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1.
Proc Natl Acad Sci U S A ; 119(45): e2211142119, 2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36322771

RESUMO

Ultradian rhythms in metabolism and physiology have been described previously in mammals. However, the underlying mechanisms for these rhythms are still elusive. Here, we report the discovery of temperature-sensitive ultradian rhythms in mammalian fibroblasts that are independent of both the cell cycle and the circadian clock. The period in each culture is stable over time but varies in different cultures (ranging from 3 to 24 h). We show that transient, single-cell metabolic pulses are synchronized into stable ultradian rhythms across contacting cells in culture by gap junction-mediated coupling. Coordinated rhythms are also apparent for other metabolic and physiological measures, including plasma membrane potential (Δψp), intracellular glutamine, α-ketoglutarate, intracellular adenosine triphosphate (ATP), cytosolic pH, and intracellular calcium. Moreover, these ultradian rhythms require extracellular glutamine, several different ion channels, and the suppression of mitochondrial ATP synthase by α-ketoglutarate, which provides a key feedback mechanism. We hypothesize that cellular coupling and metabolic feedback can be used by cells to balance energy demands for survival.


Assuntos
Relógios Circadianos , Ritmo Ultradiano , Animais , Ácidos Cetoglutáricos , Glutamina , Ciclo Celular , Ritmo Circadiano/fisiologia , Mamíferos
2.
Front Endocrinol (Lausanne) ; 13: 1054447, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36407308

RESUMO

Congenital hypogonadotropic hypogonadism (HH) is a heterogeneous genetic disorder characterized by disrupted puberty and infertility. In most cases, HH is abiding yet 10-15% undergo reversal. Men with HH and absent and partial puberty (i.e., testicular volume <4mL and >4mL respectively) have been well-studied, but the rare fertile eunuch (FE) variant remains poorly characterized. This natural history study of 240 men with HH delineates the clinical presentation, neuroendocrine profile, rate of reversal and genetics of the FE variant. We compared three HH groups: FE (n=38), absent puberty (n=139), and partial puberty (n=63). The FE group had no history of micropenis and 2/38 (5%) had cryptorchidism (p<0.0001 vs. other groups). The FE group exhibited higher rates of detectable gonadotropins, higher mean LH/FSH levels, and higher serum inhibin B levels (all p<0.0001). Neuroendocrine profiling showed pulsatile LH secretion in 30/38 (79%) of FE men (p<0.0001) and 16/36 (44%) FE men underwent spontaneous reversal of HH (p<0.001). The FE group was enriched for protein-truncating variants (PTVs) in GNRHR and FGFR1 and 4/30 (13%) exhibited oligogenic PTVs. Findings suggest men with the FE variant exhibit the mildest neuroendocrine defects of HH men and the FE sub-type represents the first identified phenotypic predictor for reversible HH.


Assuntos
Eunuquismo , Hipogonadismo , Humanos , Masculino , Gonadotropinas , Sistemas Neurossecretores
3.
Adv Exp Med Biol ; 1344: 3-20, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34773223

RESUMO

Circadian (24-h) rhythms dictate almost everything we do, setting our clocks for specific times of sleeping and eating, as well as optimal times for many other basic functions. The physiological systems that coordinate circadian rhythms are intricate, but at their core, they all can be distilled down to cell-autonomous rhythms that are then synchronized within and among tissues. At first glance, these cell-autonomous rhythms may seem rather straight-forward, but years of research in the field has shown that they are strikingly complex, responding to many different external signals, often with remarkable tissue-specificity. To understand the cellular clock system, it is important to be familiar with the major players, which consist of pairs of proteins in a triad of transcriptional/translational feedback loops. In this chapter, we will go through each of the core protein pairs one-by-one, summarizing the literature as to their regulation and their broader impacts on circadian gene expression. We will conclude by briefly examining the human genetics literature, as well as providing perspectives on the future of the study of the molecular clock.


Assuntos
Ritmo Circadiano , Sono , Ritmo Circadiano/genética , Humanos , Especificidade de Órgãos
4.
Neuron ; 109(20): 3268-3282.e6, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34416169

RESUMO

The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in mammals and is entrained by environmental light. However, the molecular basis of the response of the SCN to light is not fully understood. We used RNA/chromatin immunoprecipitation/single-nucleus sequencing with circadian behavioral assays to identify mouse SCN cell types and explore their responses to light. We identified three peptidergic cell types that responded to light in the SCN: arginine vasopressin (AVP), vasoactive intestinal peptide (VIP), and cholecystokinin (CCK). In each cell type, light-responsive subgroups were enriched for expression of neuronal Per-Arnt-Sim (PAS) domain protein 4 (NPAS4) target genes. Further, mice lacking Npas4 had a longer circadian period under constant conditions, a damped phase response curve to light, and reduced light-induced gene expression in the SCN. Our data indicate that NPAS4 is necessary for normal transcriptional responses to light in the SCN and critical for photic phase-shifting of circadian behavior.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Ritmo Circadiano/genética , Luz , Neurônios/metabolismo , Núcleo Supraquiasmático/metabolismo , Animais , Arginina Vasopressina/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Colecistocinina/metabolismo , Imunoprecipitação da Cromatina , Ritmo Circadiano/efeitos da radiação , Perfilação da Expressão Gênica , Camundongos , Camundongos Knockout , Neurônios/efeitos da radiação , Análise de Sequência de RNA , Análise de Célula Única , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/efeitos da radiação , Peptídeo Intestinal Vasoativo/metabolismo
5.
J Neurosci ; 40(48): 9306-9316, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33097636

RESUMO

Patients with sleeping sickness, caused by the parasite Trypanosoma brucei, have disruptions in both sleep timing and sleep architecture. However, the underlying cause of these sleep disturbances is not well understood. Here, we assessed the sleep architecture of male mice infected with T. brucei and found that infected mice had drastically altered sleep patterns. Interestingly, T. brucei-infected mice also had a reduced homeostatic sleep response to sleep deprivation, a response modulated by the adenosine system. We found that infected mice had a reduced electrophysiological response to an adenosine receptor antagonist and increased adenosine receptor gene expression. Although the mechanism by which T. brucei infection causes these changes remains to be determined, our findings suggest that the symptoms of sleeping sickness may be because of alterations in homeostatic adenosine signaling.SIGNIFICANCE STATEMENT Sleeping sickness is a fatal disease that disrupts the circadian clock, causes disordered temperature regulation, and induces sleep disturbance. To examine the neurologic effects of infection in the absence of other symptoms, in this study, we used a mouse model of sleeping sickness in which the acute infection was treated but brain infection remained. Using this model, we evaluated the effects of the sleeping sickness parasite, Trypanosoma brucei, on sleep patterns in mice, under both normal and sleep-deprived conditions. Our findings suggest that signaling of adenosine, a neuromodulator involved in mediating homeostatic sleep drive, may be reduced in infected mice.


Assuntos
Adenosina/fisiologia , Sono , Tripanossomíase Africana/fisiopatologia , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Eletroencefalografia , Eletromiografia , Fenômenos Eletrofisiológicos , Expressão Gênica , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/metabolismo , Privação do Sono , Trypanosoma brucei brucei
6.
Neuron ; 108(1): 164-179.e7, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32768389

RESUMO

The suprachiasmatic nucleus (SCN) acts as a master pacemaker driving circadian behavior and physiology. Although the SCN is small, it is composed of many cell types, making it difficult to study the roles of particular cells. Here we develop bioluminescent circadian reporter mice that are Cre dependent, allowing the circadian properties of genetically defined populations of cells to be studied in real time. Using a Color-Switch PER2::LUCIFERASE reporter that switches from red PER2::LUCIFERASE to green PER2::LUCIFERASE upon Cre recombination, we assess circadian rhythms in two of the major classes of peptidergic neurons in the SCN: AVP (arginine vasopressin) and VIP (vasoactive intestinal polypeptide). Surprisingly, we find that circadian function in AVP neurons, not VIP neurons, is essential for autonomous network synchrony of the SCN and stability of circadian rhythmicity.


Assuntos
Arginina Vasopressina/metabolismo , Ritmo Circadiano , Rede Nervosa/metabolismo , Proteínas Circadianas Period/genética , Neurônios do Núcleo Supraquiasmático/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Fatores de Transcrição ARNTL/genética , Animais , Técnicas de Inativação de Genes , Luciferases , Camundongos , Camundongos Transgênicos , Proteínas Circadianas Period/metabolismo , Análise de Célula Única , Núcleo Supraquiasmático/metabolismo , Imagem com Lapso de Tempo
7.
Proc Natl Acad Sci U S A ; 117(19): 10350-10356, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32358201

RESUMO

Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.


Assuntos
Relógios Circadianos , Ritmo Circadiano , Modelos Biológicos , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas Circadianas Period/metabolismo , Análise de Célula Única/métodos , Animais , Células Cultivadas , Medições Luminescentes , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Proteínas Circadianas Period/genética , Processos Estocásticos
8.
Elife ; 92020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32459177

RESUMO

Circadian oscillations are generated via transcriptional-translational negative feedback loops. However, individual cells from fibroblast cell lines have heterogeneous rhythms, oscillating independently and with different period lengths. Here we showed that heterogeneity in circadian period is heritable and used a multi-omics approach to investigate underlying mechanisms. By examining large-scale phenotype-associated gene expression profiles in hundreds of mouse clonal cell lines, we identified and validated multiple novel candidate genes involved in circadian period determination in the absence of significant genomic variants. We also discovered differentially co-expressed gene networks that were functionally associated with period length. We further demonstrated that global differential DNA methylation bidirectionally regulated these same gene networks. Interestingly, we found that depletion of DNMT1 and DNMT3A had opposite effects on circadian period, suggesting non-redundant roles in circadian gene regulation. Together, our findings identify novel gene candidates involved in periodicity, and reveal DNA methylation as an important regulator of circadian periodicity.


Assuntos
Ritmo Circadiano/genética , Epigênese Genética/genética , Animais , Células Cultivadas , Células Clonais , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA/genética , DNA Metiltransferase 3A , Técnicas de Silenciamento de Genes , Redes Reguladoras de Genes/genética , Genoma/genética , Humanos , Masculino , Camundongos , Fenótipo , Transcriptoma/genética
9.
Proc Natl Acad Sci U S A ; 116(44): 22229-22236, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31611405

RESUMO

Fumarylacetoacetate hydrolase (FAH) is the last enzyme in tyrosine catabolism, and mutations in the FAH gene are associated with hereditary tyrosinemia type I (HT1 or TYRSN1) in humans. In a behavioral screen of N-ethyl-N-nitrosourea mutagenized mice we identified a mutant line which we named "swingshift" (swst, MGI:3611216) with a nonsynonymous point mutation (N68S) in Fah that caused age-dependent disruption of sleep-wake patterns. Mice homozygous for the mutation had an earlier onset of activity (several hours before lights off) and a reduction in total activity and body weight when compared with wild-type or heterozygous mice. Despite abnormal behavioral entrainment to light-dark cycles, there were no differences in the period or phase of the central clock in mutant mice, indicating a defect downstream of the suprachiasmatic nucleus. Interestingly, these behavioral phenotypes became milder as the mice grew older and were completely rescued by the administration of NTBC [2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione], an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, which is upstream of FAH. Mechanistically, the swst mutation had no effect on the enzymatic activity of FAH, but rather promoted the degradation of the mutant protein. This led to reduced FAH protein levels and enzymatic activity in the liver and kidney (but not the brain or fibroblasts) of homozygous mice. In addition, plasma tyrosine-but not methionine, phenylalanine, or succinylacetone-increased in homozygous mice, suggesting that swst mutants provide a model of mild, chronic HT1.


Assuntos
Ritmo Circadiano , Hidrolases/genética , Mutação , Sono , Tirosinemias/genética , 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores , Animais , Células Cultivadas , Cicloexanonas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Estabilidade Enzimática , Células HEK293 , Homozigoto , Humanos , Hidrolases/deficiência , Hidrolases/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nitrobenzoatos/uso terapêutico , Especificidade de Órgãos , Núcleo Supraquiasmático/metabolismo , Tirosinemias/tratamento farmacológico , Tirosinemias/fisiopatologia
10.
J Mol Endocrinol ; 63(4): R93-R102, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31557726

RESUMO

The mammalian circadian clock has evolved as an adaptation to the 24-h light/darkness cycle on earth. Maintaining cellular activities in synchrony with the activities of the organism (such as eating and sleeping) helps different tissue and organ systems coordinate and optimize their performance. The full extent of the mechanisms by which cells maintain the clock are still under investigation, but involve a core set of clock genes that regulate large networks of gene transcription both by direct transcriptional activation/repression as well as the recruitment of proteins that modify chromatin states more broadly.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/genética , Ativação Transcricional , Animais , Metabolismo Energético/genética , Epigênese Genética , Regulação da Expressão Gênica , Humanos , Mamíferos , Transdução de Sinais
11.
J Neurosci ; 39(40): 7958-7967, 2019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31420455

RESUMO

The transcription factor, myocyte enhancer factor-2 (MEF2), is required for normal circadian behavior in Drosophila; however, its role in the mammalian circadian system has not been established. Of the four mammalian Mef2 genes, Mef2d is highly expressed in the suprachiasmatic nucleus (SCN) of the hypothalamus, a region critical for coordinating peripheral circadian clocks. Using both conventional and brain-specific Mef2d KO (Mef2d-/-) mouse lines, we demonstrate that MEF2D is essential for maintaining the length of the circadian free-running period of locomotor activity and normal sleep patterns in male mice. Crossing Mef2d-/- with Per2::luc reporter mice, we show that these behavioral changes are achieved without altering the endogenous period of the master circadian oscillator in the SCN. Together, our data suggest that alterations in behavior in Mef2d-/- mice may be the result of an effect on SCN output, rather than an effect on timekeeping within the SCN itself. These findings add to the growing body of evidence that MEF2 proteins play important roles in the brain.SIGNIFICANCE STATEMENT These studies are the first to show a role for MEF2 proteins in the brain outside of the hippocampus, and our findings suggest that these proteins may play diverse roles in the CNS. It is important to continue to build on our understanding of the roles of proteins acting in the SCN because SCN dysfunction underlies jet lag in humans and influences the response to shift work schedules, which are now known as risk factors for the development of cancer. Our work on MEF2D could be the basis for opening new lines of research in the development and regulation of circadian rhythms.


Assuntos
Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Sono/genética , Sono/fisiologia , Animais , Comportamento Animal , Proteínas CLOCK/biossíntese , Proteínas CLOCK/genética , Luz , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , RNA/biossíntese , RNA/genética , Transtornos do Sono-Vigília/genética , Transtornos do Sono-Vigília/psicologia , Núcleo Supraquiasmático/fisiologia
12.
Trends Neurosci ; 42(8): 514-517, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31178075

RESUMO

Several different potassium channels modulate the activity of sleep-promoting neurons in the Drosophila brain, but the regulation of these channels is not completely understood. A recent study (Kempf et al., Nature, 2019) found that one of the potassium channel subunits, Hyperkinetic, alters the firing properties of sleep-promoting neurons in response to NADPH oxidation. These findings are the first to link cellular redox state and mitochondrial metabolism directly to sleep.


Assuntos
Proteínas de Drosophila , Animais , Drosophila , Oxirredução , Canais de Potássio , Sono
13.
Genes Brain Behav ; 18(8): e12578, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31059591

RESUMO

Chronic fatigue is a debilitating disorder with widespread consequences, but effective treatment strategies are lacking. Novel genetic mouse models of fatigue may prove invaluable for studying its underlying physiological mechanisms and for testing treatments and interventions. In a screen of voluntary wheel-running behavior in N-ethyl-N-nitrosourea mutagenized C57BL/6J mice, we discovered two lines with low body weights and aberrant wheel-running patterns suggestive of a fatigue phenotype. Affected progeny from these lines had lower daily activity levels and exhibited low amplitude circadian rhythm alterations. Their aberrant behavior was characterized by frequent interruptions and periods of inactivity throughout the dark phase of the light-dark cycle and increased levels of activity during the rest or light phase. Expression of the behavioral phenotypes in offspring of strategic crosses was consistent with a recessive inheritance pattern. Mapping of phenotypic abnormalities showed linkage with a single locus on chromosome 1, and whole exome sequencing identified a single point mutation in the Slc2a4 gene encoding the GLUT4 insulin-responsive glucose transporter. The single nucleotide change (A-T, which we named "twiggy") was in the distal end of exon 10 and resulted in a premature stop (Y440*). Additional metabolic phenotyping confirmed that these mice recapitulate phenotypes found in GLUT4 knockout mice. However, to the best of our knowledge, this is the first time a mutation in this gene has been shown to result in extensive changes in general behavioral patterns. These findings suggest that GLUT4 may be involved in circadian behavioral abnormalities and could provide insights into fatigue in humans.


Assuntos
Ritmo Circadiano , Códon sem Sentido , Fadiga/genética , Transportador de Glucose Tipo 4/genética , Animais , Comportamento Animal , Modelos Animais de Doenças , Fadiga/fisiopatologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo
14.
Hum Mol Genet ; 27(2): 338-350, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29161432

RESUMO

A major challenge in human genetics is the validation of pathogenicity of heterozygous missense variants. This problem is well-illustrated by PROKR2 variants associated with Isolated GnRH Deficiency (IGD). Homozygous, loss of function variants in PROKR2 was initially implicated in autosomal recessive IGD; however, most IGD-associated PROKR2 variants are heterozygous. Moreover, while IGD patient cohorts are enriched for PROKR2 missense variants similar rare variants are also found in normal individuals. To elucidate the pathogenic mechanisms distinguishing IGD-associated PROKR2 variants from rare variants in controls, we assessed 59 variants using three approaches: (i) in silico prediction, (ii) traditional in vitro functional assays across three signaling pathways with mutant-alone transfections, and (iii) modified in vitro assays with mutant and wild-type expression constructs co-transfected to model in vivo heterozygosity. We found that neither in silico analyses nor traditional in vitro assessments of mutants transfected alone could distinguish IGD variants from control variants. However, in vitro co-transfections revealed that 15/34 IGD variants caused loss-of-function (LoF), including 3 novel dominant-negatives, while only 4/25 control variants caused LoF. Surprisingly, 19 IGD-associated variants were benign or exhibited LoF that could be rescued by WT co-transfection. Overall, variants that were LoF in ≥ 2 signaling assays under co-transfection conditions were more likely to be disease-associated than benign or 'rescuable' variants. Our findings suggest that in vitro modeling of WT/Mutant interactions increases the resolution for identifying causal variants, uncovers novel dominant negative mutations, and provides new insights into the pathogenic mechanisms underlying heterozygous PROKR2 variants.


Assuntos
Nanismo Hipofisário/genética , Mutação de Sentido Incorreto , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Nanismo Hipofisário/metabolismo , Hormônio Liberador de Gonadotropina/deficiência , Células HEK293 , Humanos , Hipogonadismo/genética , Linhagem , Transdução de Sinais
17.
Behav Neurosci ; 129(3): 331-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26030431

RESUMO

Mice with severe combined immunodeficiency (SCID) lack functional T and B lymphocytes, and have impaired cognitive abilities. We assessed social behaviors in male SCID and C57BL/6 (B6) juvenile mice. In a social preference task, SCID mice spent more time than B6 mice investigating a novel adult male mouse. In a social recognition task, SCID mice habituated to a novel ovariectomized mouse, but failed to show dishabituation when presented with an unfamiliar individual. We hypothesized that partial immune restoration could normalize behaviors. SCID pups (postnatal Day 7) received either saline or splenocytes from normal donors. Splenocyte-replaced SCID mice spent less time interacting with a novel mouse than saline-injected SCID or B6 control mice. Again, control SCID mice failed to dishabituate to a novel mouse, but splenocyte-replaced SCID mice showed dishabituation. In both of these studies, B6 and SCID pairs were used to produce offspring that remained with their dams until weaning. There are no studies of maternal behavior in SCID dams; therefore to investigate the potential role for this factor, we quantified maternal behavior in SCID and B6 dams; several significant differences were found. To control for differences in maternal care, we mated heterozygous SCIDs to produce offspring. These homozygous SCID and wild-type offspring reared by dams of the same genotypes displayed similar responses to a novel mouse; however, in the social recognition task, SCID males did not display dishabituation to a novel mouse. Taken together, our data indicate that Gene × Environment interactions influence social interactions in immune deficient mice.


Assuntos
Comportamento Animal/fisiologia , Síndromes de Imunodeficiência/psicologia , Comportamento Materno/fisiologia , Comportamento Social , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Interação Gene-Ambiente , Habituação Psicofisiológica/fisiologia , Síndromes de Imunodeficiência/terapia , Masculino , Camundongos Endogâmicos C57BL , Camundongos SCID , Ovariectomia , Percepção/fisiologia , Testes Psicológicos , Distribuição Aleatória , Reconhecimento Psicológico/fisiologia , Baço/citologia , Baço/transplante
18.
Psychoneuroendocrinology ; 51: 271-81, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25462900

RESUMO

Sex differences in behavior are widespread and often caused by hormonal differences between the sexes. In addition to hormones, the composition and numbers of the sex chromosomes also affect a variety of sex differences. In humans, X-chromosome genes are implicated in neurobehavioral disorders (i.e. fragile-X, autism). To investigate the role of X-chromosome genes in social behavior, we used a mouse model that has atypical sex chromosome configurations resembling Turner (45, XO) and Klinefelter syndromes (47, XXY). We examined a number of behaviors in juvenile mice. Mice with only one copy of most X-chromosome genes, regardless of gonadal sex, were less social in dyadic interaction and social preference tasks. In the elevated plus maze, mice with one X-chromosome spent less time in the distal ends of the open arms as compared to mice with two copies of X-chromosome genes. Using qRTPCR, we noted that amygdala from female mice with one X-chromosome had higher expression levels of vasopressin (Avp) as compared to mice in the other groups. Finally, in plasma from girls with Turner syndrome we detected reduced vasopressin (AVP) concentrations as compared to control patients. These novel findings link sex chromosome genes with social behavior via concentrations of AVP in brain, adding to our understanding of sex differences in neurobehavioral disorders.


Assuntos
Dosagem de Genes , Regulação da Expressão Gênica/genética , Genes Ligados ao Cromossomo X , Comportamento Social , Vasopressinas/genética , Cromossomo X/genética , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal/fisiologia , Criança , Feminino , Humanos , Masculino , Camundongos , Síndrome de Turner/sangue , Síndrome de Turner/genética , Vasopressinas/metabolismo
19.
Front Neuroendocrinol ; 35(4): 405-19, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24388960

RESUMO

Sex chromosome genes directly influence sex differences in behavior. The discovery of the Sry gene on the Y chromosome (Gubbay et al., 1990; Koopman et al., 1990) substantiated the sex chromosome mechanistic link to sex differences. Moreover, the pronounced connection between X chromosome gene mutations and mental illness produces a strong sex bias in these diseases. Yet, the dominant explanation for sex differences continues to be the gonadal hormones. Here we review progress made on behavioral differences in mouse models that uncouple sex chromosome complement from gonadal sex. We conclude that many social and cognitive behaviors are modified by sex chromosome complement, and discuss the implications for human research. Future directions need to include identification of the genes involved and interactions with these genes and gonadal hormones.


Assuntos
Comportamento Animal , Genes sry/genética , Caracteres Sexuais , Cromossomos Sexuais/genética , Cromossomo Y/genética , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Humanos , Camundongos
20.
PLoS One ; 8(9): e75037, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24040381

RESUMO

It is well known that genes and environment interact to produce behavioral phenotypes. One environmental factor with long-term effects on gene transcription and behavior is maternal care. A classic paradigm for examining maternal care and genetic interactions is to foster pups of one genetic strain to dams of a different strain ("between-strain fostering"). In addition, fostering to a dam of the same strain ("within-strain fostering") is used to reduce indirect effects, via behavioral changes in the dams, of gestation treatments on offspring. Using within-and between-strain fostering we examined the contributions of genetics/prenatal environment, maternal care, and the effects of fostering per se, on adult aggressive behavior in two inbred mouse strains, C57BL/6J (B6) and DBA/2J (DBA). We hypothesized that males reared by dams of the more aggressive DBA strain would attack intruders faster than those reared by B6 dams. Surprisingly, we found that both methods of fostering enhanced aggressive behavior, but only in B6 mice. Since all the B6 offspring are genetically identical, we asked if maternal behavior of B6 dams was affected by the relatedness of their pups. In fact, B6 dams caring for foster B6 pups displayed significantly reduced maternal behaviors. Finally, we measured vasopressin and corticotrophin releasing hormone mRNA in the amygdalae of adult B6 males reared by foster or biological dams. Both genes correlated with aggressive behavior in within-strain fostered B6 mice, but not in mice reared by their biological dams. In sum, we have demonstrated in inbred laboratory mice, that dams behave differently when rearing their own newborn pups versus pups from another dam of the same strain. These differences in maternal care affect aggression in the male offspring and transcription of Avp and Crh in the brain. It is likely that rearing by foster dams has additional effects and implications for other species.


Assuntos
Agressão , Comportamento Animal , Comportamento Materno , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Tonsila do Cerebelo/metabolismo , Animais , Hormônio Liberador da Corticotropina/metabolismo , Primers do DNA , Meio Ambiente , Feminino , Regulação da Expressão Gênica , Interação Gene-Ambiente , Masculino , Camundongos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Comportamento Social , Especificidade da Espécie , Vasopressinas/metabolismo
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