Regional brain [Met]-enkephalin in alcohol-preferring and non-alcohol-preferring inbred strains of mice

Scrutiny of the data from these studies reveals that the C58/J alcohol-preferring mice have significantly lower baseline methionine-enkephalin levels in both the corpus striatum and hypothalamus compared to C3H/CHRGL/2 non-alcohol-preferring mice. In other brain regions in these two strains, specifically, pituitary, amygdala, midbrain, and hippocampus, analysis of methionine-enkephalin levels did not show any significant differences. This suggests that the hypothalamus may indeed be a specific locus involved in the regulation of alcohol intake, via the molecular interaction between neuroamines, opioid peptides, as they are influenced by genetics and environment.     

Whole brain methionine-enkephalin of ethanol-avoiding and ethanol-preferring c57BL mice

These experiments systematically investigated ethanol preference in both the C57Bl/6N and C57Bl/6J mice utilizing three-choice 2-bottle preference test. In addition, these sublines were evaluated for whole brain methionine-enkephalin levels, which were significantly lower in C57Bl/6J mice (alcohol preferring) compared to C57Bl/6N mice (alcohol non-preferring). This finding supports the involvement of the peptidyl opiates in ethanol seeking behavior.     

Increased melatonin levels after hemorrhagic shock in male and female C3H/HeN mice

Although hemorrhagic shock leads to significant alterations of several hormones, e.g. ACTH, corticosterone and -endorphin, it is not known whether plasma melatonin levels are affected under this condition and if so, whether the effects are comparable in males and females. Using a radioimmunoassay, it was found that plasma melatonin levels were significantly increased in male and proestrus female C3H/HeN mice immediately after hemorrhagic shock. However, in male mice, by two hours after hemorrhage and resuscitation, plasma melatonin returned to levels comparable to those seen in control and sham-operated animals. Proestrus female mice, on the other hand, showed significantly increased plasma melatonin levels at two hours after surgery when compared to unoperated control animals. Although the significance and biological role of the transient increased plasma melatonin levels after hemorrhagic shock remain to be determined, it appears that the pineal gland and/or an extrapineal source of melatonin, of both male and proestrus female mice responds to severe hypotension by increased release of melatonin.     

Preferential excretion of glycated albumin in C57BL-Ks-J mice: Effects of diabetes

Urinary excretion of glycated albumin was quantitated in genetically hyperglycemic mice (C57BL-Ks-J, db/db mice), a model for non-insulin-dependent diabetes mellitus, and compared with their non-diabetic littermates. The data indicated a preferential excretion of glycated albumin in non-diabetic mice. This phenomenon of editing of glycated albumin is decreased significantly in diabetic mice. Quantitative measurements of overall excretion of glycated albumin suggested that the loss of editing in diabetic mice is due to the dilution of glycated albumin by the unmodified albumin which is excreted in large amounts in diabetic mice. Therefore, the loss of editing observed in this model resembled the one we characterized in insulin-dependent diabetic humans and a streptozotocin-diabetic rat model³.     

Whole brain methionine-enkephalin of ethanol-avoiding and ethanol-preferring C57BL mice

Summary These experiments systematically investigated ethanol preference in both the C57Bl/6N and C57Bl/6J mice utilizing three-choice 2-bottle preference test. In addition, these sublines were evaluated for whole brain methionineenkephalin levels, which were significantly lower in C57Bl/6J mice (alcohol preferring) compared to C57Bl/6N mice (alcohol non-preferring). This finding supports the involvement of the peptidyl opiates in ethanol seeking behavior.     

Ablation of LMO4 in glutamatergic neurons impairs leptin control of fat metabolism

The LIM domain only 4 (LMO4) protein is expressed in the hypothalamus, but its function there is not known. Using mice with LMO4 ablated in postnatal glutamatergic neurons, including most neurons of the paraventricular (PVN) and ventromedial (VMH) hypothalamic nuclei where LMO4 is expressed, we asked whether LMO4 is required for metabolic homeostasis. LMO4 mutant mice exhibited early onset adiposity. These mice had reduced energy expenditure and impaired thermogenesis together with reduced sympathetic outflow to adipose tissues. The peptide hormone leptin, produced from adipocytes, activates Jak/Stat3 signaling at the hypothalamus to control food intake, energy expenditure, and fat metabolism. Intracerebroventricular infusion of leptin suppressed feeding similarly in LMO4 mutant and control mice. However, leptin-induced fat loss was impaired and activation of Stat3 in the VMH was blunted in these mice. Thus, our study identifies LMO4 as a novel modulator of leptin function in selective hypothalamic nuclei to regulate fat metabolism.     

Splenic B-cell activation in lipopolysaccharide-non-responsive C3H/HeJ mice by lipopolysaccharide ofPorphyromonas gingivalis

Porphyromonas gingivalis 381 lipopolysaccharide (LPS) definitely exhibited mitogenic activity in purified B-cells, separated from spleens of LPS-responsive C3H/HeN mice and LPS-non-responsive C3H/HeJ mice by using a magnetic cell sorting system. The mitogenic activity induced byP. gingivalis LPS was incompletely inhibited by polymyxin B.P. gingivalis LPS also induced a higher production of interleukin-6 (IL-6) in splenic B-cells of C3H/HeN mice as compared withEscherichia coli LPS. Furthermore,P. gingivalis LPS, but notE. coli LPS, induced definite IL-6 production in C3H/HeJ mice.P. gingivalis LPS increased tyrosine, serine/threonine phosphorylation of proteins with various major induced bands in splenic B-cells of both C3H/HeN and C3H/HeJ mice. Additionally, radioiodinatedP. gingivalis LPS, similarly toE. coli LPS, bound to a 73-kDa protein on C3H/HeJ as well as C3H/HeN B-cells. ThusP. gingivalis LPS may activate B-cells of C3H/HeJ as well as C3H/HeN mice via the LPS-specific binding protein on the cells.     

Inhibition by SMS 201-995 of normal mammary gland growth in mice

Summary Twice daily s.c. injection of 5 ng or 50 ng of SMS 201-995 between 25 and 55 days of age induced a significant retardation of normal mammary gland growth in C3H/He virgin mice, associated with the reduced plasma GH level. Meanwhile, plasma prolactin level and the pattern of estrous cycle were affected little by SMS treatments. The results indicate an involvement of GH in normal mammary gland growth in mice.     

Evidence for a role of IFN γ in control ofListeria monocytogenes in T cell deficient mice

Summary The role of interferon (IFN) in controlling chronic infections ofListeria monocytogenes (Listeria) was studied in athymic C57BL/6nu/nu mice, and by treating thymectomized C57BL/6 +/+ mice with monoclonal rat CD4 and CD8-specific monoclonal antibodies (Mab). Mice treated with a combination of the two T cell subset antibodies were similar to athymic, nude mice in being able to contol Listeria infection, keeping the titers below 3–5 log₁₀ bacteria per organ, but they could not eliminate them completely. Treatment with antibodies to IFN of nude or CD4⁺ + CD8⁺-T cell-depleted mice suffering from chronic Listeria infection caused a marked increase of Listeria titers, in liver and spleen. This result implies a role of IFN in maintaining anti-Listeria resistance in mice lacking mature T cells.     

Persistent inverse maternal effect on corticosterone production in vitro

Summary Adrenal cells from C57BL/Tb mice produced more steroid than those from DBA/2J mice. Reciprocal differences between both backcross and F1 hybrids showed a persistent maternal effect. Mothers with high output produce offspring with reduced hormone production when adult. Corticosterone output thus depends on maternal phenotype as well as on the genotype of the isolated cells.We thank Margaret MacKendrick for her help and the Medical Research Council for a research studentship for PRWW.     

Arylsulfatase B synthesis and clearance in inbred mouse strains

Arylsulfatase B activity levels were approximately 2-3-fold higher in adult C57BL/6J liver and kidney compared to corresponding tissues from A/J inbred mice. In vivo incorporation of tritiated leucine into C57BL/6J hepatic arylsulfatase B reached a maximum approximately 15 h after injection. The label was cleared from C57BL/6J arylsulfatase B with an apparent half-life of 36 h. The relative rates of synthesis of C57BL/6J and A/J arylsulfatase B were similar; however, the A/J enzyme was cleared more rapidly from liver tissue. C57BL/6J kidney arylsulfatase B appeared to be synthesized at a 2-3-fold higher rate than the corresponding A/J enzyme. These trends suggest genetic regulation of arylsulfatase B is effected through different means in liver and kidney from adult mice of these two inbred strains.     

Effect of glucocorticoids injected into pregnant female mice and rats on weight of male sexual glands in adult offspring and testosterone level in fetus in genotype-dependent

Injection of corticosterone into CBA/Lac, C57BL/6J and BALB/c mice, or hydrocortisone into aggressive and domesticated rats, on days 16 and 18 of pregnancy decreased the weight of sexual glands in adult male offspring of the C57BL/6J and domesticated mothers but increased these values in male offspring of the CBA/Lac and aggressive mothers. When injected into pregnant aggressive and domesticated rats, corticosterone affected testosterone levels in 21-day-old male fetuses. The changes were also genotype-dependent and followed the course of changes in the weight of the accessory sex glands in adults. It is suggested that glucocorticoids given during the prenatal period can effect plasma testosterone levels of male fetuses and the development of the sexual glands in a genotype-dependent manner.     

Genetic control of hippocampal cholinergic and dynorphinergic mechanisms regulating novelty-induced exploratory behavior in house mice

Summary Neurobehavioral genetics endeavors to trace the pathways from genetic and eenvironmental determinants to neuroanatomical and neurophysiological systems and, thence, to behavior. Exploiting genetic variation as a tool, the behavioral sequelae of manipulating these neuronal systems by drugs and antisera are analyzed. Apart from research in rats, this paper deals mainly with the genetically-influenced regulation in mice of exploratory behaviors that are adaptive in novel surroundings and are hippocampally-mediated. Special attention is paid to neuropeptidergic, GABAergic, and cholinergic synaptic functions in the mouse hippocampus.The behaviorally different inbred mouse strains C57BL/6 and DBA/2 show opposite reactions (reductions and increases, respectively, in exploration rates) to peripheral and intrahippocampal injections with agents that interfere with peptidergic, cholinergic, and GABAergic neurotransmission. These findings can be explained by an interdependent over-release of opioids, arrested GABA release, and excess acetylcholine in the hippocampal neuronal network of DBA/2 mice, as compared to C57BL/6 mice where these systems are functionally well balanced. Very similar results have been obtained with the lines SRH and SRL, derived from C57BL/6 and DBA/2, and genetically selected for rearing behavior. Most probably, the opioids act to disinhibit exploratory responses. An additional genetic approach is mentioned, in which four inbred mouse strains and one derived heterogeneous stock are used for estimating genetic correlations between structural properties of the hippocampal mossy fibers and levels of hippocampal dynorphin B, on the one hand, and frequencies of exploratory responses to environmental novelty, on the other.     

Genetic control of hippocampal cholinergic and dynorphinergic mechanisms regulating novelty-induced exploratory behavior in house mice

Neurobehavioral genetics endeavors to trace the pathways from genetic and environmental determinants to neuroanatomical and neurophysiological systems and, thence, to behavior. Exploiting genetic variation as a tool, the behavioral sequelae of manipulating these neuronal systems by drugs and antisera are analyzed. Apart from research in rats, this paper deals mainly with the genetically-influenced regulation in mice of exploratory behaviors that are adaptive in novel surroundings and are hippocampally-mediated. Special attention is paid to neuropeptidergic, GABAergic, and cholinergic synaptic functions in the mouse hippocampus. The behaviorally different inbred mouse strains C57BL/6 and DBA/2 show opposite reactions (reductions and increases, respectively, in exploration rates) to peripheral and intrahippocampal injections with agents that interfere with peptidergic, cholinergic, and GABAergic neurotransmission. These findings can be explained by an interdependent over-release of opioids, arrested GABA release, and excess acetylcholine in the hippocampal neuronal network of DBA/2 mice, as compared to C57BL/6 mice where these systems are functionally well balanced. Very similar results have been obtained with the lines SRH and SRL, derived from C57BL/6 and DBA/2, and genetically selected for rearing behavior. Most probably, the opioids act to disinhibit exploratory responses. An additional genetic approach is mentioned, in which four inbred mouse strains and one derived heterogeneous stock are used for estimating genetic correlations between structural properties of the hippocampal mossy fibers and levels of hippocampal dynorphin B, on the one hand, and frequencies of exploratory responses to environmental novelty, on the other.     

Chemistry of male dominance in the house mouse,Mus domesticus

Summary Two terpenic constituents, E,E,--farnesene and E--farnesene, were found to be elevated in dominant male urine when compared to subordinate or control males. These two urinary compounds were absent in the bladder urine of males; however, they were the most prominent constituents of the preputial gland's aliquots. The results of a two-choice preference test, conducted on ICR/Alb subordinate males, gave a strong indication that these two terpenic constituents introduced into the previously attractive stimulus significantly discouraged prolonged investigations by male mice. The compounds, whether present in the urine matrix or water, rendered the stimulus with a quality behaviorally similar to the urine of dominant males. It appears that they may be synonymous with the previously described aversion signal produced by dominant males. We suggest that these compounds may play a wide-ranging role in the territorial marking behavior of male mice.     

Hypothalamic histamine modulates adaptive behavior of rats at high environmental temperature

Summary Histamine content in the rat hypothalamus was lower at 4°C and higher at 31°C compared to that at 21°C. Pretreatment with -fluoromethylhistidine, a suicide inhibitor of histidine decarboxylase, attenuated both the increased level of hypothalamic histamine and rat adaptive behavior at 31°C. Increase of histamine content in the hypothalamus appears to be an important factor contributing to rat adaptive behavior to high environmental temperature.     

Hypothalamic histamine modulates adaptive behavior of rats at high environmental temperature

Histamine content in the rat hypothalamus was lower at 4 degrees C and higher at 31 degrees C compared to that at 21 degrees C. Pretreatment with alpha-fluoromethylhistidine, a 'suicide' inhibitor of histamine decarboxylase, attenuated both the increased level of hypothalamic histamine and rat adaptive behavior at 31 degrees C. Increase of histamine content in the hypothalamus appears to be an important factor contributing to rat adaptive behavior to high environmental temperature.     

Analysis of the immune system with transgenic mice: B cell development and lymphokines

Over the last decade transgenic mice expressing genes relevant for the immune system have been generated. Transgenic expression of immunoglobulin heavy and/or light chain genes of different isotypes and different specificities have helped to better understand phenomena relevant to B cell development such as allelic exclusion of immunoglobulins and B cell tolerance. Transgenic mice expressing interleukin genes have also been used to study the ways of action of these important growth and differentiation factors in the context of the mouse immune system.     

Depletion of hypothalamic norepinephrine reduces the fever induced by polyriboinosinic acid: polyribocytidylic acid (Poly I:Poly C) in rats

Summary Administration of either Poly I:Poly C (0.05–0.50 g) or norepinephrine (2–8 g) into the anterior hypothalamic area produced a dose-related fever in rats. The fever induced by Poly I:Poly C was attenuated after selective depletion of norepinephrine in the hypothalamus. However, selective depletion of hypothalamic norepinephrine did not affect the fever induced by intrahypothalamic norepinephrine. The data indicate that Poly I:Poly C may act to induce fever through the endogenous release of norepinephrine from the rat's hypothalamus.This work was supported by grants from the National Science Council (Taipei, Republic of China).     

Ethanol ingestive behavior as a function of central neurotransmission

Uncontrollable alcohol ingestive behavior has been linked to deficits of central neurotransmission. The pineal gland plays an important role in modulating ethanol intake in numerous animal species. The opioidergic (i.e. beta-endorphin, enkephalin, and dynorphin) system is involved in both the actions of alcohol and opiates, as well as craving and/or genetic predisposition towards abuse of these two agents. Furthermore, there is significant evidence to link ingestive behaviors with the ventral tegmental accumbens-hypothalamic axis, whereby the biogenic amines dopamine and serotonin are reciprocally involved. Evidence is presented which implicates the striatum and the hypothalamus as possible specific loci for regional differences between alcohol-preferring and alcohol-nonpreferring mice. We believe that photoperiod-induced alcohol ingestive behavior may involve alterations in both pineal and hypothalamic opioid peptides.