Aggression in male rats receiving anabolic androgenic steroids: effects of social and environmental provocation.

This study examined the effects of anabolic androgenic steroids (AAS) on aggression under different social and environmental conditions. Three AAS were tested in gonadally intact male rats: testosterone propionate (TP), nandrolone (ND), and stanozolol (ST). Doses of 5 mg/kg were given 5 times/week, with gonadally intact controls receiving vehicle only (propylene glycol). Animals received six weekly tests under each condition in a counterbalanced order. Results show that the three AAS differed in their ability to elicit aggression. Males receiving TP were more aggressive than controls, ND males were similar to controls, and ST males were less aggressive than controls. In the social and environmental provocation tests TP-treated males were more aggressive than other groups, but were able to discriminate between intact and castrated opponents and between their home cage and a neutral cage. In the environmental provocation test, TP males were also more aggressive against opponents when tested in the opponent's home cage. It is suggested that chronic exposure to high levels of TP does not eliminate the ability to discriminate between social or environmental cues, as might be expected if it induces a " 'roid rage." However, TP does increase the likelihood that the animal will respond with aggression/dominance in a provoking situation. All three AAS variably affected serum testosterone and LH levels, as well as testes, seminal vesicle, and prostate weights. No effect on body weight was observed.

A time-less function for mouse timeless.

The timeless (tim) gene is essential for circadian clock function in Drosophila melanogaster. A putative mouse homolog, mTimeless (mTim), has been difficult to place in the circadian clock of mammals. Here we show that mTim is essential for embryonic development, but does not have substantiated circadian function.

Quantitative genetic variation for oviposition preference with respect to phenylthiocarbamide in Drosophila melanogaster.

Seven isogenic strains of Drosophila melanogaster were assayed for oviposition preference on food with phenylthiocarbamide (PTC) versus plain food. There was significant variation among strains for the percentage of eggs oviposited on each medium, ranging from 70 +/- 4% (SE) preference for plain food to no significant preference. Reciprocal hybrid, backcross, and F2 generations derived from two extreme parent strains revealed significant additive and nonadditive genetic variation but no evidence of maternal, paternal, or sex-chromosome effects.

Provisional QTL for circadian period of wheel running in laboratory mice: quantitative genetics of period in RI mice.

Wheel running was monitored in B x D recombinant inbred (RI) mice under dark-dark (DD) conditions, and the mean circadian period was calculated for each strain. There were significant differences for this trait among B x D recombinant inbred strains (p < .0001) and a narrow-sense heritability of 21%. Analysis of strain means and variances indicates that at least four segregating loci contribute to the genetic variance for the free-running circadian period in this population. Correlation of the strain means for the circadian period of wheel running for each RI strain against the distribution of markers at over 1500 loci along the mouse genome identified a number of provisional quantitative trait loci (QTL). There were provisional QTL for wheel running at p < .001 on chromosome 11 and at p < .01 on chromosomes 1, 6, 9, 17, and 19. Most were in agreement with a second analysis done under similar conditions.

Aging lengthens TauDD in C57BL/6J, DBA/2J, and outbred SWR male mice (Mus musculus).

The effect of aging on the free-running period (TauDD) of a circadian rhythm for wheel-running activity was observed in two inbred strains (DBA/ 2J and C57BL/6J) and one outbred strain (Tac: (SW)fBR) of laboratory mice (Mus musculus). TauDD in the DBA and C57 mice was monitored at approximately age 100 days and age 300 days. TauDD in the outbred strain was monitored at approximately age 100 days and age 600 days. TauDD increased with age in all three strains. Most studies of age effects in rodent species have shown a shortening of TauDD with age, with th exception of the C57BL inbred mice. These results show that the lengthening of TauDD with age in laboratory mice is not limited to the C57BL strain and may be a general characteristic of this species, in contrast to other rodent species examined.

Effects of fluoxetine and olfactory bulbectomy on mouse circadian activity rhythms.

Olfactory bulbectomy (OBX) in SWR outbred male mice lengthened the free-running period and delayed the phase of a circadian rhythm for wheel-running activity. OBX also increased mean levels of activity. Two weeks of daily intraperitoneal injections of Fluoxetine (8 mg/kg), a serotonin re-uptake inhibitor, reversed the effects of bulbectomy on the mean level of activity and significantly shortened the free-running period of the activity rhythm. The phase of the activity rhythm was not significantly affected by the Fluoxetine treatment. These results are consistent with a hyposerotonergic mediation of the effects of OBX on circadian period and activity level.

Quantitative trait loci (QTL) for circadian rhythms of locomotor activity in mice.

The locomotor activity of male mice (Mus musculus) was monitored by infrared photo-electric beams under three lighting regimens: LD (12 h of light and 12 h of dark), DD (constant dark), and LL (constant broad-spectrum light, 10 lux). Circadian period of locomotor activity (tau) was compared among 3 inbred strains of mice, C57BL/6J (B6), BALB/c (C), and DBA/2J (D2), and 26 recombinant inbred strains B x D (B6 x D2). The tau under both continuous low-intensity light and continuous darkness varied significantly among strains. Under DD the mean tau was 23.8 h for B6, 23.7 h for D2, and 23.6 h for C. Under LL the mean tau was 25.1 h for B6, 23.9 h for D2, and 25.5 h for C. Frequency histograms of the mean tau of 26 B x D RI mouse strains (three to seven animals per strain) in either DD or LL and the difference between them, delta tau, had distributions which appeared unimodal, suggesting polygenic inheritances. The narrow-sense heritability determined using 26 strains of B x D RI mice was about 55% for tau and about 38% for both tau in LL and delta tau. An estimated four loci contribute to the variance of tau in constant darkness and five to the variance of tau in constant low-intensity light among the strains studied. Quantitative trait locus (QTL) analysis identified several potential genetic loci associated with tau in constant darkness, tau in constant low-intensity light, and delta tau. The associations of highest probability for each of these traits were the D1Nds4 locus (p < .001) on mouse chromosome 1, the D5Ncvs52 locus (p < .05) on mouse chromosome 5, and the Pmv12 locus (p < .01) at 70 cM on mouse chromosome 5, respectively. A QTL identified for tau was associated (p < .05) with the D2NDS1 marker at 45 cM on chromosome 2 near the Ea 6 marker at 46 cM associated (p < .05) with that reported for the period of wheel running activity in seven C x B RI strains (Schwartz, W.J., and Zimmerman, P., J. Neurosci. 10:3685 1990).

Aging lengthens circadian period for wheel-running activity in C57BL mice.

Previous reports of age effects on circadian period in rodents show a slight shortening of period with age, with the exception of house mice (Mus domesticus) where a number of studies report mixed results. The present study consists of three comparisons of circadian period for wheel-running activity in young vs. older C57BL inbred mice following entrainment to 16:8 LD, 12:12 LD and 8:16 LD photoperiods. The free-running circadian period (tau(DD)) for wheel-running activity was significantly longer in older mice following entrainment to all three photoperiods. These results support a model of heterogeneous effects of aging on circadian period among different rodent species, and suggest that the lengthening of circadian period with age in house mice is not a function of age-dependent differences in after-effects imposed by prior entrainment.

Olfactory bulbectomy as a model for agitated hyposerotonergic depression.

Ablation of olfactory bulbs in rats reduced male sexual behavior, and altered the distribution of wheel-running activity between the light and dark phases of a 12:12 LD photoperiod. These effects were partially reversed by the tricyclic antidepressant amitriptyline. Olfactory bulbectomy also altered serotonin metabolism (5-HIAA/5-HT ratio) in the frontal cortex, nucleus accumbens, hippocampus and corpus striatum. These observations support the hypothesis that olfactory bulbectomy in rodents serves as a model of agitated hyposerotonergic depression.

Fluoxetine shortens circadian period for wheel running activity in mice.

Fluoxetine is a potent and specific serotonin re-uptake inhibitor and an effective antidepressant drug. Male mice were treated with either fluoxetine (8 mg/kg body weight per day) or saline. Wheel running activity was monitored for 2 weeks in a 12:12 LD cycle followed by 2 weeks in constant darkness (DD). Fluoxetine significantly shortened free-running circadian period for wheel running activity (23.93 +/- 0.08 h for fluoxetine treated mice versus 24.17 +/- 0.07 h for saline treated mice; p less than 0.03). These results are consistent with a role for serotonin in the regulation of circadian period in mice.

Olfactory bulbectomy increases basal suprachiasmatic cyclic AMP levels in male rats.

For further characterization of the olfactory bulb's role in the medication of chronobiological phenomena, we examined basal cyclic- 3',5'-adenosine monophosphate (cAMP) levels in the suprachiasmatic nuclei (SCN) and lateral hippocampus (LHIP) following bilateral olfactory bulbectomy (OBX) to assess the effects of olfactory bulb removal on the biological clock. Two groups of adult Long-Evans rats underwent OBX or sham control surgery (SHAM). Eight weeks postoperative, the animals were decapitated at the time of maximal cAMP accumulation (circadian time 9-11 h), brains were removed, frozen in liquid nitrogen, and sectioned on a cryostat. Individual brain nuclei (SCN and LHIP) were microdissected using the Palkovits punch technique and analyzed by scintillation proximity assay for cAMP. We report a 83.6% increase in basal cAMP levels in the SCN following OBX (OBX = 63.7 pmol cAMP/mg protein, SHAM = 34.7 pmol cAMP/mg protein, p less than 0.01). No significant differences in LHIP cAMP levels were found. This specific increase in SCN cAMP, at the time of maximum cAMP accumulation, may give insight into the biochemical basis for altered activity levels following OBX.

Effects of ovarian hormones on sexual receptivity, proceptivity, and motivation in olfactory bulbectomized female rats.

The purpose of the present experiment was to assess the effect of olfactory bulbectomy and ovarian hormones on female sexual motivation. Ovariectomized female rats underwent either bilateral bulbectomy or sham surgery. Females received one of four subthreshold hormone treatments: 0% estradiol (E2) plus 500 micrograms progesterone (P), 100% E2 alone, 10% E2 plus 500 micrograms P, or 100% E2 plus 500 micrograms P. Sexual motivation (as indicated by a female's preference for a sexually active male over a castrated male) and proceptivity (dart and ear wiggling sequences) were measured in a three compartment partner preference apparatus. Sexual receptivity (lordosis) was measured separately in a glass arena with a sexually active male. Results showed that olfactory bulb removal facilitates sexual receptivity and proceptivity in females exposed to 10% or 100% E2 in combination with 500 micrograms P. In contrast, sexual motivation was only demonstrated by olfactory bulbectomized females which received 100% E2 in combination with 500 micrograms P. These findings support the hypothesis that olfactory bulbectomy induces a behavioral hypersensitivity to estrogen, and suggest that sexual motivation is an estrogen-mediated response which requires a higher level of estrogen stimulation than sexual receptivity and proceptivity.

Quantitative genetic background effects on the Antennapaedia phenotype in Drosophila melanogaster.

Genetic background variation influencing expression of the Antennapaedia homeotic phenotype was examined by crossing the Antp73b allele of the Antennapaedia locus reciprocally into seven isogenically derived wild type strains of Drosophila melanogaster and their genetically heterogeneous parent strain, Dover. The parent Antp73b strain's Antennapaedia phenotype shows a small patch of untransformed antennal tissue remaining on the homeotic femur. The size of this patch was used as an assay for background variation influencing expression of the Antp73b homeotic mutation. Patch size varied approximately six-fold across the different genetic backgrounds. Effects of maternal parent, sex, and sex-linkage were also observed.

Olfactory bulb control of circadian activity rhythm in mice.

Ablation of mouse olfactory bulbs lengthened the circadian period of wheel-running activity by 43 min and delayed the onset of entrained activity by 108 min. A transient increase in activity during the light phase of the 12:12 h light-dark photoperiod also occurred following surgery. These disruptions suggest that olfactory systems can modulate mammalian circadian rhythms.

Pairing alters the effect of progesterone on nesting in female C57BL/10Sn mice.

Progesterone treatments have been shown to increase nesting levels of isolated female mice. Here we compared the effect of exogenous progesterone on the nesting behavior of C57BL/10Sn female Mus domesticus housed individually to nesting levels of the same mice housed in pairs. Progesterone increased nesting by isolated females but had no significant effect on the nesting scores of the same mice when they were grouped into pairs. The effect of exogenous progesterone on nesting levels in C57BL/10Sn females appears to depend on social circumstances.

Gene-dependent effect of lithium on circadian rhythms in mice (Mus musculus).

Lithium has been shown to lengthen free-running circadian periods in a variety of species. Here we show that lithium carbonate differentially lengthens the free-running period of a circadian wheel running rhythm in BALB/CByJ and C57BL/10Sn inbred mouse strains. This result supports previous evidence that lithium lengthens mammalian circadian rhythms, and also demonstrates that gene differences can mediate individual differences in response to lithium treatment.

Genetic association between progesterone-induced and maternal nesting in mice.

Increases in nesting during pregnancy may be mediated by progesterone in mice. If the behaviors, maternal nesting (MN) and nesting induced by exogenous progesterone (PN), are controlled by the same physiological mechanism, it would be expected that they share a common genetic basis. The present experiment was designed to quantify the extent of genetic association between PN and MN. At Wesleyan University, baseline nesting was measured on females of 4 inbred strains. Subsequently, half of the mice in each strain received progesterone implants. There were significant increases in nesting due to progesterone treatment. After 21 days, implants were removed and nesting levels returned to baseline. The mice were mated and nesting measured throughout pregnancy. The strain rank order was the same for levels of PN and MN. The genetic correlation between PN and MN estimated from analysis of covariance within and between strains was not significantly different from 1.0. These results were replicated at the University of Iowa. The high genetic correlation implies a common physiological mechanism underlying PN and MN.

Pigment mutations associated with altered circadian rhythms in mice.

Mammalian albinism is known to alter neural pathways, reduce retinal pigment, and affect diverse behaviors. Mammalian circadian rhythms have been shown to depend on visual pathways, respond to light intensity and regulate many behaviors. Here we show that mice homozygous for the recessive albino or pinkeye-dilute mutations display shorter circadian rhythms than pigmented controls. We conclude that these pigment loci, or closely linked loci, influence the expression of circadian rhythms in mice.

Gene differences modify Aschoff's rule in mice.

Nocturnal animals typically display an increase in the free running period of circadian rhythms in response to light in direct proportion to intensity. Here we show that gene differences among inbred strains of mice (Mus musculus) modify the effect of constant bright light on the free running period of a circadian rhythm for wheel running activity. Individuals with the shortest free running periods in dim red light showed the greatest increases in period following exposure to bright light. These effects may be due to gene-imposed differences in the response of a circadian pacemaker to light, or they may be due to gene-imposed differences in visual system function that alter perception of light intensity.