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1.
Sci Rep ; 10(1): 19943, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33203885

RESUMO

Behaviors are shaped by hormones, which may act either by changing brain circuits or by modifying sensory detection of relevant cues. Pup-directed behaviors have been previously shown to change via action of hormones at the brain level. Here, we investigated hormonal control of pup-induced activity in the vomeronasal organ, an olfactory sensory structure involved in the detection of non-volatile chemosignals. Vomeronasal activity decreases as males switch from a pup-aggressive state to a non-aggressive parenting state, after they socially contact a female. RNA sequencing, qPCR, and in situ hybridization were used to identify expression, in the vomeronasal sensory epithelium, of candidate GPCR hormone receptors chosen by in silico analyses and educated guesses. After identifying that oxytocin and vasopressin receptors are expressed in the vomeronasal organ, we injected the corresponding hormones in mice and showed that oxytocin administration reduced both pup-induced vomeronasal activity and aggressive behavior. Conversely, injection of an oxytocin receptor antagonist in female-primed male animals, which normally exhibit reduced vomeronasal activity, significantly increased the number of active vomeronasal neurons. These data link oxytocin to the modulation of olfactory sensory activity, providing a possible mechanism for changes in male behavior after social experience with females.


Assuntos
Agressão/fisiologia , Biomarcadores/análise , Ocitócicos/farmacologia , Ocitocina/farmacologia , Receptores de Ocitocina/metabolismo , Órgão Vomeronasal/fisiologia , Agressão/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Feminino , Masculino , Camundongos , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , RNA-Seq , Órgão Vomeronasal/efeitos dos fármacos
2.
Chem Senses ; 45(2): 97-109, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-31844905

RESUMO

Chemotherapy patients often experience chemosensory changes during and after drug therapy. The chemotherapy drug, cyclophosphamide (CYP), has known cytotoxic effects on sensory and proliferating cells of the taste system. Like the taste system, cells in the olfactory epithelia undergo continuous renewal. Therefore, we asked if a single injection of 75 mg/kg CYP would affect cell proliferation in the anterior dorsomedial region of the main olfactory epithelium (MOE) and the vomeronasal organ (VNO) from 0 to 125 days after injection. Both epithelia showed a decrease in Ki67-labeled cells compared to controls at day 1 and no Ki67+ cells at day 2 postinjection. In the sensory layer of the MOE, cell proliferation began to recover 4 days after CYP injection and by 6 days, the rate of proliferation was significantly greater than controls. Ki67+ cells peaked 30 days postinjection, then declined to control levels at day 45. Similar temporal sequences of initial CYP-induced suppression of cell proliferation followed by elevated rates peaking 30-45 days postinjection were seen in the sustentacular layer of the MOE and all 3 areas (sensory, sustentacular, marginal) of the VNO. CYP affected proliferation in the sensory layer of the MOE more than the sustentacular layer and all 3 areas of the VNO. These findings suggest that chemotherapy involving CYP is capable of affecting cell renewal of the olfactory system and likely contributes to clinical loss of function during and after chemotherapy.


Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Ciclofosfamida/efeitos adversos , Mucosa Olfatória/efeitos dos fármacos , Órgão Vomeronasal/efeitos dos fármacos , Animais , Antineoplásicos Alquilantes/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/administração & dosagem , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Olfatória/patologia , Órgão Vomeronasal/patologia
3.
Biosci Biotechnol Biochem ; 83(4): 705-708, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30516446
4.
Sci Rep ; 8(1): 8490, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855521

RESUMO

In most mammals, the vomeronasal system has a pivotal role in mediating socio-sexual behaviours. The vomeronasal organ senses pheromones through the activation of specific receptors. Pheromone binding to cognate receptors activates Ca-influx via the gating of a cation channel that generates membrane depolarisation. The ex-vivo activation of vomeronasal neurons (VSNs) by pheromonal stimuli has been largely investigated by electrophysiological and imaging techniques; however, few studies have been carried out to determine the physiological responses of VSNs, in-vivo. By tracking the phosphorylation of S6 ribosomal protein as a marker of neuronal activity, we show that S6 becomes phosphorylated (pS6) in mouse VSNs stimulated by intraspecific and heterospecific pheromonal cues. We observed that female scent induces pS6 immunoreactivity in the apical VSNs of male vomeronasal epithelium, whereas male cues stimulate S6 phosphorylation in both the basal and apical VSNs of females. We also show that this dimorphic pattern of pS6 immunoreactivity is reproduced when heterospecific stimuli are used. Moreover, we found that a consistent proportion of VSNs is activated by both heterospecific and intraspecific pheromones. Additionally, we have evidence of adaptive responses to S6 phosphorylation when stimulation with cues of the same and opposite sex and of different species is sustained.


Assuntos
Neurônios/metabolismo , Feromônios/farmacologia , Órgão Vomeronasal/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Cricetinae , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Proteína S6 Ribossômica/metabolismo , Solo/química , Órgão Vomeronasal/citologia , Órgão Vomeronasal/metabolismo
5.
J Chem Neuroanat ; 81: 42-47, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28159658

RESUMO

We studied the expression of vitamin D receptor and of vitamin D binding protein in the rat vomeronasal organ. With immunofluorescence, in situ hybridization and with reverse transcriptase PCR we found both proteins in sensory as well as in non-sensory cells. Sensory neurons contained immunoreactivity for vitamin D3 receptor in nuclei, in portions of the cytoplasm, and in apical dendrites and their microvilli. Vitamin D binding protein was observed in sensory neuron axons and cytoplasm, mostly confined to dendrites. Colocalization appeared in the contact zone of supporting cells and sensory dendrites. Both proteins were also found in single ciliated cells within the non-sensory epithelium. Vitamin D binding protein was also localized in secretory vesicles in a portion of the vomeronasal glands. Our findings suggest that the rat vomeronasal organ is a vitamin D target.


Assuntos
Sistemas de Liberação de Medicamentos , Receptores de Calcitriol/metabolismo , Proteína de Ligação a Vitamina D/metabolismo , Vitamina D/metabolismo , Órgão Vomeronasal/metabolismo , Animais , Sistemas de Liberação de Medicamentos/métodos , Feminino , Masculino , Mucosa Olfatória/química , Mucosa Olfatória/efeitos dos fármacos , Mucosa Olfatória/metabolismo , Ratos , Ratos Wistar , Receptores de Calcitriol/análise , Células Receptoras Sensoriais/química , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Vitamina D/administração & dosagem , Proteína de Ligação a Vitamina D/análise , Órgão Vomeronasal/química , Órgão Vomeronasal/efeitos dos fármacos
6.
Chem Senses ; 42(1): 13-24, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27651427

RESUMO

Chemosensory stimuli from same species (conspecific) and different species (heterospecific) elicit categorically different immediate-early gene (IEG) response patterns in medial amygdala in male hamsters and mice. All heterospecific stimuli activate anterior medial amygdala (MeA) but only especially salient heterospecific stimuli, such as those from predators activate posterior medial amygdala (MeP). We previously reported that characteristic patterns of response in separate populations of cells in MeA and MeP distinguish between different conspecific stimuli. Both gamma aminobutyric acid (GABA)-immunoreactive (ir) cells and GABA-receptor-ir cells make this distinction. Here, using zinc sulfate lesions of the main olfactory epithelium, we show evidence that main olfactory input does not contribute to the characteristic patterns of response in GABA-ir cells of male hamster amygdala, either for conspecific or heterospecific stimuli. Some GABAergic cells are output neurons carrying information from medial amygdala to behavioral executive regions of basal forebrain. Thus, the differential response to different conspecific signals can lead to differential activation of downstream circuits based on nonolfactory input. Finally, we show that an intact vomeronasal organ is necessary and sufficient to produce the characteristic patterns of response to conspecific and heterospecific chemosensory stimuli in hamster medial amygdala. Although main olfactory input may be critical in species with less prominent vomeronasal input for equivalent medial amygdala responses, work presented here suggests that hamster medial amygdala uses primarily vomeronasal input to discriminate between important unlearned conspecific social signals, to distinguish them from the social signals of other species, and may convey that information to brain circuits eliciting appropriate social behavior.


Assuntos
Tonsila do Cerebelo/metabolismo , Neurônios GABAérgicos/metabolismo , Condutos Olfatórios/metabolismo , Órgão Vomeronasal/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/patologia , Animais , Comportamento Animal , Cricetinae , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/patologia , Masculino , Condutos Olfatórios/efeitos dos fármacos , Órgão Vomeronasal/efeitos dos fármacos , Sulfato de Zinco/farmacologia
7.
Eur J Neurosci ; 40(10): 3422-35, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25195871

RESUMO

We investigated the role of voltage-activated calcium (Cav) channels for synaptic transmission at mouse olfactory and vomeronasal nerve terminals at the first synapse of the main and accessory olfactory pathways, respectively. We provided evidence for a central role of the N-type Cav channel subunit Cav2.2 in presynaptic transmitter release at these synapses. Striking Cav2.2 immunoreactivity was localised to the glomerular neuropil of the main olfactory bulb (MOB) and accessory olfactory bulb (AOB), and co-localised with presynaptic molecules such as bassoon. Voltage-clamp recordings of sensory nerve-evoked, excitatory postsynaptic currents (EPSCs) in mitral/tufted (M/T) and superficial tufted cells of the MOB and mitral cells of the AOB, in combination with established subtype-specific Cav channel toxins, indicated a predominant role of N-type channels in transmitter release at these synapses, whereas L-type, P/Q-type, and R-type channels had either no or only relatively minor contributions. In Cacna1b mutant mice lacking the Cav2.2 (α1B) subunit of N-type channels, olfactory nerve-evoked M/T cell EPSCs were not reduced but became blocker-resistant, thus indicating a major reorganisation and compensation of Cav channel subunits as a result of the Cav2.2 deletion at this synapse. Cav2.2-deficient mice also revealed that Cav2.2 was critically required for paired-pulse depression of olfactory nerve-evoked EPSCs in M/T cells of the MOB, and they demonstrated an essential requirement for Cav2.2 in vomeronasal nerve-evoked EPSCs of AOB mitral cells. Thus, Cacna1b loss-of-function mutations are unlikely to cause general anosmia but Cacna1b emerges as a strong candidate in the search for mutations causing altered olfactory perception, such as changes in general olfactory sensitivity and altered social responses to chemostimuli.


Assuntos
Canais de Cálcio Tipo N/metabolismo , Bulbo Olfatório/fisiologia , Transmissão Sináptica/fisiologia , Órgão Vomeronasal/fisiologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Tipo N/genética , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Proteínas do Tecido Nervoso/metabolismo , Bulbo Olfatório/efeitos dos fármacos , Proteína de Marcador Olfatório/metabolismo , Nervo Olfatório/efeitos dos fármacos , Nervo Olfatório/fisiologia , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Técnicas de Cultura de Tecidos , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Órgão Vomeronasal/efeitos dos fármacos , Órgão Vomeronasal/inervação
8.
Neuroscience ; 269: 43-58, 2014 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-24680884

RESUMO

In rodents, many social behaviors are driven by the sense of smell. The vomeronasal organ (VNO), part of the accessory olfactory system mediates many of these chemically driven behaviors. The VNO is heavily vascularized, and is readily accessible to circulating peptide or steroid hormones. Potentially, this allows circulating hormones to alter behavior through modulating the output of the primary sensory neurons in the VNO, the vomeronasal sensory neurons (VSNs). Based on this, we hypothesized that steroid hormones, in particular 17ß-estradiol, would modulate activity of VSNs. In this paper, we show that the estrogen receptors, GPR30 and ERα, were present in VSNs and that estradiol may be synthesized locally in the VNO. Our results also showed that 17ß-estradiol decreased responses of isolated VSNs to dilute urine, a potent natural stimulus, with respect to current amplitudes and depolarization. Further, 17ß-estradiol increased the latency of the first action potential (AP) and the AP amplitude. Additionally, calcium responses to sulfated steroids (present in the low molecular weight fraction of urine) that act as ligands for apical vomeronasal receptors were decreased by 17ß-estradiol. In conclusion, we show that estradiol modulates odorant responses mediated by VSNs and hence paves the way for future studies to better understand the mechanisms by which odorant mediated behavior is altered by endocrine status of the animal.


Assuntos
Estradiol/farmacologia , Estrogênios/farmacologia , Olfato/efeitos dos fármacos , Olfato/fisiologia , Órgão Vomeronasal/efeitos dos fármacos , Órgão Vomeronasal/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Odorantes , Estimulação Física , RNA Mensageiro/metabolismo , Receptores de Estrogênio , Receptores Acoplados a Proteínas G/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/fisiologia
9.
Peptides ; 45: 15-21, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23619348

RESUMO

A peptide pheromone of the red-bellied male newt, sodefrin was tested for its ability to increase intracellular concentrations of Ca(2+) ([Ca(2+)]i) in the dissociated vomeronasal (VN) cells of females by means of calcium imaging system. The pheromone elicited a marked elevation of [Ca(2+)]i in a small population of VN cells from sexually developed females. The population of cells exhibiting sodefrin-induced elevation of [Ca(2+)]i increased concentration-dependently. A pheromone of a different species was ineffective in this respect. The VN cells from non-reproductive females or from reproductive males scarcely responded to sodefrin in terms of elevating [Ca(2+)]i. In the cells from hypophysectomized and ovariectomized females, the sodefrin-inducible increase of [Ca(2+)]i never occurred. The cells from the operated newts supplemented with prolactin and estradiol exhibited [Ca(2+)]i responses to sodefrin with a high incidence. Thus, sex- and hormone-dependency as well as species-specificity of the responsiveness of the VN cells to sodefrin was evidenced at the cellular level. Subsequently, possibility of involvement of phospholipase C (PLC)-inositol 1,4,5-trisphosphate (IP3) and/or PLC-diacylglycerol (DAG)-protein kinase C (PKC) pathways in increasing [Ca(2+)]i in VN cells in response to sodefrin was explored using pharmacological approaches. The results indicated that PLC is involved in generating the Ca(2+) signal in all sodefrin-responsive VN cells, whereas IP3 in approximately 50% of the cells and DAG-PKC in the remaining cells. In the latter case, the increase of [Ca(2+)]i was postulated to be induced by the influx of Ca(2+) through the L-type channel. The significance of the finding is discussed.


Assuntos
Cálcio/metabolismo , Células Epiteliais/efeitos dos fármacos , Oligopeptídeos/farmacologia , Salamandridae/fisiologia , Atrativos Sexuais/farmacologia , Comportamento Sexual Animal/fisiologia , Órgão Vomeronasal/efeitos dos fármacos , Animais , Sinalização do Cálcio , Proliferação de Células , Diglicerídeos/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Estradiol/farmacologia , Feminino , Hipofisectomia , Inositol 1,4,5-Trifosfato/metabolismo , Masculino , Imagem Molecular , Ovariectomia , Ovário/fisiologia , Hipófise/fisiologia , Cultura Primária de Células , Prolactina/farmacologia , Proteína Quinase C/metabolismo , Especificidade da Espécie , Órgão Vomeronasal/citologia , Órgão Vomeronasal/metabolismo
10.
Brain Res ; 1480: 41-52, 2012 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-22960119

RESUMO

Neurons in the medial nucleus of the amygdala (MeA) play a key role in the innate maternal, reproductive, defensive, and social behaviors. However, it is unclear how activation of the vomeronasal system leads to the behavioral outputs that are associated with pheromones. Here, we characterized the electrophysiological and morphological properties of MeA neurons using whole-cell recordings in mice slice preparations. Biocytin labeling revealed that MeA neurons possessed bipolar to multipolar cell bodies and dendritic fields covering projection areas from the accessory olfactory bulb. In 70% of recorded MeA neurons, monosynaptic excitatory postsynaptic currents (EPSCs) were evoked from the accessory olfactory bulb afferent in which the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate component was dominant and was rarely followed by the N-methyl-d-aspartic acid component. Norepinephrine increased the frequency of spontaneous inhibitory postsynaptic currents in some neurons, whereas α-methyl-5-hydroxytryptamine increased spontaneous EPSCs in other neurons. Morphologically and physiologically, heterogeneous MeA neurons appear likely to produce multiplex outputs of instinctive behaviors.


Assuntos
Tonsila do Cerebelo/fisiologia , Neurônios/fisiologia , Bulbo Olfatório/fisiologia , Órgão Vomeronasal/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Forma Celular , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Camundongos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Norepinefrina/farmacologia , Bulbo Olfatório/efeitos dos fármacos , Técnicas de Patch-Clamp , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Órgão Vomeronasal/efeitos dos fármacos
11.
Adv Exp Med Biol ; 739: 93-106, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22399397

RESUMO

Evolutionally, chemosensation is an ancient but yet enigmatic sense. All organisms ranging from the simplest unicellular form to the most advanced multicellular creature possess the capability to detect chemicals in the surroundings. Conversely, all living things emit some forms of smells, either as communicating signals or as by-products of metabolism. Many species (from worms, insects to mammals) rely on the olfactory systems which express a large number of chemoreceptors to locate food and mates and to avoid danger. Most chemoreceptors expressed in olfactory organs are G-protein coupled receptors (GPCRs) and can be classified into two major categories: odorant receptors (ORs) and pheromone receptors, which principally detect general odors and pheromones, respectively. In vertebrates, these two types of receptors are often expressed in two distinct apparatuses: The main olfactory epithelium (MOE) and the vomeronasal organ (VNO), respectively. Each olfactory sensory neuron (OSN) in the MOE typically expresses one type of OR from a large repertoire. General odors activate ORs and their host OSNs (ranging from narrowly- to broadly-tuned) in a combinatorial manner and the information is sent to the brain via the main olfactory system leading to perception of smells. In contrast, pheromones stimulate relatively narrowly-tuned receptors and their host VNO neurons and the information is sent to the brain via the accessory olfactory system leading to behavioral and endocrinological changes. Recent studies indicate that the functional separation between these two systems is blurred in some cases and there are more subsystems serving chemosensory roles. This chapter focuses on the molecular and cellular mechanisms underlying odor and pheromone sensing in rodents, the best characterized vertebrate models.


Assuntos
Células Quimiorreceptoras/efeitos dos fármacos , Odorantes , Feromônios/farmacologia , Animais , Células Quimiorreceptoras/citologia , Células Quimiorreceptoras/metabolismo , Humanos , Percepção Olfatória/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Órgão Vomeronasal/citologia , Órgão Vomeronasal/efeitos dos fármacos , Órgão Vomeronasal/metabolismo , Órgão Vomeronasal/fisiologia
12.
Curr Biol ; 21(24): R998-9, 2011 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-22192835
13.
Nature ; 478(7368): 241-5, 2011 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-21937988

RESUMO

The vomeronasal organ (VNO) has a key role in mediating the social and defensive responses of many terrestrial vertebrates to species- and sex-specific chemosignals. More than 250 putative pheromone receptors have been identified in the mouse VNO, but the nature of the signals detected by individual VNO receptors has not yet been elucidated. To gain insight into the molecular logic of VNO detection leading to mating, aggression or defensive responses, we sought to uncover the response profiles of individual vomeronasal receptors to a wide range of animal cues. Here we describe the repertoire of behaviourally and physiologically relevant stimuli detected by a large number of individual vomeronasal receptors in mice, and define a global map of vomeronasal signal detection. We demonstrate that the two classes (V1R and V2R) of vomeronasal receptors use fundamentally different strategies to encode chemosensory information, and that distinct receptor subfamilies have evolved towards the specific recognition of certain animal groups or chemical structures. The association of large subsets of vomeronasal receptors with cognate, ethologically and physiologically relevant stimuli establishes the molecular foundation of vomeronasal information coding, and opens new avenues for further investigating the neural mechanisms underlying behaviour specificity.


Assuntos
Células Quimiorreceptoras/metabolismo , Órgão Vomeronasal/fisiologia , Animais , Aves , Células Quimiorreceptoras/citologia , Células Quimiorreceptoras/efeitos dos fármacos , Sinais (Psicologia) , Proteína 1 de Resposta de Crescimento Precoce/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Mamíferos , Camundongos , Feromônios/metabolismo , Feromônios/farmacologia , Comportamento Predatório/fisiologia , Receptores Odorantes/metabolismo , Caracteres Sexuais , Especificidade da Espécie , Órgão Vomeronasal/efeitos dos fármacos
14.
J Neurosci ; 30(22): 7473-83, 2010 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-20519522

RESUMO

In mammalian species, detection of pheromone cues by the vomeronasal organ (VNO) at different concentrations can elicit distinct behavioral responses and endocrine changes. It is not well understood how concentration-dependent activation of the VNO impacts innate behaviors. In this study, we find that, when mice investigate the urogenital areas of a conspecific animal, the urinary pheromones can reach the VNO at a concentration of approximately 1% of that in urine. At this level, urinary pheromones elicit responses from a subset of cells that are tuned to sex-specific cues and provide unambiguous identification of the sex and strain of animals. In contrast, low concentrations of urine do not activate these cells. Strikingly, we find a population of neurons that is only activated by low concentrations of urine. The properties of these neurons are not found in neurons responding to putative single-compound pheromones. Additional analyses show that these neurons are masked by high-concentration pheromones. Thus, an antagonistic interaction in natural pheromones results in the activation of distinct populations of cells at different concentrations. The differential activation is likely to trigger different downstream circuitry and underlies the concentration-dependent pheromone perception.


Assuntos
Sinais (Psicologia) , Neurônios/fisiologia , Feromônios/urina , Órgão Vomeronasal/citologia , Órgão Vomeronasal/fisiologia , Potenciais de Ação/genética , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Calmodulina/genética , Calmodulina/metabolismo , Relação Dose-Resposta a Droga , Potenciais Evocados/fisiologia , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Técnicas In Vitro , Lectinas/genética , Lectinas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/classificação , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp/métodos , Feromônios/farmacologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Órgão Vomeronasal/efeitos dos fármacos
15.
Chem Senses ; 35(3): 221-8, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20080804

RESUMO

Propylene glycol (PG) is commonly used as a solvent for odorous chemicals employed in studies of the olfactory system because PG has been considered to be odorless for humans and other animals. However, if laboratory rats can detect the vapor of PG and if exposure to this influences behaviors, such effects might confound data obtained from experiments exposing conscious rats to odorants dissolved in PG. Therefore, we examined this issue using differences in the acoustic startle reflex (ASR) as an index. We also conducted a habituation/dishabituation test to assess the ability of rats to detect the vapor of PG. In addition, we observed Ca(2+) responses of vomeronasal neurons (VNs) in rats exposed to PG using the confocal Ca(2+)-imaging approach. Pure PG vapor significantly enhanced the ASR at a dose of 1 x 10(-4) M, which was much lower than the dose for efficiently detecting. In Ca(2+) imaging, VNs were activated by PG at a dose of 1 x 10(-4) M or lower. These results suggest that PG vapor acts as an aversive stimulus to rats at very low doses, even lower than those required for its detection, indicating that we should consider such effect of PG when it is employed as a solvent for odorants in studies using conscious rats. In addition, our study suggests that some non-pheromonal volatile odorants might affect animal behaviors via the vomeronasal system.


Assuntos
Gases/química , Propilenoglicóis/farmacologia , Animais , Cálcio/metabolismo , Masculino , Ratos , Ratos Wistar , Filtro Sensorial/fisiologia , Órgão Vomeronasal/efeitos dos fármacos , Órgão Vomeronasal/fisiologia
16.
J Gen Physiol ; 135(1): 3-13, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20038523

RESUMO

The vomeronasal organ (VNO) is an odor detection system that mediates many pheromone-sensitive behaviors. Vomeronasal sensory neurons (VSNs), located in the VNO, are the initial site of interaction with odors/pheromones. However, how an individual VSN transduces chemical signals into electrical signals is still unresolved. Here, we show that a Ca2+-activated Cl- current contributes approximately 80% of the response to urine in mouse VSNs. Using perforated patch clamp recordings with gramicidin, which leaves intracellular chloride undisrupted, we found that the urine-induced inward current (V(hold) = -80 mV) was decreased in the presence of chloride channel blockers. This was confirmed using whole cell recordings and altering extracellular chloride to shift the reversal potential. Further, the urine-induced currents were eliminated when both extracellular Ca2+ and Na+ were removed. Using inside-out patches from dendritic tips, we recorded Ca2+-activated Cl- channel activity. Several candidates for this Ca2+-activated Cl- channel were detected in VNO by reverse transcription-polymerase chain reaction. In addition, a chloride cotransporter, Na+-K+-2Cl- isoform 1, was detected and found to mediate much of the chloride accumulation in VSNs. Collectively, our data demonstrate that chloride acts as a major amplifier for signal transduction in mouse VSNs. This amplification would increase the responsiveness to pheromones or odorants.


Assuntos
Cálcio/metabolismo , Canais de Cloreto/fisiologia , Ativação do Canal Iônico/fisiologia , Neurônios Receptores Olfatórios/fisiologia , Urina , Órgão Vomeronasal/fisiologia , Animais , Células Cultivadas , Canais de Cloreto/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurônios Receptores Olfatórios/efeitos dos fármacos , Órgão Vomeronasal/citologia , Órgão Vomeronasal/efeitos dos fármacos
17.
Cell Biol Toxicol ; 26(4): 309-17, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19924548

RESUMO

Nasal epitheliums are the first sites of the respiratory tract in contact with the external environment and may therefore be susceptible to damage from exposure to many toxic volatile substances (i.e., volatile organic components, vapors, and gases). In the field of inhalation toxicology, a number of studies have considered the main olfactory epithelium, but few have dealt with the epithelium of the vomeronasal organ (VNO). However, in several species such as in rodents, the VNO (an organ of pheromone detection) plays an important role in social interactions, and alterations of this organ are known to induce adaptative behavioral disturbances. Among volatile toxicants, health effects of inhaled gases have been thoroughly investigated, especially during CO(2) inhalation because of its increasing atmospheric concentration. Therefore, this work was designed to examine the effects of 3% CO(2) inhalation on VNO in two different exposure conditions (5 h/day and 12 h/day) in mice. Behavioral sensitivity tests to urine of congener and histological measurements of VNO were conducted before, during (weeks 1-4), and after (weeks 5-8) CO(2) inhalation exposures. Results showed no significant modifications of behavioral responses to urine, but there were significant changes of both cell number and thickness of the VNO epithelium. Moreover, the findings indicated a selectively dose-dependent effect of CO(2), and further research could use other gases in the same manner for comparison.


Assuntos
Dióxido de Carbono/administração & dosagem , Dióxido de Carbono/farmacologia , Exposição por Inalação/análise , Mucosa Olfatória/efeitos dos fármacos , Órgão Vomeronasal/efeitos dos fármacos , Animais , Dióxido de Carbono/toxicidade , Contagem de Células , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Mucosa Olfatória/citologia , Fatores de Tempo , Órgão Vomeronasal/citologia
18.
Am J Physiol Lung Cell Mol Physiol ; 297(6): L1073-81, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19801453

RESUMO

Asthma needs continuous treatment often for years. In humans, some drugs are administered via aerosol, therefore they come in contact with both respiratory and olfactory mucosa. We explored the possibility that antiasthma corticosteroid treatment could influence the olfactory function by passage through the nose. A group of mice was exposed twice daily for 42 days to fluticasone propionate aerosol and was compared with a control group. Olfactory behavior, respiratory mechanics, histology, and immunoreactivity in the olfactory system were assessed. Fluticasone-treated mice were slower in retrieving a piece of hidden food, but both groups were similarly fast when the food was visible. When a clearly detectable odor was present in the environment, all mice behaved in a similar way. Respiratory mechanics indices were similar in all mice except for the viscose resistance, which was reduced in fluticasone-treated mice. Olfactory mucosa of fluticasone-treated mice was thicker than that of controls. Slight but consistent differences in staining were present for Olfactory Marker Protein but not for other proteins. A mild impairment of olfactory function is present in mice chronically treated with fluticasone aerosol, apparently accompanied by slight modifications of the olfactory receptor cells, and suggests monitoring of olfactory function modifications in long-term steroid users.


Assuntos
Aerossóis/administração & dosagem , Aerossóis/farmacologia , Bulbo Olfatório/efeitos dos fármacos , Esteroides/administração & dosagem , Esteroides/farmacologia , Androstadienos/administração & dosagem , Androstadienos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Feminino , Fluticasona , Imuno-Histoquímica , Camundongos , Bulbo Olfatório/patologia , Mucosa Olfatória/efeitos dos fármacos , Mucosa Olfatória/patologia , Tamanho do Órgão/efeitos dos fármacos , Mecânica Respiratória/efeitos dos fármacos , Órgão Vomeronasal/efeitos dos fármacos , Órgão Vomeronasal/patologia
19.
J Neurochem ; 110(4): 1263-75, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19519663

RESUMO

In mouse, sexual, aggressive, and social behaviors are influenced by G protein-coupled vomeronasal receptor signaling in two distinct subsets of vomeronasal sensory neurons (VSNs): apical and basal VSNs. In addition, G protein-signaling by these receptors inhibits developmental death of VSNs. We show that cells of the vomeronasal nerve express the retinoic acid (RA) synthesizing enzyme retinal dehydrogenase 2. Analyses of transgenic mice with VSNs expressing a dominant-negative RA receptor indicate that basal VSNs differ from apical VSNs with regard to a transient wave of RA-regulated and caspase 3-mediated cell death during the first postnatal week. Analyses of G-protein subunit deficient mice indicate that RA and vomeronasal receptor signaling combine to regulate postnatal expression of Kirrel-2 (Kin of IRRE-like), a cell adhesion molecule regulating neural activity-dependent formation of precise axonal projections in the main olfactory system. Collectively, the results indicate a novel connection between pre-synaptic RA receptor signaling and neural activity-dependent events that together regulate neuronal survival and maintenance of synaptic contacts.


Assuntos
Neurônios/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Tretinoína/metabolismo , Órgão Vomeronasal/embriologia , Órgão Vomeronasal/metabolismo , Animais , Caspase 3/efeitos dos fármacos , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Cones de Crescimento/efeitos dos fármacos , Cones de Crescimento/metabolismo , Cones de Crescimento/ultraestrutura , Imunoglobulinas/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/fisiopatologia , Degeneração Neural/prevenção & controle , Vias Neurais/efeitos dos fármacos , Vias Neurais/embriologia , Vias Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Neurônios/efeitos dos fármacos , Condutos Olfatórios/efeitos dos fármacos , Condutos Olfatórios/embriologia , Condutos Olfatórios/metabolismo , Feromônios/fisiologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/genética , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Retinal Desidrogenase/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tretinoína/farmacologia , Órgão Vomeronasal/efeitos dos fármacos
20.
J Neurosci ; 29(24): 7658-66, 2009 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-19535577

RESUMO

It was recently reported that female mice lacking a functional vomeronasal organ (VNO) displayed male-typical sexual behavior indiscriminately toward female and male conspecifics. These results have been cited as showing that a circuit controlling male-typical sex behavior exists in both sexes, with its activation in females being tonically inhibited by VNO signaling, independent of adult sex hormones. We further assessed this hypothesis while controlling the endocrine status of female mice in which VNO function was surgically disrupted. In experiment 1, VNO-lesioned (VNOx) female mice showed no more mounting or pelvic-thrusting behavior toward an estrous female or a castrated, urine-swabbed male (presented simultaneously) than sham-operated (VNOi) females. This was true when subjects were either ovary-intact or ovariectomized and treated with estradiol, estradiol plus progesterone, or testosterone. In experiment 2, female mice given accessory olfactory bulb lesions or a sham lesion displayed equivalent frequencies of male sex behaviors when given testosterone after ovariectomy. In experiment 3, VNOx and VNOi females displayed equivalent frequencies of male sex behaviors toward an estrous female or a castrated male (presented in separate tests), again, when given testosterone after ovariectomy. Our results confirm early reports that adult testosterone can stimulate appreciable male-typical sex behavior in female mice. However, we failed to corroborate the recent claim that VNO signaling normally inhibits the activity of neural circuitry controlling the expression of male-typical mating behavior by female mice.


Assuntos
Androgênios/farmacologia , Caracteres Sexuais , Comportamento Sexual Animal/fisiologia , Testosterona/farmacologia , Órgão Vomeronasal/efeitos dos fármacos , Órgão Vomeronasal/fisiologia , Animais , Comportamento Animal , Estradiol/farmacologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Odorantes , Bulbo Olfatório/lesões , Bulbo Olfatório/fisiologia , Ovariectomia/métodos , Progesterona/farmacologia , Comportamento Sexual Animal/efeitos dos fármacos , Olfato/genética , Olfato/fisiologia , Estatísticas não Paramétricas , Canais de Cátion TRPC/deficiência , Órgão Vomeronasal/cirurgia
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