanding of individual differences. [ABSTRACT FROM AUTHOR]

The tail suspension test (TST), an antidepressant screening paradigm, uses the uncontrollable, inescapable stressor of tail suspension to elicit immobility. As hyperthermia occurs following numerous stressors, hyperthermia might exist following the TST. We tested whether tail suspension induced hyperthermia (TSIH) was a distinct variable for TST. Hyperthermia was measured by two methods: a rectal probe and a subcutaneously implanted microchip (ELAMS™). In outbred ICR male mice, TSIH was robustly demonstrated compared to control (No-TST) mice. TSIH peaked after TST and remained elevated at 120 min. Among five (129/SvEvTac, A/J, C57BL/6J, NMRI and ICR) strains examined for TSIH, significant strain variations were detected. NMRI showed the highest temperature rise (2.3 °C) and A/J mice showed the lowest (0.6 °C). Sex differences were found for the C57BL/6J and NMRI strains on TSIH. TSIH and duration of immobility were not significantly correlated (r=0.22, P=0.17) in outbred mice. Both duration of TST immobility and TSIH were measured when ICR male mice were administered diazepam, imipramine (a TCA antidepressant), venlafaxine (a SNRI antidepressant), sertraline and paroxetine (SSRI antidepressants), propranolol and nadolol (β-adrenergic receptor blockers), CP-154,526 (a CRF1 receptor antagonist), and indomethacin (a cyclo-oxygenase inhibitor). Diazepam dose-dependently increased immobility and decreased TSIH. Propranolol blocked TSIH, but nadolol had no effect. Antidepressants showed more complex patterns of effects with venlafaxine, sertraline, and paroxetine inhibiting TSIH. TSIH demonstrated inter-strain variability, sex differences and a distinct pharmacology, suggesting that TSIH provides an independent, robust physiologic parameter to supplement the TST paradigm. This TSIH method may prove useful for pharmacologic, transgenic, and mechanistic studies. [Copyright &y& Elsevier]

SummaryLeptin (ob protein) is an adipose tissue derived circulating hormone that acts at specific receptors in the hypothalamus to reduce food intake. The protein is also critically involved in energy balance and metabolic status. Here the effect of leptin on sleep architecture in rats was evaluated because food consumption and metabolic status are known to influence sleep. Sprague-Dawley rats were chronically implanted with electrodes for EEG and EMG recording and diurnal sleep parameters were quantified over 9-h periods following leptin administration. Murine recombinant leptin (rMuLep) was administered systemically to rats that either had undergone 18 h of prior food deprivation or had received food ad libitum. In the normally fed rats, leptin significantly decreased the duration of rapid eye movement sleep (REMS) by about 30% and increased the duration of slow wave sleep (SWS) by about 13%, the latter effect reflecting enhanced power in the delta frequency band. These results are consistent with studies that have linked changes in metabolic rate with effects on sleep. Leptin administration has previously been shown to alter neuroendocrine parameters that could have mediated these changes in sleep architecture. Unexpectedly, prior food deprivation negated the effect of leptin on both REMS and SWS, a result that emphasizes the significance of the apparent coupling between sleep parameters and energy status. [ABSTRACT FROM AUTHOR]

Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient–rather than permanent–inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12–30 days post-TAM displayed indices of a stress-induced anxiety phenotype–longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype–longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety and a depressive phenotype, and recovery of DCX+ cell number corresponds to normalization of these behaviors. [ABSTRACT FROM AUTHOR]

The article assesses the health impact of Gulf War syndrome on U.S. veterans as measured by a systematic case definition. According to Haley and colleagues, the case definition of Gulf War syndrome is composed of three primary symptom complexes starting during and shortly after the war. The case definition was found to be closely related with self-reported wartime exposures to low-level chemical nerve agents and other cholinesterase-inhibiting chemicals. In a case study conducted at the University of Texas Southwestern Medical Center, the level of impairment of sick Gulf War veterans was generally worse than that of patients with common illnesses known to have a substantial negative impact.

Background: Identification of the genes underlying psychiatric illness remains a thorny problem. Previously, Quantitative Trait Loci (QTL) for anxiety-like behaviors and β-carboline-induced seizure vulnerability have been mapped to the distal portion of mouse chromosome 10, with crosses of A/J and C57BL6 mice. Methods: An interval specific congenic strain for this chromosomal 10 region facilitated the genetic dissection of novelty-induced exploratory behaviors. Results: By microarray studies, an unsuspected E3 ubiquitin ligase, Really Interesting New Gene (RING) Finger 41 (Rnf41) was differentially expressed in the region of interest, being upregulated in the hippocampi of B6 compared with A/J as well as congenic A.B6chr10 versus A/J. By quantitative real-time polymerase chain reaction (qRT-PCR), Rnf41 expression levels were significantly increased 1.5- and 1.3-fold in the hippocampi of C57BL6/J and A.B6chr10 mice compared with A/J mice, respectively. Protein levels of Rnf41 were increased in hippocampi of B6 mice compared with A/J mice across postnatal development with a 5.5-fold difference at P56. Yeast two-hybrid studies searching for Rnf41 binding partners in fetal hippocampus identified several potential targets. An interaction between Rnf41 and NogoA was validated by glutathionine-S-transferase–Rnf41 pulldown experiments. Re-analysis of a microarray database of human postmortem prefrontal cortex (Brodmann''s Area 46/10) found that RNF41 messenger RNA expression levels were reduced significantly in patients with major depression and bipolar disorder compared with unaffected control subjects and confirmed by qRT-PCR. Conclusions: Overall, Rnf41 is nominated as a candidate gene for anxiety-like behaviors, depression, and vulnerability to seizures. The RNF41 and its binding partners suggest molecular pathways underlying behavior, highlighting a potential role for the ubiquitin proteasome system in psychiatric illness. [Copyright &y& Elsevier]

Background: The tail suspension test (TST) is a mouse screening test for antidepressants. Methods: An F2 intercross was derived from NMRI and 129S6 inbred strains (n = 747). Mice underwent standardized TST with 2 sessions: (1) baseline and (2) imipramine (30 mg/kg, intraperitoneally) TST. Results: A whole genome scan of this intercross mapped significant basal TST quantitative trait loci (QTL) on chromosomes (chr) 5 (peak 61 cM, Lod 5.7), 12 (peak 43 cM, Lod 5.2), and 18 (peak 51 cM, Lod 3.0). A suggestive QTL on chr 4 (peak 62 cM; Lod 3.1) overlapped regions containing previously mapped QTLs. For TST imipramine response, QTL were mapped on chr 1, 4, and 5. The chromosome 5 locus affected basal TST, antidepressant immobility response, and tail suspension-induced hyperthermia (TSIH) behaviors. An outbred NMRI F2 population provided further evidence for a chr 5 QTL. This chr 5 region harbors a cluster of gamma aminobutyric acid (GABA)-A receptor subunits and the human syntenic region includes chr 4p, 1p11, 12q24, and 22q11.24. A significant TSIH QTL (Tsih1) mapped on chr 4 near the Leptin receptor (Lepr). Conclusions: These QTL provide potential regions of interest for human genetic studies in stress-diathesis models of psychiatric illness and antidepressant responsiveness. [Copyright &y& Elsevier]

Advanced intercross lines (AIL) and interval–specific congenic strains (ISCS) were used to fine map previously coarsely defined quantitative trait loci (QTL) on Chromosomes 1,10, and 19, influencing behaviors in the open Field (OF) and light–dark (LD) paradigms in mice. F12(A × B) AIL mice ( N = 1130) were phenotyped, genotyped, and mapped. The ISCS were studied only in the telomeric Chromosome 10 region of interest, containing the exploratory and excitability QTL1 ( Exq1). The Chromosome 10 Exq1 and Chromosome 19 Exq4 loci mapped robustly in the AIL. The most significant QTL findings (2.0 LOD score intervals; peak; LOD score) came from the TD15 and LD transitions traits, yielding estimated intervals of 2.2 cM for Exq1 (71.3–73.5 cM; peak 72.3 cM; LOD 11.9) and 9.0 cM for Exq4 (29.0–38.2 cM; peak 34 cM; LOD 4.2). The replicated QTLs on Chromosome 1 failed to map in this AIL population. The ISCS data confirmed Exq1 loci in general. However, the ISCS data were complex and less definitive for localizing the Exq1 loci. These exploratory and fear-like behaviors result from inheriting “many small things,” namely, QTL explaining 2%–7% of the phenotypic variance. These results highlight the challenges of positionally cloning loci of small effect for complex traits. In particular, fine-mapping success may depend on the genetic architecture underlying complex traits. [ABSTRACT FROM AUTHOR]