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Biomedical subjects

Louis J Muglia

Publications and source records attributed to Louis J Muglia.

At least 19 recordsLinked to original sources
PubMed2006

Glucocorticoids suppress bone formation via the osteoclast.

The pathogenesis of glucocorticoid-induced (GC-induced) bone loss is unclear. For example, osteoblast apoptosis is enhanced by GCs in vivo, but they stimulate bone formation in vitro. This conundrum suggests that an intermediary cell transmits a component of the bone-suppressive effects of GCs to osteoblasts in the intact animal. Bone remodeling is characterized by tethering of the activities of osteoclasts and osteoblasts. Hence, the osteoclast is a potential modulator of the effect of GCs on osteoblasts. To define the direct impact of GCs on bone-resorptive cells, we compared the effects of dexamethasone (DEX) on WT osteoclasts with those derived from mice with disruption of the GC receptor in osteoclast lineage cells (GRoc-/- mice). While the steroid prolonged longevity of osteoclasts, their bone-degrading capacity was suppressed. The inhibitory effect of DEX on bone resorption reflects failure of osteoclasts to organize their cytoskeleton in response to M-CSF. DEX specifically arrested M-CSF activation of RhoA, Rac, and Vav3, each of which regulate the osteoclast cytoskeleton. In all circumstances GRoc-/- mice were spared the impact of DEX on osteoclasts and their precursors. Consistent with osteoclasts modulating the osteoblast-suppressive effect of DEX, GRoc-/- mice are protected from the steroid's inhibition of bone formation.

Animals↗
PubMed2006

Effects of genetically altered brain glucocorticoid receptor action on behavior and adrenal axis regulation in mice.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with vulnerability to a number of psychiatric diseases including major depression, bipolar disorder, anxiety disorders, and schizophrenia. The HPA axis is activated in response to stress and in a characteristic circadian rhythm, resulting in the release of glucocorticoid hormones from the adrenal cortex. These hormones act on peripheral target tissues to restore homeostasis to the organism and engage glucocorticoid receptors (GR) in the CNS to control the intensity and duration of the stress response. Alterations in this glucocorticoid sensing system may underlie the HPA axis changes associated with psychiatric disorders. Recently, a number of lines of mice with genetically altered GR signaling in the CNS have been generated to address this hypothesis. Here, we summarize findings from new genetic models that indicate a critical role for GR signaling in the CNS in normal regulation of the HPA axis and behavioral/emotional stability.

Animals↗
PubMed2006

Inadvertent social information and the avoidance of parasitized male mice: a role for oxytocin.

Social information can be acquired either directly or indirectly from cues inadvertently produced by individuals with similar interests and requirements ("inadvertent social information," ISI). These inadvertent cues provide "public information" that other individuals can use to guide their behavior. We show here that female mice use olfactory ISI to determine their choice of, and responses to, males and that the use of this ISI involves the gene for oxytocin (OT). Female mice (OT wild type and CF-1 strain) displayed a significant interest in, and choice of, the odors of uninfected males of varying sexual status that were associated with the odors of an another estrous female. This recognition of, and choices for, specific, individual male odors was evident 24 h later. Female mice also distinguished between males subclinically infected with the gastrointestinal nematode parasite, Heligimosomoides polygyrus, and nonparasitized males, displaying aversive responses (analgesia, increased corticosterone) to, and avoidance of, the odors of infected males. The presence of the odors of another estrous female with that of the infected male, which are indicative of potential mate interests, attenuated these aversive responses and resulted in a choice for the odors of infected male. OT gene-deficient (knockout) females were impaired in their use of this ISI to modulate their responses to either uninfected males of differing sexual states or infected males. These findings suggest that OT genes are necessary for the processing of inadvertent social information and likely the integration of both direct and indirect social information.

Animals↗
PubMed2006

Forebrain glucocorticoid receptors modulate anxiety-associated locomotor activation and adrenal responsiveness.

Stress potently modulates anxiety- and depression-related behaviors. In response to stressors, the hypothalamic-pituitary-adrenal (HPA) axis is activated, resulting in the release of glucocorticoids from the adrenal cortex. These hormones act peripherally to restore homeostasis but also feed back to the CNS to control the intensity and duration of the stress response. Glucocorticoids act in limbic areas of the CNS to mediate the psychological and behavioral effects of stress. In this study, we investigate the effect of forebrain-specific disruption of the glucocorticoid receptor (GR) on stress- and anxiety-related behaviors. We demonstrate that mice with disruption of forebrain GR show alterations in stress-induced locomotor activation in a number of anxiety-related behavioral paradigms. These changes are associated with alterations in stress-induced HPA axis activation and, importantly, are not attenuated by chronic treatment with the tricyclic antidepressant imipramine. These data demonstrate the importance of forebrain GR in regulation of physiological and behavioral stress reactivity and suggest that distinct pathways regulate despair- and anxiety-related behaviors.

Adrenal Glands↗
PubMed2006

Cortisol and its action on the glucocorticoid receptor in malnutrition and acute infection.

Severe malnutrition alone is believed to cause hypercortisolemia. Cortisol's effects are mediated through the glucocorticoid receptor, which binds the hormone in the cytosol, translocates to the nucleus, and promotes gene transcription. This observational study in marasmic children with and without acute infection tested the hypothesis that marasmus is associated with hypercortisolemia, less glucocorticoid receptor, and less receptor translocation to the nucleus. Twenty-eight Malawian children participated; 14 with marasmus and infection, 6 with marasmus without infection, and 8 well nourished with infection. Free serum cortisol, interleukin 6 and tumor necrosis factor alpha, leucine derived from whole-body proteolysis, and the amount of whole-cell and nuclear leukocyte glucocorticoid receptor were measured upon admission. Free serum cortisol concentration was increased in marasmic and well-nourished children with infection compared with uninfected children with marasmus (14.2 [8.5, 16.3], 24.4 [15.0, 39.2], 5.1 [3.5, 7.0] microg/L, median [25th, 75th percentiles]; P < .05 by Kruskal-Wallis test). The amount of whole-cell leukocyte glucocorticoid receptor was similar in all children (0.48 +/- 0.33 signal units), but the amount in the nucleus was greatest in marasmic children with infection, followed by the amount in uninfected marasmic children, and then in well-nourished infected children (0.54 +/- 0.58, 0.19 +/- 0.13, 0.02 +/- 0.5 signal units [mean +/- SD]; P < .05 for all comparisons by analysis of variance). These findings suggest that hypercortisolemia is not associated with malnutrition alone, but does occur appropriately with acute infection. The increased nuclear glucocorticoid receptor abundance in marasmus demonstrates that nutritional status modulates glucocorticoid receptor action by mechanisms in addition to circulating glucocorticoid concentrations.

Acute Disease↗
PubMed2005

Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation.

Transgenic overexpression of NMDA NR2B receptors in forebrain regions increased behavioral responses to persistent inflammatory pain. However, it is not known whether inflammation leads to the upregulation of NR2B receptors in these regions. Here, we show that peripheral inflammation increased the expression of NMDA NR2B receptors and NR2B receptor-mediated synaptic currents in the anterior cingulate cortex (ACC). In freely moving mice, the increase in NR2B receptors after inflammation contributed to enhanced NMDA receptor-mediated responses in the ACC. Inhibition of NR2B receptors in the ACC selectively reduced behavioral sensitization related to inflammation. Our results demonstrate that the upregulation of NR2B receptors in the ACC contributes to behavioral sensitization caused by inflammation.

Animals↗
PubMed2005

Vascular respiratory uncoupling increases blood pressure and atherosclerosis.

The observations that atherosclerosis often occurs in non-smokers without elevated levels of low-density lipoprotein cholesterol, and that most atherosclerosis loci so far identified in mice do not affect systemic risk factors associated with atherosclerosis, suggest that as-yet-unidentified mechanisms must contribute to vascular disease. Arterial walls undergo regional disturbances of metabolism that include the uncoupling of respiration and oxidative phosphorylation, a process that occurs to some extent in all cells and may be characteristic of blood vessels being predisposed to the development of atherosclerosis. To test the hypothesis that inefficient metabolism in blood vessels promotes vascular disease, we generated mice with doxycycline-inducible expression of uncoupling protein-1 (UCP1) in the artery wall. Here we show that UCP1 expression in aortic smooth muscle cells causes hypertension and increases dietary atherosclerosis without affecting cholesterol levels. UCP1 expression also increases superoxide production and decreases the availability of nitric oxide, evidence of oxidative stress. These results provide proof of principle that inefficient metabolism in blood vessels can cause vascular disease.

Aconitate Hydratase↗
PubMed2005

Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family.

The RGS7 (R7) family of RGS proteins bound to the divergent Gbeta subunit Gbeta5 is a crucial regulator of G protein-coupled receptor (GPCR) signaling in the visual and nervous systems. Here, we identify R7BP, a novel neuronally expressed protein that binds R7-Gbeta5 complexes and shuttles them between the plasma membrane and nucleus. Regional expression of R7BP, Gbeta5, and R7 isoforms in brain is highly coincident. R7BP is palmitoylated near its COOH terminus, which targets the protein to the plasma membrane. Depalmitoylation of R7BP translocates R7BP-R7-Gbeta5 complexes from the plasma membrane to the nucleus. Compared with nonpalmitoylated R7BP, palmitoylated R7BP greatly augments the ability of RGS7 to attenuate GPCR-mediated G protein-regulated inward rectifying potassium channel activation. Thus, by controlling plasma membrane nuclear-shuttling of R7BP-R7-Gbeta5 complexes, reversible palmitoylation of R7BP provides a novel mechanism that regulates GPCR signaling and potentially transduces signals directly from the plasma membrane to the nucleus.

Active Transport, Cell Nucleus↗
PubMed2005

Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity.

The importance of the cAMP signaling pathway in the modulation of ethanol sensitivity has been suggested by studies in organisms from Drosophila melanogaster to man. However, the involvement of specific isoforms of adenylyl cyclase (AC), the molecule that converts ATP to cAMP, has not been systemically determined in vivo. Because AC1 and AC8 are the only AC isoforms stimulated by calcium, and ethanol modulates calcium flux by the NMDA receptor, we hypothesized that these ACs would be important in the neural response to ethanol. AC1 knock-out (KO) mice and double knock-out (DKO) mice with genetic deletion of both AC1 and AC8 display substantially increased sensitivity to ethanol-induced sedation compared with wild-type (WT) mice, whereas AC8 KO mice are only minimally more sensitive. In contrast, AC8 KO and DKO mice, but not AC1 KO mice, demonstrate decreased voluntary ethanol consumption compared with WT mice. DKO mice do not display increased sleep time compared with WT mice after administration of ketamine or pentobarbital, indicating that the mechanism of enhanced ethanol sensitivity in these mice is likely distinct from the antagonism of ethanol of the NMDA receptor and potentiation of the GABA(A) receptor. Ethanol does not enhance calcium-stimulated AC activity, but the ethanol-induced phosphorylation of a discrete subset of protein kinase A (PKA) substrates is compromised in the brains of DKO mice. These results indicate that the unique activation of PKA signaling mediated by the calcium-stimulated ACs is an important component of the neuronal response to ethanol.

Adenylyl Cyclases↗
PubMed2005

Calcium-stimulated adenylyl cyclases modulate ethanol-induced neurodegeneration in the neonatal brain.

Fetal alcohol exposure results in cognitive and neurobehavioral deficits, but the effects of modifying genetic loci on the severity of these sequelas have not been well characterized. Although the cAMP signaling pathway has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in modulating ethanol-induced neurodegeneration has not been examined. Adenylyl cyclases (ACs) 1 and 8 produce cAMP in response to intracellular calcium elevation and modulate several aspects of neuronal function, including ethanol sensitivity. AC1 and AC8 are expressed widely throughout the brain of neonatal mice, and genetic deletion of both AC1 and AC8 in double-knock-out (DKO) mice enhances ethanol-induced neurodegeneration in the brains of neonatal mice. In addition, ethanol treatment induces significantly greater levels of caspase-3 activation in the brains of DKO mice compared with wild-type (WT) mice, reflecting higher numbers of apoptotic neurons. Administration of the NMDA receptor antagonist MK801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine hydrogen maleate] or the GABA(A) receptor potentiator phenobarbital, which mimics components of the effects of ethanol on neurons, results in significantly greater neurodegeneration in the brains of neonatal DKO mice than WT mice. Furthermore, loss of a single calcium-stimulated AC isoform potentiates neurodegeneration after administration of ethanol, MK801, or phenobarbital. In contrast, the levels of physiological cell death, death after hypoxia/ischemia, and excitotoxic cell death are not increased in the brains of DKO mice. Thus, AC1 and AC8 are critical modulators of neurodegeneration induced by activity blockade in the neonatal brain and represent genetic loci that may potentially modify the severity of fetal alcohol syndrome.

Adenylyl Cyclases↗
PubMed2004

Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of major depressive disorder. A number of studies have shown that this dysregulation is correlated with impaired forebrain glucocorticoid receptor (GR) function. To determine whether a primary, acquired deficit in forebrain GR signaling is an etiologic factor in the pathogenesis of depression, we generated a line of mice with time-dependent, forebrain-specific disruption of GR (FBGRKO). These mice develop a number of both physiological and behavioral abnormalities that mimic major depressive disorder in humans, including hyperactivity of the HPA axis, impaired negative feedback regulation of the HPA axis and, increased depression-like behavior. Importantly, a number of these abnormalities are normalized by chronic treatment with the tricyclic antidepressant, imipramine. Our findings suggest that imipramine's proposed activities on forebrain GR function are not essential for its antidepressant effects, and that alteration in GR expression may play a causative role in disease onset of major depressive disorder.

Animals↗
PubMed2004

Vasopressin stimulates ventromedial hypothalamic neurons via oxytocin receptors in oxytocin gene knockout male and female mice.

A wealth of neuropharmacological data demonstrates that oxytocin (OT) actions in the mammalian forebrain support a wide variety of affiliative behaviors and repress aggressive behaviors. Based on that literature, it was expected that reproductive and affiliative behaviors would be vastly decreased and aggression markedly increased in OT gene knockout (OTKO) mice. The initial publications reporting the behaviors of these mice did not include such phenotypes. Here, we compared single-unit activities recorded from the ventromedial hypothalamus in tissue slices of male and female OTKO mice and their wild-type littermate to test two hypotheses about OT functional genomics. First, we proposed that in OTKO mice, a very similar 9-amino-acid neuropeptide, arginine vasopressin (a likely gene duplication product), can 'cross over' and compensate for the lack of OT. This hypothesis was confirmed in both males and females. Further, we proposed that because of the lifelong absence of OT in OTKO, OT receptors would be more sensitive to OT in the knockout animals. We tested this idea in males and found that it was correct. Thus, an answer to the 'OTKO paradox' is put forth, with implications for OT-sensitive behaviors in a variety of species.

Animals↗
PubMed2004

Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency.

alpha-1-Antitrypsin (alpha1-AT) deficiency is the most common cause of metabolic pediatric liver disease. Hepatocellular injury is caused by toxicity of the mutant alpha-1-antitrypsin Z (alpha1-ATZ) molecule retained within hepatocytes. In these studies, we used the PiZ transgenic mouse model of alpha1-AT deficiency to examine hepatocellular proliferation in response to chronic liver injury resulting from this metabolic disease. The results showed increased hepatocellular proliferation and caspase 9 activation in male PiZ mice compared with female PiZ and wild-type mice. Hepatic alpha1-AT mRNA and protein expression also were increased in male PiZ mice, suggesting that greater hepatocellular proliferation and caspase activation in males results from increased hepatotoxicity associated with greater intracellular alpha1-ATZ accumulation. Testosterone treatment of female PiZ mice increased alpha1-ATZ expression and hepatocellular proliferation to a level comparable with that in males. In PiZ mice, hepatocytes devoid of intracellular alpha1-AT globules had a proliferative advantage compared with globule-containing hepatocytes. However, this advantage is relative because both globule-containing and globule-devoid hepatocytes exhibited comparable proliferation after partial hepatectomy. In conclusion, these data indicate that intracellular retention of mutant alpha1-ATZ is associated with a regenerative stimulus leading to increased hepatocellular proliferation, that gender-specific signals influence the degree of alpha1-AT expression and associated hepatic injury, and that hepatocytes devoid of alpha1-ATZ have a proliferative advantage over cells that accumulate the mutant protein. This selective proliferation suggests that hepatocellular transplantation may be applicable for treatment of this and other slowly progressive metabolic liver diseases.

Androgens↗
PubMed2004

Disruption of hepatic adipogenesis is associated with impaired liver regeneration in mice.

The liver responds to injury with regulated tissue regeneration. During early regeneration, the liver accumulates fat. Neither the mechanisms responsible for nor the functional significance of this transient steatosis have been determined. In this study, we examined patterns of gene expression associated with hepatic fat accumulation in regenerating liver and tested the hypothesis that disruption of hepatic fat accumulation would be associated with impaired hepatic regeneration. First, microarray-based gene expression analysis revealed that several genes typically induced during adipocyte differentiation were specifically upregulated in the regenerating liver prior to peak hepatocellular fat accumulation. These observations suggest that hepatic fat accumulation is specifically regulated during liver regeneration. Next, 2 methods were employed to disrupt hepatocellular fat accumulation in the regenerating liver. Because exogenous leptin supplementation reverses hepatic steatosis in leptin-deficient mice, the effects of leptin supplementation on liver regeneration in wild-type mice were examined. The data showed that leptin supplementation resulted in suppression of hepatocellular fat accumulation and impairment of hepatocellular proliferation during liver regeneration. Second, because glucocorticoids regulate cellular fat accumulation during adipocyte differentiation, the effects of hepatocyte-specific disruption of the glucocorticoid receptor were similarly evaluated. The results showed that hepatic fat accumulation and hepatocellular proliferation were also suppressed in mice with liver specific disruption of glucocorticoid receptor. In conclusion, suppression of hepatocellular fat accumulation is associated with impaired hepatocellular proliferation following partial hepatectomy, indicating that hepatocellular fat accumulation is specifically regulated during and may be essential for normal liver regeneration.

Animals↗
PubMed2004

Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adults.

Administration of ethanol to rodents during the synaptogenesis period induces extensive apoptotic neurodegeneration in the developing brain. This neurotoxicity may explain the reduced brain mass and neurobehavioral disturbances in human Fetal Alcohol Syndrome (FAS). Here, we report binge-like exposure of infant mice to ethanol on a single postnatal day triggered apoptotic death of neurons from diencephalic structures that comprise an extended hippocampal circuit important for spatial learning and memory. The ethanol exposure paradigm yielding these neuronal losses caused profound impairments in spatial learning and memory at 1 month of age. This impairment was significantly attenuated during subsequent development, indicating recovery of function. Recovery was not associated with increased neurogenesis, suggesting plastic reorganization of neuronal networks compensated for early neuronal losses. We hypothesize that neuroapoptotic damage in homologous regions of human brain underlies cognitive deficits in FAS and the human brain of FAS victims has a similar capacity to effect functional recovery.

Animals↗
PubMed2004

Genetic dissection of stress response pathways in vivo.

A number of lines of evidence suggest that alterations in forebrain glucocorticoid receptor (GR)-mediated regulation of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the etiology of depression. The level of expression of GR in the hippocampus is highly correlated with HPA axis activity, and a number of animal models of depression are associated with altered forebrain GR expression. We have generated a line of mice with a conditional, forebrain-specific deletion of GR (FBGRKO) to determine if a primary deficit in forebrain GR signaling is an etiologic factor in the pathogenesis of depression. These mice should prove to be valuable for identifying GR target genes in major depressive disorder (MDD) and testing pharmacological agents for efficacy in this disorder.

Animals↗
PubMed2003

Type 8 adenylyl cyclase is targeted to excitatory synapses and required for mossy fiber long-term potentiation.

Mossy fiber/CA3 long-term potentiation (LTP) is hypothesized to depend on cAMP signals generated by Ca2+-stimulated adenylyl cyclases AC1 or AC8. AC1 gene knock-out mice (AC1-/-) show a partial reduction in mossy fiber LTP, suggesting that either AC8 activity is also critical for mossy fiber LTP or that there is a component of mossy fiber LTP that is independent of CaM-activated adenylyl cyclases. To address this issue, mossy fiber LTP was examined in hippocampal slices from AC8-/- and AC1-/- x AC8-/- double knock-out mice (DKO). Despite the fact that AC8 contributes only a small fraction of the Ca2+-stimulated adenylyl cyclase activity in the hippocampus and is less sensitive to Ca2+ than AC1, AC8-/- mice exhibited mossy fiber LTP defects comparable with AC1-/- and DKO mice. Furthermore, short-term plasticity was disrupted in AC8-/- mice but not in AC1-/- mice. Because AC1 is not localized at the excitatory synapses in hippocampal neurons, we hypothesized that AC8 may be targeted to synapses, in which higher synaptic-specific Ca2+ increases occur. Here, we report that AC8 accumulates in puncta of dendrites and axons in hippocampal neurons and colocalizes with synaptic marker proteins. These data indicate that both synaptic and nonsynaptic cAMP signals, generated by different Ca2+-stimulated adenylyl cyclases, are required for mossy fiber LTP.

Adenylyl Cyclases↗